Esther M. John

All Publications

• Physical activity during adolescence and early adulthood and breast cancer risk before age 40 years. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Kehm, R. D., Genkinger, J. M., Knight, J. A., Maclnnis, R. J., Liao, Y., Li, S., Weideman, P. C., Chung, W. K., Kurian, A. W., Colonna, S. V., Andrulis, I. L., Buys, S. S., Daly, M. B., John, E. M., Hopper, J. L., Terry, M. B. 2024

  Abstract

  Breast cancer (BC) incidence is increasing in women under age 40 years, underscoring the need for research on BC risk factors for younger women.We used data from an international family cohort (n=26,348) to examine whether recreational physical activity (RPA) during adolescence and early adulthood are associated with BC risk before age 40. The cohort includes 2,502 women diagnosed with BC before age 40, including 2,408 diagnosed before study enrollment (68% within 5 years of enrollment). Women reported their average hours-per-week of moderate and strenuous RPA during adolescence (12-17 years) and early adulthood (25-34 years), which were converted to total age-adjusted metabolic equivalents-per-week and categorized into quartiles. We conducted attained age analyses until age 40 (follow-up time began at age 18) using Cox proportional hazards regression models adjusted for study center, race and ethnicity, and education.Being in the highest versus lowest quartile of RPA during adolescence and early adulthood were respectively associated with 12% [HR (95% CI): 0.88 (0.78, 0.98)] and 16% [HR (95% CI): 0.84 (0.74, 0.95) lower BC risks before age 40. Being in the highest quartile of RPA during both adolescence and early adulthood (Pearson correlation=0.52) versus neither timepoint was associated with a 22% lower risk [HR (95% CI): 0.78 (0.68, 0.89)].Findings suggest that RPA during adolescence and early adulthood may lower BC risk before age 40.Policies promoting physical activity during adolescence and early adulthood may be important for reducing the growing burden of breast cancer in younger women.

  View details for DOI 10.1158/1055-9965.EPI-24-0743

  View details for PubMedID 39404779

• Recommended Guidelines for Screening for Underlying Malignancy in Extramammary Paget's Disease Based on Anatomic Subtype. Journal of the American Academy of Dermatology Kibbi, N., Owen, J. L., Worley, B., Alam, M. 2024

  Abstract

  Extramammary Paget's disease (EMPD) may be associated with an underlying internal adenocarcinoma, referred to as secondary EMPD. Differences in this association by EMPD anatomic subtype and implications for screening are not fully understood.Define the rates of secondary EMPD and types of associated adenocarcinomas by EMPD anatomic subtype and propose a screening algorithm for underlying adenocarcinoma.Systematic literature review of EMPD (January 1990- November 2022). One hundred twenty-two studies met the inclusion criteria. A multidisciplinary expert panel reviewed the recommendation statements on adenocarcinoma screening.Perianal EMPD was associated with a high rate of underlying adenocarcinoma (25%, primarily colorectal) compared with penoscrotal and vulvar EMPD (6% each, primarily of genitourinary origin). Thorough screening in perianal EMPD includes a colonoscopy, urine cytology, and computed tomography (CT) of the chest, abdomen and pelvis. Cost-conscious screening tests in low-risk penoscrotal disease include urine cytology, heme-occult test, and prostate-specific antigen test (especially if under 70 years of age). For low-risk vulvar EMPD, urine cytology and mammography are recommended. EMPD with high-risk features may warrant more sensitive organ-specific testing.Selection bias; retrospective data without systematic follow-up.Screening for underlying adenocarcinoma in EMPD should be guided by anatomic location.

  View details for DOI 10.1016/j.jaad.2024.07.1531

  View details for PubMedID 39401611

• Risk factors for second primary breast cancer by laterality, age, and race and ethnicity. Journal of the National Cancer Institute John, E. M., Koo, J., Ingles, S. A., Keegan, T. H., Gomez, S. L., Haiman, C. A., Kurian, A. W., Kwan, M. L., Neuhausen, S. L., Shariff-Marco, S., Thomsen, C., Wu, A. H., Cheng, I. 2024

  Abstract

  Epidemiologic studies of risk factors for second primary breast cancer (SBC) have been conducted primarily in non-Hispanic White (NHW) women.A racially- and ethnically-diverse population-based pooled cohort of 9,639 women with first primary stage I-III invasive breast cancer (FBC) was linked with the California Cancer Registry; 618 contralateral SBC (CSBC) and 278 ipsilateral SBC (ISBC), diagnosed >6 months after FBC, were identified. Using Fine and Gray models accounting for competing risks, we assessed associations of CSBC and ISBC risk with FBC clinical characteristics and epidemiologic factors.In younger women (FBC at age <50 years), higher CSBC risk was associated with ER/PR-negative FBC [hazard ratio (HR)=1.68], breast cancer family history (HR = 2.20), and nulliparity (HR = 1.37). In older women (FBC at age ≥50 years), higher risk was associated with breast cancer family history (HR = 1.32), premenopausal status (HR = 1.49), overweight (HR = 1.39), and higher alcohol consumption (HR = 1.34). For ISBC, higher risk was associated with married status (HR = 1.94) in younger women, and overweight (HR = 1.60) among older women. For CSBC, HR estimates were generally similar across racial and ethnic groups. Even after adjustment for these risk factors, compared with NHW women, risk remained elevated for CSBC in younger African American, Asian American, and Hispanic women, and for ISBC in older African American and Hispanic women with ER/PR-positive FBC.Our findings support genetic risk evaluation, enhanced screening, and lifestyle changes in women at higher risk of SBC. Additional risk factors must contribute to the unequal burden of SBC across racial and ethnic groups.

  View details for DOI 10.1093/jnci/djae254

  View details for PubMedID 39392427

• Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Mutations in BRCA1 and BRCA2. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Phillips, K. A., Kotsopoulos, J., Domchek, S. M., Terry, M. B., Chamberlain, J. A., Bassett, J. K., Aeilts, A. M., Andrulis, I. L., Buys, S. S., Cui, W., Daly, M. B., Eisen, A. F., Foulkes, W. D., Friedlander, M. L., Gronwald, J., Hopper, J. L., John, E. M., Karlan, B. Y., Kim, R. H., Kurian, A. W., Lubinski, J., Metcalfe, K., Nathanson, K. L., Singer, C. F., Southey, M. C., Symecko, H., Tung, N., Narod, S. A., Milne, R. L. 2024: JCO2400176

  Abstract

  It is uncertain whether, and to what extent, hormonal contraceptives increase breast cancer (BC) risk for germline BRCA1 or BRCA2 mutation carriers.Using pooled observational data from four prospective cohort studies, associations between hormonal contraceptive use and BC risk for unaffected female BRCA1 and BRCA2 mutation carriers were assessed using Cox regression.Of 3,882 BRCA1 and 1,509 BRCA2 mutation carriers, 53% and 71%, respectively, had ever used hormonal contraceptives for at least 1 year (median cumulative duration of use, 4.8 and 5.7 years, respectively). Overall, 488 BRCA1 and 191 BRCA2 mutation carriers developed BC during median follow-up of 5.9 and 5.6 years, respectively. Although for BRCA1 mutation carriers, neither current nor past use of hormonal contraceptives for at least 1 year was statistically significantly associated with BC risk (hazard ratio [HR], 1.40 [95% CI, 0.94 to 2.08], P = .10 for current use; 1.16 [0.80 to 1.69], P = .4, 1.40 [0.99 to 1.97], P = .05, and 1.27 [0.98 to 1.63], P = .07 for past use 1-5, 6-10, and >10 years before, respectively), ever use was associated with increased risk (HR, 1.29 [95% CI, 1.04 to 1.60], P = .02). Furthermore, BC risk increased with longer cumulative duration of use, with an estimated proportional increase in risk of 3% (1%-5%, P = .002) for each additional year of use. For BRCA2 mutation carriers, there was no evidence that current or ever use was associated with increased BC risk (HR, 0.70 [95% CI, 0.33 to 1.47], P = .3 and 1.07 [0.73 to 1.57], P = .7, respectively).Hormonal contraceptives were associated with increased BC risk for BRCA1 mutation carriers, especially if used for longer durations. Decisions about their use in women with BRCA1 mutations should carefully weigh the risks and benefits for each individual.

  View details for DOI 10.1200/JCO.24.00176

  View details for PubMedID 39356978

• Development of a breast cancer risk prediction model integrating monogenic, polygenic, and epidemiologic risk. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Kalia, S. S., Boddicker, N. J., Yadav, S., Huang, H., Na, J., Hu, C., Ambrosone, C. B., Yao, S., Haiman, C. A., Chen, F., John, E. M., Kurian, A. W., Guo, B., Lindström, S., Auer, P., Lacey, J. V., Neuhausen, S. L., Martinez, M. E., Sandler, D. P., O'Brien, K. M., Taylor, J. A., Teras, L. R., Hodge, J. M., Lori, A., Bodelon, C., Trentham-Dietz, A., Burnside, E. S., Vachon, C. M., Winham, S. J., Goldgar, D. E., Domchek, S. M., Nathanson, K. L., Weitzel, J. N., Couch, F. J., Kraft, P. 2024

  Abstract

  Breast cancer has been associated with monogenic, polygenic, and epidemiologic (clinical, reproductive and lifestyle) risk factors, but studies evaluating the combined effects of these factors have been limited.We extended previous work in breast cancer risk modeling, incorporating pathogenic variants (PV) in six breast cancer predisposition genes and a 105-SNP polygenic risk score (PRS), to include an epidemiologic risk score (ERS) in a sample of non-Hispanic White women drawn from prospective cohorts and population-based case-control studies, with 23,518 cases and 22,832 controls, from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium.The model predicts 4.4-fold higher risk of breast cancer for postmenopausal women with no predisposition PV and median PRS, but with the highest versus lowest ERS. Overall, women with CHEK2 PVs had >20% lifetime risk of breast cancer. However, 15.6% of women with CHEK2 PVs and a family history of breast cancer, and 45.1% of women with CHEK2 PVs but without a family history of breast cancer, had low (<20%) predicted lifetime risk and thus were below the threshold for MRI screening. CHEK2 PV carriers at the 10th percentile of the joint distribution of ERS and PRS, without a family history of breast cancer, had a predicted lifetime risk similar to the general population.These results illustrate that an ERS, alone and combined with the PRS, can contribute to clinically relevant risk stratification.Integrating monogenic, polygenic, and epidemiologic risk factors in breast cancer risk prediction models may inform personalized screening and prevention efforts.

  View details for DOI 10.1158/1055-9965.EPI-24-0594

  View details for PubMedID 39259185

• Reply to "Critical analysis of Reiner et al.'s study on agreement of medical record abstraction and self-report of breast cancer treatment". Cancer Reiner, A. S., Knight, J. A., John, E. M., Lynch, C. F., Malone, K. E., Liang, X., Woods, M., Root, J. C., Bernstein, J. L. 2024

  View details for DOI 10.1002/cncr.35549

  View details for PubMedID 39233462

• Surgery and Suicide Deaths Among Patients With Cancer. JAMA network open Chen, M. L., Gomez, S. L., O'Hara, R., John, E. M., Morris, A. M., Kurian, A. W., Linos, E. 2024; 7 (9): e2431414

  View details for DOI 10.1001/jamanetworkopen.2024.31414

  View details for PubMedID 39226059

• Development of Melanoma and Other Nonkeratinocyte Skin Cancers After Thyroid Cancer Radiation. JAMA network open Rezaei, S. J., Chen, M. L., Kim, J., John, E. M., Sunwoo, J. B., Linos, E. 2024; 7 (9): e2434841

  View details for DOI 10.1001/jamanetworkopen.2024.34841

  View details for PubMedID 39298173

• Pregnancy-Related Factors and Breast Cancer Risk for Women Across a Range of Familial Risk. JAMA network open McDonald, J. A., Liao, Y., Knight, J. A., John, E. M., Kurian, A. W., Daly, M., Buys, S. S., Huang, Y., Frost, C. J., Andrulis, I. L., Colonna, S. V., Friedlander, M. L., Hopper, J. L., Chung, W. K., Genkinger, J. M., MacInnis, R. J., Terry, M. B. 2024; 7 (8): e2427441

  Abstract

  Few studies have investigated whether the associations between pregnancy-related factors and breast cancer (BC) risk differ by underlying BC susceptibility. Evidence regarding variation in BC risk is critical to understanding BC causes and for developing effective risk-based screening guidelines.To examine the association between pregnancy-related factors and BC risk, including modification by a of BC where scores are based on age and BC family history.This cohort study included participants from the prospective Family Study Cohort (ProF-SC), which includes the 6 sites of the Breast Cancer Family Registry (US, Canada, and Australia) and the Kathleen Cuningham Foundation Consortium (Australia). Analyses were performed in a cohort of women enrolled from 1992 to 2011 without any personal history of BC who were followed up through 2017 with a median (range) follow-up of 10 (1-23) years. Data were analyzed from March 1992 to March 2017.Parity, number of full-term pregnancies (FTP), age at first FTP, years since last FTP, and breastfeeding.BC diagnoses were obtained through self-report or report by a first-degree relative and confirmed through pathology and data linkages. Cox proportional hazards regression models estimated hazard ratios (HR) and 95% CIs for each exposure, examining modification by PARS of BC. Differences were assessed by estrogen receptor (ER) subtype.The study included 17 274 women (mean [SD] age, 46.7 [15.1] years; 791 African American or Black participants [4.6%], 1399 Hispanic or Latinx participants [8.2%], and 13 790 White participants [80.7%]) with 943 prospectively ascertained BC cases. Compared with nulliparous women, BC risk was higher after a recent pregnancy for those women with higher PARS (last FTP 0-5 years HR for interaction, 1.53; 95% CI, 1.13-2.07; P for interaction < .001). Associations between other exposures were limited to ER-negative disease. ER-negative BC was positively associated with increasing PARS and increasing years since last FTP (P for interaction < .001) with higher risk for recent pregnancy vs nulliparous women (last FTP 0-5 years HR for interaction, 1.54; 95% CI, 1.03-2.31). ER-negative BC was positively associated with increasing PARS and being aged 20 years or older vs less than 20 years at first FTP (P for interaction = .002) and inversely associated with multiparity vs nulliparity (P for interaction = .01).In this cohort study of women with no prior BC diagnoses, associations between pregnancy-related factors and BC risk were modified by PARS, with greater associations observed for ER-negative BC.

  View details for DOI 10.1001/jamanetworkopen.2024.27441

  View details for PubMedID 39186276

• Publisher Correction: Understanding the genetic complexity of puberty timing across the allele frequency spectrum. Nature genetics Kentistou, K. A., Kaisinger, L. R., Stankovic, S., Vaudel, M., Mendes de Oliveira, E., Messina, A., Walters, R. G., Liu, X., Busch, A. S., Helgason, H., Thompson, D. J., Santoni, F., Petricek, K. M., Zouaghi, Y., Huang-Doran, I., Gudbjartsson, D. F., Bratland, E., Lin, K., Gardner, E. J., Zhao, Y., Jia, R. Y., Terao, C., Riggan, M. J., Bolla, M. K., Yazdanpanah, M., Yazdanpanah, N., Bradfield, J. P., Broer, L., Campbell, A., Chasman, D. I., Cousminer, D. L., Franceschini, N., Franke, L. H., Girotto, G., He, C., Järvelin, M. R., Joshi, P. K., Kamatani, Y., Karlsson, R., Luan, J., Lunetta, K. L., Mägi, R., Mangino, M., Medland, S. E., Meisinger, C., Noordam, R., Nutile, T., Concas, M. P., Polašek, O., Porcu, E., Ring, S. M., Sala, C., Smith, A. V., Tanaka, T., van der Most, P. J., Vitart, V., Wang, C. A., Willemsen, G., Zygmunt, M., Ahearn, T. U., Andrulis, I. L., Anton-Culver, H., Antoniou, A. C., Auer, P. L., Barnes, C. L., Beckmann, M. W., Berrington de Gonzalez, A., Bogdanova, N. V., Bojesen, S. E., Brenner, H., Buring, J. E., Canzian, F., Chang-Claude, J., Couch, F. J., Cox, A., Crisponi, L., Czene, K., Daly, M. B., Demerath, E. W., Dennis, J., Devilee, P., De Vivo, I., Dörk, T., Dunning, A. M., Dwek, M., Eriksson, J. G., Fasching, P. A., Fernandez-Rhodes, L., Ferreli, L., Fletcher, O., Gago-Dominguez, M., García-Closas, M., García-Sáenz, J. A., González-Neira, A., Grallert, H., Guénel, P., Haiman, C. A., Hall, P., Hamann, U., Hakonarson, H., Hart, R. J., Hickey, M., Hooning, M. J., Hoppe, R., Hopper, J. L., Hottenga, J. J., Hu, F. B., Huebner, H., Hunter, D. J., Jernström, H., John, E. M., Karasik, D., Khusnutdinova, E. K., Kristensen, V. N., Lacey, J. V., Lambrechts, D., Launer, L. J., Lind, P. A., Lindblom, A., Magnusson, P. K., Mannermaa, A., McCarthy, M. I., Meitinger, T., Menni, C., Michailidou, K., Millwood, I. Y., Milne, R. L., Montgomery, G. W., Nevanlinna, H., Nolte, I. M., Nyholt, D. R., Obi, N., O'Brien, K. M., Offit, K., Oldehinkel, A. J., Ostrowski, S. R., Palotie, A., Pedersen, O. B., Peters, A., Pianigiani, G., Plaseska-Karanfilska, D., Pouta, A., Pozarickij, A., Radice, P., Rennert, G., Rosendaal, F. R., Ruggiero, D., Saloustros, E., Sandler, D. P., Schipf, S., Schmidt, C. O., Schmidt, M. K., Small, K., Spedicati, B., Stampfer, M., Stone, J., Tamimi, R. M., Teras, L. R., Tikkanen, E., Turman, C., Vachon, C. M., Wang, Q., Winqvist, R., Wolk, A., Zemel, B. S., Zheng, W., van Dijk, K. W., Alizadeh, B. Z., Bandinelli, S., Boerwinkle, E., Boomsma, D. I., Ciullo, M., Chenevix-Trench, G., Cucca, F., Esko, T., Gieger, C., Grant, S. F., Gudnason, V., Hayward, C., Kolčić, I., Kraft, P., Lawlor, D. A., Martin, N. G., Nøhr, E. A., Pedersen, N. L., Pennell, C. E., Ridker, P. M., Robino, A., Snieder, H., Sovio, U., Spector, T. D., Stöckl, D., Sudlow, C., Timpson, N. J., Toniolo, D., Uitterlinden, A., Ulivi, S., Völzke, H., Wareham, N. J., Widen, E., Wilson, J. F., Pharoah, P. D., Li, L., Easton, D. F., Njølstad, P. R., Sulem, P., Murabito, J. M., Murray, A., Manousaki, D., Juul, A., Erikstrup, C., Stefansson, K., Horikoshi, M., Chen, Z., Farooqi, I. S., Pitteloud, N., Johansson, S., Day, F. R., Perry, J. R., Ong, K. K. 2024

  View details for DOI 10.1038/s41588-024-01857-w

  View details for PubMedID 38982295

• Understanding the genetic complexity of puberty timing across the allele frequency spectrum. Nature genetics Kentistou, K. A., Kaisinger, L. R., Stankovic, S., Vaudel, M., Mendes de Oliveira, E., Messina, A., Walters, R. G., Liu, X., Busch, A. S., Helgason, H., Thompson, D. J., Santoni, F., Petricek, K. M., Zouaghi, Y., Huang-Doran, I., Gudbjartsson, D. F., Bratland, E., Lin, K., Gardner, E. J., Zhao, Y., Jia, R. Y., Terao, C., Riggan, M. J., Bolla, M. K., Yazdanpanah, M., Yazdanpanah, N., Bradfield, J. P., Broer, L., Campbell, A., Chasman, D. I., Cousminer, D. L., Franceschini, N., Franke, L. H., Girotto, G., He, C., Järvelin, M. R., Joshi, P. K., Kamatani, Y., Karlsson, R., Luan, J., Lunetta, K. L., Mägi, R., Mangino, M., Medland, S. E., Meisinger, C., Noordam, R., Nutile, T., Concas, M. P., Polašek, O., Porcu, E., Ring, S. M., Sala, C., Smith, A. V., Tanaka, T., van der Most, P. J., Vitart, V., Wang, C. A., Willemsen, G., Zygmunt, M., Ahearn, T. U., Andrulis, I. L., Anton-Culver, H., Antoniou, A. C., Auer, P. L., Barnes, C. L., Beckmann, M. W., Berrington de Gonzalez, A., Bogdanova, N. V., Bojesen, S. E., Brenner, H., Buring, J. E., Canzian, F., Chang-Claude, J., Couch, F. J., Cox, A., Crisponi, L., Czene, K., Daly, M. B., Demerath, E. W., Dennis, J., Devilee, P., De Vivo, I., Dörk, T., Dunning, A. M., Dwek, M., Eriksson, J. G., Fasching, P. A., Fernandez-Rhodes, L., Ferreli, L., Fletcher, O., Gago-Dominguez, M., García-Closas, M., García-Sáenz, J. A., González-Neira, A., Grallert, H., Guénel, P., Haiman, C. A., Hall, P., Hamann, U., Hakonarson, H., Hart, R. J., Hickey, M., Hooning, M. J., Hoppe, R., Hopper, J. L., Hottenga, J. J., Hu, F. B., Huebner, H., Hunter, D. J., Jernström, H., John, E. M., Karasik, D., Khusnutdinova, E. K., Kristensen, V. N., Lacey, J. V., Lambrechts, D., Launer, L. J., Lind, P. A., Lindblom, A., Magnusson, P. K., Mannermaa, A., McCarthy, M. I., Meitinger, T., Menni, C., Michailidou, K., Millwood, I. Y., Milne, R. L., Montgomery, G. W., Nevanlinna, H., Nolte, I. M., Nyholt, D. R., Obi, N., O'Brien, K. M., Offit, K., Oldehinkel, A. J., Ostrowski, S. R., Palotie, A., Pedersen, O. B., Peters, A., Pianigiani, G., Plaseska-Karanfilska, D., Pouta, A., Pozarickij, A., Radice, P., Rennert, G., Rosendaal, F. R., Ruggiero, D., Saloustros, E., Sandler, D. P., Schipf, S., Schmidt, C. O., Schmidt, M. K., Small, K., Spedicati, B., Stampfer, M., Stone, J., Tamimi, R. M., Teras, L. R., Tikkanen, E., Turman, C., Vachon, C. M., Wang, Q., Winqvist, R., Wolk, A., Zemel, B. S., Zheng, W., van Dijk, K. W., Alizadeh, B. Z., Bandinelli, S., Boerwinkle, E., Boomsma, D. I., Ciullo, M., Chenevix-Trench, G., Cucca, F., Esko, T., Gieger, C., Grant, S. F., Gudnason, V., Hayward, C., Kolčić, I., Kraft, P., Lawlor, D. A., Martin, N. G., Nøhr, E. A., Pedersen, N. L., Pennell, C. E., Ridker, P. M., Robino, A., Snieder, H., Sovio, U., Spector, T. D., Stöckl, D., Sudlow, C., Timpson, N. J., Toniolo, D., Uitterlinden, A., Ulivi, S., Völzke, H., Wareham, N. J., Widen, E., Wilson, J. F., Pharoah, P. D., Li, L., Easton, D. F., Njølstad, P. R., Sulem, P., Murabito, J. M., Murray, A., Manousaki, D., Juul, A., Erikstrup, C., Stefansson, K., Horikoshi, M., Chen, Z., Farooqi, I. S., Pitteloud, N., Johansson, S., Day, F. R., Perry, J. R., Ong, K. K. 2024

  Abstract

  Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

  View details for DOI 10.1038/s41588-024-01798-4

  View details for PubMedID 38951643

  View details for PubMedCentralID 6185946

• Agreement of medical record abstraction and self-report of breast cancer treatment with an extended recall window. Cancer Reiner, A. S., Knight, J. A., John, E. M., Lynch, C. F., Malone, K. E., Liang, X., Woods, M., Root, J. C., Bernstein, J. L. 2024

  Abstract

  Medical record abstraction (MRA) and self-report questionnaires are two methods frequently used to ascertain cancer treatment information. Prior studies have shown excellent agreement between MRA and self-report, but it is unknown how a recall window longer than 3 years may affect this agreement.The Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study is a multicenter, population-based case-control study of controls with unilateral breast cancer individually matched to cases with contralateral breast cancer. Participants who were diagnosed with a first primary breast cancer from 1985 to 2008 before the age of 55 years completed a questionnaire that included questions on treatment. First primary breast cancer treatment information was abstracted from the medical record from radiation oncology clinic notes for radiation treatment and from systemic adjuvant treatment reports for hormone therapy and chemotherapy. Agreement between MRA and self-reported treatment was assessed with the kappa statistic and corresponding 95% confidence intervals (CIs).A total of 2808 participants with MRA and self-reported chemotherapy treatment information, 2733 participants with MRA and self-reported hormone therapy information, and 2905 participants with MRA and self-reported radiation treatment information were identified. The median recall window was 12.5 years (range, 2.8-22.2 years). MRA and self-reported treatment agreement was excellent across treatment modalities (kappachemo, 98.5; 95% CI, 97.9-99.2; kappahorm, 87.7; 95% CI, 85.9-89.5; kapparad, 97.9; 95% CI, 97.0-98.7). There was no heterogeneity across recall windows (pchemo = .46; phorm = .40; prad = .61).Agreement between self-reported and MRA primary breast cancer treatment modality information was excellent for young women diagnosed with breast cancer and was maintained even among women whose recall window was more than 20 years after diagnosis.

  View details for DOI 10.1002/cncr.35459

  View details for PubMedID 38941510

• Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants that Confer Risk for Breast Cancer. Cancer research Sun, X., Verma, S. P., Jia, G., Wang, X., Ping, J., Guo, X., Shu, X. O., Chen, J., Derkach, A., Cai, Q., Liang, X., Long, J., Offit, K., Oh, J. H., Reiner, A. S., Watt, G. P., Woods, M., Yang, Y., Ambrosone, C. B., Ambs, S., Chen, Y., Concannon, P., Garcia-Closas, M., Gu, J., Haiman, C. A., Hu, J. J., Huo, D., John, E. M., Knight, J. A., Li, C. I., Lynch, C. F., Mellemkjaer, L., Nathanson, K. L., Nemesure, B., Olopade, O. I., Olshan, A. F., Pal, T., Palmer, J. R., Press, M. F., Sanderson, M., Sandler, D. P., Troester, M. A., Zheng, W., Bernstein, J. L., Buas, M. F., Shu, X. 2024

  Abstract

  Breast cancer includes several subtypes with distinct characteristic biological, pathological, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate development of improved prevention and treatment approaches. Here, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case GWAS (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared to luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to 2-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case-control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among breast cancer patients. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC.

  View details for DOI 10.1158/0008-5472.CAN-23-3854

  View details for PubMedID 38832928

• Reproductive characteristics, menopausal status, race and ethnicity, and risk of breast cancer subtypes defined by ER, PR and HER2 status: the Breast Cancer Etiology in Minorities study. Breast cancer research : BCR John, E. M., Koo, J., Phipps, A. I., Longacre, T. A., Kurian, A. W., Ingles, S. A., Wu, A. H., Hines, L. M. 2024; 26 (1): 88

  Abstract

  Associations between reproductive factors and risk of breast cancer differ by subtype defined by joint estrogen receptor (ER), progesterone receptor (PR), and HER2 expression status. Racial and ethnic differences in the incidence of breast cancer subtypes suggest etiologic heterogeneity, yet data are limited because most studies have included non-Hispanic White women only.We analyzed harmonized data for 2,794 breast cancer cases and 4,579 controls, of whom 90% self-identified as African American, Asian American or Hispanic. Questionnaire data were pooled from three population-based studies conducted in California and data on tumor characteristics were obtained from the California Cancer Registry. The study sample included 1,530 luminal A (ER-positive and/or PR-positive, HER2-negative), 442 luminal B (ER-positive and/or PR-positive, HER2-positive), 578 triple-negative (TN; ER-negative, PR-negative, HER2-negative), and 244 HER2-enriched (ER-negative, PR-negative, HER2-positive) cases. We used multivariable unconditional logistic regression models to estimate subtype-specific ORs and 95% confidence intervals associated with parity, breast-feeding, and other reproductive characteristics by menopausal status and race and ethnicity.Subtype-specific associations with reproductive factors revealed some notable differences by menopausal status and race and ethnicity. Specifically, higher parity without breast-feeding was associated with higher risk of luminal A and TN subtypes among premenopausal African American women. In contrast, among Asian American and Hispanic women, regardless of menopausal status, higher parity with a breast-feeding history was associated with lower risk of luminal A subtype. Among premenopausal women only, luminal A subtype was associated with older age at first full-term pregnancy (FTP), longer interval between menarche and first FTP, and shorter interval since last FTP, with similar OR estimates across the three racial and ethnic groups.Subtype-specific associations with reproductive factors overall and by menopausal status, and race and ethnicity, showed some differences, underscoring that understanding etiologic heterogeneity in racially and ethnically diverse study samples is essential. Breast-feeding is likely the only reproductive factor that is potentially modifiable. Targeted efforts to promote and facilitate breast-feeding could help mitigate the adverse effects of higher parity among premenopausal African American women.

  View details for DOI 10.1186/s13058-024-01834-5

  View details for PubMedID 38822357

  View details for PubMedCentralID 6223627

• Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes. Nature communications Ping, J., Jia, G., Cai, Q., Guo, X., Tao, R., Ambrosone, C., Huo, D., Ambs, S., Barnard, M. E., Chen, Y., Garcia-Closas, M., Gu, J., Hu, J. J., John, E. M., Li, C. I., Nathanson, K., Nemesure, B., Olopade, O. I., Pal, T., Press, M. F., Sanderson, M., Sandler, D. P., Yoshimatsu, T., Adejumo, P. O., Ahearn, T., Brewster, A. M., Hennis, A. J., Makumbi, T., Ndom, P., O'Brien, K. M., Olshan, A. F., Oluwasanu, M. M., Reid, S., Yao, S., Butler, E. N., Huang, M., Ntekim, A., Li, B., Troester, M. A., Palmer, J. R., Haiman, C. A., Long, J., Zheng, W. 2024; 15 (1): 3718

  Abstract

  African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.

  View details for DOI 10.1038/s41467-024-47650-5

  View details for PubMedID 38697998

  View details for PubMedCentralID PMC11065893

• Genome-wide association analyses of breast cancer in women of African ancestry identify new susceptibility loci and improve risk prediction. Nature genetics Jia, G., Ping, J., Guo, X., Yang, Y., Tao, R., Li, B., Ambs, S., Barnard, M. E., Chen, Y., Garcia-Closas, M., Gu, J., Hu, J. J., Huo, D., John, E. M., Li, C. I., Li, J. L., Nathanson, K. L., Nemesure, B., Olopade, O. I., Pal, T., Press, M. F., Sanderson, M., Sandler, D. P., Shu, X. O., Troester, M. A., Yao, S., Adejumo, P. O., Ahearn, T., Brewster, A. M., Hennis, A. J., Makumbi, T., Ndom, P., O'Brien, K. M., Olshan, A. F., Oluwasanu, M. M., Reid, S., Butler, E. N., Huang, M., Ntekim, A., Qian, H., Zhang, H., Ambrosone, C. B., Cai, Q., Long, J., Palmer, J. R., Haiman, C. A., Zheng, W. 2024; 56 (5): 819-826

  Abstract

  We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10-8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.

  View details for DOI 10.1038/s41588-024-01736-4

  View details for PubMedID 38741014

  View details for PubMedCentralID 8127622

• Disentangling the relationships of body mass index and circulating sex hormone concentrations in mammographic density using Mendelian randomization. Breast cancer research and treatment Haas, C. B., Chen, H., Harrison, T., Fan, S., Gago-Dominguez, M., Castelao, J. E., Bolla, M. K., Wang, Q., Dennis, J., Michailidou, K., Dunning, A. M., Easton, D. F., Antoniou, A. C., Hall, P., Czene, K., Andrulis, I. L., Mulligan, A. M., Milne, R. L., Fasching, P. A., Haeberle, L., Garcia-Closas, M., Ahearn, T., Gierach, G. L., Haiman, C., Maskarinec, G., Couch, F. J., Olson, J. E., John, E. M., Chenevix-Trench, G., de Gonzalez, A. B., Jones, M., Stone, J., Murphy, R., Aronson, K. J., Wernli, K. J., Hsu, L., Vachon, C., Tamimi, R. M., Lindström, S. 2024

  Abstract

  Mammographic density phenotypes, adjusted for age and body mass index (BMI), are strong predictors of breast cancer risk. BMI is associated with mammographic density measures, but the role of circulating sex hormone concentrations is less clear. We investigated the relationship between BMI, circulating sex hormone concentrations, and mammographic density phenotypes using Mendelian randomization (MR).We applied two-sample MR approaches to assess the association between genetically predicted circulating concentrations of sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG)], BMI, and mammographic density phenotypes (dense and non-dense area). We created instrumental variables from large European ancestry-based genome-wide association studies and applied estimates to mammographic density phenotypes in up to 14,000 women of European ancestry. We performed analyses overall and by menopausal status.Genetically predicted BMI was positively associated with non-dense area (IVW: β = 1.79; 95% CI = 1.58, 2.00; p = 9.57 × 10-63) and inversely associated with dense area (IVW: β = - 0.37; 95% CI = - 0.51,- 0.23; p = 4.7 × 10-7). We observed weak evidence for an association of circulating sex hormone concentrations with mammographic density phenotypes, specifically inverse associations between genetically predicted testosterone concentration and dense area (β = - 0.22; 95% CI = - 0.38, - 0.053; p = 0.009) and between genetically predicted estradiol concentration and non-dense area (β =  - 3.32; 95% CI = - 5.83, - 0.82; p = 0.009), although results were not consistent across a range of MR approaches.Our findings support a positive causal association between BMI and mammographic non-dense area and an inverse association between BMI and dense area. Evidence was weaker and inconsistent for a causal effect of circulating sex hormone concentrations on mammographic density phenotypes. Based on our findings, associations between circulating sex hormone concentrations and mammographic density phenotypes are weak at best.

  View details for DOI 10.1007/s10549-024-07306-w

  View details for PubMedID 38653906

  View details for PubMedCentralID 4376349

• Tumor-Infiltrating lymphocytes and breast cancer mortality in racially and ethnically diverse participants of the Northern California breast cancer family registry. JNCI cancer spectrum Ransohoff, J. D., Miller, I., Koo, J., Joshi, V., Kurian, A. W., Allison, K. H., John, E. M., Telli, M. L. 2024

  Abstract

  Stromal tumor-infiltrating lymphocyte (sTIL) enrichment in pre-treatment breast tumors has been associated with superior response to neoadjuvant treatment and survival. In a population-based cohort, we studied sTIL-survival associations by race and ethnicity. We assessed associations of continuous sTIL scores and sTIL-enriched breast cancers (defined as percent lymphocytic infiltration of tumor stroma or cell nests at cutoffs of 30%, 50%, and 70%) with clinical and epidemiologic characteristics and conducted multivariable survival analyses. While we identified no difference in sTIL score by race and ethnicity, higher continuous sTIL score was associated with lower breast cancer-specific mortality only among non-Hispanic White and Asian American but not African American and Hispanic women. This finding suggests that complex factors influence treatment response and survival, given that sTIL enrichment was not associated with a survival advantage among women from minoritized groups, who more often experience health disparities. Further study of patient selection for sTIL-guided treatment strategies is warranted.

  View details for DOI 10.1093/jncics/pkae023

  View details for PubMedID 38547391

• Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk. medRxiv : the preprint server for health sciences Barnes, D. R., Tyrer, J. P., Dennis, J., Leslie, G., Bolla, M. K., Lush, M., Aeilts, A. M., Aittomäki, K., Andrieu, N., Andrulis, I. L., Anton-Culver, H., Arason, A., Arun, B. K., Balmaña, J., Bandera, E. V., Barkardottir, R. B., Berger, L. P., de Gonzalez, A. B., Berthet, P., Białkowska, K., Bjørge, L., Blanco, A. M., Blok, M. J., Bobolis, K. A., Bogdanova, N. V., Brenton, J. D., Butz, H., Buys, S. S., Caligo, M. A., Campbell, I., Castillo, C., Claes, K. B., Colonna, S. V., Cook, L. S., Daly, M. B., Dansonka-Mieszkowska, A., de la Hoya, M., deFazio, A., DePersia, A., Ding, Y. C., Domchek, S. M., Dörk, T., Einbeigi, Z., Engel, C., Evans, D. G., Foretova, L., Fortner, R. T., Fostira, F., Foti, M. C., Friedman, E., Frone, M. N., Ganz, P. A., Gentry-Maharaj, A., Glendon, G., Godwin, A. K., González-Neira, A., Greene, M. H., Gronwald, J., Guerrieri-Gonzaga, A., Hamann, U., Hansen, T. V., Harris, H. R., Hauke, J., Heitz, F., Hogervorst, F. B., Hooning, M. J., Hopper, J. L., Huff, C. D., Huntsman, D. G., Imyanitov, E. N., Izatt, L., Jakubowska, A., James, P. A., Janavicius, R., John, E. M., Kar, S., Karlan, B. Y., Kennedy, C. J., Kiemeney, L. A., Konstantopoulou, I., Kupryjanczyk, J., Laitman, Y., Lavie, O., Lawrenson, K., Lester, J., Lesueur, F., Lopez-Pleguezuelos, C., Mai, P. L., Manoukian, S., May, T., McNeish, I. A., Menon, U., Milne, R. L., Modugno, F., Mongiovi, J. M., Montagna, M., Moysich, K. B., Neuhausen, S. L., Nielsen, F. C., Noguès, C., Oláh, E., Olopade, O. I., Osorio, A., Papi, L., Pathak, H., Pearce, C. L., Pedersen, I. S., Peixoto, A., Pejovic, T., Peng, P. C., Peshkin, B. N., Peterlongo, P., Powell, C. B., Prokofyeva, D., Pujana, M. A., Radice, P., Rashid, M. U., Rennert, G., Richenberg, G., Sandler, D. P., Sasamoto, N., Setiawan, V. W., Sharma, P., Sieh, W., Singer, C. F., Snape, K., Sokolenko, A. P., Soucy, P., Southey, M. C., Stoppa-Lyonnet, D., Sutphen, R., Sutter, C., Teixeira, M. R., Terry, K. L., Thomsen, L. C., Tischkowitz, M., Toland, A. E., Van Gorp, T., Vega, A., Velez Edwards, D. R., Webb, P. M., Weitzel, J. N., Wentzensen, N., Whittemore, A. S., Winham, S. J., Wu, A. H., Yadav, S., Yu, Y., Ziogas, A., Berchuck, A., Couch, F. J., Goode, E. L., Goodman, M. T., Monteiro, A. N., Offit, K., Ramus, S. J., Risch, H. A., Schildkraut, J. M., Thomassen, M., Simard, J., Easton, D. F., Jones, M. R., Chenevix-Trench, G., Gayther, S. A., Antoniou, A. C., Pharoah, P. D. 2024

  Abstract

  Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS).We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan.Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10-9). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62).This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.

  View details for DOI 10.1101/2024.02.29.24303243

  View details for PubMedID 38496424

  View details for PubMedCentralID PMC10942532

• Novel breast cancer susceptibility loci under linkage peaks identified in African ancestry consortia. Human molecular genetics Ochs-Balcom, H. M., Preus, L., Du, Z., Elston, R. C., Teerlink, C. C., Jia, G., Guo, X., Cai, Q., Long, J., Ping, J., Li, B., Stram, D. O., Shu, X. O., Sanderson, M., Gao, G., Ahearn, T., Lunetta, K. L., Zirpoli, G., Troester, M. A., Ruiz-Narváez, E. A., Haddad, S. A., Figueroa, J., John, E. M., Bernstein, L., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Mancuso, N., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Yao, S., Ogundiran, T. O., Ojengbede, O., Bolla, M. K., Dennis, J., Dunning, A. M., Easton, D. F., Michailidou, K., Pharoah, P. D., Sandler, D. P., Taylor, J. A., Wang, Q., O'Brien, K. M., Weinberg, C. R., Kitahara, C. M., Blot, W., Nathanson, K. L., Hennis, A., Nemesure, B., Ambs, S., Sucheston-Campbell, L. E., Bensen, J. T., Chanock, S. J., Olshan, A. F., Ambrosone, C. B., Olopade, O. I., Conti, D. V., Palmer, J., García-Closas, M., Huo, D., Zheng, W., Haiman, C. 2024

  Abstract

  Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs.We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG).In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10-6; rs12322371, OR = 1.14, p = 3.15×10-6), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10-6). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10-5; rs76959804, OR = 3.57, p = 1.77×10-5) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10-6). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16).The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence.

  View details for DOI 10.1093/hmg/ddae002

  View details for PubMedID 38263910

• A genome-wide association study of contralateral breast cancer in the Women's Environmental Cancer and Radiation Epidemiology Study. Breast cancer research : BCR Sun, X., Reiner, A. S., Tran, A. P., Watt, G. P., Oh, J. H., Mellemkjær, L., Lynch, C. F., Knight, J. A., John, E. M., Malone, K. E., Liang, X., Woods, M., Derkach, A., Concannon, P., Bernstein, J. L., Shu, X. 2024; 26 (1): 16

  Abstract

  Contralateral breast cancer (CBC) is the most common second primary cancer diagnosed in breast cancer survivors, yet the understanding of the genetic susceptibility of CBC, particularly with respect to common variants, remains incomplete. This study aimed to investigate the genetic basis of CBC to better understand this malignancy.We performed a genome-wide association analysis in the Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study of women with first breast cancer diagnosed at age < 55 years including 1161 with CBC who served as cases and 1668 with unilateral breast cancer (UBC) who served as controls. We observed two loci (rs59657211, 9q32, SLC31A2/FAM225A and rs3815096, 6p22.1, TRIM31) with suggestive genome-wide significant associations (P < 1 × 10-6). We also found an increased risk of CBC associated with a breast cancer-specific polygenic risk score (PRS) comprised of 239 known breast cancer susceptibility single nucleotide polymorphisms (SNPs) (rate ratio per 1-SD change: 1.25; 95% confidence interval 1.14-1.36, P < 0.0001). The protective effect of chemotherapy on CBC risk was statistically significant only among patients with an elevated PRS (Pheterogeneity = 0.04). The AUC that included the PRS and known breast cancer risk factors was significantly elevated.The present GWAS identified two previously unreported loci with suggestive genome-wide significance. We also confirm that an elevated risk of CBC is associated with a comprehensive breast cancer susceptibility PRS that is independent of known breast cancer risk factors. These findings advance our understanding of genetic risk factors involved in CBC etiology.

  View details for DOI 10.1186/s13058-024-01765-1

  View details for PubMedID 38263039

  View details for PubMedCentralID PMC10807183

• Childhood physical activity and pubertal timing: findings from the LEGACY girls study. International journal of epidemiology Kehm, R. D., Knight, J. A., Houghton, L. C., McDonald, J. A., Schwartz, L. A., Goldberg, M., Chung, W. K., Frost, C. J., Wei, Y., Bradbury, A. R., Keegan, T. H., Daly, M. B., Buys, S. S., Andrulis, I. L., John, E. M., Terry, M. B. 2024

  Abstract

  There is limited research on whether physical activity (PA) in early childhood is associated with the timing of pubertal events in girls.We used data collected over 2011-16 from the LEGACY Girls Study (n = 984; primarily aged 6-13 years at study enrolment), a multicentre North American cohort enriched for girls with a breast cancer family history (BCFH), to evaluate if PA is associated with age at thelarche, pubarche and menarche. Maternal-reported questionnaire data measured puberty outcomes, PA in early childhood (ages 3-5 years) and total metabolic equivalents of organized PA in middle childhood (ages 7-9 years). We used interval-censored Weibull parametric survival regression models with age as the time scale and adjusted for sociodemographic factors, and we tested for effect modification by BCFH. We used inverse odds weighting to test for mediation by body mass index-for-age z-score (BMIZ) measured at study enrolment.Being highly active vs inactive in early childhood was associated with later thelarche in girls with a BCFH [adjusted hazard ratio (aHR) = 0.39, 95% CI = 0.26-0.59), but not in girls without a BCFH. In all girls, irrespective of BCFH, being in the highest vs lowest quartile of organized PA in middle childhood was associated with later menarche (aHR = 0.70, 95% CI = 0.50-0.97). These associations remained after accounting for potential mediation by BMIZ.This study provides new data that PA in early childhood may be associated with later thelarche in girls with a BCFH, also further supporting an overall association between PA in middle childhood and later menarche.

  View details for DOI 10.1093/ije/dyad193

  View details for PubMedID 38205889

• Observational and genetic associations between cardiorespiratory fitness and cancer: a UK Biobank and international consortia study. British journal of cancer Watts, E. L., Gonzales, T. I., Strain, T., Saint-Maurice, P. F., Bishop, D. T., Chanock, S. J., Johansson, M., Keku, T. O., Le Marchand, L., Moreno, V., Newcomb, P. A., Newton, C. C., Pai, R. K., Purdue, M. P., Ulrich, C. M., Smith-Byrne, K., Van Guelpen, B., PRACTICAL consortium, C., Day, F. R., Wijndaele, K., Wareham, N. J., Matthews, C. E., Moore, S. C., Brage, S., Eeles, R. A., Haiman, C. A., Kote-Jarai, Z., Schumacher, F. R., Benlloch, S., Olama, A. A., Muir, K. R., Berndt, S. I., Conti, D. V., Wiklund, F., Chanock, S. J., Wang, Y., Tangen, C. M., Batra, J., Clements, J. A., Gronberg, H., Pashayan, N., Schleutker, J., Albanes, D., Weinstein, S. J., Wolk, A., West, C. M., Mucci, L. A., Cancel-Tassin, G., Koutros, S., Sorensen, K. D., Grindedal, E. M., Neal, D. E., Hamdy, F. C., Donovan, J. L., Travis, R. C., Hamilton, R. J., Ingles, S. A., Rosenstein, B. S., Lu, Y., Giles, G. G., MacInnis, R. J., Kibel, A. S., Vega, A., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Nielsen, S. F., Brenner, H., Maier, C., Kim, J., John, E. M., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R., Usmani, N., Claessens, F., Townsend, P. A., Castelao, J. E., Roobol, M. J., Menegaux, F., Khaw, K., Cannon-Albright, L., Pandha, H., Thibodeau, S. N., Hunter, D. J., Kraft, P., Blot, W. J., Riboli, E. 2023

  Abstract

  BACKGROUND: The association of fitness with cancer risk is not clear.METHODS: We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N=72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the inverse-variance weighted method.RESULTS: After a median of 11 years of follow-up, 4290 cancers of interest were diagnosed. A 3.5ml O2min-1kg-1 total-body mass increase in fitness (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviation (SD)) was associated with lower risks of endometrial (HR=0.81, 95% CI: 0.73-0.89), colorectal (0.94, 0.90-0.99), and breast cancer (0.96, 0.92-0.99). In MR analyses, a 0.5SD increase in genetically predicted O2min-1kg-1 fat-free mass was associated with a lower risk of breast cancer (OR=0.92, 95% CI: 0.86-0.98). After adjusting for adiposity, both the observational and genetic associations were attenuated.DISCUSSION: Higher fitness levels may reduce risks of endometrial, colorectal, and breast cancer, though relationships with adiposity are complex and may mediate these relationships. Increasing fitness, including via changes in body composition, may be an effective strategy for cancer prevention.

  View details for DOI 10.1038/s41416-023-02489-3

  View details for PubMedID 38057395

• Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants. Nature genetics Wang, A., Shen, J., Rodriguez, A. A., Saunders, E. J., Chen, F., Janivara, R., Darst, B. F., Sheng, X., Xu, Y., Chou, A. J., Benlloch, S., Dadaev, T., Brook, M. N., Plym, A., Sahimi, A., Hoffman, T. J., Takahashi, A., Matsuda, K., Momozawa, Y., Fujita, M., Laisk, T., Figuerêdo, J., Muir, K., Ito, S., Liu, X., Uchio, Y., Kubo, M., Kamatani, Y., Lophatananon, A., Wan, P., Andrews, C., Lori, A., Choudhury, P. P., Schleutker, J., Tammela, T. L., Sipeky, C., Auvinen, A., Giles, G. G., Southey, M. C., MacInnis, R. J., Cybulski, C., Wokolorczyk, D., Lubinski, J., Rentsch, C. T., Cho, K., Mcmahon, B. H., Neal, D. E., Donovan, J. L., Hamdy, F. C., Martin, R. M., Nordestgaard, B. G., Nielsen, S. F., Weischer, M., Bojesen, S. E., Røder, A., Stroomberg, H. V., Batra, J., Chambers, S., Horvath, L., Clements, J. A., Tilly, W., Risbridger, G. P., Gronberg, H., Aly, M., Szulkin, R., Eklund, M., Nordstrom, T., Pashayan, N., Dunning, A. M., Ghoussaini, M., Travis, R. C., Key, T. J., Riboli, E., Park, J. Y., Sellers, T. A., Lin, H. Y., Albanes, D., Weinstein, S., Cook, M. B., Mucci, L. A., Giovannucci, E., Lindstrom, S., Kraft, P., Hunter, D. J., Penney, K. L., Turman, C., Tangen, C. M., Goodman, P. J., Thompson, I. M., Hamilton, R. J., Fleshner, N. E., Finelli, A., Parent, M. É., Stanford, J. L., Ostrander, E. A., Koutros, S., Beane Freeman, L. E., Stampfer, M., Wolk, A., Håkansson, N., Andriole, G. L., Hoover, R. N., Machiela, M. J., Sørensen, K. D., Borre, M., Blot, W. J., Zheng, W., Yeboah, E. D., Mensah, J. E., Lu, Y. J., Zhang, H. W., Feng, N., Mao, X., Wu, Y., Zhao, S. C., Sun, Z., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., West, C. M., Barnett, G., Maier, C., Schnoeller, T., Luedeke, M., Kibel, A. S., Drake, B. F., Cussenot, O., Cancel-Tassin, G., Menegaux, F., Truong, T., Koudou, Y. A., John, E. M., Grindedal, E. M., Maehle, L., Khaw, K. T., Ingles, S. A., Stern, M. C., Vega, A., Gómez-Caamaño, A., Fachal, L., Rosenstein, B. S., Kerns, S. L., Ostrer, H., Teixeira, M. R., Paulo, P., Brandão, A., Watya, S., Lubwama, A., Bensen, J. T., Butler, E. N., Mohler, J. L., Taylor, J. A., Kogevinas, M., Dierssen-Sotos, T., Castaño-Vinyals, G., Cannon-Albright, L., Teerlink, C. C., Huff, C. D., Pilie, P., Yu, Y., Bohlender, R. J., Gu, J., Strom, S. S., Multigner, L., Blanchet, P., Brureau, L., Kaneva, R., Slavov, C., Mitev, V., Leach, R. J., Brenner, H., Chen, X., Holleczek, B., Schöttker, B., Klein, E. A., Hsing, A. W., Kittles, R. A., Murphy, A. B., Logothetis, C. J., Kim, J., Neuhausen, S. L., Steele, L., Ding, Y. C., Isaacs, W. B., Nemesure, B., Hennis, A. J., Carpten, J., Pandha, H., Michael, A., De Ruyck, K., De Meerleer, G., Ost, P., Xu, J., Razack, A., Lim, J., Teo, S. H., Newcomb, L. F., Lin, D. W., Fowke, J. H., Neslund-Dudas, C. M., Rybicki, B. A., Gamulin, M., Lessel, D., Kulis, T., Usmani, N., Abraham, A., Singhal, S., Parliament, M., Claessens, F., Joniau, S., Van den Broeck, T., Gago-Dominguez, M., Castelao, J. E., Martinez, M. E., Larkin, S., Townsend, P. A., Aukim-Hastie, C., Bush, W. S., Aldrich, M. C., Crawford, D. C., Srivastava, S., Cullen, J., Petrovics, G., Casey, G., Wang, Y., Tettey, Y., Lachance, J., Tang, W., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Yamoah, K., Govindasami, K., Chokkalingam, A. P., Keaton, J. M., Hellwege, J. N., Clark, P. E., Jalloh, M., Gueye, S. M., Niang, L., Ogunbiyi, O., Shittu, O., Amodu, O., Adebiyi, A. O., Aisuodionoe-Shadrach, O. I., Ajibola, H. O., Jamda, M. A., Oluwole, O. P., Nwegbu, M., Adusei, B., Mante, S., Darkwa-Abrahams, A., Diop, H., Gundell, S. M., Roobol, M. J., Jenster, G., van Schaik, R. H., Hu, J. J., Sanderson, M., Kachuri, L., Varma, R., McKean-Cowdin, R., Torres, M., Preuss, M. H., Loos, R. J., Zawistowski, M., Zöllner, S., Lu, Z., Van Den Eeden, S. K., Easton, D. F., Ambs, S., Edwards, T. L., Mägi, R., Rebbeck, T. R., Fritsche, L., Chanock, S. J., Berndt, S. I., Wiklund, F., Nakagawa, H., Witte, J. S., Gaziano, J. M., Justice, A. C., Mancuso, N., Terao, C., Eeles, R. A., Kote-Jarai, Z., Madduri, R. K., Conti, D. V., Haiman, C. A. 2023

  Abstract

  The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.

  View details for DOI 10.1038/s41588-023-01534-4

  View details for PubMedID 37945903

  View details for PubMedCentralID 8148035

• A Likelihood Ratio Approach for Utilizing Case-Control Data in the Clinical Classification of Rare Sequence Variants: Application to <i>BRCA1</i> and <i>BRCA2</i> HUMAN MUTATION Zanti, M., O'Mahony, D. G., Parsons, M. T., Li, H., Dennis, J., Aittomakkiki, K., Andrulis, I. L., Anton-Culver, H., Aronson, K. J., Augustinsson, A., Becher, H., Bojesen, S. E., Bolla, M. K., Brenner, H., Brown, M. A., Buys, S. S., Canzian, F., Caputo, S. M., Castelao, J. E., Chang-Claude, J., Czene, K., Daly, M. B., De Nicolo, A., Devilee, P., Dork, T., Dunning, A. M., Dwek, M., Eccles, D. M., Engel, C., Evans, D., Fasching, P. A., Gago-Dominguez, M., Garcia-Closas, M., Garcia-Saenz, J. A., Gentry-Maharaj, A., Geurts-Giele, W. R., Giles, G. G., Glendon, G., Goldberg, M. S., Garcia, E., Guendert, M., Guenel, P., Hahnen, E., Haiman, C. A., Hall, P., Hamann, U., Harkness, E. F., Hogervorst, F. L., Hollestelle, A., Hoppe, R., Hopper, J. L., Houdayer, C., Houlston, R. S., Howell, A., Investigators, A., Jakimovska, M., Jakubowska, A., Jernstrom, H., John, E. M., Kaaks, R., Kitahara, C. M., Koutros, S., Kraft, P., Kristensen, V. N., Lacey, J., Lambrechts, D., Leone, M., Lindblom, A., Lush, M., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M., Menon, U., Milne, R. L., Monteiro, A. N., Murphy, R. A., Neuhausen, S. L., Nevanlinna, H., Newman, W. G., Offit, K., Park, S. K., James, P., Peterlongo, P., Peto, J., Plaseska-Karanfilska, D., Punie, K., Radice, P., Rashid, M. U., Rennert, G., Romero, A., Rosenberg, E. H., Saloustros, E., Sandler, D. P., Schmidt, M. K., Schmutzler, R. K., Shu, X., Simard, J., Southey, M. C., Stone, J., Stoppa-Lyonnet, D., Tamimi, R. M., Tapper, W. J., Taylor, J. A., Teo, S., Teras, L. R., Terry, M., Thomassen, M., Troester, M. A., Vachon, C. M., Vega, A., Vreeswijk, M. G., Wang, Q., Wappenschmidt, B., Weinberg, C. R., Wolk, A., Zheng, W., Feng, B., Couch, F. J., Spurdle, A. B., Easton, D. F., Goldgar, D. E., Michailidou, K., GC-HBOC Study Collaborators 2023; 2023

  View details for DOI 10.1155/2023/9961341

  View details for Web of Science ID 001091490300001

• A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: application to BRCA1 and BRCA2. Human mutation Zanti, M., O'Mahony, D. G., Parsons, M. T., Li, H., Dennis, J., Aittomäkkiki, K., Andrulis, I. L., Anton-Culver, H., Aronson, K. J., Augustinsson, A., Becher, H., Bojesen, S. E., Bolla, M. K., Brenner, H., Brown, M. A., Buys, S. S., Canzian, F., Caputo, S. M., Castelao, J. E., Chang-Claude, J., Czene, K., Daly, M. B., De Nicolo, A., Devilee, P., Dörk, T., Dunning, A. M., Dwek, M., Eccles, D. M., Engel, C., Evans, D. G., Fasching, P. A., Gago-Dominguez, M., García-Closas, M., García-Sáenz, J. A., Gentry-Maharaj, A., Geurts-Giele, W. R., Giles, G. G., Glendon, G., Goldberg, M. S., Garcia, E. B., Güendert, M., Guénel, P., Hahnen, E., Haiman, C. A., Hall, P., Hamann, U., Harkness, E. F., Hogervorst, F. B., Hollestelle, A., Hoppe, R., Hopper, J. L., Houdayer, C., Houlston, R. S., Howell, A., Jakimovska, M., Jakubowska, A., Jernström, H., John, E. M., Kaaks, R., Kitahara, C. M., Koutros, S., Kraft, P., Kristensen, V. N., Lacey, J. V., Lambrechts, D., Léoné, M., Lindblom, A., Lubiński, J., Lush, M., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M. E., Menon, U., Milne, R. L., Monteiro, A. N., Murphy, R. A., Neuhausen, S. L., Nevanlinna, H., Newman, W. G., Offit, K., Park, S. K., James, P., Peterlongo, P., Peto, J., Plaseska-Karanfilska, D., Punie, K., Radice, P., Rashid, M. U., Rennert, G., Romero, A., Rosenberg, E. H., Saloustros, E., Sandler, D. P., Schmidt, M. K., Schmutzler, R. K., Shu, X. O., Simard, J., Southey, M. C., Stone, J., Stoppa-Lyonnet, D., Tamimi, R. M., Tapper, W. J., Taylor, J. A., Teo, S. H., Teras, L. R., Terry, M. B., Thomassen, M., Troester, M. A., Vachon, C. M., Vega, A., Vreeswijk, M. P., Wang, Q., Wappenschmidt, B., Weinberg, C. R., Wolk, A., Zheng, W., Feng, B., Couch, F. J., Spurdle, A. B., Easton, D. F., Goldgar, D. E., Michailidou, K. 2023; 2023

  Abstract

  A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance.

  View details for DOI 10.1155/2023/9961341

  View details for PubMedID 38725546

  View details for PubMedCentralID PMC11080979

• Risk of Multiple Primary Cancers in Patients With Merkel Cell Carcinoma: A SEER-Based Analysis. JAMA dermatology Eid, E., Maloney, N. J., Cai, Z. R., Zaba, L. C., Kibbi, N., John, E. M., Linos, E. 2023

  Abstract

  The risk of subsequent primary cancers after a diagnosis of cutaneous Merkel cell carcinoma (MCC) is not well established.To evaluate the risk of subsequent primary cancers after the diagnosis of a first primary cutaneous MCC.This cohort study analyzed data from 17 registries of the Surveillance, Epidemiology, and End Results (SEER) Program from January 1, 2000, to December 31, 2019. In all, 6146 patients diagnosed with a first primary cutaneous MCC were identified.The primary outcome was the relative and absolute risks of subsequent primary cancers after the diagnosis of a first primary MCC, which were calculated using the standardized incidence ratio (SIR; ratio of observed to expected cases of subsequent cancer) and the excess risk (difference between observed and expected cases of subsequent cancer divided by the person-years at risk), respectively. Data were analyzed between January 1, 2000, and December 31, 2019.Of 6146 patients with a first primary MCC diagnosed at a median (IQR) age of 76 (66-83) years, 3713 (60.4%) were men, and the predominant race and ethnicity was non-Hispanic White (5491 individuals [89.3%]). Of these patients, 725 (11.8%) developed subsequent primary cancers, with an SIR of 1.28 (95% CI, 1.19-1.38) and excess risk of 57.25 per 10 000 person-years. For solid tumors after MCC, risk was elevated for cutaneous melanoma (SIR, 2.36 [95% CI, 1.85-2.97]; excess risk, 15.27 per 10 000 person-years) and papillary thyroid carcinoma (SIR, 5.26 [95% CI, 3.25-8.04]; excess risk, 6.16 per 10 000 person-years). For hematologic cancers after MCC, risk was increased for non-Hodgkin lymphoma (SIR, 2.62 [95% CI, 2.04-3.32]; excess risk, 15.48 per 10 000 person-years).This cohort study found that patients with MCC had an increased risk of subsequently developing solid and hematologic cancers. This increased risk may be associated with increased surveillance, treatment-related factors, or shared etiologies of the other cancers with MCC. Further studies exploring possible common etiological factors shared between MCC and other primary cancers are warranted.

  View details for DOI 10.1001/jamadermatol.2023.2849

  View details for PubMedID 37703005

• Elevated Risk of Visceral Malignant Neoplasms in Extramammary Paget Disease. JAMA dermatology Maloney, N. J., Yao, H., Aasi, S. Z., John, E. M., Linos, E., Kibbi, N. 2023

  Abstract

  This cross-sectional study evaluates the incidence and types of cancers that develop years after an extramammary Paget disease (EMPD) diagnosis.

  View details for DOI 10.1001/jamadermatol.2023.2679

  View details for PubMedID 37647047

• Trends in Radiation Dose to the Contralateral Breast During Breast Cancer Radiation Therapy. Radiation research Watt, G. P., Smith, S. A., Howell, R. M., Pérez-Andújar, A., Reiner, A. S., Cerviño, L., McCormick, B., Hess, D., Knight, J. A., Malone, K. E., John, E. M., Bernstein, L., Lynch, C. F., Mellemkjær, L., Shore, R. E., Liang, X., Woods, M., Boice, J. D., Dauer, L. T., Bernstein, J. L. 2023

  Abstract

  Over 4 million survivors of breast cancer live in the United States, 35% of whom were treated before 2009. Approximately half of patients with breast cancer receive radiation therapy, which exposes the untreated contralateral breast to radiation and increases the risk of a subsequent contralateral breast cancer (CBC). Radiation oncology has strived to reduce unwanted radiation dose, but it is unknown whether a corresponding decline in actual dose received to the untreated contralateral breast has occurred. The purpose of this study was to evaluate trends in unwanted contralateral breast radiation dose to inform risk assessment of second primary cancer in the contralateral breast for long-term survivors of breast cancer. Individually estimated radiation absorbed doses to the four quadrants and areola central area of the contralateral breast were estimated for 2,132 women treated with radiation therapy for local/regional breast cancers at age <55 years diagnosed between 1985 and 2008. The two inner quadrant doses and two outer quadrant doses were averaged. Trends in dose to each of the three areas of the contralateral breast were evaluated in multivariable models. The population impact of reducing contralateral breast dose on the incidence of radiation-associated CBC was assessed by estimating population attributable risk fraction (PAR) in a multivariable model. The median dose to the inner quadrants of the contralateral breast was 1.70 Gy; to the areola, 1.20 Gy; and to the outer quadrants, 0.72 Gy. Ninety-two percent of patients received ≥1 Gy to the inner quadrants. For each calendar year of diagnosis, dose declined significantly for each location, most rapidly for the inner quadrants (0.04 Gy/year). Declines in dose were similar across subgroups defined by age at diagnosis and body mass index. The PAR for CBC due to radiation exposure >1 Gy for women <40 years of age was 17%. Radiation dose-reduction measures have reduced dose to the contralateral breast during breast radiation therapy. Reducing the dose to the contralateral breast to <1 Gy could prevent an estimated 17% of subsequent radiation-associated CBCs for women treated under 40 years of age. These dose estimates inform CBC surveillance for the growing number of breast cancer survivors who received radiation therapy as young women in recent decades. Continued reductions in dose to the contralateral breast could further reduce the incidence of radiation-associated CBC.

  View details for DOI 10.1667/RADE-23-00014.1

  View details for PubMedID 37590492

• A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry. Breast cancer research : BCR Middha, P., Wang, X., Behrens, S., Bolla, M. K., Wang, Q., Dennis, J., Michailidou, K., Ahearn, T. U., Andrulis, I. L., Anton-Culver, H., Arndt, V., Aronson, K. J., Auer, P. L., Augustinsson, A., Baert, T., Freeman, L. E., Becher, H., Beckmann, M. W., Benitez, J., Bojesen, S. E., Brauch, H., Brenner, H., Brooks-Wilson, A., Campa, D., Canzian, F., Carracedo, A., Castelao, J. E., Chanock, S. J., Chenevix-Trench, G., Cordina-Duverger, E., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Dossus, L., Dugué, P. A., Eliassen, A. H., Eriksson, M., Evans, D. G., Fasching, P. A., Figueroa, J. D., Fletcher, O., Flyger, H., Gabrielson, M., Gago-Dominguez, M., Giles, G. G., González-Neira, A., Grassmann, F., Grundy, A., Guénel, P., Haiman, C. A., Håkansson, N., Hall, P., Hamann, U., Hankinson, S. E., Harkness, E. F., Holleczek, B., Hoppe, R., Hopper, J. L., Houlston, R. S., Howell, A., Hunter, D. J., Ingvar, C., Isaksson, K., Jernström, H., John, E. M., Jones, M. E., Kaaks, R., Keeman, R., Kitahara, C. M., Ko, Y. D., Koutros, S., Kurian, A. W., Lacey, J. V., Lambrechts, D., Larson, N. L., Larsson, S., Le Marchand, L., Lejbkowicz, F., Li, S., Linet, M., Lissowska, J., Martinez, M. E., Maurer, T., Mulligan, A. M., Mulot, C., Murphy, R. A., Newman, W. G., Nielsen, S. F., Nordestgaard, B. G., Norman, A., O'Brien, K. M., Olson, J. E., Patel, A. V., Prentice, R., Rees-Punia, E., Rennert, G., Rhenius, V., Ruddy, K. J., Sandler, D. P., Scott, C. G., Shah, M., Shu, X. O., Smeets, A., Southey, M. C., Stone, J., Tamimi, R. M., Taylor, J. A., Teras, L. R., Tomczyk, K., Troester, M. A., Truong, T., Vachon, C. M., Wang, S. S., Weinberg, C. R., Wildiers, H., Willett, W., Winham, S. J., Wolk, A., Yang, X. R., Zamora, M. P., Zheng, W., Ziogas, A., Dunning, A. M., Pharoah, P. D., García-Closas, M., Schmidt, M. K., Kraft, P., Milne, R. L., Lindström, S., Easton, D. F., Chang-Claude, J. 2023; 25 (1): 93

  Abstract

  Genome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer.Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs.Assuming a 1 × 10-5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94).Overall, the contribution of G×E interactions to the heritability of breast cancer is very small. At the population level, multiplicative G×E interactions do not make an important contribution to risk prediction in breast cancer.

  View details for DOI 10.1186/s13058-023-01691-8

  View details for PubMedID 37559094

  View details for PubMedCentralID 3488186

• Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel. Journal of medical genetics Levi, H., Carmi, S., Rosset, S., Yerushalmi, R., Zick, A., Yablonski-Peretz, T., Wang, Q., Bolla, M. K., Dennis, J., Michailidou, K., Lush, M., Ahearn, T., Andrulis, I. L., Anton-Culver, H., Antoniou, A. C., Arndt, V., Augustinsson, A., Auvinen, P., Beane Freeman, L., Beckmann, M., Behrens, S., Bermisheva, M., Bodelon, C., Bogdanova, N. V., Bojesen, S. E., Brenner, H., Byers, H., Camp, N., Castelao, J., Chang-Claude, J., Chirlaque, M. D., Chung, W., Clarke, C., Collee, M. J., Colonna, S., Couch, F., Cox, A., Cross, S. S., Czene, K., Daly, M., Devilee, P., Dork, T., Dossus, L., Eccles, D. M., Eliassen, A. H., Eriksson, M., Evans, G., Fasching, P., Fletcher, O., Flyger, H., Fritschi, L., Gabrielson, M., Gago-Dominguez, M., García-Closas, M., Garcia-Saenz, J. A., Genkinger, J., Giles, G. G., Goldberg, M., Guénel, P., Hall, P., Hamann, U., He, W., Hillemanns, P., Hollestelle, A., Hoppe, R., Hopper, J., Jakovchevska, S., Jakubowska, A., Jernström, H., John, E., Johnson, N., Jones, M., Vijai, J., Kaaks, R., Khusnutdinova, E., Kitahara, C., Koutros, S., Kristensen, V., Kurian, A. W., Lacey, J., Lambrechts, D., Le Marchand, L., Lejbkowicz, F., Lindblom, A., Loibl, S., Lori, A., Lubinski, J., Mannermaa, A., Manoochehri, M., Mavroudis, D., Menon, U., Mulligan, A., Murphy, R., Nevelsteen, I., Newman, W. G., Obi, N., O'Brien, K., Offit, K., Olshan, A., Plaseska-Karanfilska, D., Olson, J., Panico, S., Park-Simon, T. W., Patel, A., Peterlongo, P., Rack, B., Radice, P., Rennert, G., Rhenius, V., Romero, A., Saloustros, E., Sandler, D., Schmidt, M. K., Schwentner, L., Shah, M., Sharma, P., Simard, J., Southey, M., Stone, J., Tapper, W. J., Taylor, J., Teras, L., Toland, A. E., Troester, M., Truong, T., van der Kolk, L. E., Weinberg, C., Wendt, C., Yang, X. R., Zheng, W., Ziogas, A., Dunning, A. M., Pharoah, P., Easton, D. F., Ben-Sachar, S., Elefant, N., Shamir, R., Elkon, R. 2023

  Abstract

  Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women.We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel.In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28).Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.

  View details for DOI 10.1136/jmg-2023-109185

  View details for PubMedID 37451831

• Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival. Cancer medicine Morra, A., Schreurs, M. A., Andrulis, I. L., Anton-Culver, H., Augustinsson, A., Beckmann, M. W., Behrens, S., Bojesen, S. E., Bolla, M. K., Brauch, H., Broeks, A., Buys, S. S., Camp, N. J., Castelao, J. E., Cessna, M. H., Chang-Claude, J., Chung, W. K., Colonna, S. V., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Daly, M. B., Dennis, J., Devilee, P., Dörk, T., Dunning, A. M., Dwek, M., Easton, D. F., Eccles, D. M., Eriksson, M., Evans, D. G., Fasching, P. A., Fehm, T. N., Figueroa, J. D., Flyger, H., Gabrielson, M., Gago-Dominguez, M., García-Closas, M., García-Sáenz, J. A., Genkinger, J., Grassmann, F., Gündert, M., Hahnen, E., Haiman, C. A., Hamann, U., Harrington, P. A., Hartikainen, J. M., Hoppe, R., Hopper, J. L., Houlston, R. S., Howell, A., Jakubowska, A., Janni, W., Jernström, H., John, E. M., Johnson, N., Jones, M. E., Kristensen, V. N., Kurian, A. W., Lambrechts, D., Le Marchand, L., Lindblom, A., Lubiński, J., Lux, M. P., Mannermaa, A., Mavroudis, D., Mulligan, A. M., Muranen, T. A., Nevanlinna, H., Nevelsteen, I., Neven, P., Newman, W. G., Obi, N., Offit, K., Olshan, A. F., Park-Simon, T. W., Patel, A. V., Peterlongo, P., Phillips, K. A., Plaseska-Karanfilska, D., Polley, E. C., Presneau, N., Pylkäs, K., Rack, B., Radice, P., Rashid, M. U., Rhenius, V., Robson, M., Romero, A., Saloustros, E., Sawyer, E. J., Schmutzler, R. K., Schuetze, S., Scott, C., Shah, M., Smichkoska, S., Southey, M. C., Tapper, W. J., Teras, L. R., Tollenaar, R. A., Tomczyk, K., Tomlinson, I., Troester, M. A., Vachon, C. M., van Veen, E. M., Wang, Q., Wendt, C., Wildiers, H., Winqvist, R., Ziogas, A., Hall, P., Pharoah, P. D., Adank, M. A., Hollestelle, A., Schmidt, M. K., Hooning, M. J. 2023

  Abstract

  Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers.To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS.Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death.There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09-1.56)].Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

  View details for DOI 10.1002/cam4.6272

  View details for PubMedID 37401034

• Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium. Breast cancer research : BCR Kast, K., John, E. M., Hopper, J. L., Andrieu, N., Noguès, C., Mouret-Fourme, E., Lasset, C., Fricker, J. P., Berthet, P., Mari, V., Salle, L., Schmidt, M. K., Ausems, M. G., Garcia, E. B., van de Beek, I., Wevers, M. R., Evans, D. G., Tischkowitz, M., Lalloo, F., Cook, J., Izatt, L., Tripathi, V., Snape, K., Musgrave, H., Sharif, S., Murray, J., Colonna, S. V., Andrulis, I. L., Daly, M. B., Southey, M. C., de la Hoya, M., Osorio, A., Foretova, L., Berkova, D., Gerdes, A. M., Olah, E., Jakubowska, A., Singer, C. F., Tan, Y., Augustinsson, A., Rantala, J., Simard, J., Schmutzler, R. K., Milne, R. L., Phillips, K. A., Terry, M. B., Goldgar, D., van Leeuwen, F. E., Mooij, T. M., Antoniou, A. C., Easton, D. F., Rookus, M. A., Engel, C. 2023; 25 (1): 72

  Abstract

  Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes.An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change.In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04-1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m2, 95% CI 0.66-0.84) and BRCA2 (HR 0.76, 95% CI 0.65-0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m2, 95% CI 1.02-1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01-1.19, respectively).Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.

  View details for DOI 10.1186/s13058-023-01673-w

  View details for PubMedID 37340476

  View details for PubMedCentralID 3148429

• Understanding the genetic complexity of puberty timing across the allele frequency spectrum. medRxiv : the preprint server for health sciences Kentistou, K. A., Kaisinger, L. R., Stankovic, S., Vaudel, M., de Oliveira, E. M., Messina, A., Walters, R. G., Liu, X., Busch, A. S., Helgason, H., Thompson, D. J., Santon, F., Petricek, K. M., Zouaghi, Y., Huang-Doran, I., Gudbjartsson, D. F., Bratland, E., Lin, K., Gardner, E. J., Zhao, Y., Jia, R., Terao, C., Riggan, M., Bolla, M. K., Yazdanpanah, M., Yazdanpanah, N., Bradfield, J. P., Broer, L., Campbell, A., Chasman, D. I., Cousminer, D. L., Franceschini, N., Franke, L. H., Girotto, G., He, C., Järvelin, M. R., Joshi, P. K., Kamatani, Y., Karlsson, R., Luan, J., Lunetta, K. L., Mägi, R., Mangino, M., Medland, S. E., Meisinger, C., Noordam, R., Nutile, T., Concas, M. P., Polašek, O., Porcu, E., Ring, S. M., Sala, C., Smith, A. V., Tanaka, T., van der Most, P. J., Vitart, V., Wang, C. A., Willemsen, G., Zygmunt, M., Ahearn, T. U., Andrulis, I. L., Anton-Culver, H., Antoniou, A. C., Auer, P. L., Barnes, C. L., Beckmann, M. W., Berrington, A., Bogdanova, N. V., Bojesen, S. E., Brenner, H., Buring, J. E., Canzian, F., Chang-Claude, J., Couch, F. J., Cox, A., Crisponi, L., Czene, K., Daly, M. B., Demerath, E. W., Dennis, J., Devilee, P., Vivo, I. D., Dörk, T., Dunning, A. M., Dwek, M., Eriksson, J. G., Fasching, P. A., Fernandez-Rhodes, L., Ferreli, L., Fletcher, O., Gago-Dominguez, M., García-Closas, M., García-Sáenz, J. A., González-Neira, A., Grallert, H., Guénel, P., Haiman, C. A., Hall, P., Hamann, U., Hakonarson, H., Hart, R. J., Hickey, M., Hooning, M. J., Hoppe, R., Hopper, J. L., Hottenga, J. J., Hu, F. B., Hübner, H., Hunter, D. J., Jernström, H., John, E. M., Karasik, D., Khusnutdinova, E. K., Kristensen, V. N., Lacey, J. V., Lambrechts, D., Launer, L. J., Lind, P. A., Lindblom, A., Magnusson, P. K., Mannermaa, A., McCarthy, M. I., Meitinger, T., Menni, C., Michailidou, K., Millwood, I. Y., Milne, R. L., Montgomery, G. W., Nevanlinna, H., Nolte, I. M., Nyholt, D. R., Obi, N., O'Brien, K. M., Offit, K., Oldehinkel, A. J., Ostrowski, S. R., Palotie, A., Pedersen, O. B., Peters, A., Pianigiani, G., Plaseska-Karanfilska, D., Pouta, A., Pozarickij, A., Radice, P., Rennert, G., Rosendaal, F. R., Ruggiero, D., Saloustros, E., Sandler, D. P., Schipf, S., Schmidt, C. O., Schmidt, M. K., Small, K., Spedicati, B., Stampfer, M., Stone, J., Tamimi, R. M., Teras, L. R., Tikkanen, E., Turman, C., Vachon, C. M., Wang, Q., Winqvist, R., Wolk, A., Zemel, B. S., Zheng, W., van Dijk, K. W., Alizadeh, B. Z., Bandinelli, S., Boerwinkle, E., Boomsma, D. I., Ciullo, M., Chenevix-Trench, G., Cucca, F., Esko, T., Gieger, C., Grant, S. F., Gudnason, V., Hayward, C., Kolčić, I., Kraft, P., Lawlor, D. A., Martin, N. G., Nøhr, E. A., Pedersen, N. L., Pennell, C. E., Ridker, P. M., Robino, A., Snieder, H., Sovio, U., Spector, T. D., Stöckl, D., Sudlow, C., Timpson, N. J., Toniolo, D., Uitterlinden, A., Ulivi, S., Völzke, H., Wareham, N. J., Widen, E., Wilson, J. F., Pharoah, P. D., Li, L., Easton, D. F., Njølstad, P., Sulem, P., Murabito, J. M., Murray, A., Manousaki, D., Juul, A., Erikstrup, C., Stefansson, K., Horikoshi, M., Chen, Z., Farooqi, I. S., Pitteloud, N., Johansson, S., Day, F. R., Perry, J. R., Ong, K. K. 2023

  Abstract

  Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ~800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ~11 and ~14-fold higher risk of delayed and precocious pubertal development, respectively. These common variant analyses were supported by exome sequence analysis of ~220,000 women, identifying several genes, including rare loss of function variants in ZNF483 which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination of in silico variant-to-gene mapping approaches and integration with dynamic gene expression data from mouse embryonic GnRH neurons. This included an uncharacterized G-protein coupled receptor GPR83, which we demonstrate amplifies signaling of MC3R, a key sensor of nutritional status. Finally, we identified several genes, including ovary-expressed genes involved in DNA damage response that co-localize with signals associated with menopause timing, leading us to hypothesize that the ovarian reserve might signal centrally to trigger puberty. Collectively these findings extend our understanding of the biological complexity of puberty timing and highlight body size dependent and independent mechanisms that potentially link reproductive timing to later life disease.

  View details for DOI 10.1101/2023.06.14.23291322

  View details for PubMedID 37503126

  View details for PubMedCentralID PMC10371120

• Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry. American journal of human genetics Darst, B. F., Shen, J., Madduri, R. K., Rodriguez, A. A., Xiao, Y., Sheng, X., Saunders, E. J., Dadaev, T., Brook, M. N., Hoffmann, T. J., Muir, K., Wan, P., Le Marchand, L., Wilkens, L., Wang, Y., Schleutker, J., MacInnis, R. J., Cybulski, C., Neal, D. E., Nordestgaard, B. G., Nielsen, S. F., Batra, J., Clements, J. A., Cancer BioResource, A. P., Grönberg, H., Pashayan, N., Travis, R. C., Park, J. Y., Albanes, D., Weinstein, S., Mucci, L. A., Hunter, D. J., Penney, K. L., Tangen, C. M., Hamilton, R. J., Parent, M. É., Stanford, J. L., Koutros, S., Wolk, A., Sørensen, K. D., Blot, W. J., Yeboah, E. D., Mensah, J. E., Lu, Y. J., Schaid, D. J., Thibodeau, S. N., West, C. M., Maier, C., Kibel, A. S., Cancel-Tassin, G., Menegaux, F., John, E. M., Grindedal, E. M., Khaw, K. T., Ingles, S. A., Vega, A., Rosenstein, B. S., Teixeira, M. R., Kogevinas, M., Cannon-Albright, L., Huff, C., Multigner, L., Kaneva, R., Leach, R. J., Brenner, H., Hsing, A. W., Kittles, R. A., Murphy, A. B., Logothetis, C. J., Neuhausen, S. L., Isaacs, W. B., Nemesure, B., Hennis, A. J., Carpten, J., Pandha, H., De Ruyck, K., Xu, J., Razack, A., Teo, S. H., Newcomb, L. F., Fowke, J. H., Neslund-Dudas, C., Rybicki, B. A., Gamulin, M., Usmani, N., Claessens, F., Gago-Dominguez, M., Castelao, J. E., Townsend, P. A., Crawford, D. C., Petrovics, G., Casey, G., Roobol, M. J., Hu, J. F., Berndt, S. I., Van Den Eeden, S. K., Easton, D. F., Chanock, S. J., Cook, M. B., Wiklund, F., Witte, J. S., Eeles, R. A., Kote-Jarai, Z., Watya, S., Gaziano, J. M., Justice, A. C., Conti, D. V., Haiman, C. A. 2023

  Abstract

  Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.

  View details for DOI 10.1016/j.ajhg.2023.05.010

  View details for PubMedID 37311464

• Evaluating Approaches for Constructing Polygenic Risk Scores for Prostate Cancer in Men of African and European Ancestry. medRxiv : the preprint server for health sciences Darst, B. F., Shen, J., Madduri, R. K., Rodriguez, A. A., Xiao, Y., Sheng, X., Saunders, E. J., Dadaev, T., Brook, M. N., Hoffmann, T. J., Muir, K., Wan, P., Le Marchand, L., Wilkens, L., Wang, Y., Schleutker, J., MacInnis, R. J., Cybulski, C., Neal, D. E., Nordestgaard, B. G., Nielsen, S. F., Batra, J., Clements, J. A., Grönberg, H., Pashayan, N., Travis, R. C., Park, J. Y., Albanes, D., Weinstein, S., Mucci, L. A., Hunter, D. J., Penney, K. L., Tangen, C. M., Hamilton, R. J., Parent, M. É., Stanford, J. L., Koutros, S., Wolk, A., Sørensen, K. D., Blot, W. J., Yeboah, E. D., Mensah, J. E., Lu, Y. J., Schaid, D. J., Thibodeau, S. N., West, C. M., Maier, C., Kibel, A. S., Cancel-Tassin, G., Menegaux, F., John, E. M., Grindedal, E. M., Khaw, K. T., Ingles, S. A., Vega, A., Rosenstein, B. S., Teixeira, M. R., Kogevinas, M., Cannon-Albright, L., Huff, C., Multigner, L., Kaneva, R., Leach, R. J., Brenner, H., Hsing, A. W., Kittles, R. A., Murphy, A. B., Logothetis, C. J., Neuhausen, S. L., Isaacs, W. B., Nemesure, B., Hennis, A. J., Carpten, J., Pandha, H., De Ruyck, K., Xu, J., Razack, A., Teo, S. H., Newcomb, L. F., Fowke, J. H., Neslund-Dudas, C., Rybicki, B. A., Gamulin, M., Usmani, N., Claessens, F., GagoDominguez, M., Castelao, J. E., Townsend, P. A., Crawford, D. C., Petrovics, G., Casey, G., Roobol, M. J., Hu, J. F., Berndt, S. I., Van Den Eeden, S. K., Easton, D. F., Chanock, S. J., Cook, M. B., Wiklund, F., Witte, J. S., Eeles, R. A., Kote-Jarai, Z., Watya, S., Gaziano, J. M., Justice, A. C., Conti, D. V., Haiman, C. A. 2023

  Abstract

  Genome-wide polygenic risk scores (GW-PRS) have been reported to have better predictive ability than PRS based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer risk variants from multi-ancestry GWAS and fine-mapping studies (PRS 269 ). GW-PRS models were trained using a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls used to develop the multi-ancestry PRS 269 . Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California/Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI=0.635-0.677) in African and 0.844 (95% CI=0.840-0.848) in European ancestry men and corresponding prostate cancer OR of 1.83 (95% CI=1.67-2.00) and 2.19 (95% CI=2.14-2.25), respectively, for each SD unit increase in the GW-PRS. However, compared to the GW-PRS, in African and European ancestry men, the PRS 269 had larger or similar AUCs (AUC=0.679, 95% CI=0.659-0.700 and AUC=0.845, 95% CI=0.841-0.849, respectively) and comparable prostate cancer OR (OR=2.05, 95% CI=1.87-2.26 and OR=2.21, 95% CI=2.16-2.26, respectively). Findings were similar in the validation data. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the multi-ancestry PRS 269 constructed with fine-mapping.

  View details for DOI 10.1101/2023.05.12.23289860

  View details for PubMedID 37292833

  View details for PubMedCentralID PMC10246022

• Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis. Diabetologia Yarmolinsky, J., Bouras, E., Constantinescu, A., Burrows, K., Bull, C. J., Vincent, E. E., Martin, R. M., Dimopoulou, O., Lewis, S. J., Moreno, V., Vujkovic, M., Chang, K. M., Voight, B. F., Tsao, P. S., Gunter, M. J., Hampe, J., Pellatt, A. J., Pharoah, P. D., Schoen, R. E., Gallinger, S., Jenkins, M. A., Pai, R. K., Gill, D., Tsilidis, K. K. 2023

  Abstract

  Epidemiological studies have generated conflicting findings on the relationship between glucose-lowering medication use and cancer risk. Naturally occurring variation in genes encoding glucose-lowering drug targets can be used to investigate the effect of their pharmacological perturbation on cancer risk.We developed genetic instruments for three glucose-lowering drug targets (peroxisome proliferator activated receptor γ [PPARG]; sulfonylurea receptor 1 [ATP binding cassette subfamily C member 8 (ABCC8)]; glucagon-like peptide 1 receptor [GLP1R]) using summary genetic association data from a genome-wide association study of type 2 diabetes in 148,726 cases and 965,732 controls in the Million Veteran Program. Genetic instruments were constructed using cis-acting genome-wide significant (p<5×10-8) SNPs permitted to be in weak linkage disequilibrium (r2<0.20). Summary genetic association estimates for these SNPs were obtained from genome-wide association study (GWAS) consortia for the following cancers: breast (122,977 cases, 105,974 controls); colorectal (58,221 cases, 67,694 controls); prostate (79,148 cases, 61,106 controls); and overall (i.e. site-combined) cancer (27,483 cases, 372,016 controls). Inverse-variance weighted random-effects models adjusting for linkage disequilibrium were employed to estimate causal associations between genetically proxied drug target perturbation and cancer risk. Co-localisation analysis was employed to examine robustness of findings to violations of Mendelian randomisation (MR) assumptions. A Bonferroni correction was employed as a heuristic to define associations from MR analyses as 'strong' and 'weak' evidence.In MR analysis, genetically proxied PPARG perturbation was weakly associated with higher risk of prostate cancer (for PPARG perturbation equivalent to a 1 unit decrease in inverse rank normal transformed HbA1c: OR 1.75 [95% CI 1.07, 2.85], p=0.02). In histological subtype-stratified analyses, genetically proxied PPARG perturbation was weakly associated with lower risk of oestrogen receptor-positive breast cancer (OR 0.57 [95% CI 0.38, 0.85], p=6.45×10-3). In co-localisation analysis, however, there was little evidence of shared causal variants for type 2 diabetes liability and cancer endpoints in the PPARG locus, although these analyses were likely underpowered. There was little evidence to support associations between genetically proxied PPARG perturbation and colorectal or overall cancer risk or between genetically proxied ABCC8 or GLP1R perturbation with risk across cancer endpoints.Our drug target MR analyses did not find consistent evidence to support an association of genetically proxied PPARG, ABCC8 or GLP1R perturbation with breast, colorectal, prostate or overall cancer risk. Further evaluation of these drug targets using alternative molecular epidemiological approaches may help to further corroborate the findings presented in this analysis.Summary genetic association data for select cancer endpoints were obtained from the public domain: breast cancer ( https://bcac.ccge.medschl.cam.ac.uk/bcacdata/ ); and overall prostate cancer ( http://practical.icr.ac.uk/blog/ ). Summary genetic association data for colorectal cancer can be accessed by contacting GECCO (kafdem at fredhutch.org). Summary genetic association data on advanced prostate cancer can be accessed by contacting PRACTICAL (practical at icr.ac.uk). Summary genetic association data on type 2 diabetes from Vujkovic et al (Nat Genet, 2020) can be accessed through dbGAP under accession number phs001672.v3.p1 (pha004945.1 refers to the European-specific summary statistics). UK Biobank data can be accessed by registering with UK Biobank and completing the registration form in the Access Management System (AMS) ( https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access ).

  View details for DOI 10.1007/s00125-023-05925-4

  View details for PubMedID 37171501

  View details for PubMedCentralID 7310804

• Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2. British journal of cancer O'Mahony, D. G., Ramus, S. J., Southey, M. C., Meagher, N. S., Hadjisavvas, A., John, E. M., Hamann, U., Imyanitov, E. N., Andrulis, I. L., Sharma, P., Daly, M. B., Hake, C. R., Weitzel, J. N., Jakubowska, A., Godwin, A. K., Arason, A., Bane, A., Simard, J., Soucy, P., Caligo, M. A., Mai, P. L., Claes, K. B., Teixeira, M. R., Chung, W. K., Lazaro, C., Hulick, P. J., Toland, A. E., Pedersen, I. S., Neuhausen, S. L., Vega, A., de la Hoya, M., Nevanlinna, H., Dhawan, M., Zampiga, V., Danesi, R., Varesco, L., Gismondi, V., Vellone, V. G., James, P. A., Janavicius, R., Nikitina-Zake, L., Nielsen, F. C., van Overeem Hansen, T., Pejovic, T., Borg, A., Rantala, J., Offit, K., Montagna, M., Nathanson, K. L., Domchek, S. M., Osorio, A., García, M. J., Karlan, B. Y., De Fazio, A., Bowtell, D., McGuffog, L., Leslie, G., Parsons, M. T., Dörk, T., Speith, L. M., Dos Santos, E. S., da Costa, A. A., Radice, P., Peterlongo, P., Papi, L., Engel, C., Hahnen, E., Schmutzler, R. K., Wappenschmidt, B., Easton, D. F., Tischkowitz, M., Singer, C. F., Tan, Y. Y., Whittemore, A. S., Sieh, W., Brenton, J. D., Yannoukakos, D., Fostira, F., Konstantopoulou, I., Soukupova, J., Vocka, M., Chenevix-Trench, G., Pharoah, P. D., Antoniou, A. C., Goldgar, D. E., Spurdle, A. B., Michailidou, K. 2023

  Abstract

  The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system.Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong).No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis.We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.

  View details for DOI 10.1038/s41416-023-02263-5

  View details for PubMedID 37076566

  View details for PubMedCentralID 1615664

• Antimicrobial exposure is associated with decreased survival in triple-negative breast cancer. Nature communications Ransohoff, J. D., Ritter, V., Purington, N., Andrade, K., Han, S., Liu, M., Liang, S. Y., John, E. M., Gomez, S. L., Telli, M. L., Schapira, L., Itakura, H., Sledge, G. W., Bhatt, A. S., Kurian, A. W. 2023; 14 (1): 2053

  Abstract

  Antimicrobial exposure during curative-intent treatment of triple-negative breast cancer (TNBC) may lead to gut microbiome dysbiosis, decreased circulating and tumor-infiltrating lymphocytes, and inferior outcomes. Here, we investigate the association of antimicrobial exposure and peripheral lymphocyte count during TNBC treatment with survival, using integrated electronic medical record and California Cancer Registry data in the Oncoshare database. Of 772 women with stage I-III TNBC treated with and without standard cytotoxic chemotherapy - prior to the immune checkpoint inhibitor era - most (654, 85%) used antimicrobials. Applying multivariate analyses, we show that each additional total or unique monthly antimicrobial prescription is associated with inferior overall and breast cancer-specific survival. This antimicrobial-mortality association is independent of changes in neutrophil count, is unrelated to disease severity, and is sustained through year three following diagnosis, suggesting antimicrobial exposure negatively impacts TNBC survival. These results may inform mechanistic studies and antimicrobial prescribing decisions in TNBC and other hormone receptor-independent cancers.

  View details for DOI 10.1038/s41467-023-37636-0

  View details for PubMedID 37045824

  View details for PubMedCentralID 5625777

• Genome-Wide Analyses Characterize Shared Heritability Among Cancers and Identify Novel Cancer Susceptibility Regions. Journal of the National Cancer Institute Lindström, S., Wang, L., Feng, H., Majumdar, A., Huo, S., Macdonald, J., Harrison, T., Turman, C., Chen, H., Mancuso, N., Bammler, T., Gallinger, S., Gruber, S. B., Gunter, M. J., Le Marchand, L., Moreno, V., Offit, K., de Vivo, I., O'Mara, T. A., Spurdle, A. B., Tomlinson, I., Fitzgerald, R., Gharahkhani, P., Gockel, I., Jankowski, J., Macgregor, S., Schumacher, J., Barnholtz-Sloan, J., Bondy, M. L., Houlston, R. S., Jenkins, R. B., Melin, B., Wrensch, M., Brennan, P., Christiani, D., Johansson, M., Mckay, J., Aldrich, M. C., Amos, C. I., Landi, M. T., Tardon, A., Bishop, D. T., Demenais, F., Goldstein, A. M., Iles, M. M., Kanetsky, P. A., Law, M. H., Amundadottir, L. T., Stolzenberg-Solomon, R., Wolpin, B. M., Klein, A., Petersen, G., Risch, H., Chanock, S. J., Purdue, M. P., Scelo, G., Pharoah, P., Kar, S., Hung, R. J., Pasaniuc, B., Kraft, P. 2023

  Abstract

  The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from twelve cancer genome-wide association studies (GWAS) to quantify pair-wise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.We collected GWAS summary statistics for twelve solid cancers based on 376,759 cancer cases and 532,864 controls of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies (TWAS) to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci.We observed wide-spread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and TWAS, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least two cancer types by testing for pleiotropy at known cancer susceptibility loci.Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer- and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.

  View details for DOI 10.1093/jnci/djad043

  View details for PubMedID 36929942

• Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry. European urology Chen, F., Madduri, R. K., Rodriguez, A. A., Darst, B. F., Chou, A., Sheng, X., Wang, A., Shen, J., Saunders, E. J., Rhie, S. K., Bensen, J. T., Ingles, S. A., Kittles, R. A., Strom, S. S., Rybicki, B. A., Nemesure, B., Isaacs, W. B., Stanford, J. L., Zheng, W., Sanderson, M., John, E. M., Park, J. Y., Xu, J., Wang, Y., Berndt, S. I., Huff, C. D., Yeboah, E. D., Tettey, Y., Lachance, J., Tang, W., Rentsch, C. T., Cho, K., Mcmahon, B. H., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Sellers, T. A., Yamoah, K., Murphy, A. B., Crawford, D. C., Patel, A. V., Bush, W. S., Aldrich, M. C., Cussenot, O., Petrovics, G., Cullen, J., Neslund-Dudas, C. M., Stern, M. C., Kote-Jarai, Z., Govindasami, K., Cook, M. B., Chokkalingam, A. P., Hsing, A. W., Goodman, P. J., Hoffmann, T. J., Drake, B. F., Hu, J. J., Keaton, J. M., Hellwege, J. N., Clark, P. E., Jalloh, M., Gueye, S. M., Niang, L., Ogunbiyi, O., Idowu, M. O., Popoola, O., Adebiyi, A. O., Aisuodionoe-Shadrach, O. I., Ajibola, H. O., Jamda, M. A., Oluwole, O. P., Nwegbu, M., Adusei, B., Mante, S., Darkwa-Abrahams, A., Mensah, J. E., Diop, H., Van Den Eeden, S. K., Blanchet, P., Fowke, J. H., Casey, G., Hennis, A. J., Lubwama, A., Thompson, I. M., Leach, R., Easton, D. F., Preuss, M. H., Loos, R. J., Gundell, S. M., Wan, P., Mohler, J. L., Fontham, E. T., Smith, G. J., Taylor, J. A., Srivastava, S., Eeles, R. A., Carpten, J. D., Kibel, A. S., Multigner, L., Parent, M. É., Menegaux, F., Cancel-Tassin, G., Klein, E. A., Andrews, C., Rebbeck, T. R., Brureau, L., Ambs, S., Edwards, T. L., Watya, S., Chanock, S. J., Witte, J. S., Blot, W. J., Michael Gaziano, J., Justice, A. C., Conti, D. V., Haiman, C. A. 2023

  Abstract

  Genetic factors play an important role in prostate cancer (PCa) susceptibility.To discover common genetic variants contributing to the risk of PCa in men of African ancestry.We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry.Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness.Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10-4).This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry.In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

  View details for DOI 10.1016/j.eururo.2023.01.022

  View details for PubMedID 36872133

• Changes in breast cancer risk and risk factor profiles among U.S.-born and immigrant Asian American women residing in the San Francisco Bay Area. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology John, E. M., Koo, J., Ingles, S. A., Kurian, A. W., Hines, L. M. 2023

  Abstract

  Breast cancer incidence rates in women of Asian descent have been increasing in the United States (U.S.) and Asia.In a case-control study of Asian American women from the San Francisco Bay Area, we assessed associations with birthplace and migration-related characteristics and compared risk factors between Asian American and non-Hispanic White women by birthplace and birth cohort.Birthplace and migration-related characteristics were associated with breast cancer risk only among women in the younger birth cohort (1951-1984) that comprised 355 cases diagnosed at age ≤55 years and 276 sister and population controls. Breast cancer risk was marginally increased among foreign-born women (OR=1.40, 95% CI=0.97-2.03) and two-fold among foreign-born Chinese women (OR=2.16, 95% CI=1.21-3.88). Two-fold increased risks were associated with migration at age ≥40 years and longer U.S. residence (≥30 years or ≥75% of life). The education level was high among both cases and controls. Differences in the prevalence of risk factors by birthplace and birth cohort suggest temporal changes in reproductive and lifestyle-related factors. The prevalence in risk factors was similar between foreign-born and U.S.-born women in the younger birth cohort, and did not fully explain the observed associations with birthplace and other migration characteristics.In contrast to studies from earlier decades, younger foreign-born Asian American women had a higher risk of breast cancer than U.S.-born Asian American women.It is important and urgent to understand what factors drive the increasing burden of breast cancer in women of Asian descent and implement effective prevention programs.

  View details for DOI 10.1158/1055-9965.EPI-22-1128

  View details for PubMedID 36780232

• Breast Cancer Diagnosis, Treatment, and Outcomes of Patients From Sex and Gender Minority Groups. JAMA oncology Eckhert, E., Lansinger, O., Ritter, V., Liu, M., Han, S., Schapira, L., John, E. M., Gomez, S., Sledge, G., Kurian, A. W. 2023

  Abstract

  Sexual orientation and gender identity data are not collected by most hospitals or cancer registries; thus, little is known about the quality of breast cancer treatment for patients from sex and gender minority (SGM) groups.To evaluate the quality of breast cancer treatment and recurrence outcomes for patients from SGM groups compared with cisgender heterosexual patients.Exposure-matched retrospective case-control study of 92 patients from SGM groups treated at an academic medical center from January 1, 2008, to January 1, 2022, matched to cisgender heterosexual patients with breast cancer by year of diagnosis, age, tumor stage, estrogen receptor status, and ERBB2 (HER2) status.Patient demographic and clinical characteristics, as well as treatment quality, as measured by missed guideline-based breast cancer screening, appropriate referral for genetic counseling and testing, mastectomy vs lumpectomy, receipt of chest reconstruction, adjuvant radiation therapy after lumpectomy, neoadjuvant chemotherapy for stage III disease, antiestrogen therapy for at least 5 years for estrogen receptor-positive disease, ERBB2-directed therapy for ERBB2-positive disease, patient refusal of an oncologist-recommended treatment, time from symptom onset to tissue diagnosis, time from diagnosis to first treatment, and time from breast cancer diagnosis to first recurrence. Results were adjusted for multiple hypothesis testing. Compared with cisgender heterosexual patients, those from SGM groups were hypothesized to have disparities in 1 or more of these quality metrics.Ninety-two patients from SGM groups were matched to 92 cisgender heterosexual patients (n = 184). The median age at diagnosis for all patients was 49 years (IQR, 43-56 years); 74 were lesbian (80%), 12 were bisexual (13%), and 6 were transgender (6%). Compared with cisgender heterosexual patients, those from SGM groups experienced a delay in time from symptom onset to diagnosis (median time to diagnosis, 34 vs 64 days; multivariable adjusted hazard ratio, 0.65; 95% CI, 0.42-0.99; P = .04), were more likely to decline an oncologist-recommended treatment modality (35 [38%] vs 18 [20%]; multivariable adjusted odds ratio, 2.27; 95% CI, 1.09-4.74; P = .03), and were more likely to experience a breast cancer recurrence (multivariable adjusted hazard ratio, 3.07; 95% CI, 1.56-6.03; P = .001).This study found that among patients with breast cancer, those from SGM groups experienced delayed diagnosis, with faster recurrence at a 3-fold higher rate compared with cisgender heterosexual patients. These results suggest disparities in the care of patients from SGM groups and warrant further study to inform interventions.

  View details for DOI 10.1001/jamaoncol.2022.7146

  View details for PubMedID 36729432

• Whole exome sequencing and replication for breast cancer among Hispanic/Latino women identifies FANCM as a susceptibility gene for estrogen-receptor-negative breast cancer. medRxiv : the preprint server for health sciences Nierenberg, J. L., Adamson, A. W., Hu, D., Huntsman, S., Patrick, C., Li, M., Steele, L., Tong, B., Shieh, Y., Fejerman, L., Gruber, S. B., Haiman, C. A., John, E. M., Kushi, L. H., Torres-Mejía, G., Ricker, C., Weitzel, J. N., Ziv, E., Neuhausen, S. L. 2023

  Abstract

  Breast cancer (BC) is one of the most common cancers globally. Genetic testing can facilitate screening and risk-reducing recommendations, and inform use of targeted treatments. However, genes included in testing panels are from studies of European-ancestry participants. We sequenced Hispanic/Latina (H/L) women to identify BC susceptibility genes.We conducted a pooled BC case-control analysis in H/L women from the San Francisco Bay area, Los Angeles County, and Mexico (4,178 cases and 4,344 controls). Whole exome sequencing was conducted on 1,043 cases and 1,188 controls and a targeted 857-gene panel on the remaining samples. Using ancestry-adjusted SKAT-O analyses, we tested the association of loss of function (LoF) variants with overall, estrogen receptor (ER)-positive, and ER-negative BC risk. We calculated odds ratios (OR) for BC using ancestry-adjusted logistic regression models. We also tested the association of single variants with BC risk.We saw a strong association of LoF variants in FANCM with ER-negative BC (p=4.1×10-7, OR [CI]: 6.7 [2.9-15.6]) and a nominal association with overall BC risk. Among known susceptibility genes, BRCA1 (p=2.3×10-10, OR [CI]: 24.9 [6.1-102.5]), BRCA2 (p=8.4×10-10, OR [CI]: 7.0 [3.5-14.0]), and PALB2 (p=1.8×10-8, OR [CI]: 6.5 [3.2-13.1]) were strongly associated with BC. There were nominally significant associations with CHEK2, RAD51D, and TP53.In H/L women, LoF variants in FANCM were strongly associated with ER-negative breast cancer risk. It previously was proposed as a possible susceptibility gene for ER-negative BC, but is not routinely tested in clinical practice. Our results demonstrate that FANCM should be added to BC gene panels.

  View details for DOI 10.1101/2023.01.25.23284924

  View details for PubMedID 36747679

  View details for PubMedCentralID PMC9901069

• Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry. Genome medicine Mueller, S. H., Lai, A. G., Valkovskaya, M., Michailidou, K., Bolla, M. K., Wang, Q., Dennis, J., Lush, M., Abu-Ful, Z., Ahearn, T. U., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Arndt, V., Aronson, K. J., Augustinsson, A., Baert, T., Freeman, L. E., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Blomqvist, C., Bogdanova, N. V., Bojesen, S. E., Bonanni, B., Brenner, H., Brucker, S. Y., Buys, S. S., Castelao, J. E., Chan, T. L., Chang-Claude, J., Chanock, S. J., Choi, J. Y., Chung, W. K., Colonna, S. V., Cornelissen, S., Couch, F. J., Czene, K., Daly, M. B., Devilee, P., Dörk, T., Dossus, L., Dwek, M., Eccles, D. M., Ekici, A. B., Eliassen, A. H., Engel, C., Evans, D. G., Fasching, P. A., Fletcher, O., Flyger, H., Gago-Dominguez, M., Gao, Y. T., García-Closas, M., García-Sáenz, J. A., Genkinger, J., Gentry-Maharaj, A., Grassmann, F., Guénel, P., Gündert, M., Haeberle, L., Hahnen, E., Haiman, C. A., Håkansson, N., Hall, P., Harkness, E. F., Harrington, P. A., Hartikainen, J. M., Hartman, M., Hein, A., Ho, W. K., Hooning, M. J., Hoppe, R., Hopper, J. L., Houlston, R. S., Howell, A., Hunter, D. J., Huo, D., Ito, H., Iwasaki, M., Jakubowska, A., Janni, W., John, E. M., Jones, M. E., Jung, A., Kaaks, R., Kang, D., Khusnutdinova, E. K., Kim, S. W., Kitahara, C. M., Koutros, S., Kraft, P., Kristensen, V. N., Kubelka-Sabit, K., Kurian, A. W., Kwong, A., Lacey, J. V., Lambrechts, D., Le Marchand, L., Li, J., Linet, M., Lo, W. Y., Long, J., Lophatananon, A., Mannermaa, A., Manoochehri, M., Margolin, S., Matsuo, K., Mavroudis, D., Menon, U., Muir, K., Murphy, R. A., Nevanlinna, H., Newman, W. G., Niederacher, D., O'Brien, K. M., Obi, N., Offit, K., Olopade, O. I., Olshan, A. F., Olsson, H., Park, S. K., Patel, A. V., Patel, A., Perou, C. M., Peto, J., Pharoah, P. D., Plaseska-Karanfilska, D., Presneau, N., Rack, B., Radice, P., Ramachandran, D., Rashid, M. U., Rennert, G., Romero, A., Ruddy, K. J., Ruebner, M., Saloustros, E., Sandler, D. P., Sawyer, E. J., Schmidt, M. K., Schmutzler, R. K., Schneider, M. O., Scott, C., Shah, M., Sharma, P., Shen, C. Y., Shu, X. O., Simard, J., Surowy, H., Tamimi, R. M., Tapper, W. J., Taylor, J. A., Teo, S. H., Teras, L. R., Toland, A. E., Tollenaar, R. A., Torres, D., Torres-Mejía, G., Troester, M. A., Truong, T., Vachon, C. M., Vijai, J., Weinberg, C. R., Wendt, C., Winqvist, R., Wolk, A., Wu, A. H., Yamaji, T., Yang, X. R., Yu, J. C., Zheng, W., Ziogas, A., Ziv, E., Dunning, A. M., Easton, D. F., Hemingway, H., Hamann, U., Kuchenbaecker, K. B. 2023; 15 (1): 7

  Abstract

  Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10-6) and AC058822.1 (P = 1.47 × 10-4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C.Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10-5), demonstrating the importance of diversifying study cohorts.

  View details for DOI 10.1186/s13073-022-01152-5

  View details for PubMedID 36703164

• Contralateral Breast Cancer Risk Among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Yadav, S., Boddicker, N. J., Na, J., Polley, E. C., Hu, C., Hart, S. N., Gnanaolivu, R. D., Larson, N., Holtegaard, S., Huang, H., Dunn, C. A., Teras, L. R., Patel, A. V., Lacey, J. V., Neuhausen, S. L., Martinez, E., Haiman, C., Chen, F., Ruddy, K. J., Olson, J. E., John, E. M., Kurian, A. W., Sandler, D. P., O'Brien, K. M., Taylor, J. A., Weinberg, C. R., Anton-Culver, H., Ziogas, A., Zirpoli, G., Goldgar, D. E., Palmer, J. R., Domchek, S. M., Weitzel, J. N., Nathanson, K. L., Kraft, P., Couch, F. J. 2023: JCO2201239

  Abstract

  To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2.The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status.Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2.Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

  View details for DOI 10.1200/JCO.22.01239

  View details for PubMedID 36623243

• Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics. American journal of human genetics Jia, G., Ping, J., Shu, X., Yang, Y., Cai, Q., Kweon, S. S., Choi, J. Y., Kubo, M., Park, S. K., Bolla, M. K., Dennis, J., Wang, Q., Guo, X., Li, B., Tao, R., Aronson, K. J., Chan, T. L., Gao, Y. T., Hartman, M., Ho, W. K., Ito, H., Iwasaki, M., Iwata, H., John, E. M., Kasuga, Y., Kim, M. K., Kurian, A. W., Kwong, A., Li, J., Lophatananon, A., Low, S. K., Mariapun, S., Matsuda, K., Matsuo, K., Muir, K., Noh, D. Y., Park, B., Park, M. H., Shen, C. Y., Shin, M. H., Spinelli, J. J., Takahashi, A., Tseng, C., Tsugane, S., Wu, A. H., Yamaji, T., Zheng, Y., Dunning, A. M., Pharoah, P. D., Teo, S. H., Kang, D., Easton, D. F., Simard, J., Shu, X. O., Long, J., Zheng, W. 2022

  Abstract

  By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p < 5.0 × 10-8 and a Bonferroni-corrected p < 4.6 × 10-6, respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy.

  View details for DOI 10.1016/j.ajhg.2022.10.011

  View details for PubMedID 36356581

• Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers. Communications biology Hakkaart, C., Pearson, J. F., Marquart, L., Dennis, J., Wiggins, G. A., Barnes, D. R., Robinson, B. A., Mace, P. D., Aittomaki, K., Andrulis, I. L., Arun, B. K., Azzollini, J., Balmana, J., Barkardottir, R. B., Belhadj, S., Berger, L., Blok, M. J., Boonen, S. E., Borde, J., Bradbury, A. R., Brunet, J., Buys, S. S., Caligo, M. A., Campbell, I., Chung, W. K., Claes, K. B., GEMO Study Collaborators, EMBRACE Collaborators, Collonge-Rame, M., Cook, J., Cosgrove, C., Couch, F. J., Daly, M. B., Dandiker, S., Davidson, R., de la Hoya, M., de Putter, R., Delnatte, C., Dhawan, M., Diez, O., Ding, Y. C., Domchek, S. M., Donaldson, A., Eason, J., Easton, D. F., Ehrencrona, H., Engel, C., Evans, D. G., Faust, U., Feliubadalo, L., Fostira, F., Friedman, E., Frone, M., Frost, D., Garber, J., Gayther, S. A., Gehrig, A., Gesta, P., Godwin, A. K., Goldgar, D. E., Greene, M. H., Hahnen, E., Hake, C. R., Hamann, U., Hansen, T. V., Hauke, J., Hentschel, J., Herold, N., Honisch, E., Hulick, P. J., Imyanitov, E. N., SWE-BRCA Investigators, kConFab Investigators, HEBON Investigators, Isaacs, C., Izatt, L., Izquierdo, A., Jakubowska, A., James, P. A., Janavicius, R., John, E. M., Joseph, V., Karlan, B. Y., Kemp, Z., Kirk, J., Konstantopoulou, I., Koudijs, M., Kwong, A., Laitman, Y., Lalloo, F., Lasset, C., Lautrup, C., Lazaro, C., Legrand, C., Leslie, G., Lesueur, F., Mai, P. L., Manoukian, S., Mari, V., Martens, J. W., McGuffog, L., Mebirouk, N., Meindl, A., Miller, A., Montagna, M., Moserle, L., Mouret-Fourme, E., Musgrave, H., Nambot, S., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Yie, J. N., Nguyen-Dumont, T., Nikitina-Zake, L., Offit, K., Olah, E., Olopade, O. I., Osorio, A., Ott, C., Park, S. K., Parsons, M. T., Pedersen, I. S., Peixoto, A., Perez-Segura, P., Peterlongo, P., Pocza, T., Radice, P., Ramser, J., Rantala, J., Rodriguez, G. C., Ronlund, K., Rosenberg, E. H., Rossing, M., Schmutzler, R. K., Shah, P. D., Sharif, S., Sharma, P., Side, L. E., Simard, J., Singer, C. F., Snape, K., Steinemann, D., Stoppa-Lyonnet, D., Sutter, C., Tan, Y. Y., Teixeira, M. R., Teo, S. H., Thomassen, M., Thull, D. L., Tischkowitz, M., Toland, A. E., Trainer, A. H., Tripathi, V., Tung, N., van Engelen, K., van Rensburg, E. J., Vega, A., Viel, A., Walker, L., Weitzel, J. N., Wevers, M. R., Chenevix-Trench, G., Spurdle, A. B., Antoniou, A. C., Walker, L. C., van Engelen, K., Wevers, M. R. 2022; 5 (1): 1061

  Abstract

  The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR)=1.21), 95% confidence interval (95% CI=1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR=0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.

  View details for DOI 10.1038/s42003-022-03978-6

  View details for PubMedID 36203093

• Pathogenic Variants in Breast Cancer Susceptibility Genes and Polygenic Risk among US Latinas and Mexican Women Nierenberg, J. L., John, E. M., Torres-Mejia, G., Haiman, C. A., Kushi, L. H., Gruber, S., Weitzel, J. N., Fejerman, L., Ziv, E., Neuhausen, S. L. WILEY. 2022: 519-520

  View details for Web of Science ID 000850044000126

• Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study. British journal of sports medicine Dixon-Suen, S. C., Lewis, S. J., Martin, R. M., English, D. R., Boyle, T., Giles, G. G., Michailidou, K., Bolla, M. K., Wang, Q., Dennis, J., Lush, M., Investigators, A., Ahearn, T. U., Ambrosone, C. B., Andrulis, I. L., Anton-Culver, H., Arndt, V., Aronson, K. J., Augustinsson, A., Auvinen, P., Beane Freeman, L. E., Becher, H., Beckmann, M. W., Behrens, S., Bermisheva, M., Blomqvist, C., Bogdanova, N. V., Bojesen, S. E., Bonanni, B., Brenner, H., Brüning, T., Buys, S. S., Camp, N. J., Campa, D., Canzian, F., Castelao, J. E., Cessna, M. H., Chang-Claude, J., Chanock, S. J., Clarke, C. L., Conroy, D. M., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Daly, M. B., Devilee, P., Dörk, T., Dwek, M., Eccles, D. M., Eliassen, A. H., Engel, C., Eriksson, M., Evans, D. G., Fasching, P. A., Fletcher, O., Flyger, H., Fritschi, L., Gabrielson, M., Gago-Dominguez, M., García-Closas, M., García-Sáenz, J. A., Goldberg, M. S., Guénel, P., Gündert, M., Hahnen, E., Haiman, C. A., Häberle, L., Håkansson, N., Hall, P., Hamann, U., Hart, S. N., Harvie, M., Hillemanns, P., Hollestelle, A., Hooning, M. J., Hoppe, R., Hopper, J., Howell, A., Hunter, D. J., Jakubowska, A., Janni, W., John, E. M., Jung, A., Kaaks, R., Keeman, R., Kitahara, C. M., Koutros, S., Kraft, P., Kristensen, V. N., Kubelka-Sabit, K., Kurian, A. W., Lacey, J. V., Lambrechts, D., Le Marchand, L., Lindblom, A., Loibl, S., Lubiński, J., Mannermaa, A., Manoochehri, M., Margolin, S., Martinez, M. E., Mavroudis, D., Menon, U., Mulligan, A. M., Murphy, R. A., Collaborators, N., Nevanlinna, H., Nevelsteen, I., Newman, W. G., Offit, K., Olshan, A. F., Olsson, H., Orr, N., Patel, A., Peto, J., Plaseska-Karanfilska, D., Presneau, N., Rack, B., Radice, P., Rees-Punia, E., Rennert, G., Rennert, H. S., Romero, A., Saloustros, E., Sandler, D. P., Schmidt, M. K., Schmutzler, R. K., Schwentner, L., Scott, C., Shah, M., Shu, X. O., Simard, J., Southey, M. C., Stone, J., Surowy, H., Swerdlow, A. J., Tamimi, R. M., Tapper, W. J., Taylor, J. A., Terry, M. B., Tollenaar, R. A., Troester, M. A., Truong, T., Untch, M., Vachon, C. M., Joseph, V., Wappenschmidt, B., Weinberg, C. R., Wolk, A., Yannoukakos, D., Zheng, W., Ziogas, A., Dunning, A. M., Pharoah, P. D., Easton, D. F., Milne, R. L., Lynch, B. M. 2022; 56 (20): 1157-1170

  Abstract

  Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.

  View details for DOI 10.1136/bjsports-2021-105132

  View details for PubMedID 36328784

• Incorporating progesterone receptor expression into the PREDICT breast prognostic model. European journal of cancer (Oxford, England : 1990) Grootes, I., Keeman, R., Blows, F. M., Milne, R. L., Giles, G. G., Swerdlow, A. J., Fasching, P. A., Abubakar, M., Andrulis, I. L., Anton-Culver, H., Beckmann, M. W., Blomqvist, C., Bojesen, S. E., Bolla, M. K., Bonanni, B., Briceno, I., Burwinkel, B., Camp, N. J., Castelao, J. E., Choi, J., Clarke, C. L., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Devilee, P., Dork, T., Dunning, A. M., Dwek, M., Easton, D. F., Eccles, D. M., Eriksson, M., Ernst, K., Evans, D. G., Figueroa, J. D., Fink, V., Floris, G., Fox, S., Gabrielson, M., Gago-Dominguez, M., Garcia-Saenz, J. A., Gonzalez-Neira, A., Haeberle, L., Haiman, C. A., Hall, P., Hamann, U., Harkness, E. F., Hartman, M., Hein, A., Hooning, M. J., Hou, M., Howell, S. J., ABCTB Investigators, kConFab Investigators, Ito, H., Jakubowska, A., Janni, W., John, E. M., Jung, A., Kang, D., Kristensen, V. N., Kwong, A., Lambrechts, D., Li, J., Lubinski, J., Manoochehri, M., Margolin, S., Matsuo, K., Taib, N. A., Mulligan, A. M., Nevanlinna, H., Newman, W. G., Offit, K., Osorio, A., Park, S. K., Park-Simon, T., Patel, A. V., Presneau, N., Pylkas, K., Rack, B., Radice, P., Rennert, G., Romero, A., Saloustros, E., Sawyer, E. J., Schneeweiss, A., Schochter, F., Schoemaker, M. J., Shen, C., Shibli, R., Sinn, P., Tapper, W. J., Tawfiq, E., Teo, S. H., Teras, L. R., Torres, D., Vachon, C. M., van Deurzen, C. H., Wendt, C., Williams, J. A., Winqvist, R., Elwood, M., Schmidt, M. K., Garcia-Closas, M., Pharoah, P. D. 2022; 173: 178-193

  Abstract

  BACKGROUND: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2).METHOD: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance.RESULTS: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curveincreased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p=0.023) and from 0.898 to 0.902 for patients with ER-positive tumours (p=2.3*10-6) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.CONCLUSION: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predictions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration.

  View details for DOI 10.1016/j.ejca.2022.06.011

  View details for PubMedID 35933885

• Urinary biomarkers of polycyclic aromatic hydrocarbons (PAHs) and timing of pubertal development: The California PAH Study. Epidemiology (Cambridge, Mass.) John, E. M., Keegan, T. H., Terry, M. B., Koo, J., Ingles, S. A., Nguyen, J. T., Thomsen, C., Santella, R. M., Nguyen, K., Yan, B. 2022

  Abstract

  BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are endocrine-disrupting chemicals. Few studies have evaluated the association between pubertal development in girls and PAH exposures quantified by urinary biomarkers.METHODS: We examined associations of urinary PAH metabolites with pubertal development in 358 girls aged 6-16 years from the San Francisco Bay Area enrolled in a prospective cohort from 2011-2013 and followed until 2020. Using baseline data, we assessed associations of urinary PAH metabolites with pubertal development stage. In prospective analyses limited to girls who at baseline had not yet started breast (N=176) or pubic hair (N=179) development or menstruation (N=267), we used multivariable Cox proportional hazards regression to assess associations of urinary PAH metabolites with onset of breast and pubic hair development, menstruation, and pubertal tempo (interval between onset of breast development and menstruation).RESULTS: We detected PAH metabolites in >98% of girls. In cross-sectional analyses using baseline data, PAH metabolites were not associated with pubertal development stage. In prospective analyses, higher concentrations (≥ median) of some PAH metabolites were associated with two-fold higher odds of earlier breast development (2-hydroxynaphthalene, 1-hydroxyphenanthrene, summed hydroxyphenanthrenes, total summed metabolites) or pubic hair development (1-hydroxynaphthalene) among girls overweight at baseline (body mass index (BMI)-for-age percentile ≥85) compared to non-overweight girls with lower metabolites concentrations. PAH metabolites were not associated with age at menarche or pubertal tempo.CONCLUSIONS: PAH exposures were widespread in our sample. Our results support the hypothesis that, in overweight girls, PAHs impact the timing of pubertal development, an important risk factor for breast cancer.

  View details for DOI 10.1097/EDE.0000000000001535

  View details for PubMedID 35895514

• Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study BRITISH JOURNAL OF SPORTS MEDICINE Dixon-Suen, S. C., Lewis, S. J., Martin, R. M., English, D. R., Boyle, T., Giles, G. G., Michailidou, K., Bolla, M. K., Wang, Q., Dennis, J., Lush, M., Ahearn, T. U., Ambrosone, C. B., Andrulis, I. L., Anton-Culver, H., Arndt, V., Aronson, K. J., Augustinsson, A., Auvinen, P., Beane Freeman, L. E., Becher, H., Beckmann, M. W., Behrens, S., Bermisheva, M., Blomqvist, C., Bogdanova, N., Bojesen, S. E., Bonanni, B., Brenner, H., Bruening, T., Buys, S. S., Camp, N. J., Campa, D., Canzian, F., Castelao, J. E., Cessna, M. H., Chang-Claude, J., Chanock, S. J., Clarke, C. L., Conroy, D. M., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Daly, M. B., Devilee, P., Doerk, T., Dwek, M., Eccles, D. M., Eliassen, A., Engel, C., Eriksson, M., Evans, D., Fasching, P. A., Fletcher, O., Flyger, H., Fritschi, L., Gabrielson, M., Gago-Dominguez, M., Garcia-Closas, M., Garcia-Saenz, J. A., Goldberg, M. S., Guenel, P., Guendert, M., Hahnen, E., Haiman, C. A., Haeberle, L., Hakansson, N., Hall, P., Hamann, U., Hart, S. N., Harvie, M., Hillemanns, P., Hollestelle, A., Hooning, M. J., Hoppe, R., Hopper, J., Howell, A., Hunter, D. J., Jakubowska, A., Janni, W., John, E. M., Jung, A., Kaaks, R., Keeman, R., Kitahara, C. M., Koutros, S., Kraft, P., Kristensen, V. N., Kubelka-Sabit, K., Kurian, A. W., Lacey, J., Lambrechts, D., Le Marchand, L., Lindblom, A., Loibl, S., Lubinski, J., Mannermaa, A., Manoochehri, M., Margolin, S., Martinez, M., Mavroudis, D., Menon, U., Mulligan, A., Murphy, R. A., Nevanlinna, H., Nevelsteen, I., Newman, W. G., Offit, K., Olshan, A. F., Olsson, H., Orr, N., Patel, A., Peto, J., Plaseska-Karanfilska, D., Presneau, N., Rack, B., Radice, P., Rees-Punia, E., Rennert, G., Rennert, H. S., Romero, A., Saloustros, E., Sandler, D. P., Schmidt, M. K., Schmutzler, R. K., Schwentner, L., Scott, C., Shah, M., Shu, X., Simard, J., Southey, M. C., Stone, J., Surowy, H., Swerdlow, A. J., Tamimi, R. M., Tapper, W. J., Taylor, J. A., Terry, M., Tollenaar, R. M., Troester, M. A., Truong, T., Untch, M., Vachon, C. M., Joseph, V., Wappenschmidt, B., Weinberg, C. R., Wolk, A., Yannoukakos, D., Zheng, W., Ziogas, A., Dunning, A. M., Pharoah, P. P., Easton, D. F., Milne, R. L., Lynch, B. M., ABCTB Investigators, NBCS Collaborators, Breast Canc Assoc Consortium 2022

  View details for DOI 10.1136/bjsports-2021-105132

  View details for Web of Science ID 000840803100001

• Women's thoughts on receiving and sharing genetic information: Considerations for genetic counseling. Journal of genetic counseling Pfledderer, C. D., Gren, L. H., Frost, C. J., Andrulis, I. L., Chung, W. K., Genkinger, J., Glendon, G., Hopper, J. L., John, E. M., Southey, M., Terry, M. B., Daly, M. B. 2022

  Abstract

  Indications for genetic testing for inherited cancer syndromes are expanding both in the academic and the community setting. However, only a fraction of individuals who are candidates for testing pursue this option. Therefore, it is important to understand those factors that impact the uptake of genetic testing in individuals affected and unaffected with cancer. A successful translation of genomic risk stratification into clinical care will require that providers of this information are aware of the attitudes, perceived risks and benefits, and concerns of individuals who will be considering testing. The purpose of this study was to assess beliefs, attitudes and preferences for genetic risk information, by personal characteristics of women affected and unaffected by breast cancer enrolled in the Breast Cancer Family Registry Cohort. Data for this analysis came from eight survey questions, which asked participants (N=9,048, 100% female) about their opinions regarding genetic information. Women reported that conveying the accuracy of the test was important and were interested in information related to personal level of risk, finding out about diseases that could be treated, and information that could be helpful to their families. Young women were most interested in how their own health needs might be impacted by genetic test results, while older women were more interested in how genetic information would benefit other members of the family. Interest in how the genetic test was performed was highest among Asian and Hispanic women. Women affected with breast cancer were more likely to report feeling sad about possibly passing down a breast cancer gene, while unaffected women were more uncertain about their future risk of cancer. The variety of informational needs identified has implications for how genetic counselors can tailor communication to individuals considering genetic testing.

  View details for DOI 10.1002/jgc4.1599

  View details for PubMedID 35794807

• Adherence to the 2020 American Cancer Society Guideline for Cancer Prevention and risk of breast cancer for women at increased familial and genetic risk in the Breast Cancer Family Registry: an evaluation of the weight, physical activity, and alcohol consumption recommendations. Breast cancer research and treatment Geczik, A. M., Ferris, J. S., Terry, M. B., Andrulis, I. L., Buys, S. S., Daly, M. B., Hopper, J. L., John, E. M., Kurian, A. W., Southey, M. C., Liao, Y., Genkinger, J. M. 2022

  Abstract

  The American Cancer Society (ACS) published an updated Guideline for Cancer Prevention (ACS Guideline) in 2020. Research suggests that adherence to the 2012 ACS Guideline might lower breast cancer risk, but there is limited evidence that this applies to women at increased familial and genetic risk of breast cancer.Using the Breast Cancer Family Registry (BCFR), a cohort enriched for increased familial and genetic risk of breast cancer, we examined adherence to three 2020 ACS Guideline recommendations (weight management (body mass index), physical activity, and alcohol consumption) with breast cancer risk in 9615 women. We used Cox proportional hazard regression modeling to calculate hazard ratios (HRs) and 95% confidence intervals (CI) overall and stratified by BRCA1 and BRCA2 pathogenic variant status, family history of breast cancer, menopausal status, and estrogen receptor-positive (ER +) breast cancer.We observed 618 incident invasive or in situ breast cancers over a median 12.9 years. Compared with being adherent to none (n = 55 cancers), being adherent to any ACS recommendation (n = 563 cancers) was associated with a 27% lower breast cancer risk (HR = 0.73, 95% CI: 0.55-0.97). This was evident for women with a first-degree family history of breast cancer (HR = 0.68, 95% CI: 0.50-0.93), women without BRCA1 or BRCA2 pathogenic variants (HR = 0.71, 95% CI: 0.53-0.95), postmenopausal women (HR = 0.63, 95% CI: 0.44-0.89), and for risk of ER+ breast cancer (HR = 0.63, 95% CI: 0.40-0.98).Adherence to the 2020 ACS Guideline recommendations for BMI, physical activity, and alcohol consumption could reduce breast cancer risk for postmenopausal women and women at increased familial risk.

  View details for DOI 10.1007/s10549-022-06656-7

  View details for PubMedID 35780210

• Transcriptome-wide association study identifies novel genes associated with breast cancer susceptibility in Latinas Kapoor, P., Mak, A. C., Kachuri, L., Hu, D., Huntsman, S., Kushi, L. H., Haiman, C., John, E. M., Torres-Mejia, G., Burchard, E. G., Neuhausen, S. L., Fejerman, L., Ziv, E. AMER ASSOC CANCER RESEARCH. 2022

  View details for Web of Science ID 000892509508068

• National claims data analysis of outcomes of hospitalized cancer patients without COVID-19 infection during versus prior to the COVID-19 pandemic. Caswell-Jin, J., Shafaee, M., Liu, M., Xiao, L., John, E. M., Bondy, M., Kurian, A. W. LIPPINCOTT WILLIAMS & WILKINS. 2022: E18679

  View details for Web of Science ID 000863680303824

• Breast cancer diagnosis and treatment during the COVID-19 pandemic in a nationwide, insured population. Breast cancer research and treatment Caswell-Jin, J. L., Shafaee, M. N., Xiao, L., Liu, M., John, E. M., Bondy, M. L., Kurian, A. W. 2022

  Abstract

  The early months of the COVID-19 pandemic led to reduced cancer screenings and delayed cancer surgeries. We used insurance claims data to understand how breast cancer incidence and treatment after diagnosis changed nationwide over the course of the pandemic.Using the Optum Research Database from January 2017 to March 2021, including approximately 19 million US adults with commercial health insurance, we identified new breast cancer diagnoses and first treatment after diagnosis. We compared breast cancer incidence and proportion of newly diagnosed patients receiving pre-operative systemic therapy pre-COVID, in the first 2 months of the COVID pandemic and in the later part of the COVID pandemic.Average monthly breast cancer incidence was 19.3 (95% CI 19.1-19.5) cases per 100,000 women and men pre-COVID, 11.6 (95% CI 10.8-12.4) per 100,000 in April-May 2020, and 19.7 (95% CI 19.3-20.1) per 100,000 in June 2020-February 2021. Use of pre-operative systemic therapy was 12.0% (11.7-12.4) pre-COVID, 37.7% (34.9-40.7) for patients diagnosed March-April 2020, and 14.8% (14.0-15.7) for patients diagnosed May 2020-January 2021. The changes in breast cancer incidence across the pandemic did not vary by demographic factors. Use of pre-operative systemic therapy across the pandemic varied by geographic region, but not by area socioeconomic deprivation or race/ethnicity.In this US-insured population, the dramatic changes in breast cancer incidence and the use of pre-operative systemic therapy experienced in the first 2 months of the pandemic did not persist, although a modest change in the initial management of breast cancer continued.

  View details for DOI 10.1007/s10549-022-06634-z

  View details for PubMedID 35624175

• Maternal and prenatal factors and age at thelarche in the LEGACY Girls Study cohort: implications for breast cancer risk. International journal of epidemiology Goldberg, M., McDonald, J. A., Houghton, L. C., Andrulis, I. L., Knight, J. A., Bradbury, A. R., Schwartz, L. A., Buys, S. S., Frost, C. J., Daly, M. B., John, E. M., Keegan, T. H., Chung, W. K., Wei, Y., Terry, M. B. 2022

  Abstract

  BACKGROUND: Earlier onset of breast development (thelarche) is associated with increased breast cancer risk. Identifying modifiable factors associated with earlier thelarche may provide an opportunity for breast cancer risk reduction starting early in life, which could especially benefit girls with a greater absolute risk of breast cancer due to family history.METHODS: We assessed associations of maternal pre-pregnancy body mass index (BMI), physical activity during pregnancy, gestational weight gain and daughters' weight and length at birth with age at thelarche using longitudinal Weibull models in 1031 girls in the Lessons in Epidemiology and Genetics of Adult Cancer from Youth (LEGACY) Girls Study-a prospective cohort of girls, half of whom have a breast cancer family history (BCFH).RESULTS: Girls whose mothers had a pre-pregnancy BMI of ≥25 and gained ≥30lbs were 57% more likely to experience earlier thelarche than girls whose mothers had a pre-pregnancy BMI of <25 and gained <30lbs [hazard ratio (HR)=1.57, 95% CI: 1.16, 2.12]. This association was not mediated by childhood BMI and was similar in girls with and without a BCFH (BCFH: HR=1.41, 95% CI: 0.87, 2.27; No BCFH: HR=1.62, 95% CI: 1.10, 2.40). Daughters of women who reported no recreational physical activity during pregnancy were more likely to experience earlier thelarche compared with daughters of physically active women. Birthweight and birth length were not associated with thelarche.CONCLUSION: Earlier thelarche, a breast cancer risk factor, was associated with three potentially modifiable maternal risk factors-pre-pregnancy BMI, gestational weight gain and physical inactivity-in a cohort of girls enriched for BCFH.

  View details for DOI 10.1093/ije/dyac108

  View details for PubMedID 35613015

• Polygenic Risk Scores for Prediction of Breast Cancer Risk in Women of African Ancestry: a Cross-Ancestry Approach. Human molecular genetics Gao, G., Zhao, F., Ahearn, T. U., Lunetta, K. L., Troester, M. A., Du, Z., Ogundiran, T. O., Ojengbede, O., Blot, W., Nathanson, K. L., Domchek, S. M., Nemesure, B., Hennis, A., Ambs, S., McClellan, J., Nie, M., Bertrand, K., Zirpoli, G., Yao, S., Olshan, A. F., Bensen, J. T., Bandera, E. V., Nyante, S., Conti, D. V., Press, M. F., Ingles, S. A., John, E. M., Bernstein, L., Hu, J. J., Deming-Halverson, S. L., Chanock, S. J., Ziegler, R. G., Rodriguez-Gil, J. L., Sucheston-Campbell, L. E., Sandler, D. P., Taylor, J. A., Kitahara, C. M., O'Brien, K. M., Bolla, M. K., Dennis, J., Dunning, A. M., Easton, D. F., Michailidou, K., Pharoah, P. D., Wang, Q., Figueroa, J., Biritwum, R., Adjei, E., Wiafe, S., GBHS Study Team, Ambrosone, C. B., Zheng, W., Olopade, O. I., Garcia-Closas, M., Palmer, J. R., Haiman, C. A., Huo, D. 2022

  Abstract

  Polygenic risk scores (PRSs) are useful for predicting breast cancer risk, but the prediction accuracy of existing PRSs in women of African ancestry (AA) remains relatively low. We aim to develop optimal PRSs for prediction of overall and estrogen receptor (ER) subtype-specific breast cancer risk in AA women. The AA dataset comprised 9235 cases and 10184 controls from four genome-wide association study (GWAS) consortia and a GWAS study in Ghana. We randomly divided samples into training and validation sets. We built PRSs using individual level AA data by a forward stepwise logistic regression and then developed joint PRSs that combined 1) the PRSs built in the AA training dataset, and 2) a 313-variant PRS previously developed in women of European ancestry. PRSs were evaluated in the AA validation set. For overall breast cancer, the odd ratio (OR) per standard deviation of the joint PRS in the validation set was 1.34 (95% CI: 1.27-1.42) with area under receiver operating characteristic curve (AUC) of 0.581. Compared to women with average risk (40th-60th PRS percentile), women in the top decile of the PRS had a 1.98-fold increased risk (95% CI: 1.63-2.39). For PRSs of ER-positive and ER-negative breast cancer, the AUCs were 0.608 and 0.576, respectively. Compared to existing methods, the proposed joint PRSs can improve prediction of breast cancer risk in AA women.

  View details for DOI 10.1093/hmg/ddac102

  View details for PubMedID 35554533

• Relevance of the MHC region for breast cancer susceptibility in Asians. Breast cancer (Tokyo, Japan) Ho, P. J., Khng, A. J., Tan, B. K., Tan, E. Y., Tan, S. M., Tan, V. K., Lim, G. H., Aronson, K. J., Chan, T. L., Choi, J. Y., Dennis, J., Ho, W. K., Hou, M. F., Ito, H., Iwasaki, M., John, E. M., Kang, D., Kim, S. W., Kurian, A. W., Kwong, A., Lophatananon, A., Matsuo, K., Mohd-Taib, N. A., Muir, K., Murphy, R. A., Park, S. K., Shen, C. Y., Shu, X. O., Teo, S. H., Wang, Q., Yamaji, T., Zheng, W., Bolla, M. K., Dunning, A. M., Easton, D. F., Pharoah, P. D., Hartman, M., Li, J. 2022

  Abstract

  Human leukocyte antigen (HLA) genes play critical roles in immune surveillance, an important defence against tumors. Imputing HLA genotypes from existing single-nucleotide polymorphism datasets is low-cost and efficient. We investigate the relevance of the major histocompatibility complex region in breast cancer susceptibility, using imputed class I and II HLA alleles, in 25,484 women of Asian ancestry.A total of 12,901 breast cancer cases and 12,583 controls from 12 case-control studies were included in our pooled analysis. HLA imputation was performed using SNP2HLA on 10,886 quality-controlled variants within the 15-55 Mb region on chromosome 6. HLA alleles (n = 175) with info scores greater than 0.8 and frequencies greater than 0.01 were included (resolution at two-digit level: 71; four-digit level: 104). We studied the associations between HLA alleles and breast cancer risk using logistic regression, adjusting for population structure and age. Associations between HLA alleles and the risk of subtypes of breast cancer (ER-positive, ER-negative, HER2-positive, HER2-negative, early-stage, and late-stage) were examined.We did not observe associations between any HLA allele and breast cancer risk at P < 5e-8; the smallest p value was observed for HLA-C*12:03 (OR = 1.29, P = 1.08e-3). Ninety-five percent of the effect sizes (OR) observed were between 0.90 and 1.23. Similar results were observed when different subtypes of breast cancer were studied (95% of ORs were between 0.85 and 1.18).No imputed HLA allele was associated with breast cancer risk in our large Asian study. Direct measurement of HLA gene expressions may be required to further explore the associations between HLA genes and breast cancer risk.

  View details for DOI 10.1007/s12282-022-01366-w

  View details for PubMedID 35543923

• Overall survival is the lowest among young women with postpartum breast cancer. European journal of cancer (Oxford, England : 1990) Shagisultanova, E., Gao, D., Callihan, E., Parris, H. J., Risendal, B., Hines, L. M., Slattery, M. L., Baumgartner, K., Schedin, P., John, E. M., Borges, V. F. 2022; 168: 119-127

  Abstract

  Women diagnosed with breast cancer prior to age 45 years (<45y) and within the first 5 years postpartum (postpartum breast cancer, PPBC) have the greatest risk for distal metastatic recurrence.Pooling data from the Colorado Young Women Breast Cancer cohort and the Breast Cancer Health Disparities Study (N = 2519 cases), we examined the association of parity, age, and clinical factors with overall survival (OS) of breast cancer over 15 years of follow-up.Women with PPBC diagnosed at <45y had the lowest OS (p < 0.0001), while OS of nulliparous cases diagnosed at <45y did not differ from OS of cases diagnosed at 45-65y regardless of parity status. After adjustment for study site, race/ethnicity, clinical stage, year of diagnosis and stratification for oestrogen receptor status, PPBC remained an independent factor associated with poor OS. Among cases diagnosed at <45y, nulliparous cases had 1.6 times better OS (hazard ratio (HR) = 0.61, 95%CI 0.42-0.87) compared to those with PPBC, with a more pronounced survival difference among stage I breast cancers (HR = 0.30, 95%CI 0.11-0.79). Among very young women diagnosed at age ≤35y, nulliparous cases had 2.3 times better OS (HR = 0.44, 95%CI 0.23-0.84) compared to PPBC.Our results suggest that postpartum status is the main driver of poor prognosis in young women with breast cancer, with the strongest association in patients diagnosed at age ≤35y and in those with stage I disease.

  View details for DOI 10.1016/j.ejca.2022.03.014

  View details for PubMedID 35525161

• Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits-The Hispanic/Latino Anthropometry Consortium. HGG advances Fernandez-Rhodes, L., Graff, M., Buchanan, V. L., Justice, A. E., Highland, H. M., Guo, X., Zhu, W., Chen, H., Young, K. L., Adhikari, K., Palmer, N. D., Below, J. E., Bradfield, J., Pereira, A. C., Glover, L., Kim, D., Lilly, A. G., Shrestha, P., Thomas, A. G., Zhang, X., Chen, M., Chiang, C. W., Pulit, S., Horimoto, A., Krieger, J. E., Guindo-Martinez, M., Preuss, M., Schumann, C., Smit, R. A., Torres-Mejia, G., Acuna-Alonzo, V., Bedoya, G., Bortolini, M., Canizales-Quinteros, S., Gallo, C., Gonzalez-Jose, R., Poletti, G., Rothhammer, F., Hakonarson, H., Igo, R., Adler, S. G., Iyengar, S. K., Nicholas, S. B., Gogarten, S. M., Isasi, C. R., Papnicolaou, G., Stilp, A. M., Qi, Q., Kho, M., Smith, J. A., Langefeld, C. D., Wagenknecht, L., Mckean-Cowdin, R., Gao, X. R., Nousome, D., Conti, D. V., Feng, Y., Allison, M. A., Arzumanyan, Z., Buchanan, T. A., Ida Chen, Y., Genter, P. M., Goodarzi, M. O., Hai, Y., Hsueh, W., Ipp, E., Kandeel, F. R., Lam, K., Li, X., Nadler, J. L., Raffel, L. J., Roll, K., Sandow, K., Tan, J., Taylor, K. D., Xiang, A. H., Yao, J., Audirac-Chalifour, A., de Jesus Peralta Romero, J., Hartwig, F., Horta, B., Blangero, J., Curran, J. E., Duggirala, R., Lehman, D. E., Puppala, S., Fejerman, L., John, E. M., Aguilar-Salinas, C., Burtt, N. P., Florez, J. C., Garcia-Ortiz, H., Gonzalez-Villalpando, C., Mercader, J., Orozco, L., Tusie-Luna, T., Blanco, E., Gahagan, S., Cox, N. J., Hanis, C., Butte, N. F., Cole, S. A., Comuzzie, A. G., Voruganti, V. S., Rohde, R., Wang, Y., Sofer, T., Ziv, E., Grant, S. F., Ruiz-Linares, A., Rotter, J. I., Haiman, C. A., Parra, E. J., Cruz, M., Loos, R. J., North, K. E. 2022; 3 (2): 100099

  Abstract

  Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n= 59,771) and generalized our findings in 9 additional studies (stage 2, n= 10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA stage 1 and existing consortia of European and African ancestries. In our HISLA stage 1 + 2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified 3 secondary signals for BMI, 28 for height, and 2 for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.

  View details for DOI 10.1016/j.xhgg.2022.100099

  View details for PubMedID 35399580

• Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci. Breast cancer research : BCR Chen, H., Fan, S., Stone, J., Thompson, D. J., Douglas, J., Li, S., Scott, C., Bolla, M. K., Wang, Q., Dennis, J., Michailidou, K., Li, C., Peters, U., Hopper, J. L., Southey, M. C., Nguyen-Dumont, T., Nguyen, T. L., Fasching, P. A., Behrens, A., Cadby, G., Murphy, R. A., Aronson, K., Howell, A., Astley, S., Couch, F., Olson, J., Milne, R. L., Giles, G. G., Haiman, C. A., Maskarinec, G., Winham, S., John, E. M., Kurian, A., Eliassen, H., Andrulis, I., Evans, D. G., Newman, W. G., Hall, P., Czene, K., Swerdlow, A., Jones, M., Pollan, M., Fernandez-Navarro, P., McConnell, D. S., Kristensen, V. N., Rothstein, J. H., Wang, P., Habel, L. A., Sieh, W., Dunning, A. M., Pharoah, P. D., Easton, D. F., Gierach, G. L., Tamimi, R. M., Vachon, C. M., Lindström, S. 2022; 24 (1): 27

  Abstract

  Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants.We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia.We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes.Our findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.

  View details for DOI 10.1186/s13058-022-01524-0

  View details for PubMedID 35414113

• Correction: Polygenic risk modeling for prediction of epithelial ovarian cancer risk. European journal of human genetics : EJHG Dareng, E. O., Tyrer, J. P., Barnes, D. R., Jones, M. R., Yang, X., Aben, K. K., Adank, M. A., Agata, S., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Aravantinos, G., Arun, B. K., Augustinsson, A., Balmana, J., Bandera, E. V., Barkardottir, R. B., Barrowdale, D., Beckmann, M. W., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Bernardini, M. Q., Bjorge, L., Black, A., Bogdanova, N. V., Bonanni, B., Borg, A., Brenton, J. D., Budzilowska, A., Butzow, R., Buys, S. S., Cai, H., Caligo, M. A., Campbell, I., Cannioto, R., Cassingham, H., Chang-Claude, J., Chanock, S. J., Chen, K., Chiew, Y., Chung, W. K., Claes, K. B., Colonna, S., GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, Cook, L. S., Couch, F. J., Daly, M. B., Dao, F., Davies, E., de la Hoya, M., de Putter, R., Dennis, J., DePersia, A., Devilee, P., Diez, O., Ding, Y. C., Doherty, J. A., Domchek, S. M., Dork, T., du Bois, A., Durst, M., Eccles, D. M., Eliassen, H. A., Engel, C., Evans, G. D., Fasching, P. A., Flanagan, J. M., Fortner, R. T., Machackova, E., Friedman, E., Ganz, P. A., Garber, J., Gensini, F., Giles, G. G., Glendon, G., Godwin, A. K., Goodman, M. T., Greene, M. H., Gronwald, J., OPAL Study Group, AOCS Group, Hahnen, E., Haiman, C. A., Hakansson, N., Hamann, U., Hansen, T. V., Harris, H. R., Hartman, M., Heitz, F., Hildebrandt, M. A., Hogdall, E., Hogdall, C. K., Hopper, J. L., Huang, R., Huff, C., Hulick, P. J., Huntsman, D. G., Imyanitov, E. N., KConFab Investigators, HEBON Investigators, Isaacs, C., Jakubowska, A., James, P. A., Janavicius, R., Jensen, A., Johannsson, O. T., John, E. M., Jones, M. E., Kang, D., Karlan, B. Y., Karnezis, A., Kelemen, L. E., Khusnutdinova, E., Kiemeney, L. A., Kim, B., Kjaer, S. K., Komenaka, I., Kupryjanczyk, J., Kurian, A. W., Kwong, A., Lambrechts, D., Larson, M. C., Lazaro, C., Le, N. D., Leslie, G., Lester, J., Lesueur, F., Levine, D. A., Li, L., Li, J., Loud, J. T., Lu, K. H., Lubinski, J., Mai, P. L., Manoukian, S., Marks, J. R., Matsuno, R. K., Matsuo, K., May, T., McGuffog, L., McLaughlin, J. R., McNeish, I. A., Mebirouk, N., Menon, U., Miller, A., Milne, R. L., Minlikeeva, A., Modugno, F., Montagna, M., Moysich, K. B., Munro, E., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Yie, J. N., Nielsen, H. R., Nielsen, F. C., Nikitina-Zake, L., Odunsi, K., Offit, K., Olah, E., Olbrecht, S., Olopade, O. I., Olson, S. H., Olsson, H., Osorio, A., Papi, L., Park, S. K., Parsons, M. T., Pathak, H., Pedersen, I. S., Peixoto, A., Pejovic, T., Perez-Segura, P., Permuth, J. B., Peshkin, B., Peterlongo, P., Piskorz, A., Prokofyeva, D., Radice, P., Rantala, J., Riggan, M. J., Risch, H. A., Rodriguez-Antona, C., Ross, E., Rossing, M. A., Runnebaum, I., Sandler, D. P., Santamarina, M., Soucy, P., Schmutzler, R. K., Setiawan, V. W., Shan, K., Sieh, W., Simard, J., Singer, C. F., Sokolenko, A. P., Song, H., Southey, M. C., Steed, H., Stoppa-Lyonnet, D., Sutphen, R., Swerdlow, A. J., Tan, Y. Y., Teixeira, M. R., Teo, S. H., Terry, K. L., Terry, M. B., OCAC Consortium, CIMBA Consortium, Thomassen, M., Thompson, P. J., Thomsen, L. C., Thull, D. L., Tischkowitz, M., Titus, L., Toland, A. E., Torres, D., Trabert, B., Travis, R., Tung, N., Tworoger, S. S., Valen, E., van Altena, A. M., van der Hout, A. H., Van Nieuwenhuysen, E., van Rensburg, E. J., Vega, A., Edwards, D. V., Vierkant, R. A., Wang, F., Wappenschmidt, B., Webb, P. M., Weinberg, C. R., Weitzel, J. N., Wentzensen, N., White, E., Whittemore, A. S., Winham, S. J., Wolk, A., Woo, Y., Wu, A. H., Yan, L., Yannoukakos, D., Zavaglia, K. M., Zheng, W., Ziogas, A., Zorn, K. K., Kleibl, Z., Easton, D., Lawrenson, K., DeFazio, A., Sellers, T. A., Ramus, S. J., Pearce, C. L., Monteiro, A. N., Cunningham, J., Goode, E. L., Schildkraut, J. M., Berchuck, A., Chenevix-Trench, G., Gayther, S. A., Antoniou, A. C., Pharoah, P. D., Lesueur, F., Mebirouk, N., Engel, C., Schmutzler, R. K., Barrowdale, D., Davies, E., Eccles, D. M., Evans, D. G., Chenevix-Trench, G., Adank, M. A., Devilee, P., van der Hout, A. H., Dareng, E. O., Tyrer, J. P., Jones, M. R., Aben, K. K., Anton-Culver, H., Antonenkova, N. N., Aravantinos, G., Beckmann, M. W., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Bernardini, M. Q., Bjorge, L., Bogdanova, N. V., Brenton, J. D., Budzilowska, A., Butzow, R., Cai, H., Campbell, I., Cannioto, R., Chang-Claude, J., Chanock, S. J., Chen, K., Chiew, Y., Cook, L. S., Dao, F., Dennis, J., Doherty, J. A., Dork, T., du Bois, A., Durst, M., Eccles, D. M., Eliassen, H. A., Fasching, P. A., Flanagan, J. M., Fortner, R. T., Giles, G. G., Goodman, M. T., Gronwald, J., Haiman, C. A., Hakansson, N., Harris, H. R., Heitz, F., Hildebrandt, M. A., Hogdall, E., Hogdall, C. K., Huang, R., Huff, C., Huntsman, D. G., Jakubowska, A., Jensen, A., Jones, M. E., Kang, D., Karlan, B. Y., Karnezis, A., Kelemen, L. E., Khusnutdinova, E., Kiemeney, L. A., Kim, B., Kjaer, S. K., Kupryjanczyk, J., Lambrechts, D., Larson, M. C., Le, N. D., Lester, J., Levine, D. A., Lu, K. H., Lubinski, J., Marks, J. R., Matsuno, R. K., Matsuo, K., May, T., McLaughlin, J. R., McNeish, I. A., Milne, R. L., Minlikeeva, A., Modugno, F., Moysich, K. B., Munro, E., Nevanlinna, H., Odunsi, K., Olbrecht, S., Olson, S. H., Olsson, H., Osorio, A., Park, S. K., Pejovic, T., Permuth, J. B., Piskorz, A., Prokofyeva, D., Riggan, M. J., Risch, H. A., Rodriguez-Antona, C., Rossing, M. A., Runnebaum, I., Sandler, D. P., Setiawan, V. W., Shan, K., Sieh, W., Song, H., Southey, M. C., Steed, H., Sutphen, R., Swerdlow, A. J., Teo, S. H., Terry, K. L., Thompson, P. J., Thomsen, L. C., Titus, L., Trabert, B., Travis, R., Tworoger, S. S., Valen, E., van Altena, A. M., Van Nieuwenhuysen, E., Edwards, D. V., Vierkant, R. A., Wang, F., Webb, P. M., Weinberg, C. R., Wentzensen, N., White, E., Whittemore, A. S., Winham, S. J., Wolk, A., Woo, Y., Wu, A. H., Yan, L., Yannoukakos, D., Zheng, W., Ziogas, A., Lawrenson, K., deFazio, A., Ramus, S. J., Pearce, C. L., Monteiro, A. N., Cunningham, J. M., Goode, E. L., Schildkraut, J. M., Berchuck, A., Gayther, S. A., Pharoah, P. D., Barnes, D. R., Yang, X., Adank, M. A., Agata, S., Andrulis, I. L., Arun, B. K., Augustinsson, A., Balmana, J., Barkardottir, R. B., Barrowdale, D., Bonanni, B., Borg, A., Buys, S. S., Caligo, M. A., Cassingham, H., Chung, W. K., Claes, K. B., Colonna, S., Couch, F. J., Daly, M. B., Davies, E., de la Hoya, M., de Putter, R., DePersia, A., Devilee, P., Diez, O., Ding, Y. C., Domchek, S. M., Eccles, D. M., Engel, C., Evans, D. G., Machackova, E., Friedman, E., Ganz, P. A., Garber, J., Gensini, F., Glendon, G., Godwin, A. K., Greene, M. H., Hahnen, E., Hamann, U., Hansen, T. V., Hartman, M., Hopper, J. L., Hulick, P. J., Imyanitov, E. N., Isaacs, C., James, P. A., Janavicius, R., Johannsson, O. T., John, E. M., Komenaka, I., Kurian, A. W., Kwong, A., Lazaro, C., Leslie, G., Lesueur, F., Li, J., Loud, J. T., Mai, P. L., Manoukian, S., McGuffog, L., Mebirouk, N., Miller, A., Montagna, M., Nathanson, K. L., Neuhausen, S. L., Yie, J. N., Nielsen, H. R., Nikitina-Zake, L., Offit, K., Olah, E., Olopade, O. I., Papi, L., Parsons, M. T., Pathak, H., Pedersen, I. S., Peixoto, A., Perez-Segura, P., Peshkin, B., Peterlongo, P., Radice, P., Rantala, J., Ross, E., Santamarina, M., Soucy, P., Schmutzler, R. K., Simard, J., Singer, C. F., Sokolenko, A. P., Stoppa-Lyonnet, D., Tan, Y. Y., Teixeira, M. R., Terry, M. B., Thomassen, M., Thull, D. L., Tischkowitz, M., Toland, A. E., Torres, D., Tung, N., van der Hout, A. H., van Rensburg, E. J., Vega, A., Wappenschmidt, B., Weitzel, J. N., Zavaglia, K. M., Zorn, K. K., Sellers, T. A., Chenevix-Trench, G., Antoniou, A. C. 2022

  View details for DOI 10.1038/s41431-022-01085-y

  View details for PubMedID 35314806

• Association of contralateral breast cancer risk with mammographic density defined at higher-than-conventional intensity thresholds. International journal of cancer Watt, G. P., Knight, J. A., Nguyen, T. L., Reiner, A. S., Malone, K. E., John, E. M., Lynch, C. F., Brooks, J. D., Woods, M., Liang, X., Bernstein, L., Pike, M. C., Hopper, J. L., Bernstein, J. L. 2022

  Abstract

  Mammographic dense area (MDA) is an established predictor of future breast cancer risk. Recent studies have found that risk prediction might be improved by redefining MDA in effect at higher-than-conventional intensity thresholds. We assessed whether such higher-intensity MDA measures gave stronger prediction of subsequent contralateral breast cancer (CBC) risk using the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study, a population-based CBC case-control study of ≥1year survivors of unilateral breast cancer diagnosed between 1990 and 2008. Three measures of MDA for the unaffected contralateral breast were made at the conventional intensity threshold ("Cumulus") and at two sequentially higher-intensity thresholds ("Altocumulus" and "Cirrocumulus") using the CUMULUS software and mammograms taken up to 3years prior to the first breast cancer diagnosis. The measures were fitted separately and together in multivariable-adjusted logistic regression models of CBC (252 CBC cases and 271 unilateral breast cancer controls). The strongest association with CBC was MDA defined using the highest intensity threshold, Cirrocumulus (odds ratio per adjusted SD [OPERA] 1.40, 95% CI 1.13-1.73); and the weakest association was MDA defined at the conventional threshold, Cumulus (1.32, 95% CI 1.05-1.66). In a model fitting the three measures together, the association of CBC with Cirrocumulus was unchanged (1.40, 95% CI 0.97-2.05), and the lower brightness measures did not contribute to the CBC model fit. These results suggest that MDA defined at a high-intensity threshold is a better predictor of CBC risk and has the potential to improve CBC risk stratification beyond conventional MDA measures. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ijc.34001

  View details for PubMedID 35315524

• Diet Quality and All-Cause Mortality in Women with Breast Cancer from the Breast Cancer Family Registry. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Haslam, D. E., John, E. M., Knight, J. A., Li, Z., Buys, S. S., Andrulis, I. L., Daly, M. B., Genkinger, J. M., Terry, M. B., Zhang, F. F. 2022

  Abstract

  The impact of diet on breast cancer survival remains inconclusive. We assessed associations of all-cause mortality with adherence to the four diet quality indices: Healthy Eating Index-2015 (HEI-2015), Alternative Healthy Eating Index (AHEI), Alternative Mediterranean Diet (aMED), and Dietary Approaches to Stop Hypertension (DASH).Dietary intake data were evaluated for 6,157 North American women enrolled in the Breast Cancer Family Registry who had been diagnosed with invasive breast cancer from 1993 to 2011 and were followed through 2018. Pre-diagnosis (n=4,557) or post-diagnosis (n=1,600) dietary intake was estimated through a food frequency questionnaire. During a median follow-up time of 11.3 years, 1,265 deaths occurred. Cox proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI).Women in the highest vs. lowest quartile of adherence to the HEI-2015, AHEI, aMED, and DASH indices had a lower risk of all-cause mortality. HR (95% CI) were 0.88 (0.74-1.04, Ptrend=0.12) for HEI-2015; 0.82 (0.69-0.97, Ptrend=0.02) for AHEI; 0.73 (0.59-0.92, Ptrend=0.02) for aMED; and 0.78 (0.65-0.94, Ptrend=0.006) for DASH. In subgroup analyses, the associations with higher adherence to the four indices were similar for pre- or post-diagnosis dietary intake and were confined to women with a body mass index <25 kg/m2 and women with hormone receptor positive tumors.Higher adherence to the HEI-2015, AHEI, aMED, and DASH indices was associated with lower mortality among women with breast cancer.Adherence to a healthy diet may improve survival of women with breast cancer.

  View details for DOI 10.1158/1055-9965.EPI-22-1198

  View details for PubMedID 36857773

• Body mass index rebound and pubertal timing in girls with and without a family history of breast cancer: the LEGACY girls study. International journal of epidemiology Houghton, L. C., Wei, Y., Wang, T., Goldberg, M., Paniagua-Avila, A., Sweeden, R. L., Bradbury, A., Daly, M., Schwartz, L. A., Keegan, T., John, E. M., Knight, J. A., Andrulis, I. L., Buys, S. S., Frost, C. J., O'Toole, K., White, M. L., Chung, W. K., Terry, M. B. 2022

  Abstract

  BACKGROUND: Heavier body mass index (BMI) is the most established predictor of earlier age at puberty. However, it is unknown whether the timing of the childhood switch to heavier BMI (age at BMI rebound) also matters for puberty.METHODS: In the LEGACY Girls Study (n = 1040), a longitudinal cohort enriched with girls with a family history of breast cancer, we collected paediatric growth chart data from 852 girls and assessed pubertal development every 6 months. Using constrained splines, we interpolated individual growth curves and then predicted BMI at ages 2, 4, 6, 8 and 9 years for 591 girls. We defined age at BMI rebound as the age at the lowest BMI between ages 2 and 8 years and assessed its association with onset of thelarche, pubarche and menarche using Weibull survival models.RESULTS: The median age at BMI rebound was 5.3 years (interquartile range: 3.6-6.7 years). A 1-year increase in age at BMI rebound was associated with delayed thelarche (HR = 0.90; 95% CI = 0.83-0.97) and menarche (HR = 0.86; 95% CI = 0.79-0.94). The magnitude of these associations remained after adjusting for weight between birth and 2 years, was stronger after adjusting for BMI at age 9, and was stronger in a subset of girls with clinically assessed breast development.CONCLUSIONS: Earlier BMI rebound is associated with earlier pubertal timing. Our observation that BMI rebound may be a driver of pubertal timing in girls with and without a family history of breast cancer provides insight into how growth and pubertal timing are associated with breast cancer risk.

  View details for DOI 10.1093/ije/dyac021

  View details for PubMedID 35157067

• Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score. Prostate cancer and prostatic diseases Huynh-Le, M., Karunamuni, R., Fan, C. C., Asona, L., Thompson, W. K., Martinez, M. E., Eeles, R. A., Kote-Jarai, Z., Muir, K. R., Lophatananon, A., Schleutker, J., Pashayan, N., Batra, J., Gronberg, H., Neal, D. E., Nordestgaard, B. G., Tangen, C. M., MacInnis, R. J., Wolk, A., Albanes, D., Haiman, C. A., Travis, R. C., Blot, W. J., Stanford, J. L., Mucci, L. A., West, C. M., Nielsen, S. F., Kibel, A. S., Cussenot, O., Berndt, S. I., Koutros, S., Sorensen, K. D., Cybulski, C., Grindedal, E. M., Menegaux, F., Park, J. Y., Ingles, S. A., Maier, C., Hamilton, R. J., Rosenstein, B. S., Lu, Y., Watya, S., Vega, A., Kogevinas, M., Wiklund, F., Penney, K. L., Huff, C. D., Teixeira, M. R., Multigner, L., Leach, R. J., Brenner, H., John, E. M., Kaneva, R., Logothetis, C. J., Neuhausen, S. L., De Ruyck, K., Ost, P., Razack, A., Newcomb, L. F., Fowke, J. H., Gamulin, M., Abraham, A., Claessens, F., Castelao, J. E., Townsend, P. A., Crawford, D. C., Petrovics, G., van Schaik, R. H., Parent, M., Hu, J. J., Zheng, W., UKGPCS collaborators, APCB (Australian Prostate Cancer BioResource), NC-LA PCaP Investigators, IMPACT Study Steering Committee and Collaborators, Canary PASS Investigators, Profile Study Steering Committee, PRACTICAL Consortium, Mills, I. G., Andreassen, O. A., Dale, A. M., Seibert, T. M. 2022

  Abstract

  BACKGROUND: Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets.METHODS: In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured.RESULTS: The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively.CONCLUSIONS: We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

  View details for DOI 10.1038/s41391-022-00497-7

  View details for PubMedID 35152271

• Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Li, S., Silvestri, V., Leslie, G., Rebbeck, T. R., Neuhausen, S. L., Hopper, J. L., Nielsen, H. R., Lee, A., Yang, X., McGuffog, L., Parsons, M. T., Andrulis, I. L., Arnold, N., Belotti, M., Borg, A., Buecher, B., Buys, S. S., Caputo, S. M., Chung, W. K., Colas, C., Colonna, S. V., Cook, J., Daly, M. B., de la Hoya, M., de Pauw, A., Delhomelle, H., Eason, J., Engel, C., Evans, D. G., Faust, U., Fehm, T. N., Fostira, F., Fountzilas, G., Frone, M., Garcia-Barberan, V., Garre, P., Gauthier-Villars, M., Gehrig, A., Glendon, G., Goldgar, D. E., Golmard, L., Greene, M. H., Hahnen, E., Hamann, U., Hanson, H., Hassan, T., Hentschel, J., Horvath, J., Izatt, L., Janavicius, R., Jiao, Y., John, E. M., Karlan, B. Y., Kim, S., Konstantopoulou, I., Kwong, A., Lauge, A., Lee, J. W., Lesueur, F., Mebirouk, N., Meindl, A., Mouret-Fourme, E., Musgrave, H., Ngeow Yuen Yie, J., Niederacher, D., Park, S. K., Pedersen, I. S., Ramser, J., Ramus, S. J., Rantala, J., Rashid, M. U., Reichl, F., Ritter, J., Rump, A., Santamarina, M., Saule, C., Schmidt, G., Schmutzler, R. K., Senter, L., Shariff, S., Singer, C. F., Southey, M. C., Stoppa-Lyonnet, D., Sutter, C., Tan, Y., Teo, S. H., Terry, M. B., Thomassen, M., Tischkowitz, M., Toland, A. E., Torres, D., Vega, A., Wagner, S. A., Wang-Gohrke, S., Wappenschmidt, B., Weber, B. H., Yannoukakos, D., Spurdle, A. B., Easton, D. F., Chenevix-Trench, G., Ottini, L., Antoniou, A. C. 1800: JCO2102112

  Abstract

  PURPOSE: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management.METHODS: We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment.RESULTS: BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers.CONCLUSION: In addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.

  View details for DOI 10.1200/JCO.21.02112

  View details for PubMedID 35077220

• Oral Contraceptive Use in BRCA1 and BRCA2 Mutation Carriers: Absolute Cancer Risks and Benefits. Journal of the National Cancer Institute Schrijver, L. H., Mooij, T. M., Pijpe, A., Sonke, G. S., Mourits, M. J., Andrieu, N., Antoniou, A. C., Easton, D. F., Engel, C., Goldgar, D., John, E. M., Kast, K., Milne, R. L., Olsson, H., Phillips, K., Terry, M. B., Hopper, J. L., van Leeuwen, F. E., Rookus, M. A. 1800

  Abstract

  BACKGROUND: To help BRCA1/2 mutation carriers make informed decisions regarding use of combined-type oral contraceptive preparation (COCP), absolute risk-benefit estimates are needed for COCP-associated cancer.METHODS: For a hypothetical cohort of 10,000 women, we calculated the increased or decreased cumulative incidence of COCP-associated (breast/ovarian/endometrial) cancer, examining 18 scenarios with differences in duration and timing of COCP use, uptake of prophylactic surgeries and menopausal hormone therapy.RESULTS: COCP use initially increased breast cancer risk, and decreased ovarian/endometrial cancer risk long-term. For 10,000 BRCA1 mutation carriers ten years of COCP use from age 20-30years resulted in 66 additional COCP-associated cancer cases by the age of 35years, on top of 625 cases expected for never users. By the age of 70years such COCP use resulted in 907 fewer cancer cases than the expected 9,093 cases in never users. Triple-negative breast cancer estimates resulted in 196 additional COCP-associated cases by age 40years, on top of 1,454 expected. For 10,000 BRCA2 mutation carriers using COCP from age 20-30years, 80 excess cancer cases were estimated by age 40years on top of 651 expected cases; by the age of 70years we calculated 382 fewer cases compared to the 6,156 cases expected. The long-term benefit of COCP use diminished after risk-reducing bilateral salpingo-oophorectomy (RRSO) followed by menopausal hormone therapy use.CONCLUSION: While COCP use in BRCA1 and BRCA2 mutation carriers initially increases breast/ovarian/endometrial cancer risk, it strongly decreases lifetime cancer risk. RRSO and menopausal hormone therapy use appear to counteract the long-term COCP-benefit.

  View details for DOI 10.1093/jnci/djac004

  View details for PubMedID 35048954

• Improvement on recovery and reproducibility for quantifying urinary mono-hydroxylated polycyclic aromatic hydrocarbons (OH-PAHs). Journal of chromatography. B, Analytical technologies in the biomedical and life sciences Nguyen, K., Pitiranggon, M., Wu, H., John, E. M., Santella, R. M., Terry, M. B., Yan, B. 1800; 1192: 123113

  Abstract

  Efficient and reproducible measurements of multiple polycyclic aromatic hydrocarbon (PAH) metabolites in urinary samples are required to evaluate the complex health effects of PAH exposure. Here, we demonstrate a highly practical, automated off-line solid-phase extraction (SPE) of deconjugated hydroxylated PAHs followed by LC-MS/MS to simultaneously measure eight mono-hydroxylated PAH compounds: 1-hydroxynaphthalene, 2-hydroxynaphthalene, 2-hydroxyfluorene, 1-hydroxyphenanthrene, 2&3-hydroxyphenanthrene, 4-hydroxyphenanthrene and 1-hydroxypyrene. Initially, we observed low recovery rates (e.g., 16% for 1-hydroxypyrene) when using previously published methods. We optimized the procedure by choosing polymeric absorbent-based cartridges, automating the sample loading step by diluting samples with 15% methanol/sodium acetate, and most importantly, replacing acetonitrile with methanol as the eluting solvent. Optimized sample preparation has improved the recovery rates to more than 69% for analytes of interest. This improvement led to higher method sensitivity and detection frequency, especially for 1-hydroxypyrene, detected in all of 100 urine samples collected in the New York site of the Legacy Girls Study. The limits of detection ranged from 7.6pg/mL to 20.3pg/mL using 1mL of urine, compared to the 2mL required in CDC, method 09-OD. The average coefficients of variance of quality control samples (n=60) ranged between 7 and 21%; variance of repeated measurements (n=45) wasless than10%. This efficient and reliable method for measuring PAH metabolites will greatly benefit epidemiology studies and biomonitoring programs.

  View details for DOI 10.1016/j.jchromb.2022.123113

  View details for PubMedID 35114472

• A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry. European urology Darst, B. F., Hughley, R., Pfennig, A., Hazra, U., Fan, C., Wan, P., Sheng, X., Xia, L., Andrews, C., Chen, F., Berndt, S. I., Kote-Jarai, Z., Govindasami, K., Bensen, J. T., Ingles, S. A., Rybicki, B. A., Nemesure, B., John, E. M., Fowke, J. H., Huff, C. D., Strom, S. S., Isaacs, W. B., Park, J. Y., Zheng, W., Ostrander, E. A., Walsh, P. C., Carpten, J., Sellers, T. A., Yamoah, K., Murphy, A. B., Sanderson, M., Crawford, D. C., Gapstur, S. M., Bush, W. S., Aldrich, M. C., Cussenot, O., Petrovics, G., Cullen, J., Neslund-Dudas, C., Kittles, R. A., Xu, J., Stern, M. C., Chokkalingam, A. P., Multigner, L., Parent, M., Menegaux, F., Cancel-Tassin, G., Kibel, A. S., Klein, E. A., Goodman, P. J., Stanford, J. L., Drake, B. F., Hu, J. J., Clark, P. E., Blanchet, P., Casey, G., Hennis, A. J., Lubwama, A., Thompson, I. M., Leach, R. J., Gundell, S. M., Pooler, L., Mohler, J. L., Fontham, E. T., Smith, G. J., Taylor, J. A., Brureau, L., Blot, W. J., Biritwum, R., Tay, E., Truelove, A., Niwa, S., Tettey, Y., Varma, R., McKean-Cowdin, R., Torres, M., Jalloh, M., Magueye Gueye, S., Niang, L., Ogunbiyi, O., Oladimeji Idowu, M., Popoola, O., Adebiyi, A. O., Aisuodionoe-Shadrach, O. I., Nwegbu, M., Adusei, B., Mante, S., Darkwa-Abrahams, A., Yeboah, E. D., Mensah, J. E., Anthony Adjei, A., Diop, H., Cook, M. B., Chanock, S. J., Watya, S., Eeles, R. A., Chiang, C. W., Lachance, J., Rebbeck, T. R., Conti, D. V., Haiman, C. A. 1800

  Abstract

  A rare African ancestry-specific germline deletion variant in HOXB13 (X285K, rs77179853) was recently reported in Martinican men with early-onset prostate cancer. Given the role of HOXB13 germline variation in prostate cancer, we investigated the association between HOXB13 X285K and prostate cancer risk in a large sample of 22 361 African ancestry men, including 11 688 prostate cancer cases. The risk allele was present only in men of West African ancestry, with an allele frequency in men that ranged from 0.40% in Ghana and 0.31% in Nigeria to 0% in Uganda and South Africa, with a range of frequencies in men with admixed African ancestry from North America and Europe (0-0.26%). HOXB13 X285K was associated with 2.4-fold increased odds of prostate cancer (95% confidence interval [CI]=1.5-3.9, p=2*10-4), with greater risk observed for more aggressive and advanced disease (Gleason ≥8: odds ratio [OR]=4.7, 95% CI=2.3-9.5, p=2*10-5; stage T3/T4: OR=4.5, 95% CI=2.0-10.0, p=2*10-4; metastatic disease: OR=5.1, 95% CI=1.9-13.7, p=0.001). We estimated that the allele arose in West Africa 1500-4600 yr ago. Further analysis is needed to understand how the HOXB13 X285K variant impacts the HOXB13 protein and function in the prostate. Understanding who carries this mutation may inform prostate cancer screening in men of West African ancestry. PATIENT SUMMARY: A rare African ancestry-specific germline deletion in HOXB13, found only in men of West African ancestry, was reported to be associated with an increased risk of overall and advanced prostate cancer. Understanding who carries this mutation may help inform screening for prostate cancer in men of West African ancestry.

  View details for DOI 10.1016/j.eururo.2021.12.023

  View details for PubMedID 35031163

• Breast Cancer Screening Strategies for Women With ATM, CHEK2, and PALB2 Pathogenic Variants: A Comparative Modeling Analysis. JAMA oncology Lowry, K. P., Geuzinge, H. A., Stout, N. K., Alagoz, O., Hampton, J., Kerlikowske, K., de Koning, H. J., Miglioretti, D. L., van Ravesteyn, N. T., Schechter, C., Sprague, B. L., Tosteson, A. N., Trentham-Dietz, A., Weaver, D., Yaffe, M. J., Yeh, J. M., Couch, F. J., Hu, C., Kraft, P., Polley, E. C., Mandelblatt, J. S., Kurian, A. W., Robson, M. E. 2022

  Abstract

  Screening mammography and magnetic resonance imaging (MRI) are recommended for women with ATM, CHEK2, and PALB2 pathogenic variants. However, there are few data to guide screening regimens for these women.To estimate the benefits and harms of breast cancer screening strategies using mammography and MRI at various start ages for women with ATM, CHEK2, and PALB2 pathogenic variants.This comparative modeling analysis used 2 established breast cancer microsimulation models from the Cancer Intervention and Surveillance Modeling Network (CISNET) to evaluate different screening strategies. Age-specific breast cancer risks were estimated using aggregated data from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium for 32 247 cases and 32 544 controls in 12 population-based studies. Data on screening performance for mammography and MRI were estimated from published literature. The models simulated US women with ATM, CHEK2, or PALB2 pathogenic variants born in 1985.Screening strategies with combinations of annual mammography alone and with MRI starting at age 25, 30, 35, or 40 years until age 74 years.Estimated lifetime breast cancer mortality reduction, life-years gained, breast cancer deaths averted, total screening examinations, false-positive screenings, and benign biopsies per 1000 women screened. Results are reported as model mean values and ranges.The mean model-estimated lifetime breast cancer risk was 20.9% (18.1%-23.7%) for women with ATM pathogenic variants, 27.6% (23.4%-31.7%) for women with CHEK2 pathogenic variants, and 39.5% (35.6%-43.3%) for women with PALB2 pathogenic variants. Across pathogenic variants, annual mammography alone from 40 to 74 years was estimated to reduce breast cancer mortality by 36.4% (34.6%-38.2%) to 38.5% (37.8%-39.2%) compared with no screening. Screening with annual MRI starting at 35 years followed by annual mammography and MRI at 40 years was estimated to reduce breast cancer mortality by 54.4% (54.2%-54.7%) to 57.6% (57.2%-58.0%), with 4661 (4635-4688) to 5001 (4979-5023) false-positive screenings and 1280 (1272-1287) to 1368 (1362-1374) benign biopsies per 1000 women. Annual MRI starting at 30 years followed by mammography and MRI at 40 years was estimated to reduce mortality by 55.4% (55.3%-55.4%) to 59.5% (58.5%-60.4%), with 5075 (5057-5093) to 5415 (5393-5437) false-positive screenings and 1439 (1429-1449) to 1528 (1517-1538) benign biopsies per 1000 women. When starting MRI at 30 years, initiating annual mammography starting at 30 vs 40 years did not meaningfully reduce mean mortality rates (0.1% [0.1%-0.2%] to 0.3% [0.2%-0.3%]) but was estimated to add 649 (602-695) to 650 (603-696) false-positive screenings and 58 (41-76) to 59 (41-76) benign biopsies per 1000 women.This analysis suggests that annual MRI screening starting at 30 to 35 years followed by annual MRI and mammography at 40 years may reduce breast cancer mortality by more than 50% for women with ATM, CHEK2, and PALB2 pathogenic variants. In the setting of MRI screening, mammography prior to 40 years may offer little additional benefit.

  View details for DOI 10.1001/jamaoncol.2021.6204

  View details for PubMedID 35175286

• Differences in Thickness-Specific Incidence and Factors Associated With Cutaneous Melanoma in the US From 2010 to 2018. JAMA oncology Chen, M. L., de Vere Hunt, I. J., John, E. M., Weinstock, M. A., Swetter, S. M., Linos, E. 2022

  Abstract

  The recent incidence of cutaneous melanoma of different thicknesses in the US is not well described.To evaluate recent patterns in the incidence of melanoma by tumor thickness and examine associations of sex, race and ethnicity, and socioeconomic status with melanoma thickness-specific incidence.This population-based cohort study analyzed data for 187 487 patients with a new diagnosis of invasive cutaneous melanoma from the Surveillance, Epidemiology, and End Results Registry from January 1, 2010, to December 31, 2018. The study was conducted from May 27 to December 29, 2021. Data were analyzed from June 21 to October 24, 2021.Age-adjusted incidence rates of melanoma were calculated by tumor thickness (categorized by Breslow thickness) and annual percentage change (APC) in incidence rates. Analyses were stratified by sex and race and ethnicity. The associations with socioeconomic status were evaluated in 134 359 patients diagnosed with melanoma from 2010 to 2016.This study included 187 487 patients with a median (IQR) age of 62 (52-72) years and 58.4% men. Melanoma incidence was higher in men compared with women across all tumor thickness groups. Individuals in lower socioeconomic status quintiles and members of minority groups were more likely to be diagnosed with thicker (T4) tumors (20.7% [169 of 816] among non-Hispanic Black patients, 11.2% [674 of 6042] among Hispanic patients, and 6.3% [10 774 of 170 155] among non-Hispanic White patients). Between 2010 and 2018, there was no significant increase in incidence of cutaneous melanoma across the full population (APC, 0.39%; 95% CI, -0.40% to 1.18%). The incidence of the thickest melanomas (T4, >4.0 mm) increased between 2010 and 2018, with an APC of 3.32% (95% CI, 2.06%-4.60%) overall, 2.50% (95% CI, 1.27%-3.73%) in men, and 4.64% (95% CI, 2.56%-6.75%) in women.In this population-based cohort study, the incidence of the thickest cutaneous melanoma tumors increased from 2010 to 2018, in contrast with the incidence patterns for thinner melanomas. The findings suggest potential stabilization of overall melanoma incidence rates in the US after nearly a century of continuous increase in incidence. Patients with low socioeconomic status and Hispanic patients were more likely to be diagnosed with thick melanoma. The continued rise in incidence of thick melanoma is unlikely to be attributable to overdiagnosis given the stability of thin melanoma rates.

  View details for DOI 10.1001/jamaoncol.2022.0134

  View details for PubMedID 35323844

• Rare germline copy number variants (CNVs) and breast cancer risk. Communications biology Dennis, J., Tyrer, J. P., Walker, L. C., Michailidou, K., Dorling, L., Bolla, M. K., Wang, Q., Ahearn, T. U., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Arndt, V., Aronson, K. J., Freeman, L. E., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bogdanova, N. V., Bojesen, S. E., Brenner, H., Castelao, J. E., Chang-Claude, J., Chenevix-Trench, G., Clarke, C. L., Collée, J. M., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Devilee, P., Dörk, T., Dossus, L., Eliassen, A. H., Eriksson, M., Evans, D. G., Fasching, P. A., Figueroa, J., Fletcher, O., Flyger, H., Fritschi, L., Gabrielson, M., Gago-Dominguez, M., García-Closas, M., Giles, G. G., González-Neira, A., Guénel, P., Hahnen, E., Haiman, C. A., Hall, P., Hollestelle, A., Hoppe, R., Hopper, J. L., Howell, A., Jager, A., Jakubowska, A., John, E. M., Johnson, N., Jones, M. E., Jung, A., Kaaks, R., Keeman, R., Khusnutdinova, E., Kitahara, C. M., Ko, Y. D., Kosma, V. M., Koutros, S., Kraft, P., Kristensen, V. N., Kubelka-Sabit, K., Kurian, A. W., Lacey, J. V., Lambrechts, D., Larson, N. L., Linet, M., Ogrodniczak, A., Mannermaa, A., Manoukian, S., Margolin, S., Mavroudis, D., Milne, R. L., Muranen, T. A., Murphy, R. A., Nevanlinna, H., Olson, J. E., Olsson, H., Park-Simon, T. W., Perou, C. M., Peterlongo, P., Plaseska-Karanfilska, D., Pylkäs, K., Rennert, G., Saloustros, E., Sandler, D. P., Sawyer, E. J., Schmidt, M. K., Schmutzler, R. K., Shibli, R., Smeets, A., Soucy, P., Southey, M. C., Swerdlow, A. J., Tamimi, R. M., Taylor, J. A., Teras, L. R., Terry, M. B., Tomlinson, I., Troester, M. A., Truong, T., Vachon, C. M., Wendt, C., Winqvist, R., Wolk, A., Yang, X. R., Zheng, W., Ziogas, A., Simard, J., Dunning, A. M., Pharoah, P. D., Easton, D. F. 2022; 5 (1): 65

  Abstract

  Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

  View details for DOI 10.1038/s42003-021-02990-6

  View details for PubMedID 35042965

• Polygenic risk modeling for prediction of epithelial ovarian cancer risk. European journal of human genetics : EJHG Dareng, E. O., Tyrer, J. P., Barnes, D. R., Jones, M. R., Yang, X., Aben, K. K., Adank, M. A., Agata, S., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Aravantinos, G., Arun, B. K., Augustinsson, A., Balmaña, J., Bandera, E. V., Barkardottir, R. B., Barrowdale, D., Beckmann, M. W., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Bernardini, M. Q., Bjorge, L., Black, A., Bogdanova, N. V., Bonanni, B., Borg, A., Brenton, J. D., Budzilowska, A., Butzow, R., Buys, S. S., Cai, H., Caligo, M. A., Campbell, I., Cannioto, R., Cassingham, H., Chang-Claude, J., Chanock, S. J., Chen, K., Chiew, Y. E., Chung, W. K., Claes, K. B., Colonna, S., Cook, L. S., Couch, F. J., Daly, M. B., Dao, F., Davies, E., de la Hoya, M., de Putter, R., Dennis, J., DePersia, A., Devilee, P., Diez, O., Ding, Y. C., Doherty, J. A., Domchek, S. M., Dörk, T., du Bois, A., Dürst, M., Eccles, D. M., Eliassen, H. A., Engel, C., Evans, G. D., Fasching, P. A., Flanagan, J. M., Fortner, R. T., Machackova, E., Friedman, E., Ganz, P. A., Garber, J., Gensini, F., Giles, G. G., Glendon, G., Godwin, A. K., Goodman, M. T., Greene, M. H., Gronwald, J., Hahnen, E., Haiman, C. A., Håkansson, N., Hamann, U., Hansen, T. V., Harris, H. R., Hartman, M., Heitz, F., Hildebrandt, M. A., Høgdall, E., Høgdall, C. K., Hopper, J. L., Huang, R. Y., Huff, C., Hulick, P. J., Huntsman, D. G., Imyanitov, E. N., Isaacs, C., Jakubowska, A., James, P. A., Janavicius, R., Jensen, A., Johannsson, O. T., John, E. M., Jones, M. E., Kang, D., Karlan, B. Y., Karnezis, A., Kelemen, L. E., Khusnutdinova, E., Kiemeney, L. A., Kim, B. G., Kjaer, S. K., Komenaka, I., Kupryjanczyk, J., Kurian, A. W., Kwong, A., Lambrechts, D., Larson, M. C., Lazaro, C., Le, N. D., Leslie, G., Lester, J., Lesueur, F., Levine, D. A., Li, L., Li, J., Loud, J. T., Lu, K. H., Lubiński, J., Mai, P. L., Manoukian, S., Marks, J. R., Matsuno, R. K., Matsuo, K., May, T., McGuffog, L., McLaughlin, J. R., McNeish, I. A., Mebirouk, N., Menon, U., Miller, A., Milne, R. L., Minlikeeva, A., Modugno, F., Montagna, M., Moysich, K. B., Munro, E., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Yie, J. N., Nielsen, H. R., Nielsen, F. C., Nikitina-Zake, L., Odunsi, K., Offit, K., Olah, E., Olbrecht, S., Olopade, O. I., Olson, S. H., Olsson, H., Osorio, A., Papi, L., Park, S. K., Parsons, M. T., Pathak, H., Pedersen, I. S., Peixoto, A., Pejovic, T., Perez-Segura, P., Permuth, J. B., Peshkin, B., Peterlongo, P., Piskorz, A., Prokofyeva, D., Radice, P., Rantala, J., Riggan, M. J., Risch, H. A., Rodriguez-Antona, C., Ross, E., Rossing, M. A., Runnebaum, I., Sandler, D. P., Santamariña, M., Soucy, P., Schmutzler, R. K., Setiawan, V. W., Shan, K., Sieh, W., Simard, J., Singer, C. F., Sokolenko, A. P., Song, H., Southey, M. C., Steed, H., Stoppa-Lyonnet, D., Sutphen, R., Swerdlow, A. J., Tan, Y. Y., Teixeira, M. R., Teo, S. H., Terry, K. L., Terry, M. B., Thomassen, M., Thompson, P. J., Thomsen, L. C., Thull, D. L., Tischkowitz, M., Titus, L., Toland, A. E., Torres, D., Trabert, B., Travis, R., Tung, N., Tworoger, S. S., Valen, E., van Altena, A. M., van der Hout, A. H., Van Nieuwenhuysen, E., van Rensburg, E. J., Vega, A., Edwards, D. V., Vierkant, R. A., Wang, F., Wappenschmidt, B., Webb, P. M., Weinberg, C. R., Weitzel, J. N., Wentzensen, N., White, E., Whittemore, A. S., Winham, S. J., Wolk, A., Woo, Y. L., Wu, A. H., Yan, L., Yannoukakos, D., Zavaglia, K. M., Zheng, W., Ziogas, A., Zorn, K. K., Kleibl, Z., Easton, D., Lawrenson, K., DeFazio, A., Sellers, T. A., Ramus, S. J., Pearce, C. L., Monteiro, A. N., Cunningham, J., Goode, E. L., Schildkraut, J. M., Berchuck, A., Chenevix-Trench, G., Gayther, S. A., Antoniou, A. C., Pharoah, P. D. 2022

  Abstract

  Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

  View details for DOI 10.1038/s41431-021-00987-7

  View details for PubMedID 35027648

• Common variants in breast cancer risk loci predispose to distinct tumor subtypes. Breast cancer research : BCR Ahearn, T. U., Zhang, H., Michailidou, K., Milne, R. L., Bolla, M. K., Dennis, J., Dunning, A. M., Lush, M., Wang, Q., Andrulis, I. L., Anton-Culver, H., Arndt, V., Aronson, K. J., Auer, P. L., Augustinsson, A., Baten, A., Becher, H., Behrens, S., Benitez, J., Bermisheva, M., Blomqvist, C., Bojesen, S. E., Bonanni, B., Børresen-Dale, A. L., Brauch, H., Brenner, H., Brooks-Wilson, A., Brüning, T., Burwinkel, B., Buys, S. S., Canzian, F., Castelao, J. E., Chang-Claude, J., Chanock, S. J., Chenevix-Trench, G., Clarke, C. L., Collée, J. M., Cox, A., Cross, S. S., Czene, K., Daly, M. B., Devilee, P., Dörk, T., Dwek, M., Eccles, D. M., Evans, D. G., Fasching, P. A., Figueroa, J., Floris, G., Gago-Dominguez, M., Gapstur, S. M., García-Sáenz, J. A., Gaudet, M. M., Giles, G. G., Goldberg, M. S., González-Neira, A., Alnæs, G. I., Grip, M., Guénel, P., Haiman, C. A., Hall, P., Hamann, U., Harkness, E. F., Heemskerk-Gerritsen, B. A., Holleczek, B., Hollestelle, A., Hooning, M. J., Hoover, R. N., Hopper, J. L., Howell, A., Jakimovska, M., Jakubowska, A., John, E. M., Jones, M. E., Jung, A., Kaaks, R., Kauppila, S., Keeman, R., Khusnutdinova, E., Kitahara, C. M., Ko, Y. D., Koutros, S., Kristensen, V. N., Krüger, U., Kubelka-Sabit, K., Kurian, A. W., Kyriacou, K., Lambrechts, D., Lee, D. G., Lindblom, A., Linet, M., Lissowska, J., Llaneza, A., Lo, W. Y., MacInnis, R. J., Mannermaa, A., Manoochehri, M., Margolin, S., Martinez, M. E., McLean, C., Meindl, A., Menon, U., Nevanlinna, H., Newman, W. G., Nodora, J., Offit, K., Olsson, H., Orr, N., Park-Simon, T. W., Patel, A. V., Peto, J., Pita, G., Plaseska-Karanfilska, D., Prentice, R., Punie, K., Pylkäs, K., Radice, P., Rennert, G., Romero, A., Rüdiger, T., Saloustros, E., Sampson, S., Sandler, D. P., Sawyer, E. J., Schmutzler, R. K., Schoemaker, M. J., Schöttker, B., Sherman, M. E., Shu, X. O., Smichkoska, S., Southey, M. C., Spinelli, J. J., Swerdlow, A. J., Tamimi, R. M., Tapper, W. J., Taylor, J. A., Teras, L. R., Terry, M. B., Torres, D., Troester, M. A., Vachon, C. M., van Deurzen, C. H., van Veen, E. M., Wagner, P., Weinberg, C. R., Wendt, C., Wesseling, J., Winqvist, R., Wolk, A., Yang, X. R., Zheng, W., Couch, F. J., Simard, J., Kraft, P., Easton, D. F., Pharoah, P. D., Schmidt, M. K., García-Closas, M., Chatterjee, N. 2022; 24 (1): 2

  Abstract

  Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions.This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.

  View details for DOI 10.1186/s13058-021-01484-x

  View details for PubMedID 34983606

• Predictors of urinary polycyclic aromatic hydrocarbon metabolites in girls from the San Francisco Bay Area. Environmental research John, E. M., Koo, J., Ingles, S. A., Keegan, T. H., Nguyen, J. T., Thomsen, C., Terry, M. B., Santella, R. M., Nguyen, K., Yan, B. 1800: 112534

  Abstract

  BACKGROUND: Polycyclic aromatic hydrocarbon (PAH) exposures from tobacco smoke, automobile exhaust, grilled or smoked meat and other sources are widespread and are a public health concern, as many are classified as probable carcinogens and suspected endocrine-disrupting chemicals. PAH exposures can be quantified using urinary biomarkers.METHODS: Seven urinary metabolites of naphthalene, fluorene, phenanthrene, and pyrene were measured in two samples collected from girls aged 6-16 years from the San Francisco Bay Area. We used Spearman correlation coefficients (SCC) to assess correlations among metabolite concentrations (corrected for specific gravity) separately in first (n = 359) and last (N = 349) samples, and to assess consistency of measurements in samples collected up to 72 months apart. Using multivariable linear regression, we assessed variation in mean metabolites across categories of participant characteristics and potential outdoor, indoor, and dietary sources of PAH exposures.RESULTS: The detection rate of PAH metabolites was high (4 metabolites in ≥98% of first samples; 5 metabolites in ≥95% of last samples). Correlations were moderate to strong between fluorene, phenanthrene and pyrene metabolites (SCC 0.43-0.82), but weaker between naphthalene and the other metabolites (SCC 0.18-0.36). SCC between metabolites in first and last samples ranged from 0.15 to 0.49. When classifying metabolite concentrations into tertiles based on single samples (first or last samples) vs. the average of the two samples, agreement was moderate to substantial (weighted kappa statistics 0.52-0.65). For specific metabolites, concentrations varied by age, race/ethnicity, and body mass index percentile, as well as by outdoor sources (season of sample collection, street traffic), indoor sources (heating with gas, cigarette smoke), and dietary sources (frequent use of grill, consumption of smoked meat or fish) of PAH exposures.CONCLUSIONS: Urinary PAH exposure was widespread in girls aged 6-16 years and associated with several sources of exposure. Tertile classification of a single urine sample provides reliable PAH exposure ranking.

  View details for DOI 10.1016/j.envres.2021.112534

  View details for PubMedID 34896321

• Mammographic texture features associated with contralateral breast cancer in the WECARE Study. NPJ breast cancer Watt, G. P., Knight, J. A., Lin, C., Lynch, C. F., Malone, K. E., John, E. M., Bernstein, L., Brooks, J. D., Reiner, A. S., Liang, X., Woods, M., Nguyen, T. L., Hopper, J. L., Pike, M. C., Bernstein, J. L. 2021; 7 (1): 146

  Abstract

  To evaluate whether mammographic texture features were associated with second primary contralateral breast cancer (CBC) risk, we created a "texture risk score" using pre-treatment mammograms in a case-control study of 212 women with CBC and 223 controls with unilateral breast cancer. The texture risk score was associated with CBC (odds per adjusted standard deviation=1.25, 95% CI 1.01-1.56) after adjustment for mammographic percent density and confounders. These results support the potential of texture features for CBC risk assessment of breast cancer survivors.

  View details for DOI 10.1038/s41523-021-00354-1

  View details for PubMedID 34845211

• Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants. Genetics in medicine : official journal of the American College of Medical Genetics Li, H., Engel, C., de la Hoya, M., Peterlongo, P., Yannoukakos, D., Livraghi, L., Radice, P., Thomassen, M., Hansen, T. V., Gerdes, A., Nielsen, H. R., Caputo, S. M., Zambelli, A., Borg, A., Solano, A., Thomas, A., Parsons, M. T., Antoniou, A. C., Leslie, G., Yang, X., Chenevix-Trench, G., Caldes, T., Kwong, A., Pedersen, I. S., Lautrup, C. K., John, E. M., Terry, M. B., Hopper, J. L., Southey, M. C., Andrulis, I. L., Tischkowitz, M., Janavicius, R., Boonen, S. E., Kroeldrup, L., Varesco, L., Hamann, U., Vega, A., Palmero, E. I., Garber, J., Montagna, M., Van Asperen, C. J., Foretova, L., Greene, M. H., Selkirk, T., Moller, P., Toland, A. E., Domchek, S. M., James, P. A., Thorne, H., Eccles, D. M., Nielsen, S. M., Manoukian, S., Pasini, B., Caligo, M. A., Lazaro, C., Kirk, J., Wappenschmidt, B., Spurdle, A. B., Couch, F. J., Schmutzler, R., Goldgar, D. E., ENIGMA Consortium, CIMBA Consortium 1800

  Abstract

  PURPOSE: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants.METHODS: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis.RESULTS: Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR]= 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P= .01), particularly for missense PVs in the BRCA1 C-terminal domain (HR= 2.8 [1.4-5.6]; P= .005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs.CONCLUSION: These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes.

  View details for DOI 10.1016/j.gim.2021.08.016

  View details for PubMedID 34906479

• Genetic Insights Into Biological Mechanisms Governing Human Ovarian Ageing OBSTETRICAL & GYNECOLOGICAL SURVEY Ruth, K. S., Day, F. R., Hussain, J. 2021; 76 (11): 678-679

  View details for DOI 10.1097/01.ogx.0000800176.90737.65

  View details for Web of Science ID 000732787100013

• Cumulative menstrual months and breast cancer risk by hormone receptor status and ethnicity: The Breast Cancer Etiology in Minorities (BEM) Study. International journal of cancer Cole, S. E., John, E. M., Hines, L. M., Phipps, A. I., Koo, J., Ingles, S. A., Baumgartner, K. B., Slattery, M. L., McKean-Cowden, R., Wu, A. H. 2021

  Abstract

  Reproductive and hormonal factors may influence breast cancer risk via endogenous estrogen exposure. Cumulative menstrual months (CMM) can be used as a surrogate measure of this exposure. Using harmonized data from four population-based breast cancer studies (7,284 cases and 7,242 controls), we examined ethnicity-specific associations between CMM and breast cancer risk using logistic regression, adjusting for menopausal status and other risk factors. Higher CMM was associated with increased breast cancer risk in non-Hispanic Whites, Hispanics and Asian Americans regardless of menopausal status (all FDR adjusted p trends=0.0004), but not in African Americans. In premenopausal African Americans, there was a suggestive trend of lower risk with higher CMM. Stratification by body mass index (BMI) among premenopausal African American women showed a nonsignificant positive association with CMM in non-obese (BMI <30 kg/m2 ) women and a significant inverse association in obese women (OR per 50 CMM=0.56, 95% CI 0.37-0.87, Ptrend =0.03). Risk patterns were similar for hormone receptor positive (HR+; ER+ or PR+) breast cancer; a positive association was found in all premenopausal and postmenopausal ethnic groups except in African Americans. HR- (ER- and PR-) breast cancer was not associated with CMM in all groups combined, except for a suggestive positive association among premenopausal Asian Americans (OR per 50 CMM=1.33, P=0.07). In summary, these results add to the accumulating evidence that established reproductive and hormonal factors impact breast cancer risk differently in African American women compared to other ethnic groups, and also differently for HR- breast cancer than HR+ breast cancer. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ijc.33791

  View details for PubMedID 34469597

• Coronary Artery Disease in Young Women After Radiation Therapy for Breast Cancer: The WECARE Study. JACC. CardioOncology Carlson, L. E., Watt, G. P., Tonorezos, E. S., Chow, E. J., Yu, A. F., Woods, M., Lynch, C. F., John, E. M., Mellemkjӕr, L., Brooks, J. D., Knight, J. A., Reiner, A. S., Liang, X., Smith, S. A., Bernstein, L., Dauer, L. T., Cervino, L. I., Howell, R. M., Shore, R. E., Boice, J. D., Bernstein, J. L., WECARE Study Collaborative Group, Bernstein, J. L., Capanu, M., Orlow, I., Robson, M., Olsen, J. H., Malone, K. E., Stovall, M., Blackmore, K., Harris, I., Langballe, R., O'Brien, C., Weathers, R., West, M., Hunter, L., Goldstein, J., Ramos, E. 2021; 3 (3): 381-392

  Abstract

  Background: Radiation therapy (RT) for breast cancer increases risk of coronary artery disease (CAD). Women treated for left- vs right-sided breast cancer receive greater heart radiation exposure, which may further increase this risk. The risk of radiation-associated CAD specifically among younger breast cancer survivors is not well defined.Objectives: The purpose of this study was to report CAD risk among participants in the Women's Environmental Cancer and Radiation Epidemiology Study.Methods: A total of 1,583 women who were<55 years of age when diagnosed with breast cancer between 1985 and 2008 completed a cardiovascular health questionnaire. Risk of radiation-associated CAD was evaluated by comparing women treated with left-sided RT with women treated with right-sided RT using multivariable Cox proportional hazards models. Effect modification by treatment and cardiovascular risk factors was examined.Results: In total, 517 women who did not receive RT and 94 women who had a pre-existing cardiovascular disease diagnosis were excluded, leaving 972 women eligible for analysis. Their median follow-up time was 14 years (range 1-29 years). The 27.5-year cumulative incidences of CAD for women receiving left- vs right-sided RT were 10.5% and 5.8%, respectively (P = 0.010). The corresponding HR of CAD for left- vs right-sided RT in the multivariable Cox model was 2.5 (95% CI: 1.3-4.7). There was no statistically significant effect modification by any factor evaluated.Conclusions: Young women treated with RT for left-sided breast cancer had over twice the risk of CAD compared with women treated with RT for right-sided breast cancer. Laterality of RT is independently associated with an increased risk of CAD and should be considered in survivorship care of younger breast cancer patients.

  View details for DOI 10.1016/j.jaccao.2021.07.008

  View details for PubMedID 34604798

• Cross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women. Nature communications Adedokun, B., Du, Z., Gao, G., Ahearn, T. U., Lunetta, K. L., Zirpoli, G., Figueroa, J., John, E. M., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Deming-Halverson, S. L., Rodriguez-Gil, J. L., Yao, S., Ogundiran, T. O., Ojengbede, O., Blot, W., Troester, M. A., Nathanson, K. L., Hennis, A., Nemesure, B., Ambs, S., Fiorica, P. N., Sucheston-Campbell, L. E., Bensen, J. T., Kushi, L. H., Torres-Mejia, G., Hu, D., Fejerman, L., Bolla, M. K., Dennis, J., Dunning, A. M., Easton, D. F., Michailidou, K., Pharoah, P. D., Wang, Q., Sandler, D. P., Taylor, J. A., O'Brien, K. M., Kitahara, C. M., Falusi, A. G., Babalola, C., Yarney, J., Awuah, B., Addai-Wiafe, B., GBHS Study Team, Chanock, S. J., Olshan, A. F., Ambrosone, C. B., Conti, D. V., Ziv, E., Olopade, O. I., Garcia-Closas, M., Palmer, J. R., Haiman, C. A., Huo, D. 2021; 12 (1): 4198

  Abstract

  Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P<0.05 from African ancestry GWAS meta-analysis (9241 cases and 10193 controls), then meta-analyze with European ancestry GWAS data (122977 cases and 105974 controls) from the Breast Cancer Association Consortium. The approach identifies four loci for overall breast cancer risk [1p13.3, 5q31.1, 15q24 (two independent signals), and 15q26.3] and two loci for estrogen receptor-negative disease (1q41 and 7q11.23) at genome-wide significance. Four of the index single nucleotide polymorphisms (SNPs) lie within introns of genes (KCNK2, C5orf56, SCAMP2, and SIN3A) and the other index SNPs are located close to GSTM4, AMPD2, CASTOR2, and RP11-168G16.2. Here we present risk loci with consistent direction of associations in African and European descendants. The study suggests that replication across multiple ancestry populations can help improve the understanding of breast cancer genetics and identify causal variants.

  View details for DOI 10.1038/s41467-021-24327-x

  View details for PubMedID 34234117

• A competing risks model with binary time varying covariates for estimation of breast cancer risks in BRCA1 families. Statistical methods in medical research Choi, Y., Jung, H., Buys, S., Daly, M., John, E. M., Hopper, J., Andrulis, I., Terry, M. B., Briollais, L. 2021: 9622802211008945

  Abstract

  Mammographic screening and prophylactic surgery such as risk-reducing salpingo oophorectomy can potentially reduce breast cancer risks among mutation carriers of BRCA families. The evaluation of these interventions is usually complicated by the fact that their effects on breast cancer may change over time and by the presence of competing risks. We introduce a correlated competing risks model to model breast and ovarian cancer risks within BRCA1 families that accounts for time-varying covariates. Different parametric forms for the effects of time-varying covariates are proposed for more flexibility and a correlated gamma frailty model is specified to account for the correlated competing events.We also introduce a new ascertainment correction approach that accounts for the selection of families through probands affected with either breast or ovarian cancer, or unaffected. Our simulation studies demonstrate the good performances of our proposed approach in terms of bias and precision of the estimators of model parameters and cause-specific penetrances over different levels of familial correlations. We applied our new approach to 498 BRCA1 mutation carrier families recruited through the Breast Cancer Family Registry. Our results demonstrate the importance of the functional form of the time-varying covariate effect when assessing the role of risk-reducing salpingo oophorectomy on breast cancer. In particular, under the best fitting time-varying covariate model, the overall effect of risk-reducing salpingo oophorectomy on breast cancer risk was statistically significant in women with BRCA1 mutation.

  View details for DOI 10.1177/09622802211008945

  View details for PubMedID 34232831

• Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24. Prostate cancer and prostatic diseases Karunamuni, R. A., Huynh-Le, M., Fan, C. C., Thompson, W., Lui, A., Martinez, M. E., Rose, B. S., Mahal, B., Eeles, R. A., Kote-Jarai, Z., Muir, K., Lophatananon, A., UKGPCS Collaborators, Tangen, C. M., Goodman, P. J., Thompson, I. M., Blot, W. J., Zheng, W., Kibel, A. S., Drake, B. F., Cussenot, O., Cancel-Tassin, G., Menegaux, F., Truong, T., Park, J. Y., Lin, H., Taylor, J. A., Bensen, J. T., Mohler, J. L., Fontham, E. T., Multigner, L., Blanchet, P., Brureau, L., Romana, M., Leach, R. J., John, E. M., Fowke, J. H., Bush, W. S., Aldrich, M. C., Crawford, D. C., Cullen, J., Petrovics, G., Parent, M., Hu, J. J., Sanderson, M., PRACTICAL Consortium, Mills, I. G., Andreassen, O. A., Dale, A. M., Seibert, T. M. 2021

  Abstract

  BACKGROUND: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ.MATERIALS AND METHODS: Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC.RESULTS: CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings.CONCLUSION: We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.

  View details for DOI 10.1038/s41391-021-00403-7

  View details for PubMedID 34127801

• The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant. Genetics in medicine : official journal of the American College of Medical Genetics Lakeman, I. M., van den Broek, A. J., Vos, J. A., Barnes, D. R., Adlard, J., Andrulis, I. L., Arason, A., Arnold, N., Arun, B. K., Balmana, J., Barrowdale, D., Benitez, J., Borg, A., Caldes, T., Caligo, M. A., Chung, W. K., Claes, K. B., GEMO Study Collaborators, EMBRACE Collaborators, Collee, J. M., Couch, F. J., Daly, M. B., Dennis, J., Dhawan, M., Domchek, S. M., Eeles, R., Engel, C., Evans, D. G., Feliubadalo, L., Foretova, L., Friedman, E., Frost, D., Ganz, P. A., Garber, J., Gayther, S. A., Gerdes, A., Godwin, A. K., Goldgar, D. E., Hahnen, E., Hake, C. R., Hamann, U., Hogervorst, F. B., Hooning, M. J., Hopper, J. L., Hulick, P. J., Imyanitov, E. N., OCGN Investigators, HEBON Investigators, KconFab Investigators, Isaacs, C., Izatt, L., Jakubowska, A., James, P. A., Janavicius, R., Jensen, U. B., Jiao, Y., John, E. M., Joseph, V., Karlan, B. Y., Kets, C. M., Konstantopoulou, I., Kwong, A., Legrand, C., Leslie, G., Lesueur, F., Loud, J. T., Lubinski, J., Manoukian, S., McGuffog, L., Miller, A., Gomes, D. M., Montagna, M., Mouret-Fourme, E., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Yie, J. N., Olah, E., Olopade, O. I., Park, S. K., Parsons, M. T., Peterlongo, P., Piedmonte, M., Radice, P., Rantala, J., Rennert, G., Risch, H. A., Schmutzler, R. K., Sharma, P., Simard, J., Singer, C. F., Stadler, Z., Stoppa-Lyonnet, D., Sutter, C., Tan, Y. Y., Teixeira, M. R., Teo, S. H., Teule, A., Thomassen, M., Thull, D. L., Tischkowitz, M., Toland, A. E., Tung, N., van Rensburg, E. J., Vega, A., Wappenschmidt, B., Devilee, P., van Asperen, C. J., Bernstein, J. L., Offit, K., Easton, D. F., Rookus, M. A., Chenevix-Trench, G., Antoniou, A. C., Robson, M., Schmidt, M. K., Barouk-Simonet, E., Belotti, M., Berthet, P., Bignon, Y., Bonadona, V., Bressac-de Paillerets, B., Buecher, B., Caputo, S., Caron, O., Castera, L., Caux-Moncoutier, V., Colas, C., Collonge-Rame, M., Coupier, I., de Pauw, A., Delnatte, C., Elan, C., Faivre, L., Ferrer, S. F., Gauthier-Villars, M., Gesta, P., Giraud, S., Golmard, L., Houdayer, C., Lasset, C., Laurent, M., Leroux, D., Longy, M., Mari, V., Mazoyer, S., Mebirouk, N., Mortemousque, I., Prieur, F., Pujol, P., Saule, C., Schuster, H., Sevenet, N., Sobol, H., Sokolowska, J., Venat-Bouvet, L., Ahmed, M., Barwell, J., Brady, A., Brennan, P., Brewer, C., Cook, J., Davidson, R., Donaldson, A., Dunning, A. M., Eason, J., Eccles, D. M., Gregory, H., Hanson, H., Harrington, P. A., Henderson, A., Hodgson, S., Kennedy, M. J., Lalloo, F., Miller, C., Morrison, P. J., Ong, K., O'Shaughnessy-Kirwan, A., Perkins, J., Porteous, M. E., Rogers, M. T., Side, L. E., Snape, K., Walker, L., Glendon, G., Mulligan, A. M., van Asperen, C. J., Aalfs, C. M., Adank, M. A., Ausems, M. G., Blok, M. J., Gomez Garcia, E. B., Heemskerk-Gerritsen, B. A., Hollestelle, A., Jager, A., Koppert, L. B., Koudijs, M., Kriege, M., Meijers-Heijboer, H. E., Mensenkamp, A. R., Mooij, T. M., Oosterwijk, J. C., van den Ouweland, A. M., van der Baan, F. H., van der Hout, A. H., van der Kolk, L. E., van der Luijt, R. B., van Deurzen, C. H., van Doorn, H. C., van Engelen, K., van Hest, L. P., van Os, T. A., Verhoef, S., Vogel, M. J., Wijnen, J. T., Beesley, J., Fox, S., Holland, H., Phillips, K., Spurdle, A. B. 2021

  Abstract

  PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.METHODS: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1=6,591 with 1,402 prevalent CBC cases; BRCA2=4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk.RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD=1.12, 95% confidence interval (CI) (1.06-1.18), C-index=0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR=1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC

  View details for DOI 10.1038/s41436-021-01198-7

  View details for PubMedID 34113011

• Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers. Nature communications Coignard, J., Lush, M., Beesley, J., O'Mara, T. A., Dennis, J., Tyrer, J. P., Barnes, D. R., McGuffog, L., Leslie, G., Bolla, M. K., Adank, M. A., Agata, S., Ahearn, T., Aittomaki, K., Andrulis, I. L., Anton-Culver, H., Arndt, V., Arnold, N., Aronson, K. J., Arun, B. K., Augustinsson, A., Azzollini, J., Barrowdale, D., Baynes, C., Becher, H., Bermisheva, M., Bernstein, L., Bialkowska, K., Blomqvist, C., Bojesen, S. E., Bonanni, B., Borg, A., Brauch, H., Brenner, H., Burwinkel, B., Buys, S. S., Caldes, T., Caligo, M. A., Campa, D., Carter, B. D., Castelao, J. E., Chang-Claude, J., Chanock, S. J., Chung, W. K., Claes, K. B., Clarke, C. L., GEMO Study Collaborators, EMBRACE Collaborators, Collee, J. M., Conroy, D. M., Czene, K., Daly, M. B., Devilee, P., Diez, O., Ding, Y. C., Domchek, S. M., Dork, T., Dos-Santos-Silva, I., Dunning, A. M., Dwek, M., Eccles, D. M., Eliassen, A. H., Engel, C., Eriksson, M., Evans, D. G., Fasching, P. A., Flyger, H., Fostira, F., Friedman, E., Fritschi, L., Frost, D., Gago-Dominguez, M., Gapstur, S. M., Garber, J., Garcia-Barberan, V., Garcia-Closas, M., Garcia-Saenz, J. A., Gaudet, M. M., Gayther, S. A., Gehrig, A., Georgoulias, V., Giles, G. G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Greene, M. H., Guenel, P., Haeberle, L., Hahnen, E., Haiman, C. A., Hakansson, N., Hall, P., Hamann, U., Harrington, P. A., Hart, S. N., He, W., Hogervorst, F. B., Hollestelle, A., Hopper, J. L., Horcasitas, D. J., Hulick, P. J., Hunter, D. J., Imyanitov, E. N., KConFab Investigators, HEBON Investigators, ABCTB Investigators, Jager, A., Jakubowska, A., James, P. A., Jensen, U. B., John, E. M., Jones, M. E., Kaaks, R., Kapoor, P. M., Karlan, B. Y., Keeman, R., Khusnutdinova, E., Kiiski, J. I., Ko, Y., Kosma, V., Kraft, P., Kurian, A. W., Laitman, Y., Lambrechts, D., Le Marchand, L., Lester, J., Lesueur, F., Lindstrom, T., Lopez-Fernandez, A., Loud, J. T., Luccarini, C., Mannermaa, A., Manoukian, S., Margolin, S., Martens, J. W., Mebirouk, N., Meindl, A., Miller, A., Milne, R. L., Montagna, M., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Nielsen, F. C., O'Brien, K. M., Olopade, O. I., Olson, J. E., Olsson, H., Osorio, A., Ottini, L., Park-Simon, T., Parsons, M. T., Pedersen, I. S., Peshkin, B., Peterlongo, P., Peto, J., Pharoah, P. D., Phillips, K., Polley, E. C., Poppe, B., Presneau, N., Pujana, M. A., Punie, K., Radice, P., Rantala, J., Rashid, M. U., Rennert, G., Rennert, H. S., Robson, M., Romero, A., Rossing, M., Saloustros, E., Sandler, D. P., Santella, R., Scheuner, M. T., Schmidt, M. K., Schmidt, G., Scott, C., Sharma, P., Soucy, P., Southey, M. C., Spinelli, J. J., Steinsnyder, Z., Stone, J., Stoppa-Lyonnet, D., Swerdlow, A., Tamimi, R. M., Tapper, W. J., Taylor, J. A., Terry, M. B., Teule, A., Thull, D. L., Tischkowitz, M., Toland, A. E., Torres, D., Trainer, A. H., Truong, T., Tung, N., Vachon, C. M., Vega, A., Vijai, J., Wang, Q., Wappenschmidt, B., Weinberg, C. R., Weitzel, J. N., Wendt, C., Wolk, A., Yadav, S., Yang, X. R., Yannoukakos, D., Zheng, W., Ziogas, A., Zorn, K. K., Park, S. K., Thomassen, M., Offit, K., Schmutzler, R. K., Couch, F. J., Simard, J., Chenevix-Trench, G., Easton, D. F., Andrieu, N., Antoniou, A. C., Bertrand, O., Caputo, S., Dupre, A., Le Mentec, M., Belotti, M., Birot, A., Buecher, B., Fourme, E., Gauthier-Villars, M., Golmard, L., Houdayer, C., Moncoutier, V., de Pauw, A., Saule, C., Sinilnikova, O., Mazoyer, S., Damiola, F., Barjhoux, L., Verny-Pierre, C., Leone, M., Boutry-Kryza, N., Calender, A., Giraud, S., Caron, O., Guillaud-Bataille, M., Bressac-de-Paillerets, B., Bignon, Y. J., Uhrhammer, N., Lasset, C., Bonadona, V., Berthet, P., Vaur, D., Castera, L., Noguchi, T., Popovici, C., Sobol, H., Bourdon, V., Noguchi, T., Remenieras, A., Nogues, C., Coupier, I., Pujol, P., Dumont, A., Revillion, F., Adenis, C., Muller, D., Barouk-Simonet, E., Bonnet, F., Bubien, V., Sevenet, N., Longy, M., Toulas, C., Guimbaud, R., Gladieff, L., Feillel, V., Leroux, D., Dreyfus, H., Rebischung, C., Peysselon, M., Coron, F., Faivre, L., Baurand, A., Jacquot, C., Bertolone, G., Lizard, S., Prieur, F., Lebrun, M., Kientz, C., Ferrer, S. F., Mari, V., Venat-Bouvet, L., Delnatte, C., Bezieau, S., Mortemousque, I., Coulet, F., Colas, C., Soubrier, F., Warcoin, M., Sokolowska, J., Bronner, M., Collonge-Rame, M., Damette, A., Gesta, P., Lallaoui, H., Chiesa, J., Molina-Gomes, D., Ingster, O., Gregory, H., Miedzybrodzka, Z., Morrison, P. J., Ong, K., Donaldson, A., Rogers, M. T., Kennedy, M. J., Porteous, M. E., Brewer, C., Davidson, R., Izatt, L., Brady, A., Barwell, J., Adlard, J., Foo, C., Lalloo, F., Side, L. E., Eason, J., Henderson, A., Walker, L., Eeles, R. A., Cook, J., Snape, K., Eccles, D., Murray, A., McCann, E., Fox, S., Campbell, I., Spurdle, A., Webb, P., de Fazio, A., Tassell, M., Kirk, J., Lindeman, G., Price, M., Southey, M., Milne, R., Deb, S., Bowtell, D., van der Hout, A. H., van den Ouweland, A. M., Mensenkamp, A. R., van Deurzen, C. H., Kets, C. M., Seynaeve, C., van Asperen, C. J., Aalfs, C. M., Gomez Garcia, E. B., van Leeuwen, F. E., de Bock, G. H., Meijers-Heijboer, H. E., Obdeijn, I. M., Collee, J. M., Gille, J. J., Oosterwijk, J. C., Wijnen, J. T., van der Kolk, L. E., Hooning, M. J., Ausems, M. G., Mourits, M. J., Blok, M. J., Rookus, M. A., Adank, M. A., van der Luijt, R. B., van Cronenburg, T. C., van der Pol, C. C., Russell, N. S., Siesling, S., Overbeek, L., Wijnands, R., de Lange, J. L., Clarke, C., Graham, D., Sachchithananthan, M., Marsh, D., Scott, R., Baxter, R., Yip, D., Carpenter, J., Davis, A., Pathmanathan, N., Simpson, P. 2021; 12 (1): 2986

  Abstract

  A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4.

  View details for DOI 10.1038/s41467-021-23162-4

  View details for PubMedID 33990587

• Smoking, Radiation Therapy, and Contralateral Breast Cancer Risk in Young Women. Journal of the National Cancer Institute Reiner, A. S., Watt, G. P., John, E. M., Lynch, C. F., Brooks, J. D., Mellemkjar, L., Boice, J. D., Knight, J. A., Concannon, P., Smith, S. A., Liang, X., Woods, M., Shore, R., Malone, K. E., Bernstein, L., WECARE Collaborative Study Group, Bernstein, J. L. 2021

  Abstract

  Evidence is mounting that cigarette smoking contributes to second primary contralateral breast cancer (CBC) risk. Whether radiation therapy (RT) interacts with smoking to modify this risk is unknown. In this multicenter, individually-matched case-control study, we examined the association between RT, smoking, and CBC risk. The study included 1,521 CBC cases and 2,212 controls with unilateral breast cancer, all diagnosed with first invasive breast cancer between 1985-2008 at age <55years. Absorbed radiation doses to contralateral breast regions were estimated with thermoluminescent dosimeters in tissue-equivalent anthropomorphic phantoms and smoking history was collected by interview. Rate ratios (RRs) and 95% confidence intervals (CIs) for CBC risk were estimated by multivariable conditional logistic regression. There was no interaction between any measure of smoking with RT to increase CBC risk (eg, the interaction of continuous RT dose with smoking at first breast cancer diagnosis [ever/never]: RR=1.00, 95% CI=0.89-1.14; continuous RT dose with years smoked: RR=1.00, 95% CI=0.99-1.01; and continuous RT dose with lifetime pack-years: RR=1.00, 95% CI=0.99-1.01). There was no evidence that RT further increased CBC risk in young women with first primary breast cancer who were current smokers or had smoking history.

  View details for DOI 10.1093/jnci/djab047

  View details for PubMedID 33779721

• Evaluating Polygenic Risk Scores for Breast Cancer in Women of African Ancestry. Journal of the National Cancer Institute Du, Z., Gao, G., Adedokun, B., Ahearn, T., Lunetta, K. L., Zirpoli, G., Troester, M. A., Ruiz-Narvaez, E. A., Haddad, S. A., Pal Choudhury, P., Figueroa, J., John, E. M., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Mancuso, N., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Yao, S., Ogundiran, T. O., Ojengbe, O., Bolla, M. K., Dennis, J., Dunning, A. M., Easton, D. F., Michailidou, K., Pharoah, P. D., Sandler, D. P., Taylor, J. A., Wang, Q., Weinberg, C. R., Kitahara, C. M., Blot, W., Nathanson, K. L., Hennis, A., Nemesure, B., Ambs, S., Sucheston-Campbell, L. E., Bensen, J. T., Chanock, S. J., Olshan, A. F., Ambrosone, C. B., Olopade, O. I., Yarney, J., Awuah, B., Addai Wiafe, B., Conti, D. V., GBHS Study Team, Palmer, J. R., Garcia-Closas, M., Huo, D., Haiman, C. A. 2021

  Abstract

  BACKGROUND: Polygenic risk scores (PRS) have been demonstrated to identify women of European, Asian and Latino ancestry at elevated risk of developing breast cancer (BC). We evaluated the performance of existing PRSs trained in European ancestry populations among women of African ancestry.METHODS: We assembled genotype data for women of African ancestry, including 9,241 cases and 10,193 controls. We evaluated associations of 179- and 313-variant PRSs with overall and subtype-specific BC risk. PRS discriminatory accuracy was assessed using area under the receiver operating characteristic curve (AUC). We also evaluated a recalibrated PRS, replacing the index variant with variants in each region that better captured risk in women of African ancestry, and estimated lifetime absolute risk of BC in African Americans by PRS category.RESULTS: For overall BC, the odds ratios per standard deviation of PRS313 was 1.27 (95%CI = 1.23 to 1.31), with an AUC of 0.571 (95%CI = 0.562 to 0.579). Compared to women with average risk (40th-60th PRS percentile), women in the top decile of PRS313 had a 1.54-fold increased risk (95% CI=1.38 to 1.72). By age 85 years, the absolute risk of overall BC was 19.6% for African American women in the top 1% of PRS313 and 6.7% for those in the lowest 1%. The recalibrated PRS did not improve BC risk prediction.CONCLUSION: The PRSs stratify BC risk in women of African ancestry, with attenuated performance compared to that reported in European, Asian and Latina populations. Future work is needed to improve BC risk stratification for women of African ancestry.

  View details for DOI 10.1093/jnci/djab050

  View details for PubMedID 33769540

• Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry. American journal of human genetics Graff, M., Justice, A. E., Young, K. L., Marouli, E., Zhang, X., Fine, R. S., Lim, E., Buchanan, V., Rand, K., Feitosa, M. F., Wojczynski, M. K., Yanek, L. R., Shao, Y., Rohde, R., Adeyemo, A. A., Aldrich, M. C., Allison, M. A., Ambrosone, C. B., Ambs, S., Amos, C., Arnett, D. K., Atwood, L., Bandera, E. V., Bartz, T., Becker, D. M., Berndt, S. I., Bernstein, L., Bielak, L. F., Blot, W. J., Bottinger, E. P., Bowden, D. W., Bradfield, J. P., Brody, J. A., Broeckel, U., Burke, G., Cade, B. E., Cai, Q., Caporaso, N., Carlson, C., Carpten, J., Casey, G., Chanock, S. J., Chen, G., Chen, M., Chen, Y. I., Chen, W., Chesi, A., Chiang, C. W., Chu, L., Coetzee, G. A., Conti, D. V., Cooper, R. S., Cushman, M., Demerath, E., Deming, S. L., Dimitrov, L., Ding, J., Diver, W. R., Duan, Q., Evans, M. K., Falusi, A. G., Faul, J. D., Fornage, M., Fox, C., Freedman, B. I., Garcia, M., Gillanders, E. M., Goodman, P., Gottesman, O., Grant, S. F., Guo, X., Hakonarson, H., Haritunians, T., Harris, T. B., Harris, C. C., Henderson, B. E., Hennis, A., Hernandez, D. G., Hirschhorn, J. N., McNeill, L. H., Howard, T. D., Howard, B., Hsing, A. W., Hsu, Y. H., Hu, J. J., Huff, C. D., Huo, D., Ingles, S. A., Irvin, M. R., John, E. M., Johnson, K. C., Jordan, J. M., Kabagambe, E. K., Kang, S. J., Kardia, S. L., Keating, B. J., Kittles, R. A., Klein, E. A., Kolb, S., Kolonel, L. N., Kooperberg, C., Kuller, L., Kutlar, A., Lange, L., Langefeld, C. D., Le Marchand, L., Leonard, H., Lettre, G., Levin, A. M., Li, Y., Li, J., Liu, Y., Liu, Y., Liu, S., Lohman, K., Lotay, V., Lu, Y., Maixner, W., Manson, J. E., McKnight, B., Meng, Y., Monda, K. L., Monroe, K., Moore, J. H., Mosley, T. H., Mudgal, P., Murphy, A. B., Nadukuru, R., Nalls, M. A., Nathanson, K. L., Nayak, U., N'Diaye, A., Nemesure, B., Neslund-Dudas, C., Neuhouser, M. L., Nyante, S., Ochs-Balcom, H., Ogundiran, T. O., Ogunniyi, A., Ojengbede, O., Okut, H., Olopade, O. I., Olshan, A., Padhukasahasram, B., Palmer, J., Palmer, C. D., Palmer, N. D., Papanicolaou, G., Patel, S. R., Pettaway, C. A., Peyser, P. A., Press, M. F., Rao, D. C., Rasmussen-Torvik, L. J., Redline, S., Reiner, A. P., Rhie, S. K., Rodriguez-Gil, J. L., Rotimi, C. N., Rotter, J. I., Ruiz-Narvaez, E. A., Rybicki, B. A., Salako, B., Sale, M. M., Sanderson, M., Schadt, E., Schreiner, P. J., Schurmann, C., Schwartz, A. G., Shriner, D. A., Signorello, L. B., Singleton, A. B., Siscovick, D. S., Smith, J. A., Smith, S., Speliotes, E., Spitz, M., Stanford, J. L., Stevens, V. L., Stram, A., Strom, S. S., Sucheston, L., Sun, Y. V., Tajuddin, S. M., Taylor, H., Taylor, K., Tayo, B. O., Thun, M. J., Tucker, M. A., Vaidya, D., Van Den Berg, D. J., Vedantam, S., Vitolins, M., Wang, Z., Ware, E. B., Wassertheil-Smoller, S., Weir, D. R., Wiencke, J. K., Williams, S. M., Williams, L. K., Wilson, J. G., Witte, J. S., Wrensch, M., Wu, X., Yao, J., Zakai, N., Zanetti, K., Zemel, B. S., Zhao, W., Zhao, J. H., Zheng, W., Zhi, D., Zhou, J., Zhu, X., Ziegler, R. G., Zmuda, J., Zonderman, A. B., Psaty, B. M., Borecki, I. B., Cupples, L. A., Liu, C., Haiman, C. A., Loos, R., Ng, M. C., North, K. E. 2021

  Abstract

  Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

  View details for DOI 10.1016/j.ajhg.2021.02.011

  View details for PubMedID 33713608

• Race, Ethnicity and Risk of Second Primary Contralateral Breast Cancer in the United States. International journal of cancer Watt, G. P., John, E. M., Bandera, E. V., Malone, K. E., Lynch, C. F., Palmer, J. R., Knight, J. A., Troester, M. A., Bernstein, J. L. 2021

  Abstract

  Breast cancer survivors have a high risk of a second primary contralateral breast cancer (CBC), but there are few studies of CBC risk in minority populations. We examined whether the incidence and risk factors for CBC differed by race/ethnicity in the United States. Women with a first invasive stage I-IIB breast cancer diagnosis at ages 20-74years between 2000 and 2015 in the Surveillance, Epidemiology, and End Results Program (SEER) 18 registries were followed through 2016 for a diagnosis of invasive CBC ≥1 year after the first breast cancer diagnosis. We used cause-specific Cox proportional hazards models to test the association between race/ethnicity and CBC, adjusting for age, hormone receptor status, radiation therapy, chemotherapy, and stage at first diagnosis, and evaluated the impact of contralateral prophylactic mastectomy, socioeconomic status, and insurance status on the association. After a median follow-up of 5.9years, 9,247 women (2.0%) were diagnosed with CBC. Relative to non-Hispanic (NH) White women, CBC risk was increased in NH Black women (hazard ratio=1.44, 95% CI 1.35-1.54) and Hispanic women (1.11, 95% CI 1.02-1.20), with the largest differences among women diagnosed at younger ages. Adjustment for contralateral prophylactic mastectomy, socioeconomic status, and health insurance did not explain the associations. Therefore, non-Hispanic Black and Hispanic women have an increased risk of CBC that is not explained by clinical or socioeconomic factors collected in SEER. Large studies of diverse breast cancer survivors with detailed data on treatment delivery and adherence are needed to inform interventions to reduce this disparity. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ijc.33501

  View details for PubMedID 33544892

• Publisher Correction: Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction. Nature genetics Conti, D. V., Darst, B. F., Moss, L. C., Saunders, E. J., Sheng, X., Chou, A., Schumacher, F. R., Olama, A. A., Benlloch, S., Dadaev, T., Brook, M. N., Sahimi, A., Hoffmann, T. J., Takahashi, A., Matsuda, K., Momozawa, Y., Fujita, M., Muir, K., Lophatananon, A., Wan, P., Le Marchand, L., Wilkens, L. R., Stevens, V. L., Gapstur, S. M., Carter, B. D., Schleutker, J., Tammela, T. L., Sipeky, C., Auvinen, A., Giles, G. G., Southey, M. C., MacInnis, R. J., Cybulski, C., Wokolorczyk, D., Lubinski, J., Neal, D. E., Donovan, J. L., Hamdy, F. C., Martin, R. M., Nordestgaard, B. G., Nielsen, S. F., Weischer, M., Bojesen, S. E., Roder, M. A., Iversen, P., Batra, J., Chambers, S., Moya, L., Horvath, L., Clements, J. A., Tilley, W., Risbridger, G. P., Gronberg, H., Aly, M., Szulkin, R., Eklund, M., Nordstrom, T., Pashayan, N., Dunning, A. M., Ghoussaini, M., Travis, R. C., Key, T. J., Riboli, E., Park, J. Y., Sellers, T. A., Lin, H., Albanes, D., Weinstein, S. J., Mucci, L. A., Giovannucci, E., Lindstrom, S., Kraft, P., Hunter, D. J., Penney, K. L., Turman, C., Tangen, C. M., Goodman, P. J., Thompson, I. M., Hamilton, R. J., Fleshner, N. E., Finelli, A., Parent, M., Stanford, J. L., Ostrander, E. A., Geybels, M. S., Koutros, S., Freeman, L. E., Stampfer, M., Wolk, A., Hakansson, N., Andriole, G. L., Hoover, R. N., Machiela, M. J., Sorensen, K. D., Borre, M., Blot, W. J., Zheng, W., Yeboah, E. D., Mensah, J. E., Lu, Y., Zhang, H., Feng, N., Mao, X., Wu, Y., Zhao, S., Sun, Z., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., West, C. M., Burnet, N., Barnett, G., Maier, C., Schnoeller, T., Luedeke, M., Kibel, A. S., Drake, B. F., Cussenot, O., Cancel-Tassin, G., Menegaux, F., Truong, T., Koudou, Y. A., John, E. M., Grindedal, E. M., Maehle, L., Khaw, K., Ingles, S. A., Stern, M. C., Vega, A., Gomez-Caamano, A., Fachal, L., Rosenstein, B. S., Kerns, S. L., Ostrer, H., Teixeira, M. R., Paulo, P., Brandao, A., Watya, S., Lubwama, A., Bensen, J. T., Fontham, E. T., Mohler, J., Taylor, J. A., Kogevinas, M., Llorca, J., Castano-Vinyals, G., Cannon-Albright, L., Teerlink, C. C., Huff, C. D., Strom, S. S., Multigner, L., Blanchet, P., Brureau, L., Kaneva, R., Slavov, C., Mitev, V., Leach, R. J., Weaver, B., Brenner, H., Cuk, K., Holleczek, B., Saum, K., Klein, E. A., Hsing, A. W., Kittles, R. A., Murphy, A. B., Logothetis, C. J., Kim, J., Neuhausen, S. L., Steele, L., Ding, Y. C., Isaacs, W. B., Nemesure, B., Hennis, A. J., Carpten, J., Pandha, H., Michael, A., De Ruyck, K., De Meerleer, G., Ost, P., Xu, J., Razack, A., Lim, J., Teo, S., Newcomb, L. F., Lin, D. W., Fowke, J. H., Neslund-Dudas, C., Rybicki, B. A., Gamulin, M., Lessel, D., Kulis, T., Usmani, N., Singhal, S., Parliament, M., Claessens, F., Joniau, S., Van den Broeck, T., Gago-Dominguez, M., Castelao, J. E., Martinez, M. E., Larkin, S., Townsend, P. A., Aukim-Hastie, C., Bush, W. S., Aldrich, M. C., Crawford, D. C., Srivastava, S., Cullen, J. C., Petrovics, G., Casey, G., Roobol, M. J., Jenster, G., van Schaik, R. H., Hu, J. J., Sanderson, M., Varma, R., McKean-Cowdin, R., Torres, M., Mancuso, N., Berndt, S. I., Van Den Eeden, S. K., Easton, D. F., Chanock, S. J., Cook, M. B., Wiklund, F., Nakagawa, H., Witte, J. S., Eeles, R. A., Kote-Jarai, Z., Haiman, C. A. 2021

  View details for DOI 10.1038/s41588-021-00786-2

  View details for PubMedID 33473200

• Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer. Prostate cancer and prostatic diseases Karunamuni, R. A., Huynh-Le, M., Fan, C. C., Thompson, W., Eeles, R. A., Kote-Jarai, Z., Muir, K., Lophatananon, A., UKGPCS collaborators, Schleutker, J., Pashayan, N., Batra, J., APCB BioResource (Australian Prostate Cancer BioResource), Gronberg, H., Walsh, E. I., Turner, E. L., Lane, A., Martin, R. M., Neal, D. E., Donovan, J. L., Hamdy, F. C., Nordestgaard, B. G., Tangen, C. M., MacInnis, R. J., Wolk, A., Albanes, D., Haiman, C. A., Travis, R. C., Stanford, J. L., Mucci, L. A., West, C. M., Nielsen, S. F., Kibel, A. S., Wiklund, F., Cussenot, O., Berndt, S. I., Koutros, S., Sorensen, K. D., Cybulski, C., Grindedal, E. M., Park, J. Y., Ingles, S. A., Maier, C., Hamilton, R. J., Rosenstein, B. S., Vega, A., IMPACT Study Steering Committee and Collaborators, Kogevinas, M., Penney, K. L., Teixeira, M. R., Brenner, H., John, E. M., Kaneva, R., Logothetis, C. J., Neuhausen, S. L., Razack, A., Newcomb, L. F., Canary PASS Investigators, Gamulin, M., Usmani, N., Claessens, F., Gago-Dominguez, M., Townsend, P. A., Roobol, M. J., Zheng, W., Profile Study Steering Committee, Mills, I. G., Andreassen, O. A., Dale, A. M., Seibert, T. M., PRACTICAL Consortium 2021

  Abstract

  BACKGROUND: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).MATERIALS AND METHOD: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.RESULTS: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.CONCLUSIONS: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

  View details for DOI 10.1038/s41391-020-00311-2

  View details for PubMedID 33420416

• Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction. Nature genetics Conti, D. V., Darst, B. F., Moss, L. C., Saunders, E. J., Sheng, X., Chou, A., Schumacher, F. R., Olama, A. A., Benlloch, S., Dadaev, T., Brook, M. N., Sahimi, A., Hoffmann, T. J., Takahashi, A., Matsuda, K., Momozawa, Y., Fujita, M., Muir, K., Lophatananon, A., Wan, P., Le Marchand, L., Wilkens, L. R., Stevens, V. L., Gapstur, S. M., Carter, B. D., Schleutker, J., Tammela, T. L., Sipeky, C., Auvinen, A., Giles, G. G., Southey, M. C., MacInnis, R. J., Cybulski, C., Wokolorczyk, D., Lubinski, J., Neal, D. E., Donovan, J. L., Hamdy, F. C., Martin, R. M., Nordestgaard, B. G., Nielsen, S. F., Weischer, M., Bojesen, S. E., Roder, M. A., Iversen, P., Batra, J., Chambers, S., Moya, L., Horvath, L., Clements, J. A., Tilley, W., Risbridger, G. P., Gronberg, H., Aly, M., Szulkin, R., Eklund, M., Nordstrom, T., Pashayan, N., Dunning, A. M., Ghoussaini, M., Travis, R. C., Key, T. J., Riboli, E., Park, J. Y., Sellers, T. A., Lin, H., Albanes, D., Weinstein, S. J., Mucci, L. A., Giovannucci, E., Lindstrom, S., Kraft, P., Hunter, D. J., Penney, K. L., Turman, C., Tangen, C. M., Goodman, P. J., Thompson, I. M., Hamilton, R. J., Fleshner, N. E., Finelli, A., Parent, M., Stanford, J. L., Ostrander, E. A., Geybels, M. S., Koutros, S., Freeman, L. E., Stampfer, M., Wolk, A., Hakansson, N., Andriole, G. L., Hoover, R. N., Machiela, M. J., Sorensen, K. D., Borre, M., Blot, W. J., Zheng, W., Yeboah, E. D., Mensah, J. E., Lu, Y., Zhang, H., Feng, N., Mao, X., Wu, Y., Zhao, S., Sun, Z., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., West, C. M., Burnet, N., Barnett, G., Maier, C., Schnoeller, T., Luedeke, M., Kibel, A. S., Drake, B. F., Cussenot, O., Cancel-Tassin, G., Menegaux, F., Truong, T., Koudou, Y. A., John, E. M., Grindedal, E. M., Maehle, L., Khaw, K., Ingles, S. A., Stern, M. C., Vega, A., Gomez-Caamano, A., Fachal, L., Rosenstein, B. S., Kerns, S. L., Ostrer, H., Teixeira, M. R., Paulo, P., Brandao, A., Watya, S., Lubwama, A., Bensen, J. T., Fontham, E. T., Mohler, J., Taylor, J. A., Kogevinas, M., Llorca, J., Castano-Vinyals, G., Cannon-Albright, L., Teerlink, C. C., Huff, C. D., Strom, S. S., Multigner, L., Blanchet, P., Brureau, L., Kaneva, R., Slavov, C., Mitev, V., Leach, R. J., Weaver, B., Brenner, H., Cuk, K., Holleczek, B., Saum, K., Klein, E. A., Hsing, A. W., Kittles, R. A., Murphy, A. B., Logothetis, C. J., Kim, J., Neuhausen, S. L., Steele, L., Ding, Y. C., Isaacs, W. B., Nemesure, B., Hennis, A. J., Carpten, J., Pandha, H., Michael, A., De Ruyck, K., De Meerleer, G., Ost, P., Xu, J., Razack, A., Lim, J., Teo, S., Newcomb, L. F., Lin, D. W., Fowke, J. H., Neslund-Dudas, C., Rybicki, B. A., Gamulin, M., Lessel, D., Kulis, T., Usmani, N., Singhal, S., Parliament, M., Claessens, F., Joniau, S., Van den Broeck, T., Gago-Dominguez, M., Castelao, J. E., Martinez, M. E., Larkin, S., Townsend, P. A., Aukim-Hastie, C., Bush, W. S., Aldrich, M. C., Crawford, D. C., Srivastava, S., Cullen, J. C., Petrovics, G., Casey, G., Roobol, M. J., Jenster, G., van Schaik, R. H., Hu, J. J., Sanderson, M., Varma, R., McKean-Cowdin, R., Torres, M., Mancuso, N., Berndt, S. I., Van Den Eeden, S. K., Easton, D. F., Chanock, S. J., Cook, M. B., Wiklund, F., Nakagawa, H., Witte, J. S., Eeles, R. A., Kote-Jarai, Z., Haiman, C. A. 2021

  Abstract

  Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

  View details for DOI 10.1038/s41588-020-00748-0

  View details for PubMedID 33398198

• The Impact of the first COVID-19 shelter-in-place announcement on social distancing, difficulty in daily activities, and levels of concern in the San Francisco Bay Area: A cross-sectional social media survey. PloS one Elser, H. n., Kiang, M. V., John, E. M., Simard, J. F., Bondy, M. n., Nelson, L. M., Chen, W. T., Linos, E. n. 2021; 16 (1): e0244819

  Abstract

  The U.S. has experienced an unprecedented number of orders to shelter in place throughout the ongoing COVID-19 pandemic. We aimed to ascertain whether social distancing; difficulty with daily activities; and levels of concern regarding COVID-19 changed after the March 16, 2020 announcement of the nation's first shelter-in-place orders (SIPO) among individuals living in the seven affected counties in the San Francisco Bay Area.We conducted an online, cross-sectional social media survey from March 14 -April 1, 2020. We measured changes in social distancing behavior; experienced difficulties with daily activities (i.e., access to healthcare, childcare, obtaining essential food and medications); and level of concern regarding COVID-19 after the March 16 shelter-in-place announcement in the San Francisco Bay Area versus elsewhere in the U.S.In this non-representative sample, the percentage of respondents social distancing all of the time increased following the shelter-in-place announcement in the Bay Area (9.2%, 95% CI: 6.6, 11.9) and elsewhere in the U.S. (3.4%, 95% CI: 2.0, 5.0). Respondents also reported increased difficulty obtaining hand sanitizer, medications, and in particular respondents reported increased difficulty obtaining food in the Bay Area (13.3%, 95% CI: 10.4, 16.3) and elsewhere (8.2%, 95% CI: 6.6, 9.7). We found limited evidence that level of concern regarding the COVID-19 crisis changed following the announcement.This study characterizes early changes in attitudes, behaviors, and difficulties. As states and localities implement, rollback, and reinstate shelter-in-place orders, ongoing efforts to more fully examine the social, economic, and health impacts of COVID-19, especially among vulnerable populations, are urgently needed.

  View details for DOI 10.1371/journal.pone.0244819

  View details for PubMedID 33444363

• Genetic insights into biological mechanisms governing human ovarian ageing. Nature Ruth, K. S., Day, F. R., Hussain, J., Martínez-Marchal, A., Aiken, C. E., Azad, A., Thompson, D. J., Knoblochova, L., Abe, H., Tarry-Adkins, J. L., Gonzalez, J. M., Fontanillas, P., Claringbould, A., Bakker, O. B., Sulem, P., Walters, R. G., Terao, C., Turon, S., Horikoshi, M., Lin, K., Onland-Moret, N. C., Sankar, A., Hertz, E. P., Timshel, P. N., Shukla, V., Borup, R., Olsen, K. W., Aguilera, P., Ferrer-Roda, M., Huang, Y., Stankovic, S., Timmers, P. R., Ahearn, T. U., Alizadeh, B. Z., Naderi, E., Andrulis, I. L., Arnold, A. M., Aronson, K. J., Augustinsson, A., Bandinelli, S., Barbieri, C. M., Beaumont, R. N., Becher, H., Beckmann, M. W., Benonisdottir, S., Bergmann, S., Bochud, M., Boerwinkle, E., Bojesen, S. E., Bolla, M. K., Boomsma, D. I., Bowker, N., Brody, J. A., Broer, L., Buring, J. E., Campbell, A., Campbell, H., Castelao, J. E., Catamo, E., Chanock, S. J., Chenevix-Trench, G., Ciullo, M., Corre, T., Couch, F. J., Cox, A., Crisponi, L., Cross, S. S., Cucca, F., Czene, K., Smith, G. D., de Geus, E. J., de Mutsert, R., De Vivo, I., Demerath, E. W., Dennis, J., Dunning, A. M., Dwek, M., Eriksson, M., Esko, T., Fasching, P. A., Faul, J. D., Ferrucci, L., Franceschini, N., Frayling, T. M., Gago-Dominguez, M., Mezzavilla, M., García-Closas, M., Gieger, C., Giles, G. G., Grallert, H., Gudbjartsson, D. F., Gudnason, V., Guénel, P., Haiman, C. A., Håkansson, N., Hall, P., Hayward, C., He, C., He, W., Heiss, G., Høffding, M. K., Hopper, J. L., Hottenga, J. J., Hu, F., Hunter, D., Ikram, M. A., Jackson, R. D., Joaquim, M. D., John, E. M., Joshi, P. K., Karasik, D., Kardia, S. L., Kartsonaki, C., Karlsson, R., Kitahara, C. M., Kolcic, I., Kooperberg, C., Kraft, P., Kurian, A. W., Kutalik, Z., La Bianca, M., LaChance, G., Langenberg, C., Launer, L. J., Laven, J. S., Lawlor, D. A., Le Marchand, L., Li, J., Lindblom, A., Lindstrom, S., Lindstrom, T., Linet, M., Liu, Y., Liu, S., Luan, J., Mägi, R., Magnusson, P. K., Mangino, M., Mannermaa, A., Marco, B., Marten, J., Martin, N. G., Mbarek, H., McKnight, B., Medland, S. E., Meisinger, C., Meitinger, T., Menni, C., Metspalu, A., Milani, L., Milne, R. L., Montgomery, G. W., Mook-Kanamori, D. O., Mulas, A., Mulligan, A. M., Murray, A., Nalls, M. A., Newman, A., Noordam, R., Nutile, T., Nyholt, D. R., Olshan, A. F., Olsson, H., Painter, J. N., Patel, A. V., Pedersen, N. L., Perjakova, N., Peters, A., Peters, U., Pharoah, P. D., Polasek, O., Porcu, E., Psaty, B. M., Rahman, I., Rennert, G., Rennert, H. S., Ridker, P. M., Ring, S. M., Robino, A., Rose, L. M., Rosendaal, F. R., Rossouw, J., Rudan, I., Rueedi, R., Ruggiero, D., Sala, C. F., Saloustros, E., Sandler, D. P., Sanna, S., Sawyer, E. J., Sarnowski, C., Schlessinger, D., Schmidt, M. K., Schoemaker, M. J., Schraut, K. E., Scott, C., Shekari, S., Shrikhande, A., Smith, A. V., Smith, B. H., Smith, J. A., Sorice, R., Southey, M. C., Spector, T. D., Spinelli, J. J., Stampfer, M., Stöckl, D., van Meurs, J. B., Strauch, K., Styrkarsdottir, U., Swerdlow, A. J., Tanaka, T., Teras, L. R., Teumer, A., Þorsteinsdottir, U., Timpson, N. J., Toniolo, D., Traglia, M., Troester, M. A., Truong, T., Tyrrell, J., Uitterlinden, A. G., Ulivi, S., Vachon, C. M., Vitart, V., Völker, U., Vollenweider, P., Völzke, H., Wang, Q., Wareham, N. J., Weinberg, C. R., Weir, D. R., Wilcox, A. N., van Dijk, K. W., Willemsen, G., Wilson, J. F., Wolffenbuttel, B. H., Wolk, A., Wood, A. R., Zhao, W., Zygmunt, M., Chen, Z., Li, L., Franke, L., Burgess, S., Deelen, P., Pers, T. H., Grøndahl, M. L., Andersen, C. Y., Pujol, A., Lopez-Contreras, A. J., Daniel, J. A., Stefansson, K., Chang-Claude, J., van der Schouw, Y. T., Lunetta, K. L., Chasman, D. I., Easton, D. F., Visser, J. A., Ozanne, S. E., Namekawa, S. H., Solc, P., Murabito, J. M., Ong, K. K., Hoffmann, E. R., Murray, A., Roig, I., Perry, J. R. 2021

  Abstract

  Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

  View details for DOI 10.1038/s41586-021-03779-7

  View details for PubMedID 34349265

• Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis. Scientific reports Escala-Garcia, M., Canisius, S., Keeman, R., Beesley, J., Anton-Culver, H., Arndt, V., Augustinsson, A., Becher, H., Beckmann, M. W., Behrens, S., Bermisheva, M., Bojesen, S. E., Bolla, M. K., Brenner, H., Canzian, F., Castelao, J. E., Chang-Claude, J., Chanock, S. J., Couch, F. J., Czene, K., Daly, M. B., Dennis, J., Devilee, P., Dörk, T., Dunning, A. M., Easton, D. F., Ekici, A. B., Eliassen, A. H., Fasching, P. A., Flyger, H., Gago-Dominguez, M., García-Closas, M., García-Sáenz, J. A., Geisler, J., Giles, G. G., Grip, M., Gündert, M., Hahnen, E., Haiman, C. A., Håkansson, N., Hall, P., Hamann, U., Hartikainen, J. M., Heemskerk-Gerritsen, B. A., Hollestelle, A., Hoppe, R., Hopper, J. L., Hunter, D. J., Jacot, W., Jakubowska, A., John, E. M., Jung, A. Y., Kaaks, R., Khusnutdinova, E., Koppert, L. B., Kraft, P., Kristensen, V. N., Kurian, A. W., Lambrechts, D., Le Marchand, L., Lindblom, A., Luben, R. N., Lubiński, J., Mannermaa, A., Manoochehri, M., Margolin, S., Mavroudis, D., Muranen, T. A., Nevanlinna, H., Olshan, A. F., Olsson, H., Park-Simon, T. W., Patel, A. V., Peterlongo, P., Pharoah, P. D., Punie, K., Radice, P., Rennert, G., Rennert, H. S., Romero, A., Roylance, R., Rüdiger, T., Ruebner, M., Saloustros, E., Sawyer, E. J., Schmutzler, R. K., Schoemaker, M. J., Scott, C., Southey, M. C., Surowy, H., Swerdlow, A. J., Tamimi, R. M., Teras, L. R., Thomas, E., Tomlinson, I., Troester, M. A., Vachon, C. M., Wang, Q., Winqvist, R., Wolk, A., Ziogas, A., Michailidou, K., Chenevix-Trench, G., Bachelot, T., Schmidt, M. K. 2021; 11 (1): 19787

  Abstract

  Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10-8 and 4.42 × 10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.

  View details for DOI 10.1038/s41598-021-99409-3

  View details for PubMedID 34611289

• Treatment and Monitoring Variability in US Metastatic Breast Cancer Care. JCO clinical cancer informatics Caswell-Jin, J. L., Callahan, A., Purington, N., Han, S. S., Itakura, H., John, E. M., Blayney, D. W., Sledge, G. W., Shah, N. H., Kurian, A. W. 2021; 5: 600-614

  Abstract

  Treatment and monitoring options for patients with metastatic breast cancer (MBC) are increasing, but little is known about variability in care. We sought to improve understanding of MBC care and its correlates by analyzing real-world claims data using a search engine with a novel query language to enable temporal electronic phenotyping.Using the Advanced Cohort Engine, we identified 6,180 women who met criteria for having estrogen receptor-positive, human epidermal growth factor receptor 2-negative MBC from IBM MarketScan US insurance claims (2007-2014). We characterized treatment, monitoring, and hospice usage, along with clinical and nonclinical factors affecting care.We observed wide variability in treatment modality and monitoring across patients and geography. Most women received first-recorded therapy with endocrine (67%) versus chemotherapy, underwent more computed tomography (CT) (76%) than positron emission tomography-CT, and were monitored using tumor markers (58%). Nearly half (46%) met criteria for aggressive disease, which were associated with receiving chemotherapy first, monitoring primarily with CT, and more frequent imaging. Older age was associated with endocrine therapy first, less frequent imaging, and less use of tumor markers. After controlling for clinical factors, care strategies varied significantly by nonclinical factors (median regional income with first-recorded therapy and imaging type, geographic region with these and with imaging frequency and use of tumor markers; P < .0001).Variability in US MBC care is explained by patient and disease factors and by nonclinical factors such as geographic region, suggesting that treatment decisions are influenced by local practice patterns and/or resources. A search engine designed to express complex electronic phenotypes from longitudinal patient records enables the identification of variability in patient care, helping to define disparities and areas for improvement.

  View details for DOI 10.1200/CCI.21.00031

  View details for PubMedID 34043432

• Risk of Breast Cancer Among Carriers of Pathogenic Variants in Breast Cancer Predisposition Genes Varies by Polygenic Risk Score. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Gao, C., Polley, E. C., Hart, S. N., Huang, H., Hu, C., Gnanaolivu, R., Lilyquist, J., Boddicker, N. J., Na, J., Ambrosone, C. B., Auer, P. L., Bernstein, L., Burnside, E. S., Eliassen, A. H., Gaudet, M. M., Haiman, C., Hunter, D. J., Jacobs, E. J., John, E. M., Lindström, S., Ma, H., Neuhausen, S. L., Newcomb, P. A., O'Brien, K. M., Olson, J. E., Ong, I. M., Patel, A. V., Palmer, J. R., Sandler, D. P., Tamimi, R., Taylor, J. A., Teras, L. R., Trentham-Dietz, A., Vachon, C. M., Weinberg, C. R., Yao, S., Weitzel, J. N., Goldgar, D. E., Domchek, S. M., Nathanson, K. L., Couch, F. J., Kraft, P. 2021: JCO2001992

  Abstract

  This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population.A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor-specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC.The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk.PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.

  View details for DOI 10.1200/JCO.20.01992

  View details for PubMedID 34101481

• Recreational Physical Activity and Outcomes After Breast Cancer in Women at High Familial Risk. JNCI cancer spectrum Kehm, R. D., MacInnis, R. J., John, E. M., Liao, Y., Kurian, A. W., Genkinger, J. M., Knight, J. A., Colonna, S. V., Chung, W. K., Milne, R., Zeinomar, N., Dite, G. S., Southey, M. C., Giles, G. G., McLachlan, S. A., Whitaker, K. D., Friedlander, M. L., Weideman, P. C., Glendon, G., Nesci, S., Phillips, K. A., Andrulis, I. L., Buys, S. S., Daly, M. B., Hopper, J. L., Terry, M. B. 2021; 5 (6): pkab090

  Abstract

  Recreational physical activity (RPA) is associated with improved survival after breast cancer (BC) in average-risk women, but evidence is limited for women who are at increased familial risk because of a BC family history or BRCA1 and BRCA2 pathogenic variants (BRCA1/2 PVs).We estimated associations of RPA (self-reported average hours per week within 3 years of BC diagnosis) with all-cause mortality and second BC events (recurrence or new primary) after first invasive BC in women in the Prospective Family Study Cohort (n = 4610, diagnosed 1993-2011, aged 22-79 years at diagnosis). We fitted Cox proportional hazards regression models adjusted for age at diagnosis, demographics, and lifestyle factors. We tested for multiplicative interactions (Wald test statistic for cross-product terms) and additive interactions (relative excess risk due to interaction) by age at diagnosis, body mass index, estrogen receptor status, stage at diagnosis, BRCA1/2 PVs, and familial risk score estimated from multigenerational pedigree data. Statistical tests were 2-sided.We observed 1212 deaths and 473 second BC events over a median follow-up from study enrollment of 11.0 and 10.5 years, respectively. After adjusting for covariates, RPA (any vs none) was associated with lower all-cause mortality of 16.1% (95% confidence interval [CI] = 2.4% to 27.9%) overall, 11.8% (95% CI = -3.6% to 24.9%) in women without BRCA1/2 PVs, and 47.5% (95% CI = 17.4% to 66.6%) in women with BRCA1/2 PVs (RPA*BRCA1/2 multiplicative interaction P = .005; relative excess risk due to interaction = 0.87, 95% CI = 0.01 to 1.74). RPA was not associated with risk of second BC events.Findings support that RPA is associated with lower all-cause mortality in women with BC, particularly in women with BRCA1/2 PVs.

  View details for DOI 10.1093/jncics/pkab090

  View details for PubMedID 34950851

  View details for PubMedCentralID PMC8692829

• Weight is more informative than body mass index for predicting post-menopausal breast cancer risk: Prospective Family Study Cohort (ProF-SC). Cancer prevention research (Philadelphia, Pa.) Ye, Z., Li, S., Dite, G. S., Nguyen, T. L., MacInnis, R. J., Andrulis, I. L., Buys, S. S., Daly, M. B., John, E. M., Kurian, A. W., Genkinger, J. M., Chung, W. K., Phillips, K. A., Thorne, H., Winship, I. M., Milne, R. L., Dugué, P. A., Southey, M. C., Giles, G. G., Terry, M. B., Hopper, J. L. 2021

  Abstract

  We considered whether weight is more informative than body mass index = weight/height2 (BMI) when predicting breast cancer risk for post-menopausal women, and if the weight association differs by underlying familial risk. We studied 6,761 women post-menopausal at baseline with a wide range of familial risk from 2,364 families in the Prospective Family Study Cohort (ProF-SC). Participants were followed for on average 11.45 years and there were 416 incident breast cancers. We used Cox regression to estimate risk associations with log-transformed weight and BMI after adjusting for underlying familial risk. We compared model fits using the Akaike Information Criterion (AIC) and nested models using the likelihood ratio test. The AIC for the weight-only model was 6.22 units lower than for the BMI-only model, and the log risk gradient was 23% greater. Adding BMI or height to weight did not improve fit (ΔAIC=0.90 and 0.83, respectively; both P=0.3). Conversely, adding weight to BMI or height gave better fits (ΔAIC=5.32 and 11.64; P=0.007 and 0.0002, respectively). Adding height improved only the BMI model (ΔAIC=5.47; P=0.006). There was no evidence that the BMI or weight associations differed by underlying familial risk (P>0.2). Weight is more informative than BMI for predicting breast cancer risk, consistent with non-adipose as well as adipose tissue being etiologically relevant. The independent but multiplicative associations of weight and familial risk suggest that, in terms of absolute breast cancer risk, the association with weight is more important the greater a woman's underlying familial risk.

  View details for DOI 10.1158/1940-6207.CAPR-21-0164

  View details for PubMedID 34965921

• Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment. Breast cancer research : BCR Morra, A., Escala-Garcia, M., Beesley, J., Keeman, R., Canisius, S., Ahearn, T. U., Andrulis, I. L., Anton-Culver, H., Arndt, V., Auer, P. L., Augustinsson, A., Beane Freeman, L. E., Becher, H., Beckmann, M. W., Behrens, S., Bojesen, S. E., Bolla, M. K., Brenner, H., Brüning, T., Buys, S. S., Caan, B., Campa, D., Canzian, F., Castelao, J. E., Chang-Claude, J., Chanock, S. J., Cheng, T. D., Clarke, C. L., Colonna, S. V., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Daly, M. B., Dennis, J., Dörk, T., Dossus, L., Dunning, A. M., Dwek, M., Eccles, D. M., Ekici, A. B., Eliassen, A. H., Eriksson, M., Evans, D. G., Fasching, P. A., Flyger, H., Fritschi, L., Gago-Dominguez, M., García-Sáenz, J. A., Giles, G. G., Grip, M., Guénel, P., Gündert, M., Hahnen, E., Haiman, C. A., Håkansson, N., Hall, P., Hamann, U., Hart, S. N., Hartikainen, J. M., Hartmann, A., He, W., Hooning, M. J., Hoppe, R., Hopper, J. L., Howell, A., Hunter, D. J., Jager, A., Jakubowska, A., Janni, W., John, E. M., Jung, A. Y., Kaaks, R., Keupers, M., Kitahara, C. M., Koutros, S., Kraft, P., Kristensen, V. N., Kurian, A. W., Lacey, J. V., Lambrechts, D., Le Marchand, L., Lindblom, A., Linet, M., Luben, R. N., Lubiński, J., Lush, M., Mannermaa, A., Manoochehri, M., Margolin, S., Martens, J. W., Martinez, M. E., Mavroudis, D., Michailidou, K., Milne, R. L., Mulligan, A. M., Muranen, T. A., Nevanlinna, H., Newman, W. G., Nielsen, S. F., Nordestgaard, B. G., Olshan, A. F., Olsson, H., Orr, N., Park-Simon, T. W., Patel, A. V., Peissel, B., Peterlongo, P., Plaseska-Karanfilska, D., Prajzendanc, K., Prentice, R., Presneau, N., Rack, B., Rennert, G., Rennert, H. S., Rhenius, V., Romero, A., Roylance, R., Ruebner, M., Saloustros, E., Sawyer, E. J., Schmutzler, R. K., Schneeweiss, A., Scott, C., Shah, M., Smichkoska, S., Southey, M. C., Stone, J., Surowy, H., Swerdlow, A. J., Tamimi, R. M., Tapper, W. J., Teras, L. R., Terry, M. B., Tollenaar, R. A., Tomlinson, I., Troester, M. A., Truong, T., Vachon, C. M., Wang, Q., Hurson, A. N., Winqvist, R., Wolk, A., Ziogas, A., Brauch, H., García-Closas, M., Pharoah, P. D., Easton, D. F., Chenevix-Trench, G., Schmidt, M. K. 2021; 23 (1): 86

  Abstract

  Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15).Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy.We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.

  View details for DOI 10.1186/s13058-021-01450-7

  View details for PubMedID 34407845

• Polygenic risk scores for prediction of breast cancer risk in Asian populations. Genetics in medicine : official journal of the American College of Medical Genetics Ho, W. K., Tai, M. C., Dennis, J., Shu, X., Li, J., Ho, P. J., Millwood, I. Y., Lin, K., Jee, Y. H., Lee, S. H., Mavaddat, N., Bolla, M. K., Wang, Q., Michailidou, K., Long, J., Wijaya, E. A., Hassan, T., Rahmat, K., Tan, V. K., Tan, B. K., Tan, S. M., Tan, E. Y., Lim, S. H., Gao, Y. T., Zheng, Y., Kang, D., Choi, J. Y., Han, W., Lee, H. B., Kubo, M., Okada, Y., Namba, S., Park, S. K., Kim, S. W., Shen, C. Y., Wu, P. E., Park, B., Muir, K. R., Lophatananon, A., Wu, A. H., Tseng, C. C., Matsuo, K., Ito, H., Kwong, A., Chan, T. L., John, E. M., Kurian, A. W., Iwasaki, M., Yamaji, T., Kweon, S. S., Aronson, K. J., Murphy, R. A., Koh, W. P., Khor, C. C., Yuan, J. M., Dorajoo, R., Walters, R. G., Chen, Z., Li, L., Lv, J., Jung, K. J., Kraft, P., Pharoah, P. D., Dunning, A. M., Simard, J., Shu, X. O., Yip, C. H., Taib, N. A., Antoniou, A. C., Zheng, W., Hartman, M., Easton, D. F., Teo, S. H. 2021

  Abstract

  Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups.The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases).The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk.PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.

  View details for DOI 10.1016/j.gim.2021.11.008

  View details for PubMedID 34906514

• Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Yadav, S., Hu, C., Nathanson, K. L., Weitzel, J. N., Goldgar, D. E., Kraft, P., Gnanaolivu, R. D., Na, J., Huang, H., Boddicker, N. J., Larson, N., Gao, C., Yao, S., Weinberg, C., Vachon, C. M., Trentham-Dietz, A., Taylor, J. A., Sandler, D. R., Patel, A., Palmer, J. R., Olson, J. E., Neuhausen, S., Martinez, E., Lindstrom, S., Lacey, J. V., Kurian, A. W., John, E. M., Haiman, C., Bernstein, L., Auer, P. W., Anton-Culver, H., Ambrosone, C. B., Karam, R., Chao, E., Yussuf, A., Pesaran, T., Dolinsky, J. S., Hart, S. N., LaDuca, H., Polley, E. C., Domchek, S. M., Couch, F. J. 2021: JCO2100640

  Abstract

  To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast.The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC).The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC.The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

  View details for DOI 10.1200/JCO.21.00640

  View details for PubMedID 34672684

• Performance of the IBIS/Tyrer-Cuzick model of breast cancer risk by race and ethnicity in the Women's Health Initiative. Cancer Kurian, A. W., Hughes, E., Simmons, T., Bernhisel, R., Probst, B., Meek, S., Caswell-Jin, J. L., John, E. M., Lanchbury, J. S., Slavin, T. P., Wagner, S., Gutin, A., Rohan, T. E., Shadyab, A. H., Manson, J. E., Lane, D., Chlebowski, R. T., Stefanick, M. L. 2021

  Abstract

  The IBIS/Tyrer-Cuzick model is used clinically to guide breast cancer screening and prevention, but was developed primarily in non-Hispanic White women. Little is known about its long-term performance in a racially/ethnically diverse population.The Women's Health Initiative study enrolled postmenopausal women from 1993-1998. Women were included who were aged <80 years at enrollment with no prior breast cancer or mastectomy and with data required for IBIS/Tyrer-Cuzick calculation (weight; height; ages at menarche, first birth, and menopause; menopausal hormone therapy use; and family history of breast or ovarian cancer). Calibration was assessed by the ratio of observed breast cancer cases to the number expected by the IBIS/Tyrer-Cuzick model (O/E; calculated as the sum of cumulative hazards). Differential discrimination was tested for by self-reported race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, Asian or Pacific Islander, and American Indian or Alaskan Native) using Cox regression. Exploratory analyses, including simulation of a protective single-nucleotide polymorphism (SNP), rs140068132 at 6q25, were performed.During follow-up (median 18.9 years, maximum 23.4 years), 6783 breast cancer cases occurred among 90,967 women. IBIS/Tyrer-Cuzick was well calibrated overall (O/E ratio = 0.95; 95% CI, 0.93-0.97) and in most racial/ethnic groups, but overestimated risk for Hispanic women (O/E ratio = 0.75; 95% CI, 0.62-0.90). Discrimination did not differ by race/ethnicity. Exploratory simulation of the protective SNP suggested improved IBIS/Tyrer-Cuzick calibration for Hispanic women (O/E ratio = 0.80; 95% CI, 0.66-0.96).The IBIS/Tyrer-Cuzick model is well calibrated for several racial/ethnic groups over 2 decades of follow-up. Studies that incorporate genetic and other risk factors, particularly among Hispanic women, are essential to improve breast cancer-risk prediction.

  View details for DOI 10.1002/cncr.33767

  View details for PubMedID 34228814

• Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element. American journal of human genetics Baxter, J. S., Johnson, N., Tomczyk, K., Gillespie, A., Maguire, S., Brough, R., Fachal, L., Michailidou, K., Bolla, M. K., Wang, Q., Dennis, J., Ahearn, T. U., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Arndt, V., Aronson, K. J., Augustinsson, A., Becher, H., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bogdanova, N. V., Bojesen, S. E., Brenner, H., Brucker, S. Y., Cai, Q., Campa, D., Canzian, F., Castelao, J. E., Chan, T. L., Chang-Claude, J., Chanock, S. J., Chenevix-Trench, G., Choi, J. Y., Clarke, C. L., Colonna, S., Conroy, D. M., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Daly, M. B., Devilee, P., Dörk, T., Dossus, L., Dwek, M., Eccles, D. M., Ekici, A. B., Eliassen, A. H., Engel, C., Fasching, P. A., Figueroa, J., Flyger, H., Gago-Dominguez, M., Gao, C., García-Closas, M., García-Sáenz, J. A., Ghoussaini, M., Giles, G. G., Goldberg, M. S., González-Neira, A., Guénel, P., Gündert, M., Haeberle, L., Hahnen, E., Haiman, C. A., Hall, P., Hamann, U., Hartman, M., Hatse, S., Hauke, J., Hollestelle, A., Hoppe, R., Hopper, J. L., Hou, M. F., Ito, H., Iwasaki, M., Jager, A., Jakubowska, A., Janni, W., John, E. M., Joseph, V., Jung, A., Kaaks, R., Kang, D., Keeman, R., Khusnutdinova, E., Kim, S. W., Kosma, V. M., Kraft, P., Kristensen, V. N., Kubelka-Sabit, K., Kurian, A. W., Kwong, A., Lacey, J. V., Lambrechts, D., Larson, N. L., Larsson, S. C., Le Marchand, L., Lejbkowicz, F., Li, J., Long, J., Lophatananon, A., Lubiński, J., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Matsuo, K., Mavroudis, D., Mayes, R., Menon, U., Milne, R. L., Mohd Taib, N. A., Muir, K., Muranen, T. A., Murphy, R. A., Nevanlinna, H., O'Brien, K. M., Offit, K., Olson, J. E., Olsson, H., Park, S. K., Park-Simon, T. W., Patel, A. V., Peterlongo, P., Peto, J., Plaseska-Karanfilska, D., Presneau, N., Pylkäs, K., Rack, B., Rennert, G., Romero, A., Ruebner, M., Rüdiger, T., Saloustros, E., Sandler, D. P., Sawyer, E. J., Schmidt, M. K., Schmutzler, R. K., Schneeweiss, A., Schoemaker, M. J., Shah, M., Shen, C. Y., Shu, X. O., Simard, J., Southey, M. C., Stone, J., Surowy, H., Swerdlow, A. J., Tamimi, R. M., Tapper, W. J., Taylor, J. A., Teo, S. H., Teras, L. R., Terry, M. B., Toland, A. E., Tomlinson, I., Truong, T., Tseng, C. C., Untch, M., Vachon, C. M., van den Ouweland, A. M., Wang, S. S., Weinberg, C. R., Wendt, C., Winham, S. J., Winqvist, R., Wolk, A., Wu, A. H., Yamaji, T., Zheng, W., Ziogas, A., Pharoah, P. D., Dunning, A. M., Easton, D. F., Pettitt, S. J., Lord, C. J., Haider, S., Orr, N., Fletcher, O. 2021

  Abstract

  A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31).

  View details for DOI 10.1016/j.ajhg.2021.05.013

  View details for PubMedID 34146516

• Mendelian randomisation study of smoking exposure in relation to breast cancer risk. British journal of cancer Park, H. A., Neumeyer, S., Michailidou, K., Bolla, M. K., Wang, Q., Dennis, J., Ahearn, T. U., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Arndt, V., Aronson, K. J., Augustinsson, A., Baten, A., Beane Freeman, L. E., Becher, H., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bogdanova, N. V., Bojesen, S. E., Brauch, H., Brenner, H., Brucker, S. Y., Burwinkel, B., Campa, D., Canzian, F., Castelao, J. E., Chanock, S. J., Chenevix-Trench, G., Clarke, C. L., Conroy, D. M., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Daly, M. B., Devilee, P., Dörk, T., Dos-Santos-Silva, I., Dwek, M., Eccles, D. M., Eliassen, A. H., Engel, C., Eriksson, M., Evans, D. G., Fasching, P. A., Flyger, H., Fritschi, L., García-Closas, M., García-Sáenz, J. A., Gaudet, M. M., Giles, G. G., Glendon, G., Goldberg, M. S., Goldgar, D. E., González-Neira, A., Grip, M., Guénel, P., Hahnen, E., Haiman, C. A., Håkansson, N., Hall, P., Hamann, U., Han, S., Harkness, E. F., Hart, S. N., He, W., Heemskerk-Gerritsen, B. A., Hopper, J. L., Hunter, D. J., Jager, A., Jakubowska, A., John, E. M., Jung, A., Kaaks, R., Kapoor, P. M., Keeman, R., Khusnutdinova, E., Kitahara, C. M., Koppert, L. B., Koutros, S., Kristensen, V. N., Kurian, A. W., Lacey, J., Lambrechts, D., Le Marchand, L., Lo, W. Y., Lubiński, J., Mannermaa, A., Manoochehri, M., Margolin, S., Martinez, M. E., Mavroudis, D., Meindl, A., Menon, U., Milne, R. L., Muranen, T. A., Nevanlinna, H., Newman, W. G., Nordestgaard, B. G., Offit, K., Olshan, A. F., Olsson, H., Park-Simon, T. W., Peterlongo, P., Peto, J., Plaseska-Karanfilska, D., Presneau, N., Radice, P., Rennert, G., Rennert, H. S., Romero, A., Saloustros, E., Sawyer, E. J., Schmidt, M. K., Schmutzler, R. K., Schoemaker, M. J., Schwentner, L., Scott, C., Shah, M., Shu, X. O., Simard, J., Smeets, A., Southey, M. C., Spinelli, J. J., Stevens, V., Swerdlow, A. J., Tamimi, R. M., Tapper, W. J., Taylor, J. A., Terry, M. B., Tomlinson, I., Troester, M. A., Truong, T., Vachon, C. M., van Veen, E. M., Vijai, J., Wang, S., Wendt, C., Winqvist, R., Wolk, A., Ziogas, A., Dunning, A. M., Pharoah, P. D., Easton, D. F., Zheng, W., Kraft, P., Chang-Claude, J. 2021

  Abstract

  Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk.We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy.Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10-2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect.Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.

  View details for DOI 10.1038/s41416-021-01432-8

  View details for PubMedID 34341517

• Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores. Journal of the National Cancer Institute Barnes, D. R., Silvestri, V., Leslie, G., McGuffog, L., Dennis, J., Yang, X., Adlard, J., Agnarsson, B. A., Ahmed, M., Aittomäki, K., Andrulis, I. L., Arason, A., Arnold, N., Auber, B., Azzollini, J., Balmaña, J., Barkardottir, R. B., Barrowdale, D., Barwell, J., Belotti, M., Benitez, J., Berthet, P., Boonen, S. E., Borg, Å., Bozsik, A., Brady, A., Brennan, P., Brewer, C., Brunet, J., Bucalo, A., Buys, S. S., Caldés, T., Caligo, M. A., Campbell, I., Cassingham, H., Lotte Christensen, L., Cini, G., Claes, K. B., Cook, J., Coppa, A., Cortesi, L., Damante, G., Darder, E., Davidson, R., de la Hoya, M., De Leeneer, K., de Putter, R., Del Valle, J., Diez, O., Chun Ding, Y., Domchek, S. M., Donaldson, A., Eason, J., Eeles, R., Engel, C., Gareth Evans, D., Feliubadaló, L., Fostira, F., Frone, M., Frost, D., Gallagher, D., Gehrig, A., Giraud, S., Glendon, G., Godwin, A. K., Goldgar, D. E., Greene, M. H., Gregory, H., Gross, E., Hahnen, E., Hamann, U., Hansen, T. V., Hanson, H., Hentschel, J., Horvath, J., Izatt, L., Izquierdo, A., James, P. A., Janavicius, R., Birk Jensen, U., Johannsson, O. T., John, E. M., Kramer, G., Kroeldrup, L., Kruse, T. A., Lautrup, C., Lazaro, C., Lesueur, F., Lopez-Fernández, A., Mai, P. L., Manoukian, S., Matrai, Z., Matricardi, L., Maxwell, K. N., Mebirouk, N., Meindl, A., Montagna, M., Monteiro, A. N., Morrison, P. J., Muranen, T. A., Murray, A., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Nguyen-Dumont, T., Niederacher, D., Olah, E., Olopade, O. I., Palli, D., Parsons, M. T., Sokilde Pedersen, I., Peissel, B., Perez-Segura, P., Peterlongo, P., Petersen, A. H., Pinto, P., Porteous, M. E., Pottinger, C., Angel Pujana, M., Radice, P., Ramser, J., Rantala, J., Robson, M., Rogers, M. T., Rønlund, K., Rump, A., María Sánchez de Abajo, A., Shah, P. D., Sharif, S., Side, L. E., Singer, C. F., Stadler, Z., Steele, L., Stoppa-Lyonnet, D., Sutter, C., Yen Tan, Y., Teixeira, M. R., Teulé, A., Thull, D. L., Tischkowitz, M., Toland, A. E., Tommasi, S., Toss, A., Trainer, A. H., Tripathi, V., Valentini, V., van Asperen, C. J., Venturelli, M., Viel, A., Vijai, J., Walker, L., Wang-Gohrke, S., Wappenschmidt, B., Whaite, A., Zanna, I., Offit, K., Thomassen, M., Couch, F. J., Schmutzler, R. K., Simard, J., Easton, D. F., Chenevix-Trench, G., Antoniou, A. C., Ottini, L. 2021

  Abstract

  Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.483 BRCA1 and 1,318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were three versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen-receptor (ER) negative (PRSER-) or ER-positive (PRSER+) breast cancer risk.PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07-1.83) for BRCA1 and 1.33 (95% CI = 1.16-1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for both BRCA1 (OR = 1.73, 95% CI = 1.28-2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34-1.91) carriers. The estimated breast cancer ORs were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and to inform clinical management.

  View details for DOI 10.1093/jnci/djab147

  View details for PubMedID 34320204

• CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers. British journal of cancer Johnson, N. n., Maguire, S. n., Morra, A. n., Kapoor, P. M., Tomczyk, K. n., Jones, M. E., Schoemaker, M. J., Gilham, C. n., Bolla, M. K., Wang, Q. n., Dennis, J. n., Ahearn, T. U., Andrulis, I. L., Anton-Culver, H. n., Antonenkova, N. N., Arndt, V. n., Aronson, K. J., Augustinsson, A. n., Baynes, C. n., Freeman, L. E., Beckmann, M. W., Benitez, J. n., Bermisheva, M. n., Blomqvist, C. n., Boeckx, B. n., Bogdanova, N. V., Bojesen, S. E., Brauch, H. n., Brenner, H. n., Burwinkel, B. n., Campa, D. n., Canzian, F. n., Castelao, J. E., Chanock, S. J., Chenevix-Trench, G. n., Clarke, C. L., Conroy, D. M., Couch, F. J., Cox, A. n., Cross, S. S., Czene, K. n., Dörk, T. n., Eliassen, A. H., Engel, C. n., Evans, D. G., Fasching, P. A., Figueroa, J. n., Floris, G. n., Flyger, H. n., Gago-Dominguez, M. n., Gapstur, S. M., García-Closas, M. n., Gaudet, M. M., Giles, G. G., Goldberg, M. S., González-Neira, A. n., Guénel, P. n., Hahnen, E. n., Haiman, C. A., Håkansson, N. n., Hall, P. n., Hamann, U. n., Harrington, P. A., Hart, S. N., Hooning, M. J., Hopper, J. L., Howell, A. n., Hunter, D. J., Jager, A. n., Jakubowska, A. n., John, E. M., Kaaks, R. n., Keeman, R. n., Khusnutdinova, E. n., Kitahara, C. M., Kosma, V. M., Koutros, S. n., Kraft, P. n., Kristensen, V. N., Kurian, A. W., Lambrechts, D. n., Le Marchand, L. n., Linet, M. n., Lubiński, J. n., Mannermaa, A. n., Manoukian, S. n., Margolin, S. n., Martens, J. W., Mavroudis, D. n., Mayes, R. n., Meindl, A. n., Milne, R. L., Neuhausen, S. L., Nevanlinna, H. n., Newman, W. G., Nielsen, S. F., Nordestgaard, B. G., Obi, N. n., Olshan, A. F., Olson, J. E., Olsson, H. n., Orban, E. n., Park-Simon, T. W., Peterlongo, P. n., Plaseska-Karanfilska, D. n., Pylkäs, K. n., Rennert, G. n., Rennert, H. S., Ruddy, K. J., Saloustros, E. n., Sandler, D. P., Sawyer, E. J., Schmutzler, R. K., Scott, C. n., Shu, X. O., Simard, J. n., Smichkoska, S. n., Sohn, C. n., Southey, M. C., Spinelli, J. J., Stone, J. n., Tamimi, R. M., Taylor, J. A., Tollenaar, R. A., Tomlinson, I. n., Troester, M. A., Truong, T. n., Vachon, C. M., van Veen, E. M., Wang, S. S., Weinberg, C. R., Wendt, C. n., Wildiers, H. n., Winqvist, R. n., Wolk, A. n., Zheng, W. n., Ziogas, A. n., Dunning, A. M., Pharoah, P. D., Easton, D. F., Howie, A. F., Peto, J. n., Dos-Santos-Silva, I. n., Swerdlow, A. J., Chang-Claude, J. n., Schmidt, M. K., Orr, N. n., Fletcher, O. n. 2021

  Abstract

  Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk.We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry.For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10-18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10-8).The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.

  View details for DOI 10.1038/s41416-020-01185-w

  View details for PubMedID 33495599

• Association of Risk-Reducing Salpingo-Oophorectomy With Breast Cancer Risk in Women With BRCA1 and BRCA2 Pathogenic Variants. JAMA oncology Choi, Y. H., Terry, M. B., Daly, M. B., MacInnis, R. J., Hopper, J. L., Colonna, S. n., Buys, S. S., Andrulis, I. L., John, E. M., Kurian, A. W., Briollais, L. n. 2021

  Abstract

  Women with pathogenic variants in BRCA1 and BRCA2 are at high risk of developing breast and ovarian cancers. They usually undergo intensive cancer surveillance and may also consider surgical interventions, such as risk-reducing mastectomy or risk-reducing salpingo-oophorectomy (RRSO). Risk-reducing salpingo-oophorectomy has been shown to reduce ovarian cancer risk, but its association with breast cancer risk is less clear.To assess the association of RRSO with the risk of breast cancer in women with BRCA1 and BRCA2 pathogenic variants.This case series included families enrolled in the Breast Cancer Family Registry between 1996 and 2000 that carried an inherited pathogenic variant in BRCA1 (498 families) or BRCA2 (378 families). A survival analysis approach was used that was designed specifically to assess the time-varying association of RRSO with breast cancer risk and accounting for other potential biases. Data were analyzed from August 2019 to November 2020.Risk-reducing salpingo-oophorectomy.In all analyses, the primary end point was the time to a first primary breast cancer.A total of 876 families were evaluated, including 498 with BRCA1 (2650 individuals; mean [SD] event age, 55.8 [19.1] years; 437 White probands [87.8%]) and 378 with BRCA2 (1925 individuals; mean [SD] event age, 57.0 [18.6] years; 299 White probands [79.1%]). Risk-reducing salpingo-oophorectomy was associated with a reduced risk of breast cancer for BRCA1 and BRCA2 pathogenic variant carriers within 5 years after surgery (hazard ratios [HRs], 0.28 [95% CI, 0.10-0.63] and 0.19 [95% CI, 0.06-0.71], respectively), whereas the corresponding HRs were weaker after 5 years postsurgery (HRs, 0.64 [95% CI, 0.38-0.97] and 0.99 [95% CI; 0.84-1.00], respectively). For BRCA1 and BRCA2 pathogenic variant carriers who underwent RRSO at age 40 years, the cause-specific cumulative risk of breast cancer was 49.7% (95% CI, 40.0-60.3) and 52.7% (95% CI, 47.9-58.7) by age 70 years, respectively, compared with 61.0% (95% CI, 56.7-66.0) and 54.0% (95% CI, 49.3-60.1), respectively, for women without RRSO.Although the primary indication for RRSO is the prevention of ovarian cancer, it is also critical to assess its association with breast cancer risk in order to guide clinical decision-making about RRSO use and timing. The results of this case series suggest a reduced risk of breast cancer associated with RRSO in the immediate 5 years after surgery in women carrying BRCA1 and BRCA2 pathogenic variants, and a longer-term association with cumulative breast cancer risk in women carrying BRCA1 pathogenic variants.

  View details for DOI 10.1001/jamaoncol.2020.7995

  View details for PubMedID 33630024

• Polygenic hazard score is associated with prostate cancer in multi-ethnic populations. Nature communications Huynh-Le, M., Fan, C. C., Karunamuni, R., Thompson, W. K., Martinez, M. E., Eeles, R. A., Kote-Jarai, Z., Muir, K., Schleutker, J., Pashayan, N., Batra, J., Gronberg, H., Neal, D. E., Donovan, J. L., Hamdy, F. C., Martin, R. M., Nielsen, S. F., Nordestgaard, B. G., Wiklund, F., Tangen, C. M., Giles, G. G., Wolk, A., Albanes, D., Travis, R. C., Blot, W. J., Zheng, W., Sanderson, M., Stanford, J. L., Mucci, L. A., West, C. M., Kibel, A. S., Cussenot, O., Berndt, S. I., Koutros, S., Sorensen, K. D., Cybulski, C., Grindedal, E. M., Menegaux, F., Khaw, K., Park, J. Y., Ingles, S. A., Maier, C., Hamilton, R. J., Thibodeau, S. N., Rosenstein, B. S., Lu, Y., Watya, S., Vega, A., Kogevinas, M., Penney, K. L., Huff, C., Teixeira, M. R., Multigner, L., Leach, R. J., Cannon-Albright, L., Brenner, H., John, E. M., Kaneva, R., Logothetis, C. J., Neuhausen, S. L., De Ruyck, K., Pandha, H., Razack, A., Newcomb, L. F., Fowke, J. H., Gamulin, M., Usmani, N., Claessens, F., Gago-Dominguez, M., Townsend, P. A., Bush, W. S., Roobol, M. J., Parent, M., Hu, J. J., Mills, I. G., Andreassen, O. A., Dale, A. M., Seibert, T. M., UKGPCS collaborators, APCB (Australian Prostate Cancer BioResource), NC-LA PCaP Investigators, IMPACT Study Steering Committee and Collaborators, Canary PASS Investigators, Profile Study Steering Committee, PRACTICAL Consortium 2021; 12 (1): 1236

  Abstract

  Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score≥7, stage T3-T4, PSA≥10ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n=71,856), Asian (n=2,382), and African (n=6,253) genetic ancestries (p<10-180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.

  View details for DOI 10.1038/s41467-021-21287-0

  View details for PubMedID 33623038

• A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers. Nature communications Coignard, J. n., Lush, M. n., Beesley, J. n., O'Mara, T. A., Dennis, J. n., Tyrer, J. P., Barnes, D. R., McGuffog, L. n., Leslie, G. n., Bolla, M. K., Adank, M. A., Agata, S. n., Ahearn, T. n., Aittomäki, K. n., Andrulis, I. L., Anton-Culver, H. n., Arndt, V. n., Arnold, N. n., Aronson, K. J., Arun, B. K., Augustinsson, A. n., Azzollini, J. n., Barrowdale, D. n., Baynes, C. n., Becher, H. n., Bermisheva, M. n., Bernstein, L. n., Białkowska, K. n., Blomqvist, C. n., Bojesen, S. E., Bonanni, B. n., Borg, A. n., Brauch, H. n., Brenner, H. n., Burwinkel, B. n., Buys, S. S., Caldés, T. n., Caligo, M. A., Campa, D. n., Carter, B. D., Castelao, J. E., Chang-Claude, J. n., Chanock, S. J., Chung, W. K., Claes, K. B., Clarke, C. L., Collée, J. M., Conroy, D. M., Czene, K. n., Daly, M. B., Devilee, P. n., Diez, O. n., Ding, Y. C., Domchek, S. M., Dörk, T. n., Dos-Santos-Silva, I. n., Dunning, A. M., Dwek, M. n., Eccles, D. M., Eliassen, A. H., Engel, C. n., Eriksson, M. n., Evans, D. G., Fasching, P. A., Flyger, H. n., Fostira, F. n., Friedman, E. n., Fritschi, L. n., Frost, D. n., Gago-Dominguez, M. n., Gapstur, S. M., Garber, J. n., Garcia-Barberan, V. n., García-Closas, M. n., García-Sáenz, J. A., Gaudet, M. M., Gayther, S. A., Gehrig, A. n., Georgoulias, V. n., Giles, G. G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., González-Neira, A. n., Greene, M. H., Guénel, P. n., Haeberle, L. n., Hahnen, E. n., Haiman, C. A., Håkansson, N. n., Hall, P. n., Hamann, U. n., Harrington, P. A., Hart, S. N., He, W. n., Hogervorst, F. B., Hollestelle, A. n., Hopper, J. L., Horcasitas, D. J., Hulick, P. J., Hunter, D. J., Imyanitov, E. N., Jager, A. n., Jakubowska, A. n., James, P. A., Jensen, U. B., John, E. M., Jones, M. E., Kaaks, R. n., Kapoor, P. M., Karlan, B. Y., Keeman, R. n., Khusnutdinova, E. n., Kiiski, J. I., Ko, Y. D., Kosma, V. M., Kraft, P. n., Kurian, A. W., Laitman, Y. n., Lambrechts, D. n., Le Marchand, L. n., Lester, J. n., Lesueur, F. n., Lindstrom, T. n., Lopez-Fernández, A. n., Loud, J. T., Luccarini, C. n., Mannermaa, A. n., Manoukian, S. n., Margolin, S. n., Martens, J. W., Mebirouk, N. n., Meindl, A. n., Miller, A. n., Milne, R. L., Montagna, M. n., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H. n., Nielsen, F. C., O'Brien, K. M., Olopade, O. I., Olson, J. E., Olsson, H. n., Osorio, A. n., Ottini, L. n., Park-Simon, T. W., Parsons, M. T., Pedersen, I. S., Peshkin, B. n., Peterlongo, P. n., Peto, J. n., Pharoah, P. D., Phillips, K. A., Polley, E. C., Poppe, B. n., Presneau, N. n., Pujana, M. A., Punie, K. n., Radice, P. n., Rantala, J. n., Rashid, M. U., Rennert, G. n., Rennert, H. S., Robson, M. n., Romero, A. n., Rossing, M. n., Saloustros, E. n., Sandler, D. P., Santella, R. n., Scheuner, M. T., Schmidt, M. K., Schmidt, G. n., Scott, C. n., Sharma, P. n., Soucy, P. n., Southey, M. C., Spinelli, J. J., Steinsnyder, Z. n., Stone, J. n., Stoppa-Lyonnet, D. n., Swerdlow, A. n., Tamimi, R. M., Tapper, W. J., Taylor, J. A., Terry, M. B., Teulé, A. n., Thull, D. L., Tischkowitz, M. n., Toland, A. E., Torres, D. n., Trainer, A. H., Truong, T. n., Tung, N. n., Vachon, C. M., Vega, A. n., Vijai, J. n., Wang, Q. n., Wappenschmidt, B. n., Weinberg, C. R., Weitzel, J. N., Wendt, C. n., Wolk, A. n., Yadav, S. n., Yang, X. R., Yannoukakos, D. n., Zheng, W. n., Ziogas, A. n., Zorn, K. K., Park, S. K., Thomassen, M. n., Offit, K. n., Schmutzler, R. K., Couch, F. J., Simard, J. n., Chenevix-Trench, G. n., Easton, D. F., Andrieu, N. n., Antoniou, A. C. 2021; 12 (1): 1078

  Abstract

  Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.

  View details for DOI 10.1038/s41467-020-20496-3

  View details for PubMedID 33597508

• A Population-Based Study of Genes Previously Implicated in Breast Cancer. The New England journal of medicine Hu, C. n., Hart, S. N., Gnanaolivu, R. n., Huang, H. n., Lee, K. Y., Na, J. n., Gao, C. n., Lilyquist, J. n., Yadav, S. n., Boddicker, N. J., Samara, R. n., Klebba, J. n., Ambrosone, C. B., Anton-Culver, H. n., Auer, P. n., Bandera, E. V., Bernstein, L. n., Bertrand, K. A., Burnside, E. S., Carter, B. D., Eliassen, H. n., Gapstur, S. M., Gaudet, M. n., Haiman, C. n., Hodge, J. M., Hunter, D. J., Jacobs, E. J., John, E. M., Kooperberg, C. n., Kurian, A. W., Le Marchand, L. n., Lindstroem, S. n., Lindstrom, T. n., Ma, H. n., Neuhausen, S. n., Newcomb, P. A., O'Brien, K. M., Olson, J. E., Ong, I. M., Pal, T. n., Palmer, J. R., Patel, A. V., Reid, S. n., Rosenberg, L. n., Sandler, D. P., Scott, C. n., Tamimi, R. n., Taylor, J. A., Trentham-Dietz, A. n., Vachon, C. M., Weinberg, C. n., Yao, S. n., Ziogas, A. n., Weitzel, J. N., Goldgar, D. E., Domchek, S. M., Nathanson, K. L., Kraft, P. n., Polley, E. C., Couch, F. J. 2021

  Abstract

  Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants.In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed.Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer.This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.).

  View details for DOI 10.1056/NEJMoa2005936

  View details for PubMedID 33471974

• Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk AMERICAN JOURNAL OF HUMAN GENETICS Kramer, I., Hooning, M. J., Mavaddat, N., Hauptmann, M., Keeman, R., Steyerberg, E. W., Giardiello, D., Antoniou, A. C., Pharoah, P. P., Canisius, S., Abu-Ful, Z., Andrulis, I. L., Anton-Culver, H., Aronson, K. J., Augustinsson, A., Becher, H., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bogdanova, N., Bojesen, S. E., Bolla, M. K., Bonanni, B., Brauch, H., Bremer, M., Brucker, S. Y., Burwinkel, B., Castelao, J. E., Chan, T. L., Chang-Claude, J., Chanock, S. J., Chenevix-Trench, G., Choi, J., Clarke, C. L., Collee, J., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Daly, M. B., Devilee, P., Dork, T., dos-Santos-Silva, I., Dunning, A. M., Dwek, M., Eccles, D. M., Evans, D., Fasching, P. A., Flyger, H., Gago-Dominguez, M., Garcia-Closas, M., Garcia-Saenz, J. A., Giles, G. G., Goldgar, D. E., Gonzalez-Neira, A., Haiman, C. A., Hakansson, N., Hamann, U., Hartman, M., Heemskerk-Gerritsen, B. M., Hollestelle, A., Hopper, J. L., Hou, M., Howell, A., Ito, H., Jakimovska, M., Jakubowska, A., Janni, W., John, E. M., Jung, A., Kang, D., Kets, C., Khusnutdinova, E., Ko, Y., Kristensen, V. N., Kurian, A. W., Kwong, A., Lambrechts, D., Le Marchand, L., Li, J., Lindblom, A., Mannermaa, A., Manoochehri, M., Margolin, S., Matsuo, K., Mavroudis, D., Meindl, A., Milne, R. L., Mulligan, A., Muranen, T. A., Neuhausen, S. L., Nevanlinna, H., Newman, W. G., Olshan, A. F., Olson, J. E., Olsson, H., Park-Simon, T., Peto, J., Petridis, C., Plaseska-Karanfilska, D., Presneau, N., Pylkas, K., Radice, P., Rennert, G., Romero, A., Roylance, R., Saloustros, E., Sawyer, E. J., Schmutzler, R. K., Schwentner, L., Scott, C., See, M., Shah, M., Shen, C., Shu, X., Siesling, S., Slager, S., Sohn, C., Southey, M. C., Spinelli, J. J., Stone, J., Tapper, W. J., Tengstrom, M., Teo, S., Terry, M., Tollenaar, R. M., Tomlinson, I., Troester, M. A., Vachon, C. M., van Ongeval, C., van Veen, E. M., Winqvist, R., Wolk, A., Zheng, W., Ziogas, A., Easton, D. F., Hall, P., Schmidt, M. K., NBCS Collaborators, ABCTB Investigators, kConFab Investigators 2020; 107 (5): 837–48

  View details for Web of Science ID 000587855200005

• The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor. Cancers Brandao, A., Paulo, P., Maia, S., Pinheiro, M., Peixoto, A., Cardoso, M., Silva, M. P., Santos, C., Eeles, R. A., Kote-Jarai, Z., Muir, K., Ukgpcs Collaborators, Schleutker, J., Wang, Y., Pashayan, N., Batra, J., Apcb BioResource, Gronberg, H., Neal, D. E., Nordestgaard, B. G., Tangen, C. M., Southey, M. C., Wolk, A., Albanes, D., Haiman, C. A., Travis, R. C., Stanford, J. L., Mucci, L. A., West, C. M., Nielsen, S. F., Kibel, A. S., Cussenot, O., Berndt, S. I., Koutros, S., Sorensen, K. D., Cybulski, C., Grindedal, E. M., Park, J. Y., Ingles, S. A., Maier, C., Hamilton, R. J., Rosenstein, B. S., Vega, A., The Impact Study Steering Committee And Collaborators, Kogevinas, M., Wiklund, F., Penney, K. L., Brenner, H., John, E. M., Kaneva, R., Logothetis, C. J., Neuhausen, S. L., Ruyck, K. D., Razack, A., Newcomb, L. F., Canary Pass Investigators, Lessel, D., Usmani, N., Claessens, F., Gago-Dominguez, M., Townsend, P. A., Roobol, M. J., The Profile Study Steering Committee, The Practical Consortium, Teixeira, M. R. 2020; 12 (11)

  Abstract

  The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.

  View details for DOI 10.3390/cancers12113254

  View details for PubMedID 33158149

• Pre-Pubertal Internalizing Symptoms and Timing of Puberty Onset in Girls. American journal of epidemiology Knight, J. A., Kehm, R. D., Schwartz, L., Frost, C. J., Chung, W. K., Colonna, S., Keegan, T. H., Goldberg, M., Houghton, L. C., Hanna, D., Glendon, G., Daly, M. B., Buys, S. S., Andrulis, I. L., John, E. M., Bradbury, A. R., Terry, M. B. 2020

  Abstract

  Stressful environments have been associated with earlier menarche. We hypothesized that anxiety, and possibly other internalizing symptoms, are also associated with earlier puberty in girls. The LEGACY Girls Study (2011-2016) includes 1040 girls aged 6 to 13 years at recruitment with growth and development assessed every 6 months. Pre-pubertal maternal reports of daughter's internalizing symptoms were available for breast onset (N=447), pubic hair onset (N=456), and menarche (N=681). Using Cox Proportional Hazard Regression, we estimated prospective hazard ratios (HRs) and 95% confidence intervals (CIs) for the relationship between one standard deviation of the percentiles of pre-pubertal anxiety, depression, and somatization symptoms and the timing of each pubertal outcome. Multivariable models included age, race/ethnicity, study center, maternal education, body mass index percentile, and breast cancer family history. Additional models included maternal self-reported anxiety. One standard deviation increase of maternally-reported anxiety in girls at baseline was associated with earlier subsequent onset of breast (HR 1.22, 95% CI 1.09-1.36) and pubic hair (HR 1.15, 95% CI 1.01-1.30) development, but not menarche (HR 0.94, 95% CI 0.83-1.07). The association of anxiety with earlier breast development persisted after adjustment for maternal anxiety. Increased anxiety in young girls may indicate risk for earlier pubertal onset.

  View details for DOI 10.1093/aje/kwaa223

  View details for PubMedID 33057572

• African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer. International journal of cancer Karunamuni, R. A., Huynh-Le, M., Fan, C. C., Thompson, W., Eeles, R. A., Kote-Jarai, Z., Muir, K., UKGPCS collaborators, Lophatananon, A., Tangen, C. M., Goodman, P. J., Thompson, I. M., Blot, W. J., Zheng, W., Kibel, A. S., Drake, B. F., Cussenot, O., Cancel-Tassin, G., Menegaux, F., Truong, T., Park, J. Y., Lin, H., Bensen, J. T., Fontham, E. T., Mohler, J. L., Taylor, J. A., Multigner, L., Blanchet, P., Brureau, L., Romana, M., Leach, R. J., John, E. M., Fowke, J., Bush, W. S., Aldrich, M., Crawford, D. C., Srivastava, S., Cullen, J. C., Petrovics, G., Parent, M., Hu, J. J., Sanderson, M., Mills, I. G., Andreassen, O. A., Dale, A. M., Seibert, T. M., PRACTICAL Consortium, Haiman, C. A., Schumacher, F. R., Benlloch, S., Olama, A. A., Berndt, S. I., Conti, D. V., Wiklund, F., Chanock, S., Gapstur, S. M., Stevens, V. L., Batra, J., Clements, J., BioResource, A., Gronberg, H., Pashayan, N., Schleutker, J., Albanes, D., Weinstein, S., Wolk, A., West, C., Mucci, L., Koutros, S., Sorensen, K. D., Grindedal, E. M., Neal, D. E., Hamdy, F. C., Donovan, J. L., Travis, R. C., Hamilton, R. J., Ingles, S. A., Rosenstein, B. S., Lu, Y., Giles, G. G., Vega, A., Kogevinas, M., Penney, K. L., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R., Usmani, N., Claessens, F., Townsend, P. A., Gago-Dominguez, M., Roobol, M. J., Khaw, K., Cannon-Albright, L., Pandha, H., Thibodeau, S. N., Kraft, P., Riboli, E. 2020

  Abstract

  Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46), showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify SNPs that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6,253 men with African genetic ancestry. Ten iterations of a ten-fold cross-validation search were conducted, to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African were compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890, and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47 to 4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65 to 0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ijc.33282

  View details for PubMedID 32930425

• Association of germline variation with the survival of women with BRCA1/2 pathogenic variants and breast cancer NPJ BREAST CANCER Muranen, T. A., Khan, S., Fagerholm, R., Aittomaeki, K., Cunningham, J. M., Dennis, J., Leslie, G., McGuffog, L., Parsons, M. T., Simard, J., Slager, S., Soucy, P., Easton, D. F., Tischkowitz, M., Spurdle, A. B., Schmutzler, R. K., Wappenschmidt, B., Hahnen, E., Hooning, M. J., Singer, C. F., Wagner, G., Thomassen, M., Pedersen, I., Domchek, S. M., Nathanson, K. L., Lazaro, C., Rossing, C., Andrulis, I. L., Teixeira, M. R., James, P., Garber, J., Weitzel, J. N., Jakubowska, A., Yannoukakos, D., John, E. M., Southey, M. C., Schmidt, M. K., Antoniou, A. C., Chenevix-Trench, G., Blomqvist, C., Nevanlinna, H., KConFab Investigators, HEBON Investigators, SWE BRCA Investigators 2020; 6 (1): 44

  Abstract

  Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in BRCA1 or BRCA2 genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of BRCA1 carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03-6.30, P = 3.1 × 10-9). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics.

  View details for DOI 10.1038/s41523-020-00185-6

  View details for Web of Science ID 000567882100001

  View details for PubMedID 32964118

  View details for PubMedCentralID PMC7483417

• Association of germline variation with the survival of women with BRCA1/2 pathogenic variants and breast cancer. NPJ breast cancer Muranen, T. A., Khan, S., Fagerholm, R., Aittomäki, K., Cunningham, J. M., Dennis, J., Leslie, G., McGuffog, L., Parsons, M. T., Simard, J., Slager, S., Soucy, P., Easton, D. F., Tischkowitz, M., Spurdle, A. B., Schmutzler, R. K., Wappenschmidt, B., Hahnen, E., Hooning, M. J., Singer, C. F., Wagner, G., Thomassen, M., Pedersen, I. S., Domchek, S. M., Nathanson, K. L., Lazaro, C., Rossing, C. M., Andrulis, I. L., Teixeira, M. R., James, P., Garber, J., Weitzel, J. N., Jakubowska, A., Yannoukakos, D., John, E. M., Southey, M. C., Schmidt, M. K., Antoniou, A. C., Chenevix-Trench, G., Blomqvist, C., Nevanlinna, H. 2020; 6 (1): 44

  Abstract

  Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in BRCA1 or BRCA2 genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of BRCA1 carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03-6.30, P = 3.1 × 10-9). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics.

  View details for DOI 10.1038/s41523-020-00185-6

  View details for PubMedID 34504104

• A case-control study of the joint effect of reproductive factors and radiation treatment for first breast cancer and risk of contralateral breast cancer in the WECARE study. Breast (Edinburgh, Scotland) Brooks, J. D., Boice, J. D., Shore, R. E., Reiner, A. S., Smith, S. A., Bernstein, L., Knight, J. A., Lynch, C. F., John, E. M., Malone, K. E., Mellemkjar, L., Langballe, R., Liang, X., Woods, M., Tischkowitz, M., Concannon, P., Stram, D. O., WECARE Study Collaborative Group, Bernstein, J. L. 2020; 54: 62–69

  Abstract

  OBJECTIVE: To examined the impact of reproductive factors on the relationship between radiation treatment (RT) for a first breast cancer and risk of contralateral breast cancer (CBC).METHODS: The Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study is a multi-center, population-based case-control study where cases are women with asynchronous CBC (N=1521) and controls are women with unilateral breast cancer (N=2211). Rate ratios (RR) and 95% confidence intervals (CI) were estimated using conditional logistic regression to assess the independent and joint effects of RT (ever/never and location-specific stray radiation dose to the contralateral breast [0, >0-<1Gy, ≥1Gy]) and reproductive factors (e.g., parity).RESULTS: Nulliparous women treated with RT (≥1Gy dose) were at increased risk of CBC compared with nulliparous women not treated with RT, although this relationship did not reach statistical significance (RR=1.34, 95% CI 0.87, 2.07). Women treated with RT who had an interval pregnancy (i.e., pregnancy after first diagnosis and before second diagnosis [in cases]/reference date [in controls]) had an increased risk of CBC compared with those who had an interval pregnancy with no RT (RR=4.60, 95% CI 1.16, 18.28). This was most apparent for women with higher radiation doses to the contralateral breast.CONCLUSION: Among young female survivors of breast cancer, we found some evidence suggesting that having an interval pregnancy could increase a woman's risk of CBC following RT for a first breast cancer. While sampling variability precludes strong interpretations, these findings suggest a role for pregnancy and hormonal factors in radiation-associated CBC.

  View details for DOI 10.1016/j.breast.2020.07.007

  View details for PubMedID 32927238

• Cross-ancestry genome-wide association study identifies six new loci for breast cancer in women of African and european ancestry Adedokun, B., Du, Z., Gao, G., Ahearn, T., Lunetta, K. L., Zirpoli, G., Figueroa, J., John, E. M., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Yao, S., Ogundiran, T. O., Ojengbede, O., Blot, W., Troester, M., Nathanson, K. L., Hennis, A., Nemesure, B., Ambs, S., Sucheston-Campbell, L. E., Bensen, J. T., Chanock, S. J., Olshan, A. F., Ambrosone, C. B., Conti, D., Olopade, O., Garcia-Closas, M., Palmer, J. R., Haiman, C. A., Huo, D. AMER ASSOC CANCER RESEARCH. 2020

  View details for DOI 10.1158/1538-7445.AM2020-4613

  View details for Web of Science ID 000590059301302

• External validation of the BOADICEA model for predicting ovarian cancer risk: The Breast Cancer Family Registry Ferris, J. S., Genkinger, J. M., Terry, M., Liao, Y., MacInnis, R. J., Andrulis, I. L., Buys, S. S., Daly, M. B., John, E. M., Hopper, J. L. AMER ASSOC CANCER RESEARCH. 2020

  View details for DOI 10.1158/1538-7445.AM2020-4623

  View details for Web of Science ID 000590059301308

• Integrating genomic and transcriptomic data to identify genetic loci associated with breast cancer risk in women of African ancestry Jia, G., Ping, J., Yang, Y., Sanderson, M., Cai, Q., Guo, X., Blot, W. J., Li, B., Bandera, E. V., Bolla, M. K., Garcia-Closas, M., Easton, D. F., Fadden, M. K., Gu, J., Huo, D., John, E. M., Lunetta, K. L., Olopade, O. I., Shu, X., Troester, M. A., Yao, S., Olshan, A. F., Ambrosone, C. B., Haiman, C. A., Long, J., Palmer, J. R., Zheng, W., Breast Canc Assoc Consortium AMER ASSOC CANCER RESEARCH. 2020

  View details for DOI 10.1158/1538-7445.AM2020-28

  View details for Web of Science ID 000590059300002

• Evaluating a polygenic risk score for breast cancer in women of African ancestry Du, Z., Gao, G., Adedokun, B., Ahearn, T., Lunetta, K. L., Zirpoli, G., Troester, M., Ruiz-Narvaez, E. A., Haddad, S., Figueroa, J., John, E. M., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Yao, S., Ogundiran, T. O., Ojengbede, O. A., Blot, W., Nathanson, K. L., Hennis, A., Nemesure, B., Ambs, S., Sucheston-Campbell, L. E., Bensen, J. T., Chanock, S. J., Olshan, A. F., Ambrosone, C. B., Conti, D. V., Olopade, O. I., Palmer, J. R., Garcia-Closas, M., Huo, D., Haiman, C. A. AMER ASSOC CANCER RESEARCH. 2020

  View details for DOI 10.1158/1538-7445.AM2020-2320

  View details for Web of Science ID 000590059300370

• Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants. Genetics in medicine : official journal of the American College of Medical Genetics Barnes, D. R., Rookus, M. A., McGuffog, L., Leslie, G., Mooij, T. M., Dennis, J., Mavaddat, N., Adlard, J., Ahmed, M., Aittomaki, K., Andrieu, N., Andrulis, I. L., Arnold, N., Arun, B. K., Azzollini, J., Balmana, J., Barkardottir, R. B., Barrowdale, D., Benitez, J., Berthet, P., Bialkowska, K., Blanco, A. M., Blok, M. J., Bonanni, B., Boonen, S. E., Borg, A., Bozsik, A., Bradbury, A. R., Brennan, P., Brewer, C., Brunet, J., Buys, S. S., Caldes, T., Caligo, M. A., Campbell, I., Christensen, L. L., Chung, W. K., Claes, K. B., Colas, C., GEMO Study Collaborators, EMBRACE Collaborators, Collonge-Rame, M., Cook, J., Daly, M. B., Davidson, R., de la Hoya, M., de Putter, R., Delnatte, C., Devilee, P., Diez, O., Ding, Y. C., Domchek, S. M., Dorfling, C. M., Dumont, M., Eeles, R., Ejlertsen, B., Engel, C., Evans, D. G., Faivre, L., Foretova, L., Fostira, F., Friedlander, M., Friedman, E., Frost, D., Ganz, P. A., Garber, J., Gehrig, A., Gerdes, A., Gesta, P., Giraud, S., Glendon, G., Godwin, A. K., Goldgar, D. E., Gonzalez-Neira, A., Greene, M. H., Gschwantler-Kaulich, D., Hahnen, E., Hamann, U., Hanson, H., Hentschel, J., Hogervorst, F. B., Hooning, M. J., Horvath, J., Hu, C., Hulick, P. J., Imyanitov, E. N., kConFab Investigators, HEBON Investigators, GENEPSO Investigators, Isaacs, C., Izatt, L., Izquierdo, A., Jakubowska, A., James, P. A., Janavicius, R., John, E. M., Joseph, V., Karlan, B. Y., Kast, K., Koudijs, M., Kruse, T. A., Kwong, A., Laitman, Y., Lasset, C., Lazaro, C., Lester, J., Lesueur, F., Liljegren, A., Loud, J. T., Lubinski, J., Mai, P. L., Manoukian, S., Mari, V., Mebirouk, N., Meijers-Heijboer, H. E., Meindl, A., Mensenkamp, A. R., Miller, A., Montagna, M., Mouret-Fourme, E., Mukherjee, S., Mulligan, A. M., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Niederacher, D., Nielsen, F. C., Nikitina-Zake, L., Nogues, C., Olah, E., Olopade, O. I., Ong, K., O'Shaughnessy-Kirwan, A., Osorio, A., Ott, C., Papi, L., Park, S. K., Parsons, M. T., Pedersen, I. S., Peissel, B., Peixoto, A., Peterlongo, P., Pfeiler, G., Phillips, K., Prajzendanc, K., Pujana, M. A., Radice, P., Ramser, J., Ramus, S. J., Rantala, J., Rennert, G., Risch, H. A., Robson, M., Ronlund, K., Salani, R., Schuster, H., Senter, L., Shah, P. D., Sharma, P., Side, L. E., Singer, C. F., Slavin, T. P., Soucy, P., Southey, M. C., Spurdle, A. B., Steinemann, D., Steinsnyder, Z., Stoppa-Lyonnet, D., Sutter, C., Tan, Y. Y., Teixeira, M. R., Teo, S. H., Thull, D. L., Tischkowitz, M., Tognazzo, S., Toland, A. E., Trainer, A. H., Tung, N., van Engelen, K., van Rensburg, E. J., Vega, A., Vierstraete, J., Wagner, G., Walker, L., Wang-Gohrke, S., Wappenschmidt, B., Weitzel, J. N., Yadav, S., Yang, X., Yannoukakos, D., Zimbalatti, D., Offit, K., Thomassen, M., Couch, F. J., Schmutzler, R. K., Simard, J., Easton, D. F., Chenevix-Trench, G., Antoniou, A. C., Consortium of Investigators of Modifiers of BRCA and BRCA2, Berthet, P., Colas, C., Collonge-Rame, M., Delnatte, C., Faivre, L., Giraud, S., Lasset, C., Mari, V., Mebirouk, N., Mouret-Fourme, E., Schuster, H., Stoppa-Lyonnet, D., Adlard, J., Ahmed, M., Antoniou, A., Barrowdale, D., Brennan, P., Brewer, C., Cook, J., Davidson, R., Easton, D., Eeles, R., Evans, D. G., Frost, D., Hanson, H., Izatt, L., Ong, K., Side, L., O'Shaughnessy-Kirwan, A., Tischkowitz, M., Walker, L., Chenevix-Trench, G., Phillips, K., Spurdle, A., Blok, M., Devilee, P., Hogervorst, F., Hooning, M., Koudijs, M., Mensenkamp, A., Meijers-Heijboer, H., Rookus, M., Engelen, K. v., Andrieu, N., Nogues, C. 2020

  Abstract

  PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers.METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort.RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation=1.29 [95% CI 1.25-1.33], P=3*10-72). For BRCA2, the strongest association was with overall BC PRS (HR=1.31 [95% CI 1.27-1.36], P=7*10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR=1.32 [95% CI 1.25-1.40], P=3*10-22) and BRCA2 (HR=1.44 [95% CI 1.30-1.60], P=4*10-12) carriers. The associations in the prospective cohort were similar.CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

  View details for DOI 10.1038/s41436-020-0862-x

  View details for PubMedID 32665703

• Infancy and childhood infections and pubertal timing in the LEGACY Girls' Study Huang, Y., Andrulis, I. L., Bradbury, A. R., Buys, S. S., Daly, M. B., John, E. M., Schwartz, L. A., Terry, M., McDonald, J. A. AMER ASSOC CANCER RESEARCH. 2020: 37

  View details for Web of Science ID 000546012200045

• Breast cancer risk in U.S-born Latina women: potential role of reactive electrophiles Serrano-Gomez, S. J., Schiffman, C., Grigoryan, H., Carlsson, H., Dudoit, S., John, E. M., Rappaport, S. M., Fejerman, L. AMER ASSOC CANCER RESEARCH. 2020

  View details for DOI 10.1158/1538-7755.DISP18-C065

  View details for Web of Science ID 000577495000416

• A meta-analysis of genome-wide association study and eQTL analysis of multiple myeloma among African Americans Du, Z., Weinhold, N., Song, G., Rand, K. A., Van den Berg, D. J., Hwang, A. E., Sheng, X., Hom, V., Ailawadhi, S., Nooka, A. K., Singhal, S., Pawlish, K., Peters, E., Bock, C., Mohrbacher, A., Stram, A., Berndt, S., Blot, W. J., Casey, G., Stevens, V. L., Kittles, R., Goodman, P. J., Diver, W., Hennis, A., Nemesure, B., Klein, E. A., Rybicki, B. A., Stanford, J. L., Witte, J. S., Signorello, L., John, E. M., Bernstein, L., Stroup, A., Stephens, O. W., Zangari, M., Van Rhee, F., Olshan, A., Zheng, W., Hu, J. J., Ziegler, R., Nyante, S. J., Ingles, S., Press, M., Carpten, J., Chanock, S., Mehta, J., Colditz, G. A., Wolf, J., Martin, T. G., Tomasson, M., Fiala, M. A., Terebelo, H., Janakiraman, N., Kolonel, L., Anderson, K. C., Le Marchand, L., Auclair, D., Chiu, B., Ziv, E., Stram, D., Vij, R., Bernal-Mizrachi, L., Morgan, G. J., Zonder, J. A., Huff, C., Lonial, S., Orlowski, R. Z., Conti, D., Haiman, C. A. AMER ASSOC CANCER RESEARCH. 2020

  View details for DOI 10.1158/1538-7755.DISP19-PR05

  View details for Web of Science ID 000580647800526

• Contribution of Germline Predisposition Gene Mutations to Breast Cancer Risk in African American Women. Journal of the National Cancer Institute Palmer, J. R., Polley, E. C., Hu, C., John, E. M., Haiman, C., Hart, S. N., Gaudet, M., Pal, T., Anton-Culver, H., Trentham-Dietz, A., Bernstein, L., Ambrosone, C. B., Bandera, E. V., Bertrand, K. A., Bethea, T. N., Gao, C., Gnanaolivu, R. D., Huang, H., Lee, K. Y., LeMarchand, L., Na, J., Sandler, D. P., Shah, P. D., Yadav, S., Yang, W., Weitzel, J. N., Domchek, S. M., Goldgar, D. E., Nathanson, K. L., Kraft, P., Couch, F. J. 2020

  Abstract

  BACKGROUND: The risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes are not well defined. Thus, whether multigene germline hereditary cancer testing panels are applicable to this population is unknown. We assessed associations between mutations in panel-based genes and breast cancer risk in 5054 AA women with breast cancer and 4993 unaffected AA women drawn from 10 epidemiologic studies.METHODS: Germline DNA samples were sequenced for mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel. Prevalence of mutations and odds ratios (ORs) for associations with breast cancer risk were estimated with adjustment for study design, age, and family history of breast cancer.RESULTS: Pathogenic mutations were identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations inBRCA1,BRCA2, andPALB2were associated with high risks of breast cancer (OR = 47.55, 95% confidence interval [CI] = 10.43 to >100; OR = 7.25, 95% CI = 4.07 to 14.12; OR = 8.54, 95% CI = 3.67 to 24.95, respectively). RAD51D mutations were associated with high risk of ER-negative disease (OR = 7.82, 95% CI = 1.61 to 57.42). Moderate risks were observed for CHEK2, ATM, ERCC3, and FANCC mutations with ER-positive cancer, and RECQL mutations with all breast cancer.CONCLUSIONS: The study identifies genes that predispose to breast cancer in the AA population, demonstrates the validity of current breast cancer testing panels for use in AA women, and provides a basis for increased referral of AA patients for cancer genetic testing.

  View details for DOI 10.1093/jnci/djaa040

  View details for PubMedID 32427313

• Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses. Nature genetics Zhang, H., Ahearn, T. U., Lecarpentier, J., Barnes, D., Beesley, J., Qi, G., Jiang, X., O'Mara, T. A., Zhao, N., Bolla, M. K., Dunning, A. M., Dennis, J., Wang, Q., Ful, Z. A., Aittomaki, K., Andrulis, I. L., Anton-Culver, H., Arndt, V., Aronson, K. J., Arun, B. K., Auer, P. L., Azzollini, J., Barrowdale, D., Becher, H., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bialkowska, K., Blanco, A., Blomqvist, C., Bogdanova, N. V., Bojesen, S. E., Bonanni, B., Bondavalli, D., Borg, A., Brauch, H., Brenner, H., Briceno, I., Broeks, A., Brucker, S. Y., Bruning, T., Burwinkel, B., Buys, S. S., Byers, H., Caldes, T., Caligo, M. A., Calvello, M., Campa, D., Castelao, J. E., Chang-Claude, J., Chanock, S. J., Christiaens, M., Christiansen, H., Chung, W. K., Claes, K. B., Clarke, C. L., Cornelissen, S., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Daly, M. B., Devilee, P., Diez, O., Domchek, S. M., Dork, T., Dwek, M., Eccles, D. M., Ekici, A. B., Evans, D. G., Fasching, P. A., Figueroa, J., Foretova, L., Fostira, F., Friedman, E., Frost, D., Gago-Dominguez, M., Gapstur, S. M., Garber, J., Garcia-Saenz, J. A., Gaudet, M. M., Gayther, S. A., Giles, G. G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Greene, M. H., Gronwald, J., Guenel, P., Haberle, L., Hahnen, E., Haiman, C. A., Hake, C. R., Hall, P., Hamann, U., Harkness, E. F., Heemskerk-Gerritsen, B. A., Hillemanns, P., Hogervorst, F. B., Holleczek, B., Hollestelle, A., Hooning, M. J., Hoover, R. N., Hopper, J. L., Howell, A., Huebner, H., Hulick, P. J., Imyanitov, E. N., kConFab Investigators, ABCTB Investigators, Isaacs, C., Izatt, L., Jager, A., Jakimovska, M., Jakubowska, A., James, P., Janavicius, R., Janni, W., John, E. M., Jones, M. E., Jung, A., Kaaks, R., Kapoor, P. M., Karlan, B. Y., Keeman, R., Khan, S., Khusnutdinova, E., Kitahara, C. M., Ko, Y., Konstantopoulou, I., Koppert, L. B., Koutros, S., Kristensen, V. N., Laenkholm, A., Lambrechts, D., Larsson, S. C., Laurent-Puig, P., Lazaro, C., Lazarova, E., Lejbkowicz, F., Leslie, G., Lesueur, F., Lindblom, A., Lissowska, J., Lo, W., Loud, J. T., Lubinski, J., Lukomska, A., MacInnis, R. J., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M. E., Matricardi, L., McGuffog, L., McLean, C., Mebirouk, N., Meindl, A., Menon, U., Miller, A., Mingazheva, E., Montagna, M., Mulligan, A. M., Mulot, C., Muranen, T. A., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Neven, P., Newman, W. G., Nielsen, F. C., Nikitina-Zake, L., Nodora, J., Offit, K., Olah, E., Olopade, O. I., Olsson, H., Orr, N., Papi, L., Papp, J., Park-Simon, T., Parsons, M. T., Peissel, B., Peixoto, A., Peshkin, B., Peterlongo, P., Peto, J., Phillips, K., Piedmonte, M., Plaseska-Karanfilska, D., Prajzendanc, K., Prentice, R., Prokofyeva, D., Rack, B., Radice, P., Ramus, S. J., Rantala, J., Rashid, M. U., Rennert, G., Rennert, H. S., Risch, H. A., Romero, A., Rookus, M. A., Rubner, M., Rudiger, T., Saloustros, E., Sampson, S., Sandler, D. P., Sawyer, E. J., Scheuner, M. T., Schmutzler, R. K., Schneeweiss, A., Schoemaker, M. J., Schottker, B., Schurmann, P., Senter, L., Sharma, P., Sherman, M. E., Shu, X., Singer, C. F., Smichkoska, S., Soucy, P., Southey, M. C., Spinelli, J. J., Stone, J., Stoppa-Lyonnet, D., EMBRACE Study, GEMO Study Collaborators, Swerdlow, A. J., Szabo, C. I., Tamimi, R. M., Tapper, W. J., Taylor, J. A., Teixeira, M. R., Terry, M., Thomassen, M., Thull, D. L., Tischkowitz, M., Toland, A. E., Tollenaar, R. A., Tomlinson, I., Torres, D., Troester, M. A., Truong, T., Tung, N., Untch, M., Vachon, C. M., van den Ouweland, A. M., van der Kolk, L. E., van Veen, E. M., vanRensburg, E. J., Vega, A., Wappenschmidt, B., Weinberg, C. R., Weitzel, J. N., Wildiers, H., Winqvist, R., Wolk, A., Yang, X. R., Yannoukakos, D., Zheng, W., Zorn, K. K., Milne, R. L., Kraft, P., Simard, J., Pharoah, P. D., Michailidou, K., Antoniou, A. C., Schmidt, M. K., Chenevix-Trench, G., Easton, D. F., Chatterjee, N., Garcia-Closas, M. 2020

  Abstract

  Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P<5.0*10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate<0.05). Five loci showed associations (P<0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

  View details for DOI 10.1038/s41588-020-0609-2

  View details for PubMedID 32424353

• Radiation treatment, ATM, BRCA1/2, and CHEK2*1100delC pathogenic variants, and risk of contralateral breast cancer. Journal of the National Cancer Institute Reiner, A. S., Robson, M. E., Mellemkjar, L., Tischkowitz, M., John, E. M., Lynch, C. F., Brooks, J. D., Boice, J. D., Knight, J. A., Teraoka, S. N., Liang, X., Woods, M., Shen, R., Shore, R. E., Stram, D. O., Thomas, D. C., Malone, K. E., Bernstein, L., Riaz, N., Woodward, W., Powell, S., Goldgar, D., Concannon, P., WECARE Study Collaborative Group, Bernstein, J. L. 2020

  Abstract

  Whether radiation therapy (RT) affects contralateral breast cancer (CBC) risk in women with pathogenic germline variants in moderate- to high-penetrance breast cancer-associated genes is unknown. In a population-based case-control study, we examined the association between RT, variants in ATM, BRCA1/2, or CHEK2*1100delC, and CBC risk. We analyzed 708 cases of women with CBC, and 1,399 controls with unilateral breast cancer, all diagnosed with first invasive breast cancer between 1985-2000, <55 years of age at diagnosis, and screened for variants in breast cancer-associated genes. Rate ratios and 95% confidence intervals were estimated using multivariable conditional logistic regression. RT did not modify the association between known pathogenic variants and CBC risk (e.g., BRCA1/2 pathogenic variant carriers without RT, RR: 3.52, 95% CI: 1.76-7.01; BRCA1/2 pathogenic variant carriers with RT, RR: 4.46, 95% CI: 2.96-6.71), suggesting that modifying RT plans for young women with breast cancer is unwarranted. Rare ATM missense variants, not currently identified as pathogenic, were associated with increased risk of RT-associated CBC (carriers of ATM rare missense variants of uncertain significance without RT, RR: 0.38, 95% CI: 0.09-1.55; carriers of ATM rare missense variants of uncertain significance with RT, RR: 2.98, 95% CI: 1.31-6.80). Further mechanistic studies will aid clinical decision-making related to RT.

  View details for DOI 10.1093/jnci/djaa031

  View details for PubMedID 32119081

• Transcriptome-wide association study of breast cancer risk by estrogen-receptor status. Genetic epidemiology Feng, H., Gusev, A., Pasaniuc, B., Wu, L., Long, J., Abu-Full, Z., Aittomaki, K., Andrulis, I. L., Anton-Culver, H., Antoniou, A. C., Arason, A., Arndt, V., Aronson, K. J., Arun, B. K., Asseryanis, E., Auer, P. L., Azzollini, J., Balmana, J., Barkardottir, R. B., Barnes, D. R., Barrowdale, D., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bialkowska, K., Blanco, A., Blomqvist, C., Boeckx, B., Bogdanova, N. V., Bojesen, S. E., Bolla, M. K., Bonanni, B., Borg, A., Brauch, H., Brenner, H., Briceno, I., Broeks, A., Bruning, T., Burwinkel, B., Cai, Q., Caldes, T., Caligo, M. A., Campbell, I., Canisius, S., Campa, D., Carter, B. D., Carter, J., Castelao, J. E., Chang-Claude, J., Chanock, S. J., Christiansen, H., Chung, W. K., Claes, K. B., Clarke, C. L., GEMO Study Collaborators, EMBRACE Collaborators, GC-HBOC study Collaborators, Couch, F. J., Cox, A., Cross, S. S., Cybulski, C., Czene, K., Daly, M. B., de la Hoya, M., De Leeneer, K., Dennis, J., Devilee, P., Diez, O., Domchek, S. M., Dork, T., Dos-Santos-Silva, I., Dunning, A. M., Dwek, M., Eccles, D. M., Ejlertsen, B., Ellberg, C., Engel, C., Eriksson, M., Fasching, P. A., Fletcher, O., Flyger, H., Fostira, F., Friedman, E., Fritschi, L., Frost, D., Gabrielson, M., Ganz, P. A., Gapstur, S. M., Garber, J., Garcia-Closas, M., Garcia-Saenz, J. A., Gaudet, M. M., Giles, G. G., Glendon, G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Greene, M. H., Gronwald, J., Guenel, P., Haiman, C. A., Hall, P., Hamann, U., Hake, C., He, W., Heyworth, J., Hogervorst, F. B., Hollestelle, A., Hooning, M. J., Hoover, R. N., Hopper, J. L., Huang, G., Hulick, P. J., Humphreys, K., Imyanitov, E. N., ABCTB Investigators, HEBON Investigators, BCFR Investigators, OCGN Investigators, Isaacs, C., Jakimovska, M., Jakubowska, A., James, P., Janavicius, R., Jankowitz, R. C., John, E. M., Johnson, N., Joseph, V., Jung, A., Karlan, B. Y., Khusnutdinova, E., Kiiski, J. I., Konstantopoulou, I., Kristensen, V. N., Laitman, Y., Lambrechts, D., Lazaro, C., Leroux, D., Leslie, G., Lester, J., Lesueur, F., Lindor, N., Lindstrom, S., Lo, W., Loud, J. T., Lubinski, J., Makalic, E., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martens, J. W., Martinez, M. E., Matricardi, L., Maurer, T., Mavroudis, D., McGuffog, L., Meindl, A., Menon, U., Michailidou, K., Kapoor, P. M., Miller, A., Montagna, M., Moreno, F., Moserle, L., Mulligan, A. M., Muranen, T. A., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Nevelsteen, I., Nielsen, F. C., Nikitina-Zake, L., Offit, K., Olah, E., Olopade, O. I., Olsson, H., Osorio, A., Papp, J., Park-Simon, T., Parsons, M. T., Pedersen, I. S., Peixoto, A., Peterlongo, P., Peto, J., Pharoah, P. D., Phillips, K., Plaseska-Karanfilska, D., Poppe, B., Pradhan, N., Prajzendanc, K., Presneau, N., Punie, K., Pylkas, K., Radice, P., Rantala, J., Rashid, M. U., Rennert, G., Risch, H. A., Robson, M., Romero, A., Saloustros, E., Sandler, D. P., Santos, C., Sawyer, E. J., Schmidt, M. K., Schmidt, D. F., Schmutzler, R. K., Schoemaker, M. J., Scott, R. J., Sharma, P., Shu, X., Simard, J., Singer, C. F., Skytte, A., Soucy, P., Southey, M. C., Spinelli, J. J., Spurdle, A. B., Stone, J., Swerdlow, A. J., Tapper, W. J., Taylor, J. A., Teixeira, M. R., Terry, M. B., Teule, A., Thomassen, M., Thone, K., Thull, D. L., Tischkowitz, M., Toland, A. E., Tollenaar, R. A., Torres, D., Truong, T., Tung, N., Vachon, C. M., van Asperen, C. J., van den Ouweland, A. M., van Rensburg, E. J., Vega, A., Viel, A., Vieiro-Balo, P., Wang, Q., Wappenschmidt, B., Weinberg, C. R., Weitzel, J. N., Wendt, C., Winqvist, R., Yang, X. R., Yannoukakos, D., Ziogas, A., Milne, R. L., Easton, D. F., Chenevix-Trench, G., Zheng, W., Kraft, P., Jiang, X. 2020

  Abstract

  Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.

  View details for DOI 10.1002/gepi.22288

  View details for PubMedID 32115800

• Correction to: Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers. Breast cancer research : BCR Mavaddat, N., Antoniou, A. C., Mooij, T. M., Hooning, M. J., Heemskerk-Gerritsen, B. A., GENEPSO, Nogues, C., Gauthier-Villars, M., Caron, O., Gesta, P., Pujol, P., Lortholary, A., EMBRACE, Barrowdale, D., Frost, D., Evans, D. G., Izatt, L., Adlard, J., Eeles, R., Brewer, C., Tischkowitz, M., Henderson, A., Cook, J., Eccles, D., HEBON, van Engelen, K., Mourits, M. J., Ausems, M. G., Koppert, L. B., Hopper, J. L., John, E. M., Chung, W. K., Andrulis, I. L., Daly, M. B., Buys, S. S., kConFab Investigators, Benitez, J., Caldes, T., Jakubowska, A., Simard, J., Singer, C. F., Tan, Y., Olah, E., Navratilova, M., Foretova, L., Gerdes, A., Roos-Blom, M., Van Leeuwen, F. E., Arver, B., Olsson, H., Schmutzler, R. K., Engel, C., Kast, K., Phillips, K., Terry, M. B., Milne, R. L., Goldgar, D. E., Rookus, M. A., Andrieu, N., Easton, D. F., IBCCS, k. a. 2020; 22 (1): 25

  Abstract

  After publication of the original article [1], we were notified that columns in Table 2 were erroneously displayed.

  View details for DOI 10.1186/s13058-020-01259-w

  View details for PubMedID 32102695

• Menstrual and reproductive characteristics and breast cancer risk by hormone receptor status and race/ethnicity: The Breast Cancer Etiology in Minorities (BEM) Study. International journal of cancer John, E. M., Phipps, A. I., Hines, L. M., Koo, J., Ingles, S. A., Baumgartner, K. B., Slattery, M. L., Wu, A. H. 2020

  Abstract

  We pooled multiethnic data from four population-based studies and examined associations of menstrual and reproductive characteristics with breast cancer (BC) risk by tumor hormone receptor (HR) status [defined by estrogen receptor (ER) and progesterone receptor (PR)]. We estimated odds ratios and 95% confidence intervals using multivariable logistic regression, stratified by age (<50, ≥50years) and race/ethnicity, for 5,186 HR+ (ER+ or PR+) cases, 1,365 HR- (ER- and PR-) cases, and 7,480 controls. For HR+ BC, later menarche and earlier menopause were associated with lower risk in non-Hispanic whites (NHWs) and Hispanics, and higher parity and longer breast-feeding were associated with lower risk in Hispanics and Asian Americans, and suggestively in NHWs. Positive associations with later first full-term pregnancy (FTP), longer interval between menarche and first FTP, and shorter time since last FTP were limited to younger Hispanics and Asian Americans. Except for nulliparity, reproductive characteristics were not associated with risk in African Americans. For HR- BC, lower risk was associated with later menarche, except in African Americans and older Asian Americans, and with longer breast-feeding in Hispanics and Asian Americans only. In younger African Americans, HR- BC risk associated with higher parity (≥3 vs. 1 FTP) was increased four-fold in women who never breast-fed, but not in those with a breast-feeding history, suggesting that breast-feeding may mitigate the adverse effect of higher parity in younger African American women. Further work needs to evaluate why menstrual and reproductive risk factors vary in importance according to age and race/ethnicity. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ijc.32923

  View details for PubMedID 32064598

• A network analysis to identify mediators of germline-driven differences in breast cancer prognosis. Nature communications Escala-Garcia, M., Abraham, J., Andrulis, I. L., Anton-Culver, H., Arndt, V., Ashworth, A., Auer, P. L., Auvinen, P., Beckmann, M. W., Beesley, J., Behrens, S., Benitez, J., Bermisheva, M., Blomqvist, C., Blot, W., Bogdanova, N. V., Bojesen, S. E., Bolla, M. K., Borresen-Dale, A., Brauch, H., Brenner, H., Brucker, S. Y., Burwinkel, B., Caldas, C., Canzian, F., Chang-Claude, J., Chanock, S. J., Chin, S., Clarke, C. L., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Daly, M. B., Dennis, J., Devilee, P., Dunn, J. A., Dunning, A. M., Dwek, M., Earl, H. M., Eccles, D. M., Eliassen, A. H., Ellberg, C., Evans, D. G., Fasching, P. A., Figueroa, J., Flyger, H., Gago-Dominguez, M., Gapstur, S. M., Garcia-Closas, M., Garcia-Saenz, J. A., Gaudet, M. M., George, A., Giles, G. G., Goldgar, D. E., Gonzalez-Neira, A., Grip, M., Guenel, P., Guo, Q., Haiman, C. A., Hakansson, N., Hamann, U., Harrington, P. A., Hiller, L., Hooning, M. J., Hopper, J. L., Howell, A., Huang, C., Huang, G., Hunter, D. J., Jakubowska, A., John, E. M., Kaaks, R., Kapoor, P. M., Keeman, R., Kitahara, C. M., Koppert, L. B., Kraft, P., Kristensen, V. N., Lambrechts, D., Le Marchand, L., Lejbkowicz, F., Lindblom, A., Lubinski, J., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M. E., Maurer, T., Mavroudis, D., Meindl, A., Milne, R. L., Mulligan, A. M., Neuhausen, S. L., Nevanlinna, H., Newman, W. G., Olshan, A. F., Olson, J. E., Olsson, H., Orr, N., Peterlongo, P., Petridis, C., Prentice, R. L., Presneau, N., Punie, K., Ramachandran, D., Rennert, G., Romero, A., Sachchithananthan, M., Saloustros, E., Sawyer, E. J., Schmutzler, R. K., Schwentner, L., Scott, C., Simard, J., Sohn, C., Southey, M. C., Swerdlow, A. J., Tamimi, R. M., Tapper, W. J., Teixeira, M. R., Terry, M. B., Thorne, H., Tollenaar, R. A., Tomlinson, I., Troester, M. A., Truong, T., Turnbull, C., Vachon, C. M., van der Kolk, L. E., Wang, Q., Winqvist, R., Wolk, A., Yang, X. R., Ziogas, A., Pharoah, P. D., Hall, P., Wessels, L. F., Chenevix-Trench, G., Bader, G. D., Dork, T., Easton, D. F., Canisius, S., Schmidt, M. K. 2020; 11 (1): 312

  Abstract

  Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.

  View details for DOI 10.1038/s41467-019-14100-6

  View details for PubMedID 31949161

• Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers. Breast cancer research : BCR Mavaddat, N., Antoniou, A. C., Mooij, T. M., Hooning, M. J., Heemskerk-Gerritsen, B. A., GENEPSO, Nogues, C., Gauthier-Villars, M., Caron, O., Gesta, P., Pujol, P., Lortholary, A., EMBRACE, Barrowdale, D., Frost, D., Evans, D. G., Izatt, L., Adlard, J., Eeles, R., Brewer, C., Tischkowitz, M., Henderson, A., Cook, J., Eccles, D., HEBON, van Engelen, K., Mourits, M. J., Ausems, M. G., Koppert, L. B., Hopper, J. L., John, E. M., Chung, W. K., Andrulis, I. L., Daly, M. B., Buys, S. S., kConFab Investigators, Benitez, J., Caldes, T., Jakubowska, A., Simard, J., Singer, C. F., Tan, Y., Olah, E., Navratilova, M., Foretova, L., Gerdes, A., Roos-Blom, M., Van Leeuwen, F. E., Arver, B., Olsson, H., Schmutzler, R. K., Engel, C., Kast, K., Phillips, K., Terry, M. B., Milne, R. L., Goldgar, D. E., Rookus, M. A., Andrieu, N., Easton, D. F., IBCCS, kConFab, BCFR, Nogues, C., Laborde, L., Breysse, E., Stoppa-Lyonnet, D., Gauthier-Villars, M., Buecher, B., Caron, O., Fourme-Mouret, E., Fricker, J., Lasset, C., Bonadona, V., Berthet, P., Faivre, L., Luporsi, E., Mari, V., Gladieff, L., Gesta, P., Sobol, H., Eisinger, F., Nogues, C., Longy, M., Dugast, C., Colas, C., Coupier, I., Pujol, P., Corsini, C., Lortholary, A., Vennin, P., Adenis, C., Nguyen, T. D., Delnatte, C., Tinat, J., Tennevet, I., Limacher, J., Maugard, C., Bignon, Y., Demange, L., Penet, C., Dreyfus, H., Cohen-Haguenauer, O., Venat-Bouvet, L., Leroux, D., Dreyfus, H., Zattara-Cannoni, H., Fert-Ferrer, S., Bera, O., Ellis, S., Hogervorst, F. B., Collee, J. M., van Asperen, C. J., Mensenkamp, A. R., Ausems, M. G., Meijers-Heijboer, H. E., van Engelen, K., Blok, M. J., Oosterwijk, J. C., Verloop, J., van den Broek, E. 2020; 22 (1): 8

  Abstract

  BACKGROUND: The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause.METHODS: A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women.RESULTS: There was no association between RRSO and breast cancer for BRCA1 (HR=1.23; 95% CI 0.94-1.61) or BRCA2 (HR=0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR=0.51; 95% CI 0.26-0.99 for 5years or longer after RRSO). Estimates for premenopausal women were similar.CONCLUSION: We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5years following RRSO. These results may inform counselling and management of carriers with respect to RRSO.

  View details for DOI 10.1186/s13058-020-1247-4

  View details for PubMedID 31948486

• A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry. Blood advances Du, Z., Weinhold, N., Song, G. C., Rand, K. A., Van Den Berg, D. J., Hwang, A. E., Sheng, X., Hom, V., Ailawadhi, S., Nooka, A. K., Singhal, S., Pawlish, K., Peters, E. S., Bock, C., Mohrbacher, A., Stram, A., Berndt, S. I., Blot, W. J., Casey, G., Stevens, V. L., Kittles, R., Goodman, P. J., Diver, W. R., Hennis, A., Nemesure, B., Klein, E. A., Rybicki, B. A., Stanford, J. L., Witte, J. S., Signorello, L., John, E. M., Bernstein, L., Stroup, A. M., Stephens, O. W., Zangari, M., Van Rhee, F., Olshan, A., Zheng, W., Hu, J. J., Ziegler, R., Nyante, S. J., Ingles, S. A., Press, M. F., Carpten, J. D., Chanock, S. J., Mehta, J., Colditz, G. A., Wolf, J., Martin, T. G., Tomasson, M., Fiala, M. A., Terebelo, H., Janakiraman, N., Kolonel, L., Anderson, K. C., Le Marchand, L., Auclair, D., Chiu, B. C., Ziv, E., Stram, D., Vij, R., Bernal-Mizrachi, L., Morgan, G. J., Zonder, J. A., Huff, C. A., Lonial, S., Orlowski, R. Z., Conti, D. V., Haiman, C. A., Cozen, W. 2020; 4 (1): 181–90

  Abstract

  Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 * 10-6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 * 10-12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.

  View details for DOI 10.1182/bloodadvances.2019000491

  View details for PubMedID 31935283

• Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes. Nature genetics Fachal, L. n., Aschard, H. n., Beesley, J. n., Barnes, D. R., Allen, J. n., Kar, S. n., Pooley, K. A., Dennis, J. n., Michailidou, K. n., Turman, C. n., Soucy, P. n., Lemaçon, A. n., Lush, M. n., Tyrer, J. P., Ghoussaini, M. n., Marjaneh, M. M., Jiang, X. n., Agata, S. n., Aittomäki, K. n., Alonso, M. R., Andrulis, I. L., Anton-Culver, H. n., Antonenkova, N. N., Arason, A. n., Arndt, V. n., Aronson, K. J., Arun, B. K., Auber, B. n., Auer, P. L., Azzollini, J. n., Balmaña, J. n., Barkardottir, R. B., Barrowdale, D. n., Beeghly-Fadiel, A. n., Benitez, J. n., Bermisheva, M. n., Białkowska, K. n., Blanco, A. M., Blomqvist, C. n., Blot, W. n., Bogdanova, N. V., Bojesen, S. E., Bolla, M. K., Bonanni, B. n., Borg, A. n., Bosse, K. n., Brauch, H. n., Brenner, H. n., Briceno, I. n., Brock, I. W., Brooks-Wilson, A. n., Brüning, T. n., Burwinkel, B. n., Buys, S. S., Cai, Q. n., Caldés, T. n., Caligo, M. A., Camp, N. J., Campbell, I. n., Canzian, F. n., Carroll, J. S., Carter, B. D., Castelao, J. E., Chiquette, J. n., Christiansen, H. n., Chung, W. K., Claes, K. B., Clarke, C. L., Collée, J. M., Cornelissen, S. n., Couch, F. J., Cox, A. n., Cross, S. S., Cybulski, C. n., Czene, K. n., Daly, M. B., de la Hoya, M. n., Devilee, P. n., Diez, O. n., Ding, Y. C., Dite, G. S., Domchek, S. M., Dörk, T. n., Dos-Santos-Silva, I. n., Droit, A. n., Dubois, S. n., Dumont, M. n., Duran, M. n., Durcan, L. n., Dwek, M. n., Eccles, D. M., Engel, C. n., Eriksson, M. n., Evans, D. G., Fasching, P. A., Fletcher, O. n., Floris, G. n., Flyger, H. n., Foretova, L. n., Foulkes, W. D., Friedman, E. n., Fritschi, L. n., Frost, D. n., Gabrielson, M. n., Gago-Dominguez, M. n., Gambino, G. n., Ganz, P. A., Gapstur, S. M., Garber, J. n., García-Sáenz, J. A., Gaudet, M. M., Georgoulias, V. n., Giles, G. G., Glendon, G. n., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., González-Neira, A. n., Tibiletti, M. G., Greene, M. H., Grip, M. n., Gronwald, J. n., Grundy, A. n., Guénel, P. n., Hahnen, E. n., Haiman, C. A., Håkansson, N. n., Hall, P. n., Hamann, U. n., Harrington, P. A., Hartikainen, J. M., Hartman, M. n., He, W. n., Healey, C. S., Heemskerk-Gerritsen, B. A., Heyworth, J. n., Hillemanns, P. n., Hogervorst, F. B., Hollestelle, A. n., Hooning, M. J., Hopper, J. L., Howell, A. n., Huang, G. n., Hulick, P. J., Imyanitov, E. N., Isaacs, C. n., Iwasaki, M. n., Jager, A. n., Jakimovska, M. n., Jakubowska, A. n., James, P. A., Janavicius, R. n., Jankowitz, R. C., John, E. M., Johnson, N. n., Jones, M. E., Jukkola-Vuorinen, A. n., Jung, A. n., Kaaks, R. n., Kang, D. n., Kapoor, P. M., Karlan, B. Y., Keeman, R. n., Kerin, M. J., Khusnutdinova, E. n., Kiiski, J. I., Kirk, J. n., Kitahara, C. M., Ko, Y. D., Konstantopoulou, I. n., Kosma, V. M., Koutros, S. n., Kubelka-Sabit, K. n., Kwong, A. n., Kyriacou, K. n., Laitman, Y. n., Lambrechts, D. n., Lee, E. n., Leslie, G. n., Lester, J. n., Lesueur, F. n., Lindblom, A. n., Lo, W. Y., Long, J. n., Lophatananon, A. n., Loud, J. T., Lubiński, J. n., MacInnis, R. J., Maishman, T. n., Makalic, E. n., Mannermaa, A. n., Manoochehri, M. n., Manoukian, S. n., Margolin, S. n., Martinez, M. E., Matsuo, K. n., Maurer, T. n., Mavroudis, D. n., Mayes, R. n., McGuffog, L. n., McLean, C. n., Mebirouk, N. n., Meindl, A. n., Miller, A. n., Miller, N. n., Montagna, M. n., Moreno, F. n., Muir, K. n., Mulligan, A. M., Muñoz-Garzon, V. M., Muranen, T. A., Narod, S. A., Nassir, R. n., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H. n., Neven, P. n., Nielsen, F. C., Nikitina-Zake, L. n., Norman, A. n., Offit, K. n., Olah, E. n., Olopade, O. I., Olsson, H. n., Orr, N. n., Osorio, A. n., Pankratz, V. S., Papp, J. n., Park, S. K., Park-Simon, T. W., Parsons, M. T., Paul, J. n., Pedersen, I. S., Peissel, B. n., Peshkin, B. n., Peterlongo, P. n., Peto, J. n., Plaseska-Karanfilska, D. n., Prajzendanc, K. n., Prentice, R. n., Presneau, N. n., Prokofyeva, D. n., Pujana, M. A., Pylkäs, K. n., Radice, P. n., Ramus, S. J., Rantala, J. n., Rau-Murthy, R. n., Rennert, G. n., Risch, H. A., Robson, M. n., Romero, A. n., Rossing, M. n., Saloustros, E. n., Sánchez-Herrero, E. n., Sandler, D. P., Santamariña, M. n., Saunders, C. n., Sawyer, E. J., Scheuner, M. T., Schmidt, D. F., Schmutzler, R. K., Schneeweiss, A. n., Schoemaker, M. J., Schöttker, B. n., Schürmann, P. n., Scott, C. n., Scott, R. J., Senter, L. n., Seynaeve, C. M., Shah, M. n., Sharma, P. n., Shen, C. Y., Shu, X. O., Singer, C. F., Slavin, T. P., Smichkoska, S. n., Southey, M. C., Spinelli, J. J., Spurdle, A. B., Stone, J. n., Stoppa-Lyonnet, D. n., Sutter, C. n., Swerdlow, A. J., Tamimi, R. M., Tan, Y. Y., Tapper, W. J., Taylor, J. A., Teixeira, M. R., Tengström, M. n., Teo, S. H., Terry, M. B., Teulé, A. n., Thomassen, M. n., Thull, D. L., Tischkowitz, M. n., Toland, A. E., Tollenaar, R. A., Tomlinson, I. n., Torres, D. n., Torres-Mejía, G. n., Troester, M. A., Truong, T. n., Tung, N. n., Tzardi, M. n., Ulmer, H. U., Vachon, C. M., van Asperen, C. J., van der Kolk, L. E., van Rensburg, E. J., Vega, A. n., Viel, A. n., Vijai, J. n., Vogel, M. J., Wang, Q. n., Wappenschmidt, B. n., Weinberg, C. R., Weitzel, J. N., Wendt, C. n., Wildiers, H. n., Winqvist, R. n., Wolk, A. n., Wu, A. H., Yannoukakos, D. n., Zhang, Y. n., Zheng, W. n., Hunter, D. n., Pharoah, P. D., Chang-Claude, J. n., García-Closas, M. n., Schmidt, M. K., Milne, R. L., Kristensen, V. N., French, J. D., Edwards, S. L., Antoniou, A. C., Chenevix-Trench, G. n., Simard, J. n., Easton, D. F., Kraft, P. n., Dunning, A. M. 2020

  Abstract

  Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

  View details for DOI 10.1038/s41588-019-0537-1

  View details for PubMedID 31911677

• An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk. Nature communications Wu, L. n., Yang, Y. n., Guo, X. n., Shu, X. O., Cai, Q. n., Shu, X. n., Li, B. n., Tao, R. n., Wu, C. n., Nikas, J. B., Sun, Y. n., Zhu, J. n., Roobol, M. J., Giles, G. G., Brenner, H. n., John, E. M., Clements, J. n., Grindedal, E. M., Park, J. Y., Stanford, J. L., Kote-Jarai, Z. n., Haiman, C. A., Eeles, R. A., Zheng, W. n., Long, J. n. 2020; 11 (1): 3905

  Abstract

  It remains elusive whether some of the associations identified in genome-wide association studies of prostate cancer (PrCa) may be due to regulatory effects of genetic variants on CpG sites, which may further influence expression of PrCa target genes. To search for CpG sites associated with PrCa risk, here we establish genetic models to predict methylation (N = 1,595) and conduct association analyses with PrCa risk (79,194 cases and 61,112 controls). We identify 759 CpG sites showing an association, including 15 located at novel loci. Among those 759 CpG sites, methylation of 42 is associated with expression of 28 adjacent genes. Among 22 genes, 18 show an association with PrCa risk. Overall, 25 CpG sites show consistent association directions for the methylation-gene expression-PrCa pathway. We identify DNA methylation biomarkers associated with PrCa, and our findings suggest that specific CpG sites may influence PrCa via regulating expression of candidate PrCa target genes.

  View details for DOI 10.1038/s41467-020-17673-9

  View details for PubMedID 32764609

• Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants. Nature communications Shu, X. n., Long, J. n., Cai, Q. n., Kweon, S. S., Choi, J. Y., Kubo, M. n., Park, S. K., Bolla, M. K., Dennis, J. n., Wang, Q. n., Yang, Y. n., Shi, J. n., Guo, X. n., Li, B. n., Tao, R. n., Aronson, K. J., Chan, K. Y., Chan, T. L., Gao, Y. T., Hartman, M. n., Kee Ho, W. n., Ito, H. n., Iwasaki, M. n., Iwata, H. n., John, E. M., Kasuga, Y. n., Soon Khoo, U. n., Kim, M. K., Kong, S. Y., Kurian, A. W., Kwong, A. n., Lee, E. S., Li, J. n., Lophatananon, A. n., Low, S. K., Mariapun, S. n., Matsuda, K. n., Matsuo, K. n., Muir, K. n., Noh, D. Y., Park, B. n., Park, M. H., Shen, C. Y., Shin, M. H., Spinelli, J. J., Takahashi, A. n., Tseng, C. n., Tsugane, S. n., Wu, A. H., Xiang, Y. B., Yamaji, T. n., Zheng, Y. n., Milne, R. L., Dunning, A. M., Pharoah, P. D., García-Closas, M. n., Teo, S. H., Shu, X. O., Kang, D. n., Easton, D. F., Simard, J. n., Zheng, W. n. 2020; 11 (1): 1217

  Abstract

  Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P < 5 × 10-8. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). In addition, we replicated the associations for 78 of the 166 known risk variants at P < 0.05 in Asians. These findings improve our understanding of breast cancer genetics and etiology and extend previous findings from studies of European descendants to Asian women.

  View details for DOI 10.1038/s41467-020-15046-w

  View details for PubMedID 32139696

  View details for PubMedCentralID PMC7057957

• A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry. European urology Darst, B. F., Wan, P. n., Sheng, X. n., Bensen, J. T., Ingles, S. A., Rybicki, B. A., Nemesure, B. n., John, E. M., Fowke, J. H., Stevens, V. L., Berndt, S. I., Huff, C. D., Strom, S. S., Park, J. Y., Zheng, W. n., Ostrander, E. A., Walsh, P. C., Srivastava, S. n., Carpten, J. n., Sellers, T. A., Yamoah, K. n., Murphy, A. B., Sanderson, M. n., Crawford, D. C., Gapstur, S. M., Bush, W. S., Aldrich, M. C., Cussenot, O. n., Yeager, M. n., Petrovics, G. n., Cullen, J. n., Neslund-Dudas, C. n., Kittles, R. A., Xu, J. n., Stern, M. C., Kote-Jarai, Z. n., Govindasami, K. n., Chokkalingam, A. P., Multigner, L. n., Parent, M. E., Menegaux, F. n., Cancel-Tassin, G. n., Kibel, A. S., Klein, E. A., Goodman, P. J., Drake, B. F., Hu, J. J., Clark, P. E., Blanchet, P. n., Casey, G. n., Hennis, A. J., Lubwama, A. n., Thompson, I. M., Leach, R. n., Gundell, S. M., Pooler, L. n., Xia, L. n., Mohler, J. L., Fontham, E. T., Smith, G. J., Taylor, J. A., Eeles, R. A., Brureau, L. n., Chanock, S. J., Watya, S. n., Stanford, J. L., Mandal, D. n., Isaacs, W. B., Cooney, K. n., Blot, W. J., Conti, D. V., Haiman, C. A. 2020

  Abstract

  Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.

  View details for DOI 10.1016/j.eururo.2020.04.060

  View details for PubMedID 32409115

• European polygenic risk score for prediction of breast cancer shows similar performance in Asian women. Nature communications Ho, W. K., Tan, M. M., Mavaddat, N. n., Tai, M. C., Mariapun, S. n., Li, J. n., Ho, P. J., Dennis, J. n., Tyrer, J. P., Bolla, M. K., Michailidou, K. n., Wang, Q. n., Kang, D. n., Choi, J. Y., Jamaris, S. n., Shu, X. O., Yoon, S. Y., Park, S. K., Kim, S. W., Shen, C. Y., Yu, J. C., Tan, E. Y., Chan, P. M., Muir, K. n., Lophatananon, A. n., Wu, A. H., Stram, D. O., Matsuo, K. n., Ito, H. n., Chan, C. W., Ngeow, J. n., Yong, W. S., Lim, S. H., Lim, G. H., Kwong, A. n., Chan, T. L., Tan, S. M., Seah, J. n., John, E. M., Kurian, A. W., Koh, W. P., Khor, C. C., Iwasaki, M. n., Yamaji, T. n., Tan, K. M., Tan, K. T., Spinelli, J. J., Aronson, K. J., Hasan, S. N., Rahmat, K. n., Vijayananthan, A. n., Sim, X. n., Pharoah, P. D., Zheng, W. n., Dunning, A. M., Simard, J. n., van Dam, R. M., Yip, C. H., Taib, N. A., Hartman, M. n., Easton, D. F., Teo, S. H., Antoniou, A. C. 2020; 11 (1): 3833

  Abstract

  Polygenic risk scores (PRS) have been shown to predict breast cancer risk in European women, but their utility in Asian women is unclear. Here we evaluate the best performing PRSs for European-ancestry women using data from 17,262 breast cancer cases and 17,695 controls of Asian ancestry from 13 case-control studies, and 10,255 Chinese women from a prospective cohort (413 incident breast cancers). Compared to women in the middle quintile of the risk distribution, women in the highest 1% of PRS distribution have a ~2.7-fold risk and women in the lowest 1% of PRS distribution has ~0.4-fold risk of developing breast cancer. There is no evidence of heterogeneity in PRS performance in Chinese, Malay and Indian women. A PRS developed for European-ancestry women is also predictive of breast cancer risk in Asian women and can help in developing risk-stratified screening programmes in Asia.

  View details for DOI 10.1038/s41467-020-17680-w

  View details for PubMedID 32737321

• Hospital Characteristics and Breast Cancer Survival in the California Breast Cancer Survivorship Consortium. JCO oncology practice Shariff-Marco, S. n., Ellis, L. n., Yang, J. n., Koo, J. n., John, E. M., Keegan, T. H., Cheng, I. n., Monroe, K. R., Vigen, C. n., Kwan, M. L., Lu, Y. n., Bernstein, L. n., Wu, A. H., Gomez, S. L., Kurian, A. W. 2020; 16 (6): e517–e528

  Abstract

  Racial/ethnic disparities in breast cancer survival are well documented, but the influence of health care institutions is unclear. We therefore examined the effect of hospital characteristics on survival.Harmonized data pooled from 5 case-control and prospective cohort studies within the California Breast Cancer Survivorship Consortium were linked to the California Cancer Registry and the California Neighborhoods Data System. The study included 9,701 patients with breast cancer who were diagnosed between 1993 and 2007. First reporting hospitals were classified by hospital type-National Cancer Institute (NCI) -designated cancer center, American College of Surgeons (ACS) Cancer Program, other-and hospital composition of the neighborhood socioeconomic status and race/ethnicity of patients with cancer. Multivariable Cox proportional hazards models adjusted for clinical and patient-level prognostic factors were used to examine the influence of hospital characteristics on survival.Fewer than one half of women received their initial care at an NCI-designated cancer center (5%) or ACS program (38%) hospital. Receipt of initial care in ACS program hospitals varied by race/ethnicity-highest among non-Latina White patients (45%), and lowest among African Americans (21%). African-American women had superior breast cancer survival when receiving initial care in ACS hospitals versus other hospitals (non-ACS program and non-NCI-designated cancer center; hazard ratio, 0.67; 95% CI, 0.55 to 0.83). Other hospital characteristics were not associated with survival.African American women may benefit significantly from breast cancer care in ACS program hospitals; however, most did not receive initial care at such facilities. Future research should identify the aspects of ACS program hospitals that are associated with higher survival and evaluate strategies by which to enhance access to and use of high-quality hospitals, particularly among African American women.

  View details for DOI 10.1200/OP.20.00064

  View details for PubMedID 32521220

• Combined associations of a polygenic risk score and classical risk factors with breast cancer risk. Journal of the National Cancer Institute Kapoor, P. M., Mavaddat, N. n., Choudhury, P. P., Wilcox, A. N., Lindström, S. n., Behrens, S. n., Michailidou, K. n., Dennis, J. n., Bolla, M. K., Wang, Q. n., Jung, A. n., Abu-Ful, Z. n., Ahearn, T. n., Andrulis, I. L., Anton-Culver, H. n., Arndt, V. n., Aronson, K. J., Auer, P. L., Freeman, L. E., Becher, H. n., Beckmann, M. W., Beeghly-Fadiel, A. n., Benitez, J. n., Bernstein, L. n., Bojesen, S. E., Brauch, H. n., Brenner, H. n., Brüning, T. n., Cai, Q. n., Campa, D. n., Canzian, F. n., Carracedo, A. n., Carter, B. D., Castelao, J. E., Chanock, S. J., Chatterjee, N. n., Chenevix-Trench, G. n., Clarke, C. L., Couch, F. J., Cox, A. n., Cross, S. S., Czene, K. n., Dai, J. Y., Earp, H. S., Ekici, A. B., Eliassen, A. H., Eriksson, M. n., Evans, D. G., Fasching, P. A., Figueroa, J. n., Fritschi, L. n., Gabrielson, M. n., Gago-Dominguez, M. n., Gao, C. n., Gapstur, S. M., Gaudet, M. M., Giles, G. G., González-Neira, A. n., Guénel, P. n., Haeberle, L. n., Haiman, C. A., Håkansson, N. n., Hall, P. n., Hamann, U. n., Hatse, S. n., Heyworth, J. n., Holleczek, B. n., Hoover, R. N., Hopper, J. L., Howell, A. n., Hunter, D. J., John, E. M., Jones, M. E., Kaaks, R. n., Keeman, R. n., Kitahara, C. M., Ko, Y. D., Koutros, S. n., Kurian, A. W., Lambrechts, D. n., Marchand, L. L., Lee, E. n., Lejbkowicz, F. n., Linet, M. n., Lissowska, J. n., Llaneza, A. n., MacInnis, R. J., Martinez, M. E., Maurer, T. n., McLean, C. n., Neuhausen, S. L., Newman, W. G., Norman, A. n., O'Brien, K. M., Olshan, A. F., Olson, J. E., Olsson, H. n., Orr, N. n., Perou, C. M., Pita, G. n., Polley, E. C., Prentice, R. L., Rennert, G. n., Rennert, H. S., Ruddy, K. J., Sandler, D. P., Saunders, C. n., Schoemaker, M. J., Schöttker, B. n., Schumacher, F. n., Scott, C. n., Scott, R. J., Shu, X. O., Smeets, A. n., Southey, M. C., Spinelli, J. J., Stone, J. n., Swerdlow, A. J., Tamimi, R. M., Taylor, J. A., Troester, M. A., Vachon, C. M., van Veen, E. M., Wang, X. n., Weinberg, C. R., Weltens, C. n., Willett, W. n., Winham, S. J., Wolk, A. n., Yang, X. R., Zheng, W. n., Ziogas, A. n., Dunning, A. M., Pharoah, P. D., Schmidt, M. K., Kraft, P. n., Easton, D. F., Milne, R. L., García-Closas, M. n., Chang-Claude, J. n. 2020

  Abstract

  We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72,284 cases and 80,354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression, and a newly developed case-only method, for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history), and on average 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

  View details for DOI 10.1093/jnci/djaa056

  View details for PubMedID 32359158

• Plasma glucocorticogenic activity, race/ethnicity and alcohol intake among San Francisco Bay Area women. PloS one Tachachartvanich, P., Sanchez, S. S., Gomez, S. L., John, E. M., Smith, M. T., Fejerman, L. 2020; 15 (6): e0233904

  Abstract

  Racial and ethnic minorities are at higher risk for a variety of diseases. While sociodemographic and lifestyle factors contribute to racial/ethnic health disparities, the biological processes underlying these associations remain poorly understood. Stress and its biological consequences through the glucocorticoid receptor (GR) have been hypothesized to mediate adverse disease outcomes. In fasting morning samples of 503 control women from the San Francisco Bay Area Breast Cancer Study, we used a sensitive Chemical-Activated LUciferase gene eXpression (CALUX) assay to examine the association of sociodemographic and lifestyle factors with plasma glucocorticogenic (G) activity in three racial/ethnic groups. The G activity is a sensitive measure that reflects biological activity of total plasma glucocorticoids including cortisol and glucocorticoid-like compounds. Associations between G activity and sociodemographic and lifestyle factors were examined using multivariable linear regression models. Latina and non-Latina Black (NLB) women had 9% (P = 0.053) and 14% (P = 0.008) lower morning G activity than non-Latina White (NLW) women, respectively. Additionally, we replicated a previously reported association between G activity and alcohol intake (women who drank >10gms had 19% higher G activity than non-drinkers, P = 0.004) in Latina and NLB women. Further research should assess the association between G activity and health outcomes in a prospective cohort so as to characterize the relationship between total plasma G activity in pre-disease state and disease outcomes across different racial/ethnic populations.

  View details for DOI 10.1371/journal.pone.0233904

  View details for PubMedID 32479509

• Common Childhood Viruses and Pubertal Timing: The LEGACY Girls Study. American journal of epidemiology McDonald, J. A., Cherubin, S. n., Goldberg, M. n., Wei, Y. n., Chung, W. K., Schwartz, L. A., Knight, J. A., Schooling, C. M., Santella, R. M., Bradbury, A. R., Buys, S. S., Andrulis, I. L., John, E. M., Daly, M. B., Terry, M. B. 2020

  Abstract

  Earlier pubertal development is only partially explained by childhood body mass index (BMI); the role of other factors like childhood infections is less understood. Using data from the LEGACY Girls Study (2011 - 2016), we prospectively examined the associations between childhood viral infections (Cytomegalovirus (CMV), Epstein Barr Virus (EBV), Herpes Simplex Virus 1 (HSV1), HSV2 and pubertal timing. We measured exposures based on seropositivity in pre-menarcheal girls (n=490). Breast and pubic hair development were classified based on mother-reported Tanner Stage (TS: TS2+ compared with TS1), adjusting for age, BMI, and sociodemographic factors. The average age at first blood draw was 9.8 years (Stdev=1.9 years). The prevalences were 31% CMV+, 37% EBV+, 14% HSV1+, 0.4% HSV2+, and 16% for both CMV+/EBV+. CMV+ infection without co-infection was associated with developing breasts an average of 7 months earlier (Hazard Ratio (HR)=2.12, 95% CI 1.32, 3.40). CMV+ infection without co-infection and HSV1+ and/or HSV2+ infection were associated with developing pubic hair 9 months later (HR 0.41, 95% CI 0.24, 0.71, HR 0.42, 95% CI 0.22, 0.81, respectively). Infection was not associated with menarche. If replicated in larger cohorts with blood collection prior to any breast development, this study supports that childhood infections may play a role in altering pubertal timing.

  View details for DOI 10.1093/aje/kwaa240

  View details for PubMedID 33128063

• Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk. American journal of human genetics Kramer, I. n., Hooning, M. J., Mavaddat, N. n., Hauptmann, M. n., Keeman, R. n., Steyerberg, E. W., Giardiello, D. n., Antoniou, A. C., Pharoah, P. D., Canisius, S. n., Abu-Ful, Z. n., Andrulis, I. L., Anton-Culver, H. n., Aronson, K. J., Augustinsson, A. n., Becher, H. n., Beckmann, M. W., Behrens, S. n., Benitez, J. n., Bermisheva, M. n., Bogdanova, N. V., Bojesen, S. E., Bolla, M. K., Bonanni, B. n., Brauch, H. n., Bremer, M. n., Brucker, S. Y., Burwinkel, B. n., Castelao, J. E., Chan, T. L., Chang-Claude, J. n., Chanock, S. J., Chenevix-Trench, G. n., Choi, J. Y., Clarke, C. L., Collée, J. M., Couch, F. J., Cox, A. n., Cross, S. S., Czene, K. n., Daly, M. B., Devilee, P. n., Dörk, T. n., Dos-Santos-Silva, I. n., Dunning, A. M., Dwek, M. n., Eccles, D. M., Evans, D. G., Fasching, P. A., Flyger, H. n., Gago-Dominguez, M. n., García-Closas, M. n., García-Sáenz, J. A., Giles, G. G., Goldgar, D. E., González-Neira, A. n., Haiman, C. A., Håkansson, N. n., Hamann, U. n., Hartman, M. n., Heemskerk-Gerritsen, B. A., Hollestelle, A. n., Hopper, J. L., Hou, M. F., Howell, A. n., Ito, H. n., Jakimovska, M. n., Jakubowska, A. n., Janni, W. n., John, E. M., Jung, A. n., Kang, D. n., Kets, C. M., Khusnutdinova, E. n., Ko, Y. D., Kristensen, V. N., Kurian, A. W., Kwong, A. n., Lambrechts, D. n., Le Marchand, L. n., Li, J. n., Lindblom, A. n., Lubiński, J. n., Mannermaa, A. n., Manoochehri, M. n., Margolin, S. n., Matsuo, K. n., Mavroudis, D. n., Meindl, A. n., Milne, R. L., Mulligan, A. M., Muranen, T. A., Neuhausen, S. L., Nevanlinna, H. n., Newman, W. G., Olshan, A. F., Olson, J. E., Olsson, H. n., Park-Simon, T. W., Peto, J. n., Petridis, C. n., Plaseska-Karanfilska, D. n., Presneau, N. n., Pylkäs, K. n., Radice, P. n., Rennert, G. n., Romero, A. n., Roylance, R. n., Saloustros, E. n., Sawyer, E. J., Schmutzler, R. K., Schwentner, L. n., Scott, C. n., See, M. H., Shah, M. n., Shen, C. Y., Shu, X. O., Siesling, S. n., Slager, S. n., Sohn, C. n., Southey, M. C., Spinelli, J. J., Stone, J. n., Tapper, W. J., Tengström, M. n., Teo, S. H., Terry, M. B., Tollenaar, R. A., Tomlinson, I. n., Troester, M. A., Vachon, C. M., van Ongeval, C. n., van Veen, E. M., Winqvist, R. n., Wolk, A. n., Zheng, W. n., Ziogas, A. n., Easton, D. F., Hall, P. n., Schmidt, M. K. 2020

  Abstract

  Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.

  View details for DOI 10.1016/j.ajhg.2020.09.001

  View details for PubMedID 33022221

• Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk. Scientific reports Liu, J. n., Prager-van der Smissen, W. J., Collée, J. M., Bolla, M. K., Wang, Q. n., Michailidou, K. n., Dennis, J. n., Ahearn, T. U., Aittomäki, K. n., Ambrosone, C. B., Andrulis, I. L., Anton-Culver, H. n., Antonenkova, N. N., Arndt, V. n., Arnold, N. n., Aronson, K. J., Augustinsson, A. n., Auvinen, P. n., Becher, H. n., Beckmann, M. W., Behrens, S. n., Bermisheva, M. n., Bernstein, L. n., Bogdanova, N. V., Bogdanova-Markov, N. n., Bojesen, S. E., Brauch, H. n., Brenner, H. n., Briceno, I. n., Brucker, S. Y., Brüning, T. n., Burwinkel, B. n., Cai, Q. n., Cai, H. n., Campa, D. n., Canzian, F. n., Castelao, J. E., Chang-Claude, J. n., Chanock, S. J., Choi, J. Y., Christiaens, M. n., Clarke, C. L., Couch, F. J., Czene, K. n., Daly, M. B., Devilee, P. n., Dos-Santos-Silva, I. n., Dwek, M. n., Eccles, D. M., Eliassen, A. H., Fasching, P. A., Figueroa, J. n., Flyger, H. n., Fritschi, L. n., Gago-Dominguez, M. n., Gapstur, S. M., García-Closas, M. n., García-Sáenz, J. A., Gaudet, M. M., Giles, G. G., Goldberg, M. S., Goldgar, D. E., Guénel, P. n., Haiman, C. A., Håkansson, N. n., Hall, P. n., Harrington, P. A., Hart, S. N., Hartman, M. n., Hillemanns, P. n., Hopper, J. L., Hou, M. F., Hunter, D. J., Huo, D. n., Ito, H. n., Iwasaki, M. n., Jakimovska, M. n., Jakubowska, A. n., John, E. M., Kaaks, R. n., Kang, D. n., Keeman, R. n., Khusnutdinova, E. n., Kim, S. W., Kraft, P. n., Kristensen, V. N., Kurian, A. W., Le Marchand, L. n., Li, J. n., Lindblom, A. n., Lophatananon, A. n., Luben, R. N., Lubiński, J. n., Mannermaa, A. n., Manoochehri, M. n., Manoukian, S. n., Margolin, S. n., Mariapun, S. n., Matsuo, K. n., Maurer, T. n., Mavroudis, D. n., Meindl, A. n., Menon, U. n., Milne, R. L., Muir, K. n., Mulligan, A. M., Neuhausen, S. L., Nevanlinna, H. n., Offit, K. n., Olopade, O. I., Olson, J. E., Olsson, H. n., Orr, N. n., Park, S. K., Peterlongo, P. n., Peto, J. n., Plaseska-Karanfilska, D. n., Presneau, N. n., Rack, B. n., Rau-Murthy, R. n., Rennert, G. n., Rennert, H. S., Rhenius, V. n., Romero, A. n., Ruebner, M. n., Saloustros, E. n., Schmutzler, R. K., Schneeweiss, A. n., Scott, C. n., Shah, M. n., Shen, C. Y., Shu, X. O., Simard, J. n., Sohn, C. n., Southey, M. C., Spinelli, J. J., Tamimi, R. M., Tapper, W. J., Teo, S. H., Terry, M. B., Torres, D. n., Truong, T. n., Untch, M. n., Vachon, C. M., van Asperen, C. J., Wolk, A. n., Yamaji, T. n., Zheng, W. n., Ziogas, A. n., Ziv, E. n., Torres-Mejía, G. n., Dörk, T. n., Swerdlow, A. J., Hamann, U. n., Schmidt, M. K., Dunning, A. M., Pharoah, P. D., Easton, D. F., Hooning, M. J., Martens, J. W., Hollestelle, A. n. 2020; 10 (1): 9688

  Abstract

  In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.

  View details for DOI 10.1038/s41598-020-65665-y

  View details for PubMedID 32546843

• Racial/ethnic disparities in survival after breast cancer diagnosis by estrogen and progesterone receptor status: A pooled analysis. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology John, E. M., McGuire, V. n., Kurian, A. W., Koo, J. n., Shariff-Marco, S. n., Gomez, S. L., Cheng, I. n., Keegan, T. H., Kwan, M. L., Bernstein, L. n., Vigen, C. n., Wu, A. H. 2020

  Abstract

  Limited studies have investigated racial/ethnic survival disparities for breast cancer (BC) defined by estrogen receptor (ER) and progesterone receptor (PR) status in a multiethnic population.Using multivariable Cox proportional hazards models, we assessed associations of race/ethnicity with ER/PR-specific BC mortality in 10,366 Californian women diagnosed with BC from 1993-2009. We evaluated joint associations of race/ethnicity, healthcare, sociodemographic, and lifestyle factors with mortality.Among women with ER/PR+ BC, BC-specific mortality was similar among Hispanic and Asian American women, but higher among African American women (hazard ratio (HR) 1.31, 95% confidence interval 1.05-1.63) compared to non-Hispanic White (NHW) women. BC-specific mortality was modified by surgery type, hospital type, education, neighborhood socioeconomic status (SES), smoking history, and alcohol consumption. Among African American women, BC-specific mortality was higher among those treated at non-accredited hospitals (HR 1.57, CI 1.21-2.04) and those from lower SES neighborhoods (HR 1.48, CI 1.16-1.88) compared to NHW women without these characteristics. BC-specific mortality was higher among African American women with at least some college education (HR 1.42, CI 1.11-1.82) compared to NHW women with similar education. For ER-/PR- disease, BC-specific mortality did not differ by race/ethnicity and associations of race/ethnicity with BC-specific mortality varied only by neighborhood SES among African American women.Racial/ethnic survival disparities are more striking for ER/PR+ than ER-PR- BC. Social determinants and lifestyle factors may explain some of the survival disparities for ER/PR+ BC.Addressing these factors may help reduce the higher mortality of African American women with ER/PR+ BC.

  View details for DOI 10.1158/1055-9965.EPI-20-1291

  View details for PubMedID 33355191

• Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). JAMA oncology Silvestri, V. n., Leslie, G. n., Barnes, D. R., Agnarsson, B. A., Aittomäki, K. n., Alducci, E. n., Andrulis, I. L., Barkardottir, R. B., Barroso, A. n., Barrowdale, D. n., Benitez, J. n., Bonanni, B. n., Borg, A. n., Buys, S. S., Caldés, T. n., Caligo, M. A., Capalbo, C. n., Campbell, I. n., Chung, W. K., Claes, K. B., Colonna, S. V., Cortesi, L. n., Couch, F. J., de la Hoya, M. n., Diez, O. n., Ding, Y. C., Domchek, S. n., Easton, D. F., Ejlertsen, B. n., Engel, C. n., Evans, D. G., Feliubadalò, L. n., Foretova, L. n., Fostira, F. n., Géczi, L. n., Gerdes, A. M., Glendon, G. n., Godwin, A. K., Goldgar, D. E., Hahnen, E. n., Hogervorst, F. B., Hopper, J. L., Hulick, P. J., Isaacs, C. n., Izquierdo, A. n., James, P. A., Janavicius, R. n., Jensen, U. B., John, E. M., Joseph, V. n., Konstantopoulou, I. n., Kurian, A. W., Kwong, A. n., Landucci, E. n., Lesueur, F. n., Loud, J. T., Machackova, E. n., Mai, P. L., Majidzadeh-A, K. n., Manoukian, S. n., Montagna, M. n., Moserle, L. n., Mulligan, A. M., Nathanson, K. L., Nevanlinna, H. n., Ngeow Yuen Ye, J. n., Nikitina-Zake, L. n., Offit, K. n., Olah, E. n., Olopade, O. I., Osorio, A. n., Papi, L. n., Park, S. K., Pedersen, I. S., Perez-Segura, P. n., Petersen, A. H., Pinto, P. n., Porfirio, B. n., Pujana, M. A., Radice, P. n., Rantala, J. n., Rashid, M. U., Rosenzweig, B. n., Rossing, M. n., Santamariña, M. n., Schmutzler, R. K., Senter, L. n., Simard, J. n., Singer, C. F., Solano, A. R., Southey, M. C., Steele, L. n., Steinsnyder, Z. n., Stoppa-Lyonnet, D. n., Tan, Y. Y., Teixeira, M. R., Teo, S. H., Terry, M. B., Thomassen, M. n., Toland, A. E., Torres-Esquius, S. n., Tung, N. n., van Asperen, C. J., Vega, A. n., Viel, A. n., Vierstraete, J. n., Wappenschmidt, B. n., Weitzel, J. N., Wieme, G. n., Yoon, S. Y., Zorn, K. K., McGuffog, L. n., Parsons, M. T., Hamann, U. n., Greene, M. H., Kirk, J. A., Neuhausen, S. L., Rebbeck, T. R., Tischkowitz, M. n., Chenevix-Trench, G. n., Antoniou, A. C., Friedman, E. n., Ottini, L. n. 2020

  Abstract

  The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population.To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers.Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected.BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview.Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier.Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.

  View details for DOI 10.1001/jamaoncol.2020.2134

  View details for PubMedID 32614418

• Comparing Five-Year and Lifetime Risks of Breast Cancer in the Prospective Family Study Cohort. Journal of the National Cancer Institute MacInnis, R. J., Knight, J. A., Chung, W. K., Milne, R. L., Whittemore, A. S., Buchsbaum, R. n., Liao, Y. n., Zeinomar, N. n., Dite, G. S., Southey, M. C., Goldgar, D. n., Giles, G. G., Kurian, A. W., Andrulis, I. L., John, E. M., Daly, M. B., Buys, S. S., Phillips, K. A., Hopper, J. L., Terry, M. B. 2020

  Abstract

  Clinical guidelines often use predicted lifetime risk from birth to define criteria for making decisions regarding breast cancer screening rather than thresholds based on absolute 5-year risk from current age.We used the Prospective Family Cohort Study of 14,657 women without breast cancer at baseline in which, during a median follow-up of 10 years, 482 women were diagnosed with invasive breast cancer. We examined the performances of the IBIS and BOADICEA risk models when using alternative thresholds by comparing predictions based on 5-year risk with those based on lifetime risk from birth and remaining lifetime risk. All statistical tests were two-sided.Using IBIS, the areas under the receiver-operating characteristic curves were 0.66 (95% confidence interval = 0.63 to 0.68) and 0.56 (95% confidence interval = 0.54 to 0.59) for 5-year and lifetime risks, respectively (Pdiff<0.001). For equivalent sensitivities, the 5-year incidence almost always had higher specificities than lifetime risk from birth. For women aged 20-39 years, 5-year risk performed better than lifetime risk from birth. For women aged 40 years or more, receiver-operating characteristic curves were similar for 5-year and lifetime IBIS risk from birth. Classifications based on remaining lifetime risk were inferior to 5-year risk estimates. Results were similar using BOADICEA.Our analysis shows that risk stratification using clinical models will likely be more accurate when based on predicted 5-year risk compared with risks based on predicted lifetime and remaining lifetime, particularly for women aged 20-39 years.

  View details for DOI 10.1093/jnci/djaa178

  View details for PubMedID 33301022

• Implications of the COVID-19 San Francisco Bay Area Shelter-in-Place Announcement: A Cross-Sectional Social Media Survey. medRxiv : the preprint server for health sciences Elser, H. n., Kiang, M. V., John, E. M., Simard, J. F., Bondy, M. n., Nelson, L. M., Chen, W. T., Linos, E. n. 2020

  Abstract

  The U.S. has experienced an unprecedented number of shelter-in-place orders throughout the COVID-19 pandemic. There is limited empirical research that examines the impact of these orders. We aimed to rapidly ascertain whether social distancing; difficulty with daily activities (obtaining food, essential medications and childcare); and levels of concern regarding COVID-19 changed after the March 16, 2020 announcement of shelter-in-place orders for seven counties in the San Francisco Bay Area.We conducted an online, cross-sectional social media survey from March 14 - April 1, 2020. We measured changes in social distancing behavior; experienced difficulties with daily activities (i.e., access to healthcare, childcare, obtaining essential food and medications); and level of concern regarding COVID-19 after the March 16 shelter-in-place announcement in the San Francisco Bay Area and elsewhere in the U.S.The percentage of respondents social distancing all of the time increased following the shelter-in-place announcement in the Bay Area (9.2%, 95% CI: 6.6, 11.9) and elsewhere in the U.S. (3.4%, 95% CI: 2.0, 5.0). Respondents also reported increased difficulty with obtaining food, hand sanitizer, and medications, particularly with obtaining food for both respondents from the Bay Area (13.3%, 95% CI: 10.4, 16.3) and elsewhere (8.2%, 95% CI: 6.6, 9.7). We found limited evidence that level of concern regarding the COVID-19 crisis changed following the shelter-in-place announcement.These results capture early changes in attitudes, behaviors, and difficulties. Further research that specifically examines social, economic, and health impacts of COVID-19, especially among vulnerable populations, is urgently needed. =.

  View details for DOI 10.1101/2020.06.29.20143156

  View details for PubMedID 32637974

  View details for PubMedCentralID PMC7340200

• Alcohol consumption, cigarette smoking, and risk of breast cancer for BRCA1 and BRCA2 mutation carriers: results from The BRCA1 and BRCA2 Cohort Consortium. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Li, H., Terry, M. B., Antoniou, A. C., Phillips, K., Kast, K., Mooij, T. M., Engel, C., Nogues, C., Stoppa-Lyonnet, D., Lasset, C., Berthet, P., Mari, V., Caron, O., Barrowdale, D., Frost, D., Brewer, C., Evans, D. G., Izatt, L., Side, L., Walker, L., Tischkowitz, M., Rogers, M. T., Porteous, M. E., Meijers-Heijboer, H. E., Gille, J. J., Blok, M. J., Hoogerbrugge, N., Daly, M. B., Andrulis, I. L., Buys, S. S., John, E. M., McLachlan, S., Friedlander, M., Tan, Y. Y., Osorio, A., Caldes, T., Jakubowska, A., Simard, J., Singer, C. F., Olah, E., Navratilova, M., Foretova, L., Gerdes, A., Roos-Blom, M., Arver, B., Olsson, H., Schmutzler, R. K., Hopper, J. L., Milne, R. L., Easton, D. F., Van Leeuwen, F. E., Rookus, M. A., Andrieu, N., Goldgar, D. E. 2019

  Abstract

  BACKGROUND: Tobacco smoking and alcohol consumption have been intensively studied in the general population to assess their effects on the risk of breast cancer (BC), but very few studies have examined these effects in BRCA1 and BRCA2 mutation carriers. Given the high BC risk for mutation carriers and the importance of BRCA1 and BRCA2 in DNA repair, better evidence on the associations of these lifestyle factors with BC risk is essential.METHODS: Using a large international pooled cohort of BRCA1 and BRCA2 mutation carriers, we conducted retrospective (5,707 BRCA1 mutation carriers; 3,525 BRCA2 mutation carriers) and prospective (2,276 BRCA1 mutation carriers; 1,610 BRCA2 mutation carriers) analyses of alcohol and tobacco consumption using Cox proportional hazards models.RESULTS: For both BRCA1 and BRCA2 mutation carriers, none of the smoking-related variables was associated with BC risk, except smoking for more than five years before a first full-term pregnancy (FFTP) when compared to parous women who never smoked. For BRCA1 mutation carriers, the HR from retrospective analysis (HRR) was 1.19 (95%CI:1.02,1.39) and the HR from prospective analysis (HRP) was 1.36 (95%CI:0.99,1.87). For BRCA2 mutation carriers, smoking for more than five years before a FFTP showed an association of a similar magnitude, but the confidence limits were wider (HRR=1.25,95%CI:1.01,1.55 and HRP=1.30,95%CI:0.83,2.01). For both carrier groups, alcohol consumption was not associated with BC risk.CONCLUSIONS: The finding that smoking during the pre-reproductive years increases BC risk for mutation carriers warrants further investigation.IMPACT: This is the largest prospective study of BRCA mutation carriers to assess these important risk factors.

  View details for DOI 10.1158/1055-9965.EPI-19-0546

  View details for PubMedID 31792088

• Accuracy of Risk Estimates from the iPrevent Breast Cancer Risk Assessment and Management Tool JNCI CANCER SPECTRUM Phillips, K., Liao, Y., Milne, R. L., MacInnis, R. J., Collins, I. M., Buchsbaum, R., Weideman, P. C., Bickerstaffe, A., Nesci, S., Chung, W. K., Southey, M. C., Knight, J. A., Whittemore, A. S., Dite, G. S., Goldgar, D., Giles, G. G., Glendon, G., Cuzick, J., Antoniou, A. C., Andrulis, I. L., John, E. M., Daly, M. B., Buys, S. S., Hopper, J. L., Terry, M., KConFab Investigators 2019; 3 (4): pkz066

  Abstract

  iPrevent is an online breast cancer (BC) risk management decision support tool. It uses an internal switching algorithm, based on a woman's risk factor data, to estimate her absolute BC risk using either the International Breast Cancer Intervention Study (IBIS) version 7.02, or Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm version 3 models, and then provides tailored risk management information. This study assessed the accuracy of the 10-year risk estimates using prospective data.iPrevent-assigned 10-year invasive BC risk was calculated for 15 732 women aged 20-70 years and without BC at recruitment to the Prospective Family Study Cohort. Calibration, the ratio of the expected (E) number of BCs to the observed (O) number and discriminatory accuracy were assessed.During the 10 years of follow-up, 619 women (3.9%) developed BC compared with 702 expected (E/O = 1.13; 95% confidence interval [CI] =1.05 to 1.23). For women younger than 50 years, 50 years and older, and BRCA1/2-mutation carriers and noncarriers, E/O was 1.04 (95% CI = 0.93 to 1.16), 1.24 (95% CI = 1.11 to 1.39), 1.13 (95% CI = 0.96 to 1.34), and 1.13 (95% CI = 1.04 to 1.24), respectively. The C-statistic was 0.70 (95% CI = 0.68 to 0.73) overall and 0.74 (95% CI = 0.71 to 0.77), 0.63 (95% CI = 0.59 to 0.66), 0.59 (95% CI = 0.53 to 0.64), and 0.65 (95% CI = 0.63 to 0.68), respectively, for the subgroups above. Applying the newer IBIS version 8.0b in the iPrevent switching algorithm improved calibration overall (E/O = 1.06, 95% CI = 0.98 to 1.15) and in all subgroups, without changing discriminatory accuracy.For 10-year BC risk, iPrevent had good discriminatory accuracy overall and was well calibrated for women aged younger than 50 years. Calibration may be improved in the future by incorporating IBIS version 8.0b.

  View details for DOI 10.1093/jncics/pkz066

  View details for Web of Science ID 000503271700014

  View details for PubMedID 31853515

  View details for PubMedCentralID PMC6901082

• Comprehensive Investigation of White Blood Cell and Gene Expression Profiles As Risk Factors for Multiple Myeloma in African Americans Kachuri, L., Du, Z., Weinhold, N., Song, G., Rand, K., Van den Berg, D., Hwang, A., Sheng, X., Hom, V., Ailawadhi, S., Nooka, A. K., Singhal, S., Peters, E. S., Bock, C., Mohrbacher, A., Stram, A., Berndt, S. I., Blot, W. J., John, E. M., Bernstein, L., Stroup, A., Zangari, M., van Rhee, F., Olshan, A., Zheng, W., Ingles, S., Press, M., Carpten, J., Chanock, S. J., Mehta, J., Colditz, G. A., Wolf, J., Martin, T. G., Fiala, M. A., Terebelo, H. R., Janakiraman, N., Kolonel, L., Anderson, K. C., Le Marchand, L., Auclair, D., Chiu, B., Stram, D., Vij, R., Bernal-Mizrachi, L., Morgan, G., Zonder, J. A., Huff, C., Lonial, S., Orlowski, R. Z., Conti, D., Haiman, C. A., Ziv, E., Witte, J. S., Cozen, W. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-129298

  View details for Web of Science ID 000577164603111

• Recreational physical activity is associated with reduced breast cancer risk in adult women at high risk for breast cancer: a cohort study of women selected for familial and genetic risk. Cancer research Kehm, R. D., Genkinger, J. M., MacInnis, R. J., John, E. M., Phillips, K., Dite, G. S., Milne, R. L., Zeinomar, N., Liao, Y., Knight, J. A., Southey, M. C., Chung, W. K., Giles, G. G., McLachlan, S., Whitaker, K. D., Friedlander, M., Weideman, P. C., Glendon, G., Nesci, S., Investigators, k., Andrulis, I. L., Buys, S. S., Daly, M. B., Hopper, J. L., Terry, M. B. 2019

  Abstract

  While physical activity is associated with lower breast cancer risk for average-risk women, it is not known if this association applies to women at high familial/genetic risk. We examined the association of recreational physical activity (self-reported by questionnaire) with breast cancer risk using the Prospective Family Study Cohort (ProF-SC), which is enriched with women who have a breast cancer family history (N=15,550). We examined associations of adult and adolescent recreational physical activity (quintiles of age-adjusted total metabolic equivalents (METs) per week) with breast cancer risk using multivariable Cox proportional hazards regression, adjusted for demographics, lifestyle factors, and body mass index. We tested for multiplicative interactions of physical activity with predicted absolute breast cancer familial risk based on pedigree data and with BRCA1 and BRCA2 mutation status. Baseline recreational physical activity level in the highest 4 quintiles compared with the lowest quintile was associated with a 20% lower breast cancer risk (HR=0.80, 95% CI=0.68, 0.93). The association was not modified by familial risk or BRCA mutation status (p-interactions>0.05). No overall association was found for adolescent recreational physical activity. Recreational physical activity in adulthood may lower breast cancer risk for women across the spectrum of familial risk.

  View details for DOI 10.1158/0008-5472.CAN-19-1847

  View details for PubMedID 31578201

• A polygenic risk score for breast cancer in U.S. Latinas and Latin-American women. Journal of the National Cancer Institute Shieh, Y., Fejerman, L., Lott, P. C., Marker, K., Sawyer, S. D., Hu, D., Huntsman, S., Torres, J., Echeverry, M., Bohorquez, M. E., Martinez-Chequer, J. C., Polanco-Echeverry, G., Estrada-Florez, A. P., COLUMBUS Consortium, Haiman, C. A., John, E. M., Kushi, L. H., Torres-Mejia, G., Vidaurre, T., Weitzel, J. N., Zambrano, S. C., Carvajal-Carmona, L. G., Ziv, E., Neuhausen, S. L., Benavides, J., Bohorquez, M., Bolanos, F., Carvajal-Carmona, L. G., Carmona, J., Criollo, A., Echeverry, M., Estrada, A., Mateus, G., Murillo, R., Ramirez, J., Sanchez, Y., Sanabria, C., Serrano, M. L., Suarez, J. J., Velez, A. 2019

  Abstract

  BACKGROUND: Over 180 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified; these SNPs can be combined into polygenic risk scores (PRS) to predict breast cancer risk. Since most SNPs were identified in predominantly European populations, little is known about the performance of PRS in non-Europeans. We tested the performance of a 180-SNP PRS in Latinas, a large ethnic group with variable levels of Indigenous American, European, and African ancestry.METHODS: We conducted a pooled case-control analysis of U.S. Latinas and Latin-American women (4,658 cases, 7,622 controls). We constructed a 180-SNP PRS consisting of SNPs associated with breast cancer risk (p<5 x 10-8). We evaluated the association between the PRS and breast cancer risk using multivariable logistic regression and assessed discrimination using area under the receiver operating characteristic curve (AUROC). We also assessed PRS performance across quartiles of Indigenous American genetic ancestry. All statistical tests were two-sided.RESULTS: Of 180 SNPs tested, 142 showed directionally consistent associations compared with European populations, and 39 were nominally statistically significant (p<0.05). The PRS was associated with breast cancer risk, with an odds ratio (OR) per standard deviation increment of 1.58 (95% CI 1.52 to 1.64) and AUCROC of 0.63 (95% CI 0.62 to 0.64). The discrimination of the PRS was similar between the top and bottom quartiles of Indigenous American ancestry.CONCLUSIONS: The 180-SNP PRS predicts breast cancer risk in Latinas, with similar performance as reported for Europeans. The performance of the PRS did not vary substantially according to Indigenous American ancestry.

  View details for DOI 10.1093/jnci/djz174

  View details for PubMedID 31553449

• Benign breast disease increases breast cancer risk independent of underlying familial risk profile: Findings from a Prospective Family Study Cohort INTERNATIONAL JOURNAL OF CANCER Zeinomar, N., Phillips, K., Daly, M. B., Milne, R. L., Dite, G. S., MacInnis, R. J., Liao, Y., Kehm, R. D., Knight, J. A., Southey, M. C., Chung, W. K., Giles, G. G., McLachlan, S., Friedlander, M. L., Weideman, P. C., Glendon, G., Nesci, S., Andrulis, I. L., Buys, S. S., John, E. M., Hopper, J. L., Terry, M., kConFab Investigators 2019; 145 (2): 370–79

  View details for DOI 10.1002/ijc.32112

  View details for Web of Science ID 000468195900008

• A polygenic risk score predicts breast cancer risk in Latinas Shieh, Y., Fejerman, L., Sawyer, S. D., Hu, D., Huntsman, S., John, E. M., Kushi, L. H., Torres-Mejia, G., Weitzel, J. N., Haiman, C. A., Ziv, E., Neuhausen, S. L. AMER ASSOC CANCER RESEARCH. 2019

  View details for DOI 10.1158/1538-7445.SABCS18-2419

  View details for Web of Science ID 000488279400378

• Runs of homozygosity and testicular cancer risk ANDROLOGY Loveday, C., Sud, A., Litchfield, K., Levy, M., Holroyd, A., Broderick, P., Kote-Jarai, Z., Dunning, A. M., Muir, K., Peto, J., Eeles, R., Easton, D. F., Dudakia, D., Orr, N., Pashayan, N., Rustin, G., Srihari, N. N., Cole, D., Askill, C., Bertelli, G., Barber, J., Gilby, E., White, J., Baybrooke, J., Leahy, M., Welch, R., Chakraborti, P., Joffe, J., Brown, R., Faust, G., Simmonds, P., Mazhar, D., Stockdale, A., Hrounda, D., Humber, C., Appel, W., Hong, A., Howard, G., Douglas, F., Bloomfield, D., Butt, M., Kelly, K., Mehra, R., Brown, R., Rogers, P., Chakraborti, P., Hatton, M., Hennig, I., McAteer, J., Savage, P., Seckl, M., Gale, J., Rustin, G., Clark, P., Woby, S., Rathmell, A., Lamont, A., Sarwar, N., Stuart, N., Chowdhury, S., Beesley, S., Winkler, M., Hamid, A., Pathak, S., Madhavan, K., Highley, M., Money-Kryle, J., Brock, C., Sreenivasan, T., Henderson, B. E., Haiman, C. A., Schumacher, F. R., Al Olama, A., Benlloch, S., Berndt, S. I., Conti, D. V., Wiklund, F., Chanock, S., Gapster, S., Stevens, V. L., Tangen, C. M., Batra, J., Clements, J., Gronberg, H., Schleutker, J., Albanes, D., Wolk, A., West, C., Mucci, L., Cancel-Tassin, G., Koutros, S., Sorensen, K., Maehle, L., Neal, D. E., Hamdy, F. C., Donovan, J. L., Travis, R. C., Hamilton, R. J., Ingles, S., Rosenstein, B. S., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., John, E. M., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R., Usmani, N., Claessens, F., Townsend, P. A., Dominguez, M., Roobol, M. J., Menegaux, F., Khaw, K., Cannon-Albrigh, L., Pandha, H., Thibodeau, S. N., Reid, A., Huddart, R. A., Houlston, R. S., Turnbull, C., UK Testicular Canc Collaboration, PRACTICAL Consortium, Australian Prostate Canc Res Ctr 2019; 7 (4): 555–64

  Abstract

  Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types.To examine whether RoH are associated with TGCT risk.We performed a genome-wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform.Global measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13-11p14.3, 5q14.1-5q22.3 and 13q14.11-13q.14.13, were, however, nominally statistically significant at p < 0.01. Intriguingly, RoH200 at 11p13-11p14.3 encompasses Wilms tumour 1 (WT1), a recognized cancer susceptibility gene with roles in sex determination and developmental transcriptional regulation, processes repeatedly implicated in TGCT aetiology.Overall, our data do not support a major role in the risk of TGCT for recessively acting alleles acting through homozygosity, as measured by RoH in outbred populations of cases and controls.

  View details for DOI 10.1111/andr.12667

  View details for Web of Science ID 000475940600021

  View details for PubMedID 31310061

• The genetic interplay between body mass index, breast size and breast cancer risk: a Mendelian randomization analysis. International journal of epidemiology Ooi, B. N., Loh, H., Ho, P. J., Milne, R. L., Giles, G., Gao, C., Kraft, P., John, E. M., Swerdlow, A., Brenner, H., Wu, A. H., Haiman, C., Evans, D. G., Zheng, W., Fasching, P. A., Castelao, J. E., Kwong, A., Shen, X., Czene, K., Hall, P., Dunning, A., Easton, D., Hartman, M., Li, J. 2019

  Abstract

  BACKGROUND: Evidence linking breast size to breast cancer risk has been inconsistent, and its interpretation is often hampered by confounding factors such as body mass index (BMI). Here, we used linkage disequilibrium score regression and two-sample Mendelian randomization (MR) to examine the genetic associations between BMI, breast size and breast cancer risk.METHODS: Summary-level genotype data from 23andMe, Inc (breast size, n=33790), the Breast Cancer Association Consortium (breast cancer risk, n=228951) and the Genetic Investigation of ANthropometric Traits (BMI, n=183507) were used for our analyses. In assessing causal relationships, four complementary MR techniques [inverse variance weighted (IVW), weighted median, weighted mode and MR-Egger regression] were used to test the robustness of the results.RESULTS: The genetic correlation (rg) estimated between BMI and breast size was high (rg=0.50, P=3.89x10-43). All MR methods provided consistent evidence that higher genetically predicted BMI was associated with larger breast size [odds ratio (ORIVW): 2.06 (1.80-2.35), P=1.38x10-26] and lower overall breast cancer risk [ORIVW: 0.81 (0.74-0.89), P=9.44x10-6]. No evidence of a relationship between genetically predicted breast size and breast cancer risk was found except when using the weighted median and weighted mode methods, and only with oestrogen receptor (ER)-negative risk. There was no evidence of reverse causality in any of the analyses conducted (P>0.050).CONCLUSION: Our findings indicate a potential positive causal association between BMI and breast size and a potential negative causal association between BMI and breast cancer risk. We found no clear evidence for a direct relationship between breast size and breast cancer risk.

  View details for DOI 10.1093/ije/dyz124

  View details for PubMedID 31243447

• A Genome-wide Association Study of Prostate Cancer in Latinos. International journal of cancer Du, Z., Hopp, H., Ingles, S. A., Huff, C., Sheng, X., Weaver, B., Stern, M., Hoffmann, T. J., John, E. M., Van Den Eeden, S. K., Strom, S., Leach, R. J., Thompson, I. M., Witte, J. S., Conti, D. V., Haiman, C. A. 2019

  Abstract

  Latinos represent less than 1% of samples analyzed to date in genome-wide association studies of cancer. The clinical value of genetic information in guiding personalized medicine in populations of non-European ancestry will require additional discovery and risk locus characterization efforts across populations. In the present study, we performed a GWAS of PrCa in 2,820 Latino PrCa cases and 5,293 controls to search for novel PrCa risk loci and to examine the generalizability of known PrCa risk loci in Latino men. We also conducted a genetic admixture mapping scan to identify PrCa risk alleles associated with local ancestry. Genome-wide significant associations were observed with 84 variants all located at the known PrCa risk regions at 8q24 (128.484-128.548) and 10q11.22 (MSMB gene). In admixture mapping, we observed genome-wide significant associations with local African ancestry at 8q24. Of the 162 established PrCa risk variants that are common in Latino men, 135 (83.3%) had effects that were directionally consistent as previously reported, among which 55 (34.0%) were statistically significant with P<0.05. A polygenic risk model of the known PrCa risk variants showed that, compared to men with average risk (25th -75th percentile of the polygenic risk score distribution), men in the top 10% had a 3.19-fold (95% CI: 2.65, 3.84) increased PrCa risk. In conclusion, we found that the known PrCa risk variants can effectively stratify PrCa risk in Latino men. Larger studies in Latino populations will be required to discover and characterize genetic risk variants for PrCa and improve risk stratification for this population. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ijc.32525

  View details for PubMedID 31226226

• Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers. British journal of cancer Qian, F., Rookus, M. A., Leslie, G., Risch, H. A., Greene, M. H., Aalfs, C. M., Adank, M. A., Adlard, J., Agnarsson, B. A., Ahmed, M., Aittomaki, K., Andrulis, I. L., Arnold, N., Arun, B. K., Ausems, M. G., Azzollini, J., Barrowdale, D., Barwell, J., Benitez, J., Bialkowska, K., Bonadona, V., Borde, J., Borg, A., Bradbury, A. R., Brunet, J., Buys, S. S., Caldes, T., Caligo, M. A., Campbell, I., Carter, J., Chiquette, J., Chung, W. K., Claes, K. B., Collee, J. M., Collonge-Rame, M., Couch, F. J., Daly, M. B., Delnatte, C., Diez, O., Domchek, S. M., Dorfling, C. M., Eason, J., Easton, D. F., Eeles, R., Engel, C., Evans, D. G., Faivre, L., Feliubadalo, L., Foretova, L., Friedman, E., Frost, D., Ganz, P. A., Garber, J., Garcia-Barberan, V., Gehrig, A., Glendon, G., Godwin, A. K., Gomez Garcia, E. B., Hamann, U., Hauke, J., Hopper, J. L., Hulick, P. J., Imyanitov, E. N., Isaacs, C., Izatt, L., Jakubowska, A., Janavicius, R., John, E. M., Karlan, B. Y., Kets, C. M., Laitman, Y., Lazaro, C., Leroux, D., Lester, J., Lesueur, F., Loud, J. T., Lubinski, J., Lukomska, A., McGuffog, L., Mebirouk, N., Meijers-Heijboer, H. E., Meindl, A., Miller, A., Montagna, M., Mooij, T. M., Mouret-Fourme, E., Nathanson, K. L., Nehoray, B., Neuhausen, S. L., Nevanlinna, H., Nielsen, F. C., Offit, K., Olah, E., Ong, K., Oosterwijk, J. C., Ottini, L., Parsons, M. T., Peterlongo, P., Pfeiler, G., Pradhan, N., Radice, P., Ramus, S. J., Rantala, J., Rennert, G., Robson, M., Rodriguez, G. C., Salani, R., Scheuner, M. T., Schmutzler, R. K., Shah, P. D., Side, L. E., Simard, J., Singer, C. F., Steinemann, D., Stoppa-Lyonnet, D., Tan, Y. Y., Teixeira, M. R., Terry, M. B., Thomassen, M., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tung, N., van Asperen, C. J., van Engelen, K., van Rensburg, E. J., Venat-Bouvet, L., Vierstraete, J., Wagner, G., Walker, L., Weitzel, J. N., Yannoukakos, D., KConFab Investigators, HEBON Investigators, GEMO Study Collaborators, EMBRACE Collaborators, Antoniou, A. C., Goldgar, D. E., Olopade, O. I., Chenevix-Trench, G., Rebbeck, T. R., Huo, D., CIMBA 2019

  Abstract

  BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown.METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models.RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR=1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR=1.25 (95% CI: 1.06-1.48) and HR=1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction<0.05).CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

  View details for DOI 10.1038/s41416-019-0492-8

  View details for PubMedID 31213659

• The functional ALDH2 polymorphism is associated with breast cancer risk: A pooled analysis from the Breast Cancer Association Consortium MOLECULAR GENETICS & GENOMIC MEDICINE Ugai, T., Milne, R. L., Ito, H., Aronson, K. J., Bolla, M. K., Chan, T., Chan, C. W., Choi, J., Conroy, D. M., Dennis, J., Dunning, A. M., Easton, D. F., Gaborieau, V., Gonzalez-Neira, A., Hartman, M., Healey, C. S., Iwasaki, M., John, E. M., Kang, D., Kim, S., Kwong, A., Lophatananon, A., Michailidou, K., Taib, N., Muir, K., Park, S. K., Pharoah, P. P., Sangrajrang, S., Shen, C., Shu, X., Spinelli, J. J., Teo, S. H., Tessier, D. C., Tseng, C., Tsugane, S., Vincent, D., Wang, Q., Wu, A. H., Wu, P., Zheng, W., Matsuo, K. 2019; 7 (6)

  View details for DOI 10.1002/mgg3.707

  View details for Web of Science ID 000476745400047

• Genetic predisposition to breast cancer among African American women. Palmer, J. R., Hu, C., Hart, S., Gnanaolivu, R., Gao, C., Anton-Culver, H., Trentham-Dietz, A., Bernstein, L., Weitzel, J. N., Domchek, S. M., Goldgar, D., Nathanson, K., Pal, T., John, E. M., Gaudet, M., Haiman, C., Yao, S., Kraft, P., Polley, E., Couch, F. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.104

  View details for Web of Science ID 000487345803489

• Association analyses identify 31 new risk loci for colorectal cancer susceptibility NATURE COMMUNICATIONS Law, P. J., Timofeeva, M., Fernandez-Rozadilla, C., Timofeeva, A., Broderick, P., Studd, J., Fernandez-Tajes, J., Farrington, S., Svinti, V., Palles, C., Orlando, G., Sud, A., Holroyd, A., Penegar, S., Theodoratou, E., Vaughan-Shaw, P., Campbell, H., Zgaga, L., Hayward, C., Campbell, A., Harris, S., Deary, I. J., Starr, O., Gatcombe, L., Pinna, M., Briggs, S., Martin, L., Jaeger, E., Sharma-Oates, A., East, J., Leedham, S., Arnold, R., Johnstone, E., Wang, H., Kerr, D., Kerr, R., Maughan, T., Kaplan, R., Al-Tassan, N., Palin, K., Hanninen, U. A., Cajuso, T., Tanskanen, T., Kondelin, J., Kaasinen, E., Sarin, A., Eriksson, J. G., Rissanen, H., Knekt, P., Pukkala, E., Jousilahti, P., Salomaa, V., Ripatti, S., Palotie, A., Renkonen-Sinisalo, L., Lepisto, A., Bohm, J., Mecklin, J., Buchanan, D. D., Win, A., Hopper, J., Jenkins, M. E., Lindor, N. M., Newcomb, P. A., Gallinger, S., Duggan, D., Casey, G., Hoffmann, P., Nothen, M. M., Jockel, K., Easton, D. F., Pharoah, P. P., Peto, J., Canzian, F., Swerdlow, A., Eeles, R. A., Kote-Jarai, Z., Muir, K., Pashayan, N., Harkin, A., Allan, K., McQueen, J., Paul, J., Iveson, T., Saunders, M., Butterbach, K., Chang-Claude, J., Hoffmeister, M., Brenner, H., Kirac, I., Matosevic, P., Hofer, P., Brezina, S., Gsur, A., Cheadle, J. P., Aaltonen, L. A., Tomlinson, I., Houlston, R. S., Dunlop, M. G., Henderson, B. E., Haiman, C. A., Schumacher, F. R., Al Olama, A., Benlloch, S., Berndt, S., Conti, D., Wiklund, F., Chanock, S., Gapstur, S., Stevens, V. L., Tangen, C. M., Batra, J., Clements, J., Gronberg, H., Schleutker, J., Albanes, D., Wolk, A., West, C., Mucci, L., Cancel-Tassin, G., Koutros, S., Sorensen, K., Grindeda, E., Neal, D. E., Hamdy, F. C., Donovan, J. L., Travis, R. C., Hamilton, R. J., Ingles, S., Rosenstein, B. S., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Maier, C., Kim, J., John, E. M., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Gamulin, M., Kaneva, R., Usmani, N., Claessens, F., Townsend, P. A., Gago-Dominguez, M., Roobol, M. J., Menegaux, F., Khaw, K., Cannon-Albright, L., Pandha, H., Thibodeau, S. N., PRACTICAL Consortium 2019; 10: 2154

  Abstract

  Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.

  View details for DOI 10.1038/s41467-019-09775-w

  View details for Web of Science ID 000467836900008

  View details for PubMedID 31089142

  View details for PubMedCentralID PMC6517433

• A Pooled Analysis of Breastfeeding and Breast Cancer Risk by Hormone Receptor Status in Parous Hispanic Women. Epidemiology (Cambridge, Mass.) Sangaramoorthy, M., Hines, L. M., Torres-Mejía, G., Phipps, A. I., Baumgartner, K. B., Wu, A. H., Koo, J., Ingles, S. A., Slattery, M. L., John, E. M. 2019; 30 (3): 449-457

  Abstract

  Data on breastfeeding and breast cancer risk are sparse and inconsistent for Hispanic women.Pooling data for nearly 6,000 parous Hispanic women from four population-based studies conducted between 1995 and 2007 in the United States and Mexico, we examined the association of breastfeeding with risk of breast cancer overall and subtypes defined by estrogen receptor (ER) and progesterone receptor (PR) status, and the joint effects of breastfeeding, parity, and age at first birth. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression.Among parous Hispanic women, older age at first birth was associated with increased breast cancer risk, whereas parity was associated with reduced risk. These associations were found for hormone receptor positive (HR+) breast cancer only and limited to premenopausal women. Age at first birth and parity were not associated with risk of ER- and PR- breast cancer. Increasing duration of breastfeeding was associated with decreasing breast cancer risk (≥25 vs. 0 months: OR = 0.73; 95% CI = 0.60, 0.89; Ptrend = 0.03), with no heterogeneity by menopausal status or subtype. At each parity level, breastfeeding further reduced HR+ breast cancer risk. Additionally, breastfeeding attenuated the increase in risk of HR+ breast cancer associated with older age at first birth.Our findings suggest that breastfeeding is associated with reduced risk of both HR+ and ER- and PR- breast cancer among Hispanic women, as reported for other populations, and may attenuate the increased risk in women with a first pregnancy at older ages.

  View details for DOI 10.1097/EDE.0000000000000981

  View details for PubMedID 30964816

  View details for PubMedCentralID PMC6472273

• Regular use of aspirin and other non-steroidal anti-inflammatory drugs and breast cancer risk for women at familial or genetic risk: a cohort study BREAST CANCER RESEARCH Kehm, R. D., Hopper, J. L., John, E. M., Phillips, K., MacInnis, R. J., Dite, G. S., Milne, R. L., Liao, Y., Zeinomar, N., Knight, J. A., Southey, M. C., Vahdat, L., Kornhauser, N., Cigler, T., Chung, W. K., Giles, G. G., McLachlan, S., Friedlander, M. L., Weideman, P. C., Glendon, G., Nesci, S., Andrulis, I. L., Buys, S. S., Daly, M. B., Terry, M., kConFab Investigators 2019; 21

  View details for DOI 10.1186/s13058-019-1135-y

  View details for Web of Science ID 000464990900001

• Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer NATURE COMMUNICATIONS Ferreira, M. A., Gamazon, E. R., Al-Ejeh, F., Aittomaki, K., Andrulis, I. L., Anton-Culver, H., Arason, A., Arndt, V., Aronson, K. J., Arun, B. K., Asseryanis, E., Azzollini, J., Balmana, J., Barnes, D. R., Barrowdale, D., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bialkowska, K., Blomqvist, C., Bogdanova, N., Bojesen, S. E., Bolla, M. K., Borg, A., Brauch, H., Brenner, H., Broeks, A., Burwinkel, B., Caldes, T., Caligo, M. A., Campa, D., Campbell, I., Canzian, F., Carter, J., Carter, B. D., Castelao, J. E., Chang-Claude, J., Chanock, S. J., Christiansen, H., Chung, W. K., Claes, K. M., Clarke, C. L., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Daly, M. B., de la Hoya, M., Dennis, J., Devilee, P., Diez, O., Doerk, T., Dunning, A. M., Dwek, M., Eccles, D. M., Ejlertsen, B., Ellberg, C., Engel, C., Eriksson, M., Fasching, P. A., Fletcher, O., Flyger, H., Friedman, E., Frost, D., Gabrielson, M., Gago-Dominguez, M., Ganz, P. A., Gapstur, S. M., Garber, J., Garcia-Closas, M., Garcia-Saenz, J. A., Gaudet, M. M., Giles, G. G., Glendon, G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Greene, M. H., Gronwald, J., Guenel, P., Haiman, C. A., Hall, P., Hamann, U., He, W., Heyworth, J., Hogervorst, F. L., Hollestelle, A., Hoover, R. N., Hopper, J. L., Hulick, P. J., Humphreys, K., Imyanitov, E. N., Isaacs, C., Jakimovska, M., Jakubowska, A., James, P. A., Janavicius, R., Jankowitz, R. C., John, E. M., Johnson, N., Joseph, V., Karlan, B. Y., Khusnutdinova, E., Kiiski, J., Ko, Y., Jones, M. E., Konstantopoulou, I., Kristensen, V. N., Laitman, Y., Lambrechts, D., Lazaro, C., Leslie, G., Lester, J., Lesueur, F., Lindstrom, S., Long, J., Loud, J. T., Lubinski, J., Makalic, E., Mannermaa, A., Manoochehri, M., Margolin, S., Maurer, T., Mavroudis, D., McGuffog, L., Meindl, A., Menon, U., Michailidou, K., Miller, A., Montagna, M., Moreno, F., Moserle, L., Mulligan, A., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Nevelsteen, I., Nielsen, F. C., Nikitina-Zake, L., Nussbaum, R. L., Offit, K., Olah, E., Olopade, O., Olsson, H., Osorio, A., Papp, J., Park-Simon, T., Parsons, M. T., Pedersen, I., Peixoto, A., Peterlongo, P., Pharoah, P. P., Plaseska-Karanfilska, D., Poppe, B., Presneau, N., Radice, P., Rantala, J., Rennert, G., Risch, H. A., Saloustros, E., Sanden, K., Sawyer, E. J., Schmidt, M. K., Schmutzler, R. K., Sharma, P., Shu, X., Simard, J., Singer, C. F., Soucy, P., Southey, M. C., Spinelli, J. J., Spurdle, A. B., Stone, J., Swerdlow, A. J., Tapper, W. J., Taylor, J. A., Teixeira, M. R., Terry, M., Teule, A., Thomassen, M., Thoene, K., Thull, D. L., Tischkowitz, M., Toland, A. E., Torres, D., Truong, T., Tung, N., Vachon, C. M., van Asperen, C. J., van den Ouweland, A. W., van Rensburg, E. J., Vega, A., Viel, A., Wang, Q., Wappenschmidt, B., Weitzel, J. N., Wendt, C., Winqvist, R., Yang, X. R., Yannoukakos, D., Ziogas, A., Kraft, P., Antoniou, A. C., Zheng, W., Easton, D. F., Milne, R. L., Beesley, J., Chenevix-Trench, G., Arnold, N., Auber, B., Bogdanova-Markov, N., Borde, J., Caliebe, A., Ditsch, N., Dworniczak, B., Engert, S., Faust, U., Gehrig, A., Hahnen, E., Hauke, J., Hentschel, J., Herold, N., Honisch, E., Just, W., Kast, K., Larsen, M., Lemke, J., Huu Phuc Nguyen, Niederacher, D., Ott, C., Platzer, K., Pohl-Rescigno, E., Ramser, J., Rhiem, K., Steinemann, D., Sutter, C., Varon-Mateeva, R., Wang-Gohrke, S., Weber, B. F., Prieur, F., Pujol, P., Sagne, C., Sevenet, N., Sobol, H., Sokolowska, J., Stoppa-Lyonnet, D., Venat-Bouvet, L., Adlard, J., Ahmed, M., Barwell, J., Brady, A., Brewer, C., Cook, J., Davidson, R., Donaldson, A., Eason, J., Eeles, R., Evans, D., Gregory, H., Hanson, H., Henderson, A., Hodgson, S., Izatt, L., Kennedy, M., Lalloo, F., Miller, C., Morrison, P. J., Ong, K., Perkins, J., Porteous, M. E., Rogers, M. T., Side, L. E., Snape, K., Walker, L., Harrington, P. A., Heemskerk-Gerritsen, B. M., Rookus, M. A., Seynaeve, C. M., van der Baan, F. H., van der Hout, A. H., van der Kolk, L. E., van der Luijt, R. B., van Deurzen, C. M., van Doorn, H. C., van Engelen, K., van Hest, L., van Os, T. M., Verhoef, S., Vogel, M. J., Wijnen, J. T., Miron, A., Kapuscinski, M., Bane, A., Ross, E., Buys, S. S., Conner, T. A., Balleine, R., Baxter, R., Braye, S., Carpenter, J., Dahlstrom, J., Forbes, J., Lee, S. C., Marsh, D., Morey, A., Pathmanathan, N., Simpson, P., Spigelman, A., Wilcken, N., Yip, D., GC-HBOC Study Collaborators, GEMO Study Collaborators, EMBRACE Collaborators, HEBON Investigators, BCFR Investigators, ABCTB Investigators 2019; 10

  View details for DOI 10.1038/s41467-018-08053-5

  View details for Web of Science ID 000464494100010

• Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer. Nature communications Ferreira, M. A., Gamazon, E. R., Al-Ejeh, F., Aittomaki, K., Andrulis, I. L., Anton-Culver, H., Arason, A., Arndt, V., Aronson, K. J., Arun, B. K., Asseryanis, E., Azzollini, J., Balmana, J., Barnes, D. R., Barrowdale, D., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bialkowska, K., Blomqvist, C., Bogdanova, N. V., Bojesen, S. E., Bolla, M. K., Borg, A., Brauch, H., Brenner, H., Broeks, A., Burwinkel, B., Caldes, T., Caligo, M. A., Campa, D., Campbell, I., Canzian, F., Carter, J., Carter, B. D., Castelao, J. E., Chang-Claude, J., Chanock, S. J., Christiansen, H., Chung, W. K., Claes, K. B., Clarke, C. L., EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, Couch, F. J., Cox, A., Cross, S. S., Czene, K., Daly, M. B., de la Hoya, M., Dennis, J., Devilee, P., Diez, O., Dork, T., Dunning, A. M., Dwek, M., Eccles, D. M., Ejlertsen, B., Ellberg, C., Engel, C., Eriksson, M., Fasching, P. A., Fletcher, O., Flyger, H., Friedman, E., Frost, D., Gabrielson, M., Gago-Dominguez, M., Ganz, P. A., Gapstur, S. M., Garber, J., Garcia-Closas, M., Garcia-Saenz, J. A., Gaudet, M. M., Giles, G. G., Glendon, G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Greene, M. H., Gronwald, J., Guenel, P., Haiman, C. A., Hall, P., Hamann, U., He, W., Heyworth, J., Hogervorst, F. B., Hollestelle, A., Hoover, R. N., Hopper, J. L., Hulick, P. J., Humphreys, K., Imyanitov, E. N., ABCTB Investigators, HEBON Investigators, BCFR Investigators, Isaacs, C., Jakimovska, M., Jakubowska, A., James, P. A., Janavicius, R., Jankowitz, R. C., John, E. M., Johnson, N., Joseph, V., Karlan, B. Y., Khusnutdinova, E., Kiiski, J. I., Ko, Y., Jones, M. E., Konstantopoulou, I., Kristensen, V. N., Laitman, Y., Lambrechts, D., Lazaro, C., Leslie, G., Lester, J., Lesueur, F., Lindstrom, S., Long, J., Loud, J. T., Lubinski, J., Makalic, E., Mannermaa, A., Manoochehri, M., Margolin, S., Maurer, T., Mavroudis, D., McGuffog, L., Meindl, A., Menon, U., Michailidou, K., Miller, A., Montagna, M., Moreno, F., Moserle, L., Mulligan, A. M., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Nevelsteen, I., Nielsen, F. C., Nikitina-Zake, L., Nussbaum, R. L., Offit, K., Olah, E., Olopade, O. I., Olsson, H., Osorio, A., Papp, J., Park-Simon, T., Parsons, M. T., Pedersen, I. S., Peixoto, A., Peterlongo, P., Pharoah, P. D., Plaseska-Karanfilska, D., Poppe, B., Presneau, N., Radice, P., Rantala, J., Rennert, G., Risch, H. A., Saloustros, E., Sanden, K., Sawyer, E. J., Schmidt, M. K., Schmutzler, R. K., Sharma, P., Shu, X., Simard, J., Singer, C. F., Soucy, P., Southey, M. C., Spinelli, J. J., Spurdle, A. B., Stone, J., Swerdlow, A. J., Tapper, W. J., Taylor, J. A., Teixeira, M. R., Terry, M. B., Teule, A., Thomassen, M., Thone, K., Thull, D. L., Tischkowitz, M., Toland, A. E., Torres, D., Truong, T., Tung, N., Vachon, C. M., van Asperen, C. J., van den Ouweland, A. M., van Rensburg, E. J., Vega, A., Viel, A., Wang, Q., Wappenschmidt, B., Weitzel, J. N., Wendt, C., Winqvist, R., Yang, X. R., Yannoukakos, D., Ziogas, A., Kraft, P., Antoniou, A. C., Zheng, W., Easton, D. F., Milne, R. L., Beesley, J., Chenevix-Trench, G., Adlard, J., Ahmed, M., Barwell, J., Brady, A., Brewer, C., Cook, J., Davidson, R., Donaldson, A., Eason, J., Eeles, R., Evans, D. G., Gregory, H., Hanson, H., Henderson, A., Hodgson, S., Izatt, L., Kennedy, M. J., Lalloo, F., Miller, C., Morrison, P. J., Ong, K., Perkins, J., Porteous, M. E., Rogers, M. T., Side, L. E., Snape, K., Walker, L., Harrington, P. A., Arnold, N., Auber, B., Bogdanova-Markov, N., Borde, J., Caliebe, A., Ditsch, N., Dworniczak, B., Engert, S., Faust, U., Gehrig, A., Hahnen, E., Hauke, J., Hentschel, J., Herold, N., Honisch, E., Just, W., Kast, K., Larsen, M., Lemke, J., Nguyen, H. P., Niederacher, D., Ott, C., Platzer, K., Pohl-Rescigno, E., Ramser, J., Rhiem, K., Steinemann, D., Sutter, C., Varon-Mateeva, R., Wang-Gohrke, S., Weber, B. H., Prieur, F., Pujol, P., Sagne, C., Sevenet, N., Sobol, H., Sokolowska, J., Stoppa-Lyonnet, D., Venat-Bouvet, L., Balleine, R., Baxter, R., Braye, S., Carpenter, J., Dahlstrom, J., Forbes, J., Lee, S. C., Marsh, D., Morey, A., Pathmanathan, N., Simpson, P., Spigelman, A., Wilcken, N., Yip, D., Heemskerk-Gerritsen, B. A., Rookus, M. A., Seynaeve, C. M., van der Baan, F. H., van der Hout, A. H., van der Kolk, L. E., van der Luijt, R. B., van Deurzen, C. H., van Doorn, H. C., van Engelen, K., van Hest, L., van Os, T. A., Verhoef, S., Vogel, M. J., Wijnen, J. T., Miron, A., Kapuscinski, M., Bane, A., Ross, E., Buys, S. S., Conner, T. A. 2019; 10 (1): 1741

  Abstract

  Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

  View details for PubMedID 30988301

• 10-year performance of four models of breast cancer risk:a validation study LANCET ONCOLOGY Terry, M., Liao, Y., Whittemore, A. S., Leoce, N., Buchsbaum, R., Zeinotnar, N., Dite, G. S., Chung, W. K., Knight, J. A., Southey, M. C., Milne, R. L., Goldgar, D., Giles, G. G., McLachlan, S., Friedlander, M. L., Weideman, P. C., Glendon, G., Nesci, S., Andrulis, I. L., John, E. M., Phillips, K., Daly, M. B., Buys, S. S., Hopper, J. L., MacInnis, R. 2019; 20 (4): 504–17

  View details for DOI 10.1016/S1470-2045(18)30902-1

  View details for Web of Science ID 000463009600033

• Enrollment and biospecimen collection in a multiethnic family cohort: the Northern California site of the Breast Cancer Family Registry CANCER CAUSES & CONTROL John, E. M., Sangaramoorthy, M., Koo, J., Whittemore, A. S., West, D. W. 2019; 30 (4): 395–408

  View details for DOI 10.1007/s10552-019-01154-6

  View details for Web of Science ID 000464841100010

• Genome-wide association study of germline variants and breast cancer-specific mortality BRITISH JOURNAL OF CANCER Escala-Garcia, M., Guo, Q., Doerk, T., Canisius, S., Keeman, R., Dennis, J., Beesley, J., Lecarpentier, J., Bolla, M. K., Wang, Q., Abraham, J., Andrulis, I. L., Anton-Culver, H., Arndt, V., Auer, P. L., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bernstein, L., Blomqvist, C., Boeckx, B., Bojesen, S. E., Bonanni, B., Borresen-Dale, A., Brauch, H., Brenner, H., Brentnall, A., Brinton, L., Broberg, P., Brock, I. W., Brucker, S. Y., Burwinkel, B., Caldas, C., Caldes, T., Campa, D., Canzian, F., Carracedo, A., Carter, B. D., Castelao, J. E., Chang-Claude, J., Chanock, S. J., Chenevix-Trench, G., Cheng, T., Chin, S., Clarke, C. L., Cordina-Duverger, E., Couch, F. J., Cox, D. G., Cox, A., Cross, S. S., Czene, K., Daly, M. B., Devilee, P., Dunn, J. A., Dunning, A. M., Durcan, L., Dwek, M., Earl, H. M., Ekici, A. B., Eliassen, A., Ellberg, C., Engel, C., Eriksson, M., Evans, D., Figueroa, J., Flesch-Janys, D., Flyger, H., Gabrielson, M., Gago-Dominguez, M., Galle, E., Gapstur, S. M., Garcia-Closas, M., Garcia-Saenz, J. A., Gaudet, M. M., George, A., Georgoulias, V., Giles, G. G., Glendon, G., Goldgar, D. E., Gonzalez-Neira, A., Alnaes, G., Grip, M., Guenel, P., Haeberle, L., Hahnen, E., Haiman, C. A., Hakansson, N., Hall, P., Hamann, U., Hankinson, S., Harkness, E. F., Harrington, P. A., Hart, S. N., Hartikainen, J. M., Hein, A., Hillemanns, P., Hiller, L., Holleczek, B., Hollestelle, A., Hooning, M. J., Hoover, R. N., Hopper, J. L., Howell, A., Huang, G., Humphreys, K., Hunter, D. J., Janni, W., John, E. M., Jones, M. E., Jukkola-Vuorinen, A., Jung, A., Kaaks, R., Kabisch, M., Kaczmarek, K., Kerin, M. J., Khan, S., Khusnutdinova, E., Kiiski, J., Kitahara, C. M., Knight, J. A., Ko, Y., Koppert, L. B., Kosma, V., Kraft, P., Kristensen, V. N., Kruger, U., Kuehl, T., Lambrechts, D., Le Marchand, L., Lee, E., Lejbkowicz, F., Li, L., Lindblom, A., Lindstrom, S., Linet, M., Lissowska, J., Lo, W., Loibl, S., Lubinski, J., Lux, M. P., MacInnis, R. J., Maierthaler, M., Maishman, T., Makalic, E., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M., Mavroudis, D., McLean, C., Meindl, A., Middha, P., Miller, N., Milne, R. L., Moreno, F., Mulligan, A., Mulot, C., Nassir, R., Neuhausen, S. L., Newman, W. T., Nielsen, S. F., Nordestgaard, B. G., Norman, A., Olsson, H., Orr, N., Pankratz, V., Park-Simon, T., Perez, J. A., Perez-Barrios, C., Peterlongo, P., Petridis, C., Pinchev, M., Prajzendanc, K., Prentice, R., Presneau, N., Prokofieva, D., Pylkas, K., Rack, B., Radice, P., Ramachandran, D., Rennert, G., Rennert, H. S., Rhenius, V., Romero, A., Roylance, R., Saloustros, E., Sawyer, E. J., Schmidt, D. F., Schmutzler, R. K., Schneeweiss, A., Schoemaker, M. J., Schumacher, F., Schwentner, L., Scott, R. J., Scott, C., Seynaeve, C., Shah, M., Simard, J., Smeets, A., Sohn, C., Southey, M. C., Swerdlow, A. J., Talhouk, A., Tamimi, R. M., Tapper, W. J., Teixeira, M. R., Tengstrom, M., Terry, M., Thoene, K., Tollenaar, R. M., Tomlinson, I., Torres, D., Truong, T., Turman, C., Turnbull, C., Ulmer, H., Untch, M., Vachon, C., van Asperen, C. J., van den Ouweland, A. W., van Veen, E. M., Wendt, C., Whittemore, A. S., Willett, W., Winqvist, R., Wolk, A., Yang, X. R., Zhang, Y., Easton, D. F., Fasching, P. A., Nevanlinna, H., Eccles, D. M., Pharoah, P. P., Schmidt, M. K., NBCS Collaborators 2019; 120 (6): 647–57

  View details for DOI 10.1038/s41416-019-0393-x

  View details for Web of Science ID 000461700900011

• Enrollment and biospecimen collection in a multiethnic family cohort: the Northern California site of the Breast Cancer Family Registry. Cancer causes & control : CCC John, E. M., Sangaramoorthy, M., Koo, J., Whittemore, A. S., West, D. W. 2019

  Abstract

  PURPOSE: Racial/ethnic minorities are often assumed to be less willing to participate in and provide biospecimens for biomedical research. We examined racial/ethnic differences in enrollment of women with breast cancer (probands) and their first-degree relatives in the Northern California site of the Breast Cancer Family Registry from 1996 to 2011.METHODS: We evaluated participation in several study components, including biospecimen collection, for probands and relatives by race/ethnicity, cancer history, and other factors.RESULTS: Of 4,780 eligible probands, 76% enrolled in the family registry by completing the family history and risk factor questionnaires and 68% also provided a blood or mouthwash sample. Enrollment was highest (81%) for non-Hispanic whites (NHWs) and intermediate (73-76%) for Hispanics, African Americans, and all Asian American subgroups, except Filipina women (66%). Of 4,279 eligible relatives, 77% enrolled in the family registry, and 65% also provided a biospecimen sample. Enrollment was highest for NHWs (87%) and lowest for Chinese (68%) and Filipinas (67%). Among those enrolled, biospecimen collection rates were similar for NHW, Hispanic, and African American women, both for probands (92-95%) and relatives (82-87%), but lower for some Asian-American subgroups (probands: 72-88%; relatives: 71-88%), foreign-born Asian Americans, and probands those who were more recent immigrants or had low English language proficiency.CONCLUSIONS: These results show that racial/ethnic minority populations are willing to provide biospecimen samples for research, although some Asian American subgroups in particular may need more directed recruitment methods. To address long-standing and well-documented cancer health disparities, minority populations need equal opportunities to contribute to biomedical research.

  View details for PubMedID 30835011

• Risk-Reducing Oophorectomy and Breast Cancer Risk Across the Spectrum of Familial Risk JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Terry, M., Daly, M. B., Phillips, K., Ma, X., Zeinomar, N., Leoce, N., Dite, G. S., MacInnis, R. J., Chung, W. K., Knight, J. A., Southey, M. C., Milne, R. L., Goldgar, D., Giles, G. G., Weideman, P. C., Glendon, G., Buchsbaum, R., Andrulis, I. L., John, E. M., Buys, S. S., Hopper, J. L., kConFab Investigators 2019; 111 (3): 331–34

  View details for DOI 10.1093/jnci/djy182

  View details for Web of Science ID 000467901100015

• Genome-wide association study of germline variants and breast cancer-specific mortality. British journal of cancer Escala-Garcia, M., Guo, Q., Dork, T., Canisius, S., Keeman, R., Dennis, J., Beesley, J., Lecarpentier, J., Bolla, M. K., Wang, Q., Abraham, J., Andrulis, I. L., Anton-Culver, H., Arndt, V., Auer, P. L., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bernstein, L., Blomqvist, C., Boeckx, B., Bojesen, S. E., Bonanni, B., Borresen-Dale, A., Brauch, H., Brenner, H., Brentnall, A., Brinton, L., Broberg, P., Brock, I. W., Brucker, S. Y., Burwinkel, B., Caldas, C., Caldes, T., Campa, D., Canzian, F., Carracedo, A., Carter, B. D., Castelao, J. E., Chang-Claude, J., Chanock, S. J., Chenevix-Trench, G., Cheng, T. D., Chin, S., Clarke, C. L., NBCS Collaborators, Cordina-Duverger, E., Couch, F. J., Cox, D. G., Cox, A., Cross, S. S., Czene, K., Daly, M. B., Devilee, P., Dunn, J. A., Dunning, A. M., Durcan, L., Dwek, M., Earl, H. M., Ekici, A. B., Eliassen, A. H., Ellberg, C., Engel, C., Eriksson, M., Evans, D. G., Figueroa, J., Flesch-Janys, D., Flyger, H., Gabrielson, M., Gago-Dominguez, M., Galle, E., Gapstur, S. M., Garcia-Closas, M., Garcia-Saenz, J. A., Gaudet, M. M., George, A., Georgoulias, V., Giles, G. G., Glendon, G., Goldgar, D. E., Gonzalez-Neira, A., Alnas, G. I., Grip, M., Guenel, P., Haeberle, L., Hahnen, E., Haiman, C. A., Hakansson, N., Hall, P., Hamann, U., Hankinson, S., Harkness, E. F., Harrington, P. A., Hart, S. N., Hartikainen, J. M., Hein, A., Hillemanns, P., Hiller, L., Holleczek, B., Hollestelle, A., Hooning, M. J., Hoover, R. N., Hopper, J. L., Howell, A., Huang, G., Humphreys, K., Hunter, D. J., Janni, W., John, E. M., Jones, M. E., Jukkola-Vuorinen, A., Jung, A., Kaaks, R., Kabisch, M., Kaczmarek, K., Kerin, M. J., Khan, S., Khusnutdinova, E., Kiiski, J. I., Kitahara, C. M., Knight, J. A., Ko, Y., Koppert, L. B., Kosma, V., Kraft, P., Kristensen, V. N., Kruger, U., Kuhl, T., Lambrechts, D., Le Marchand, L., Lee, E., Lejbkowicz, F., Li, L., Lindblom, A., Lindstrom, S., Linet, M., Lissowska, J., Lo, W., Loibl, S., Lubinski, J., Lux, M. P., MacInnis, R. J., Maierthaler, M., Maishman, T., Makalic, E., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M. E., Mavroudis, D., McLean, C., Meindl, A., Middha, P., Miller, N., Milne, R. L., Moreno, F., Mulligan, A. M., Mulot, C., Nassir, R., Neuhausen, S. L., Newman, W. T., Nielsen, S. F., Nordestgaard, B. G., Norman, A., Olsson, H., Orr, N., Pankratz, V. S., Park-Simon, T., Perez, J. I., Perez-Barrios, C., Peterlongo, P., Petridis, C., Pinchev, M., Prajzendanc, K., Prentice, R., Presneau, N., Prokofieva, D., Pylkas, K., Rack, B., Radice, P., Ramachandran, D., Rennert, G., Rennert, H. S., Rhenius, V., Romero, A., Roylance, R., Saloustros, E., Sawyer, E. J., Schmidt, D. F., Schmutzler, R. K., Schneeweiss, A., Schoemaker, M. J., Schumacher, F., Schwentner, L., Scott, R. J., Scott, C., Seynaeve, C., Shah, M., Simard, J., Smeets, A., Sohn, C., Southey, M. C., Swerdlow, A. J., Talhouk, A., Tamimi, R. M., Tapper, W. J., Teixeira, M. R., Tengstrom, M., Terry, M. B., Thone, K., Tollenaar, R. A., Tomlinson, I., Torres, D., Truong, T., Turman, C., Turnbull, C., Ulmer, H., Untch, M., Vachon, C., van Asperen, C. J., van den Ouweland, A. M., van Veen, E. M., Wendt, C., Whittemore, A. S., Willett, W., Winqvist, R., Wolk, A., Yang, X. R., Zhang, Y., Easton, D. F., Fasching, P. A., Nevanlinna, H., Eccles, D. M., Pharoah, P. D., Schmidt, M. K. 2019

  Abstract

  BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).RESULTS: We did not find any variant associated with breast cancer-specific mortality at P<5*10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP=7%, P=1.28*10-7, hazard ratio [HR]=0.88, 95% confidence interval [CI]=0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP=11%, P=1.38*10-7, HR=1.27, 95% CI=1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster.CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP<15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

  View details for PubMedID 30787463

• 10-year performance of four models of breast cancer risk: a validation study. The Lancet. Oncology Terry, M. B., Liao, Y., Whittemore, A. S., Leoce, N., Buchsbaum, R., Zeinomar, N., Dite, G. S., Chung, W. K., Knight, J. A., Southey, M. C., Milne, R. L., Goldgar, D., Giles, G. G., McLachlan, S., Friedlander, M. L., Weideman, P. C., Glendon, G., Nesci, S., Andrulis, I. L., John, E. M., Phillips, K., Daly, M. B., Buys, S. S., Hopper, J. L., MacInnis, R. J. 2019

  Abstract

  BACKGROUND: Independent validation is essential to justify use of models of breast cancer risk prediction and inform decisions about prevention options and screening. Few independent validations had been done using cohorts for common breast cancer risk prediction models, and those that have been done had small sample sizes and short follow-up periods, and used earlier versions of the prediction tools. We aimed to validate the relative performance of four commonly used models of breast cancer risk and assess the effect of limited data input on each one's performance.METHODS: In this validation study, we used the Breast Cancer Prospective Family Study Cohort (ProF-SC), which includes 18 856 women from Australia, Canada, and the USA who did not have breast cancer at recruitment, between March 17, 1992, and June 29, 2011. We selected women from the cohort who were 20-70 years old and had no previous history of bilateral prophylactic mastectomy or ovarian cancer, at least 2 months of follow-up data, and information available about family history of breast cancer. We used this selected cohort to calculate 10-year risk scores and compare four models of breast cancer risk prediction: the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm model (BOADICEA), BRCAPRO, the Breast Cancer Risk Assessment Tool (BCRAT), and the International Breast Cancer Intervention Study model (IBIS). We compared model calibration based on the ratio of the expected number of breast cancer cases to the observed number of breast cancer cases in the cohort, and on the basis of their discriminatory ability to separate those who will and will not have breast cancer diagnosed within 10 years as measured with the concordance statistic (C-statistic). We did subgroup analyses to compare the performance of the models at 10 years in BRCA1 or BRCA2 mutation carriers (ie, BRCA-positive women), tested non-carriers and untested participants (ie, BRCA-negative women), and participants younger than 50 years at recruitment. We also assessed the effect that limited data input (eg, restriction of the amount of family history and non-genetic information included) had on the models' performance.FINDINGS: After median follow-up of 11·1 years (IQR 6·0-14·4), 619 (4%) of 15 732 women selected from the ProF-SC cohort study were prospectively diagnosed with breast cancer after recruitment, of whom 519 (84%) had histologically confirmed disease. BOADICEA and IBIS were well calibrated in the overall validation cohort, whereas BRCAPRO and BCRAT underpredicted risk (ratio of expected cases to observed cases 1·05 [95% CI 0·97-1·14] for BOADICEA, 1·03 [0·96-1·12] for IBIS, 0·59 [0·55-0·64] for BRCAPRO, and 0·79 [0·73-0·85] for BRCAT). The estimated C-statistics for the complete validation cohort were 0·70 (95% CI 0·68-0·72) for BOADICEA, 0·71 (0·69-0·73) for IBIS, 0·68 (0·65-0·70) for BRCAPRO, and 0·60 (0·58-0·62) for BCRAT. In subgroup analyses by BRCA mutation status, the ratio of expected to observed cases for BRCA-negative women was 1·02 (95% CI 0·93-1·12) for BOADICEA, 1·00 (0·92-1·10) for IBIS, 0·53 (0·49-0·58) for BRCAPRO, and 0·97 (0·89-1·06) for BCRAT. For BRCA-positive participants, BOADICEA and IBIS were well calibrated, but BRCAPRO underpredicted risk (ratio of expected to observed cases 1·17 [95% CI 0·99-1·38] for BOADICEA, 1·14 [0·96-1·35] for IBIS, and 0·80 [0·68-0·95] for BRCAPRO). We noted similar patterns of calibration for women younger than 50 years at recruitment. Finally, BOADICEA and IBIS predictive scores were not appreciably affected by limiting input data to family history for first-degree and second-degree relatives.INTERPRETATION: Our results suggest that models that include multigenerational family history, such as BOADICEA and IBIS, have better ability to predict breast cancer risk, even for women at average or below-average risk of breast cancer. Although BOADICEA and IBIS performed similarly, further improvements in the accuracy of predictions could be possible with hybrid models that incorporate the polygenic risk component of BOADICEA and the non-family-history risk factors included in IBIS.FUNDING: US National Institutes of Health, National Cancer Institute, Breast Cancer Research Foundation, Australian National Health and Medical Research Council, Victorian Health Promotion Foundation, Victorian Breast Cancer Research Consortium, Cancer Australia, National Breast Cancer Foundation, Queensland Cancer Fund, Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and Cancer Foundation of Western Australia.

  View details for PubMedID 30799262

• A pooled analysis of breast-feeding and breast cancer risk by hormone receptor status in parous Hispanic women. Epidemiology (Cambridge, Mass.) Sangaramoorthy, M., Hines, L. M., Torres-Mejia, G., Phipps, A. I., Baumgartner, K. B., Wu, A. H., Koo, J., Ingles, S. A., Slattery, M. L., John, E. M. 2019

  Abstract

  BACKGROUND: Data on breast-feeding and breast cancer risk are sparse and inconsistent for Hispanic women.METHODS: Pooling data for nearly 6,000 parous Hispanic women from four population-based studies conducted between 1995 and 2007 in the U.S. and Mexico, we examined the association of breast-feeding with risk of breast cancer overall and subtypes defined by estrogen receptor (ER) and progesterone receptor (PR) status, as well as the joint effects of breast-feeding, parity, and age at first birth. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression.RESULTS: Among parous Hispanic women, older age at first birth was associated with increased breast cancer risk, whereas parity was associated with reduced risk. These associations were found for hormone receptor positive (HR+) breast cancer only and limited to premenopausal women. Age at first birth and parity were not associated with risk of ER-PR- breast cancer. Increasing duration of breast-feeding was associated with decreasing breast cancer risk (≥25 vs. 0 months: OR=0.73, 95% CI=0.60-0.89, Ptrend =0.03), with no heterogeneity by menopausal status or subtype. At each parity level, breast-feeding further reduced HR+ breast cancer risk. Additionally, breast-feeding attenuated the increase in risk of HR+ breast cancer associated with older age at first birth.CONCLUSIONS: Our findings suggest that breast-feeding is associated with reduced risk of both HR+ and ER-PR- breast cancer among Hispanic women, as reported for other populations, and may attenuate the increased risk in women with a first pregnancy at older ages.

  View details for DOI 10.1097/EDE.0000000000000981

  View details for PubMedID 30789436

• Benign Breast Disease Increases Breast Cancer Risk Independent of Underlying Familial Risk Profile: Findings from a Prospective Family Study Cohort (ProF-SC). International journal of cancer Zeinomar, N., Phillips, K., Daly, M. B., Milne, R. L., Dite, G. S., MacInnis, R. J., Liao, Y., Kehm, R. D., Knight, J. A., Southey, M. C., Chung, W. K., Giles, G. G., McLachlan, S., Friedlander, M. L., Weideman, P. C., Glendon, G., Nesci, S., kConFab Investigators, Andrulis, I. L., Buys, S. S., John, E. M., Hopper, J. L., Terry, M. B. 2019

  Abstract

  Benign breast disease(BBD) is an established breast cancer(BC) risk factor, but it is unclear whether the magnitude of the association applies to women at familial or genetic risk. This information is needed to improve BC risk assessment in clinical settings. Using the Prospective Family Study Cohort (ProF-SC), we used Cox proportional hazards models to estimate hazard ratios(HRs) and 95% confidence intervals(CIs) for the association of BBD with BC risk. We also examined whether the association with BBD differed by underlying familial risk profile(FRP), calculated using absolute risk estimates from the BOADICEA model. During 176,756 person-years of follow-up (median: 10.9 years, maximum: 23.7) of 17,154 women unaffected with BC at baseline, we observed 968 incident cases of BC. A total of 4,704 (27%) women reported a history of BBD diagnosis. A history of BBD was associated with a greater risk of BC: HR = 1.31(95% CI: 1.14 - 1.50), and did not differ by underlying FRP, with HRs of 1.35(95% CI: 1.11-1.65), 1.26(95% CI: 1.00-1.60), and 1.40(95% CI: 1.01-1.93), for categories of full lifetime BOADICEA score <20%, 20% - <35%, ≥ 35%, respectively. There was no difference in the association for women with BRCA1 mutations (HR: 1.64; 95% CI: 1.04-2.58), women with BRCA2 mutations (HR: 1.34; 95% CI: 0.78-2.3) or for women without a known BRCA1 or BRCA2 mutation (HR: 1.31; 95% CI: 1.13-1.53) (pinteraction = 0.95). Women with a history of BBD have an increased risk of BC that is independent of, and multiplies, their underlying familial and genetic risk. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30725480

• Association of Prepubertal and Adolescent Androgen Concentrations With Timing of Breast Development and Family History of Breast Cancer. JAMA network open Houghton, L. C., Knight, J. A., Wei, Y., Romeo, R. D., Goldberg, M., Andrulis, I. L., Bradbury, A. R., Buys, S. S., Daly, M. B., John, E. M., Chung, W. K., Santella, R. M., Stanczyk, F. Z., Terry, M. B. 2019; 2 (2): e190083

  Abstract

  Importance: Early breast development is a risk factor for breast cancer, and girls with a breast cancer family history (BCFH) experience breast development earlier than girls without a BCFH.Objectives: To assess whether prepubertal androgen concentrations are associated with timing of breast development (analysis 1) and to compare serum androgen concentrations in girls with and without a BCFH (analysis 2).Design, Setting, and Participants: Prospective cohort study of 104 girls aged 6 to 13 years at baseline using data collected between August 16, 2011, and March 24, 2016, from the Lessons in Epidemiology and Genetics of Adult Cancer From Youth (LEGACY) Girls Study, New York site.Exposures: Analysis 1 included serum concentrations of dehydroepiandrosterone sulfate, androstenedione, and testosterone (free and total) measured before breast development and divided at the median into high and low categories. Analysis 2 included the degree of BCFH: first-degree was defined as having a mother with breast cancer and second-degree was defined as having a grandmother or aunt with breast cancer.Main Outcomes and Measures: Analysis 1 included age at onset of breast development measured using the Pubertal Development Scale (scores range from 1-4; scores ≥2 indicate breast development), and analysis 2 included serum androgen concentrations. We also assessed breast cancer-specific distress using the 8-item Child Impact of Events Scale.Results: Our analyses included 36 girls for the prospective model, 92 girls for the cross-sectional model, and 104 girls for the longitudinal model. Of the 104 girls, the mean (SD) age at baseline was 10.3 (2.5) years, and 41 (39.4%) were non-Hispanic white, 41 (39.4%) were Hispanic, 13 (12.5%) were non-Hispanic black, and 9 (8.7%) were other race/ethnicity. Forty-two girls (40.4%) had a positive BCFH. Girls with prepubertal androstenedione concentrations above the median began breast development 1.5 years earlier than girls with concentrations below the median (Weibull survival model-estimated median age, 9.4 [95% CI, 9.0-9.8] years vs 10.9 [95% CI, 10.4-11.5] years; P=.001). Similar patterns were observed for dehydroepiandrosterone sulfate (1.1 years earlier: age, 9.6 [95% CI, 9.1-10.1] years vs 10.7 [95% CI, 10.2-11.3] years; P=.009), total testosterone (1.4 years earlier: age, 9.5 [95% CI, 9.1-9.9] years vs 10.9 [95% CI, 10.4-11.5] years; P=.001), and free testosterone (1.1 years earlier: age, 9.7 [95% CI, 9.2-10.1] years vs 10.8 [95% CI, 10.2-11.4] years; P=.01). Compared with girls without BCFH, girls with a first-degree BCFH, but not a second-degree BCFH, had 240% higher androstenedione concentrations (geometric means: no BCFH, 0.49 ng/mL vs first-degree BCFH, 1.8 ng/mL vs second-degree, 1.6 ng/mL; P=.01), 10% higher total testosterone concentrations (12.7 ng/dL vs 14.0 ng/dL vs 13.7 ng/dL; P=.01), and 92% higher free testosterone concentrations (1.3 pg/mL vs 2.5 pg/mL vs 0.3 pg/mL; P=.14). The dehydroepiandrosterone sulfate concentration did not differ between BCFH-positive and BCFH-negative girls but was elevated in girls with breast cancer-specific distress.Conclusions and Relevance: Our findings suggest that androgen concentrations may differ between girls with and without a BCFH and that elevated hormone concentrations during adolescence may be another factor to help explain the familial clustering of breast cancer.

  View details for PubMedID 30794303

• Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci (vol 50, pg 928, 2018) NATURE GENETICS Schumacher, F. R., Al Olama, A., Berndt, S. I., Benlloch, S., Ahmed, M., Saunders, E. J., Dadaev, T., Leongamornlert, D., Anokian, E., Cieza-Borrella, C., Goh, C., Brook, M. N., Sheng, X., Fachal, L., Dennis, J., Tyrer, J., Muir, K., Lophatananon, A., Stevens, V. L., Gapstur, S. M., Carter, B. D., Tangen, C. M., Goodman, P. J., Thompson, I. M., Batra, J., Chambers, S., Moya, L., Clements, J., Horvath, L., Tilley, W., Risbridger, G. P., Gronberg, H., Aly, M., Nordstrom, T., Pharoah, P., Pashayan, N., Schleutker, J., Tammela, T. J., Sipeky, C., Auvinen, A., Albanes, D., Weinstein, S., Wolk, A., Hakansson, N., West, C. L., Dunning, A. M., Burnet, N., Mucci, L. A., Giovannucci, E., Andriole, G. L., Cussenot, O., Cancel-Tassin, G., Koutros, S., Freeman, L., Sorensen, K., Orntoft, T., Borre, M., Maehle, L., Grindedal, E., Neal, D. E., Donovan, J. L., Hamdy, F. C., Martin, R. M., Travis, R. C., Key, T. J., Hamilton, R. J., Fleshner, N. E., Finelli, A., Ingles, S., Stern, M. C., Rosenstein, B. S., Kerns, S. L., Ostrer, H., Lu, Y., Zhang, H., Feng, N., Mao, X., Guo, X., Wang, G., Sun, Z., Giles, G. G., Southey, M. C., MacInnis, R. J., FitzGerald, L. M., Kibel, A. S., Drake, B. F., Vega, A., Gomez-Caamano, A., Szulkin, R., Eklund, M., Kogevinas, M., Llorca, J., Castano-Vinyals, G., Penney, K. L., Stampfer, M., Park, J. Y., Sellers, T. A., Lin, H., Stanford, J. L., Cybulski, C., Wokolorczyk, D., Lubinski, J., Ostrander, E. A., Geybels, M. S., Nordestgaard, B. G., Nielsen, S. F., Weischer, M., Bisbjerg, R., Roder, M., Iversen, P., Brenner, H., Cuk, K., Holleczek, B., Maier, C., Luedeke, M., Schnoeller, T., Kim, J., Logothetis, C. J., John, E. M., Teixeira, M. R., Paulo, P., Cardoso, M., Neuhausen, S. L., Steele, L., Ding, Y., De Ruyck, K., De Meerleer, G., Ost, P., Razack, A., Lim, J., Teo, S., Lin, D. W., Newcomb, L. F., Lessel, D., Gamulin, M., Kulis, T., Kaneva, R., Usmani, N., Singhal, S., Slavov, C., Mitev, V., Parliament, M., Claessens, F., Joniau, S., Van den Broeck, T., Larkin, S., Townsend, P. A., Aukim-Hastie, C., Gago-Dominguez, M., Castelao, J., Martinez, M., Roobol, M. J., Jenster, G., van Schaik, R. N., Menegaux, F., Truong, T., Koudou, Y., Xu, J., Khaw, K., Cannon-Albright, L., Pandha, H., Michael, A., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., Lindstrom, S., Turman, C., Ma, J., Hunter, D. J., Riboli, E., Siddiq, A., Canzian, F., Kolonel, L. N., Le Marchand, L., Hoover, R. N., Machiela, M. J., Cui, Z., Kraft, P., Amos, C. I., Conti, D. V., Easton, D. F., Wiklund, F., Chanock, S. J., Henderson, B. E., Kote-Jarai, Z., Haiman, C. A., Eeles, R. A., Profile Study Australian Prostate, IMPACT Study, Canary PASS Investigators Breast, PRACTIVAL Prostate Canc Assoc Grp, Canc Prostate Sweden CAPS, Prostate Canc Genome-Wide Assoc, Genetic Assoc Mech Oncol GAME-ON, Elucidating Loci Involved Prostate 2019; 51 (2): 363

  View details for DOI 10.1038/s41588-018-0330-6

  View details for Web of Science ID 000457314300023

• Association of Prepubertal and Adolescent Androgen Concentrations With Timing of Breast Development and Family History of Breast Cancer JAMA NETWORK OPEN Houghton, L. C., Knight, J. A., Wei, Y., Romeo, R. D., Goldberg, M., Andrulis, I. L., Bradbury, A. R., Buys, S. S., Daly, M. B., John, E. M., Chung, W. K., Santella, R. M., Stanczyk, F. Z., Terry, M. 2019; 2 (2)

  View details for DOI 10.1001/jamanetworkopen.2019.0083

  View details for Web of Science ID 000465423800026

• Shared heritability and functional enrichment across six solid cancers. Nature communications Jiang, X., Finucane, H. K., Schumacher, F. R., Schmit, S. L., Tyrer, J. P., Han, Y., Michailidou, K., Lesseur, C., Kuchenbaecker, K. B., Dennis, J., Conti, D. V., Casey, G., Gaudet, M. M., Huyghe, J. R., Albanes, D., Aldrich, M. C., Andrew, A. S., Andrulis, I. L., Anton-Culver, H., Antoniou, A. C., Antonenkova, N. N., Arnold, S. M., Aronson, K. J., Arun, B. K., Bandera, E. V., Barkardottir, R. B., Barnes, D. R., Batra, J., Beckmann, M. W., Benitez, J., Benlloch, S., Berchuck, A., Berndt, S. I., Bickeboller, H., Bien, S. A., Blomqvist, C., Boccia, S., Bogdanova, N. V., Bojesen, S. E., Bolla, M. K., Brauch, H., Brenner, H., Brenton, J. D., Brook, M. N., Brunet, J., Brunnstrom, H., Buchanan, D. D., Burwinkel, B., Butzow, R., Cadoni, G., Caldes, T., Caligo, M. A., Campbell, I., Campbell, P. T., Cancel-Tassin, G., Cannon-Albright, L., Campa, D., Caporaso, N., Carvalho, A. L., Chan, A. T., Chang-Claude, J., Chanock, S. J., Chen, C., Christiani, D. C., Claes, K. B., Claessens, F., Clements, J., Collee, J. M., Correa, M. C., Couch, F. J., Cox, A., Cunningham, J. M., Cybulski, C., Czene, K., Daly, M. B., deFazio, A., Devilee, P., Diez, O., Gago-Dominguez, M., Donovan, J. L., Dork, T., Duell, E. J., Dunning, A. M., Dwek, M., Eccles, D. M., Edlund, C. K., Edwards, D. R., Ellberg, C., Evans, D. G., Fasching, P. A., Ferris, R. L., Liloglou, T., Figueiredo, J. C., Fletcher, O., Fortner, R. T., Fostira, F., Franceschi, S., Friedman, E., Gallinger, S. J., Ganz, P. A., Garber, J., Garcia-Saenz, J. A., Gayther, S. A., Giles, G. G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Goode, E. L., Goodman, M. T., Goodman, G., Grankvist, K., Greene, M. H., Gronberg, H., Gronwald, J., Guenel, P., Hakansson, N., Hall, P., Hamann, U., Hamdy, F. C., Hamilton, R. J., Hampe, J., Haugen, A., Heitz, F., Herrero, R., Hillemanns, P., Hoffmeister, M., Hogdall, E., Hong, Y., Hopper, J. L., Houlston, R., Hulick, P. J., Hunter, D. J., Huntsman, D. G., Idos, G., Imyanitov, E. N., Ingles, S. A., Isaacs, C., Jakubowska, A., James, P., Jenkins, M. A., Johansson, M., Johansson, M., John, E. M., Joshi, A. D., Kaneva, R., Karlan, B. Y., Kelemen, L. E., Kuhl, T., Khaw, K., Khusnutdinova, E., Kibel, A. S., Kiemeney, L. A., Kim, J., Kjaer, S. K., Knight, J. A., Kogevinas, M., Kote-Jarai, Z., Koutros, S., Kristensen, V. N., Kupryjanczyk, J., Lacko, M., Lam, S., Lambrechts, D., Landi, M. T., Lazarus, P., Le, N. D., Lee, E., Lejbkowicz, F., Lenz, H., Leslie, G., Lessel, D., Lester, J., Levine, D. A., Li, L., Li, C. I., Lindblom, A., Lindor, N. M., Liu, G., Loupakis, F., Lubinski, J., Maehle, L., Maier, C., Mannermaa, A., Marchand, L. L., Margolin, S., May, T., McGuffog, L., Meindl, A., Middha, P., Miller, A., Milne, R. L., MacInnis, R. J., Modugno, F., Montagna, M., Moreno, V., Moysich, K. B., Mucci, L., Muir, K., Mulligan, A. M., Nathanson, K. L., Neal, D. E., Ness, A. R., Neuhausen, S. L., Nevanlinna, H., Newcomb, P. A., Newcomb, L. F., Nielsen, F. C., Nikitina-Zake, L., Nordestgaard, B. G., Nussbaum, R. L., Offit, K., Olah, E., Olama, A. A., Olopade, O. I., Olshan, A. F., Olsson, H., Osorio, A., Pandha, H., Park, J. Y., Pashayan, N., Parsons, M. T., Pejovic, T., Penney, K. L., Peters, W. H., Phelan, C. M., Phipps, A. I., Plaseska-Karanfilska, D., Pring, M., Prokofyeva, D., Radice, P., Stefansson, K., Ramus, S. J., Raskin, L., Rennert, G., Rennert, H. S., van Rensburg, E. J., Riggan, M. J., Risch, H. A., Risch, A., Roobol, M. J., Rosenstein, B. S., Rossing, M. A., De Ruyck, K., Saloustros, E., Sandler, D. P., Sawyer, E. J., Schabath, M. B., Schleutker, J., Schmidt, M. K., Setiawan, V. W., Shen, H., Siegel, E. M., Sieh, W., Singer, C. F., Slattery, M. L., Sorensen, K. D., Southey, M. C., Spurdle, A. B., Stanford, J. L., Stevens, V. L., Stintzing, S., Stone, J., Sundfeldt, K., Sutphen, R., Swerdlow, A. J., Tajara, E. H., Tangen, C. M., Tardon, A., Taylor, J. A., Teare, M. D., Teixeira, M. R., Terry, M. B., Terry, K. L., Thibodeau, S. N., Thomassen, M., Bjorge, L., Tischkowitz, M., Toland, A. E., Torres, D., Townsend, P. A., Travis, R. C., Tung, N., Tworoger, S. S., Ulrich, C. M., Usmani, N., Vachon, C. M., Van Nieuwenhuysen, E., Vega, A., Aguado-Barrera, M. E., Wang, Q., Webb, P. M., Weinberg, C. R., Weinstein, S., Weissler, M. C., Weitzel, J. N., West, C. M., White, E., Whittemore, A. S., Wichmann, H., Wiklund, F., Winqvist, R., Wolk, A., Woll, P., Woods, M., Wu, A. H., Wu, X., Yannoukakos, D., Zheng, W., Zienolddiny, S., Ziogas, A., Zorn, K. K., Lane, J. M., Saxena, R., Thomas, D., Hung, R. J., Diergaarde, B., McKay, J., Peters, U., Hsu, L., Garcia-Closas, M., Eeles, R. A., Chenevix-Trench, G., Brennan, P. J., Haiman, C. A., Simard, J., Easton, D. F., Gruber, S. B., Pharoah, P. D., Price, A. L., Pasaniuc, B., Amos, C. I., Kraft, P., Lindstrom, S. 2019; 10 (1): 431

  Abstract

  Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg=0.57, p=4.6*10-8), breast and ovarian cancer (rg=0.24, p=7*10-5), breast and lung cancer (rg=0.18, p=1.5*10-6) and breast and colorectal cancer (rg=0.15, p=1.1*10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

  View details for PubMedID 30683880

• Shared heritability and functional enrichment across six solid cancers NATURE COMMUNICATIONS Jiang, X., Finucane, H. K., Schumacher, F. R., Schmit, S. L., Tyrer, J. P., Han, Y., Michailidou, K., Lesseur, C., Kuchenbaecker, K. B., Dennis, J., Conti, D. V., Casey, G., Gaudet, M. M., Huyghe, J. R., Albanes, D., Aldrich, M. C., Andrew, A. S., Andrulis, I. L., Anton-Culver, H., Antoniou, A. C., Antonenkova, N. N., Arnold, S. M., Aronson, K. J., Arun, B. K., Bandera, E. V., Barkardottir, R. B., Barnes, D. R., Batra, J., Beckmann, M. W., Benitez, J., Benlloch, S., Berchuck, A., Berndt, S. I., Bickeboeller, H., Bien, S. A., Blomqvist, C., Boccia, S., Bogdanova, N. V., Bojesen, S. E., Bolla, M. K., Brauch, H., Brenner, H., Brenton, J. D., Brook, M. N., Brunet, J., Brunnstrom, H., Buchanan, D. D., Burwinkel, B., Butzow, R., Cadoni, G., Caldes, T., Caligo, M. A., Campbell, I., Campbell, P. T., Cancel-Tassin, G., Cannon-Albright, L., Campa, D., Caporaso, N., Carvalho, A. L., Chan, A. T., Chang-Claude, J., Chanock, S. J., Chen, C., Christiani, D. C., Claes, K. M., Claessens, F., Clements, J., Collee, J., Correa, M., Couch, F. J., Cox, A., Cunningham, J. M., Cybulski, C., Czene, K., Daly, M. B., defazio, A., Devilee, P., Diez, O., Gago-Dominguez, M., Donovan, J. L., Doerk, T., Duell, E. J., Dunning, A. M., Dwek, M., Eccles, D. M., Edlund, C. K., Edwards, D., Ellberg, C., Evans, D., Fasching, P. A., Ferris, R. L., Liloglou, T., Figueiredo, J. C., Fletcher, O., Fortner, R. T., Fostira, F., Franceschi, S., Friedman, E., Gallinger, S. J., Ganz, P. A., Garber, J., Garcia-Saenz, J. A., Gayther, S. A., Giles, G. G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Goode, E. L., Goodman, M. T., Goodman, G., Grankvist, K., Greene, M. H., Gronberg, H., Gronwald, J., Guenel, P., Hakansson, N., Hall, P., Hamann, U., Hamdy, F. C., Hamilton, R. J., Hampe, J., Haugen, A., Heitz, F., Herrero, R., Hillemanns, P., Hoffmeister, M., Hogdall, E., Hong, Y., Hopper, J. L., Houlston, R., Hulick, P. J., Hunter, D. J., Huntsman, D. G., Idos, G., Imyanitov, E. N., Ingles, S., Isaacs, C., Jakubowska, A., James, P., Jenkins, M. A., Johansson, M., Johansson, M., John, E. M., Joshi, A. D., Kaneva, R., Karlan, B. Y., Kelemen, L. E., Kuhl, T., Khaw, K., Khusnutdinova, E., Kibel, A. S., Kiemeney, L. A., Kim, J., Kjaer, S. K., Knight, J. A., Kogevinas, M., Kote-Jarai, Z., Koutros, S., Kristensen, V. N., Kupryjanczyk, J., Lacko, M., Lam, S., Lambrechts, D., Landi, M., Lazarus, P., Le, N. D., Lee, E., Lejbkowicz, F., Lenz, H., Leslie, G., Lessel, D., Lester, J., Levine, D. A., Li, L., Li, C. I., Lindblom, A., Lindor, N. M., Liu, G., Loupakis, F., Lubinski, J., Maehle, L., Maier, C., Mannermaa, A., Le Marchand, L., Margolin, S., May, T., McGuffog, L., Meindl, A., Middha, P., Miller, A., Milne, R. L., MacInnis, R. J., Modugno, F., Montagna, M., Moreno, V., Moysich, K. B., Mucci, L., Muir, K., Mulligan, A., Nathanson, K. L., Neal, D. E., Ness, A. R., Neuhausen, S. L., Nevanlinna, H., Newcomb, P. A., Newcomb, L. F., Nielsen, F., Nikitina-Zake, L., Nordestgaard, B. G., Nussbaum, R. L., Offit, K., Olah, E., Al Olama, A., Olopade, O. I., Olshan, A. F., Olsson, H., Osorio, A., Pandha, H., Park, J. Y., Pashayan, N., Parsons, M. T., Pejovic, T., Penney, K. L., Peters, W. M., Phelan, C. M., Phipps, A. I., Plaseska-Karanfilska, D., Pring, M., Prokofyeva, D., Radice, P., Stefansson, K., Ramus, S. J., Raskin, L., Rennert, G., Rennert, H. S., van Rensburg, E. J., Riggan, M. J., Risch, H. A., Risch, A., Roobol, M. J., Rosenstein, B. S., Rossing, M., De Ruyck, K., Saloustros, E., Sandler, D. P., Sawyer, E. J., Schabath, M. B., Schleutker, J., Schmidt, M. K., Setiawan, V., Shen, H., Siegel, E. M., Sieh, W., Singer, C. F., Slattery, M. L., Sorensen, K., Southey, M. C., Spurdle, A. B., Stanford, J. L., Stevens, V. L., Stintzing, S., Stone, J., Sundfeldt, K., Sutphen, R., Swerdlow, A. J., Tajara, E. H., Tangen, C. M., Tardon, A., Taylor, J. A., Teare, M., Teixeira, M. R., Terry, M., Terry, K. L., Thibodeau, S. N., Thomassen, M., Bjorge, L., Tischkowitz, M., Toland, A. E., Torres, D., Townsend, P. A., Travis, R. C., Tung, N., Tworoger, S. S., Ulrich, C. M., Usmani, N., Vachon, C. M., Van Nieuwenhuysen, E., Vega, A., Aguado-Barrera, M., Wang, Q., Webb, P. M., Weinberg, C. R., Weinstein, S., Weissler, M. C., Weitzel, J. N., West, C. L., White, E., Whittemore, A. S., Wichmann, H., Wiklund, F., Winqvist, R., Wolk, A., Woll, P., Woods, M., Wu, A. H., Wu, X., Yannoukakos, D., Zheng, W., Zienolddiny, S., Ziogas, A., Zorn, K. K., Lane, J. M., Saxena, R., Thomas, D., Hung, R. J., Diergaarde, B., Mckay, J., Peters, U., Hsu, L., Garcia-Closas, M., Eeles, R. A., Chenevix-Trench, G., Brennan, P. J., Haiman, C. A., Simard, J., Easton, D. F., Gruber, S. B., Pharoah, P. P., Price, A. L., Pasaniuc, B., Amos, C. I., Kraft, P., Lindstrom, S. 2019; 10

  View details for DOI 10.1038/s41467-018-08054-4

  View details for Web of Science ID 000456696700007

• Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia (vol 9, 1340, 2018) NATURE COMMUNICATIONS Vijayakrishnan, J., Studd, J., Broderick, P., Kinnersley, B., Holroyd, A., Law, P. J., Kumar, R., Allan, J. M., Harrison, C. J., Moorman, A. V., Vora, A., Roman, E., Rachakonda, S., Kinsey, S. E., Sheridan, E., Thompson, P. D., Irving, J. A., Koehler, R., Hoffmann, P., Noethen, M. M., Heilmann-Heimbach, S., Joeckel, K., Easton, D. F., Pharaoh, P. P., Dunning, A. M., Peto, J., Canzian, F., Swerdlow, A., Eeles, R. A., Kote-Jarai, Z., Muir, K., Pashayan, N., Henderson, B. E., Haiman, C. A., Benlloch, S., Schumacher, F. R., Al Olama, A., Berndt, S. I., Conti, D. V., Wiklund, F., Chanock, S., Stevens, V. L., Tangen, C. M., Batra, J., Clements, J., Gronberg, H., Schleutker, J., Albanes, D., Weinstein, S., Wolk, A., West, C., Mucci, L., Cancel-Tassin, G., Koutros, S., Sorensen, K., Maehle, L., Neal, D. E., Travis, R. C., Hamilton, R. J., Ingles, S., Rosenstein, B., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., John, E. M., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R., Usmani, N., Claessens, F., Townsend, P. A., Gago-Dominguez, M., Roobol, M. J., Menegaux, F., Greaves, M., Zimmerman, M., Bartram, C. R., Schrappe, M., Stanulla, M., Hemminki, K., Houlston, R. S., PRACTICAL Consortium 2019; 10: 419

  Abstract

  The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

  View details for DOI 10.1038/s41467-018-08106-9

  View details for Web of Science ID 000456165300001

  View details for PubMedID 30664635

  View details for PubMedCentralID PMC6341085

• Germline variation at 8q24 and prostate cancer risk in men of European ancestry (vol 9, 4616, 2018) NATURE COMMUNICATIONS Matejcic, M., Saunders, E. J., Dadaev, T., Brook, M. N., Wang, K., Sheng, X., Al Olama, A., Schumacher, F. R., Ingles, S. A., Govindasami, K., Benlloch, S., Berndt, S. I., Albanes, D., Koutros, S., Muir, K., Stevens, V. L., Gapstur, S. M., Tangen, C. M., Batra, J., Clements, J., Gronberg, H., Pashayan, N., Schleutker, J., Wolk, A., West, C., Mucci, L., Kraft, P., Cancel-Tassin, G., Sorensen, K. D., Maehle, L., Grindedal, E. M., Strom, S. S., Neal, D. E., Hamdy, F. C., Donovan, J. L., Travis, R. C., Hamilton, R. J., Rosenstein, B., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Bensen, J. T., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R., Usmani, N., Claessens, F., Townsend, P. A., Gago-Dominguez, M., Roobol, M. J., Menegaux, F., Khaw, K., Cannon-Albright, L. A., Pandha, H., Thibodeau, S. N., Schaid, D. J., Wiklund, F., Chanock, S. J., Easton, D. F., Eeles, R. A., Kote-Jarai, Z., Conti, D. V., Haiman, C. A., Henderson, B. E., Stern, M. C., Thwaites, A., Guy, M., Whitmore, I., Morgan, A., Fisher, C., Hazel, S., Livni, N., Cook, M., Fachal, L., Weinstein, S., Freeman, L., Hoover, R. N., Machiela, M. J., Lophatananon, A., Carter, B. D., Goodman, P., Moya, L., Srinivasan, S., Kedda, M., Yeadon, T., Eckert, A., Eklund, M., Cavalli-Bjoerkman, C., Dunning, A. M., Sipeky, C., Hakansson, N., Elliott, R., Ranu, H., Giovannucci, E., Turman, C., Hunter, D. J., Cussenot, O., Orntoft, T., Lane, A., Lewis, S. J., Davis, M., Key, T. J., Brown, P., Kulkarni, G. S., Zlotta, A. R., Fleshner, N. E., Finelli, A., Mao, X., Marzec, J., MacInnis, R. J., Milne, R., Hopper, J. L., Aguado, M., Bustamante, M., Castano-Vinyals, G., Gracia-Lavedan, E., Cecchini, L., Stampfer, M., Ma, J., Sellers, T. A., Geybels, M. S., Park, H., Zachariah, B., Kolb, S., Wokolorczyk, D., Lubinski, J., Kluzniak, W., Nielsen, S. F., Weisher, M., Cuk, K., Vogel, W., Luedeke, M., Logothetis, C. J., Paulo, P., Cardoso, M., Maia, S., Silva, M. P., Steele, L., Ding, Y., De Meerleer, G., De Langhe, S., Thierens, H., Lim, J., Tan, M. H., Ong, A. T., Lin, D. W., Kachakova, D., Mitkova, A., Mitev, V., Parliament, M., Jenster, G., Bangma, C., Schroder, F. H., Truong, T., Koudou, Y., Michael, A., Kierzek, A., Karlsson, A., Broms, M., Wu, H., Aukim-Hastie, C., Tillmans, L., Riska, S., McDonnell, S. K., Dearnaley, D., Spurdle, A., Gardiner, R., Hayes, V., Butler, L., Taylor, R., Papargiris, M., Saunders, P., Kujala, P., Talala, K., Taari, K., Bentzen, S., Hicks, B., Vogt, A., Hutchinson, A., Cox, A., George, A., Toi, A., Evans, A., van der Kwast, T. H., Imai, T., Saito, S., Zhao, S., Ren, G., Zhang, Y., Yu, Y., Wu, Y., Wu, J., Zhou, B., Pedersen, J., Lobato-Busto, R., Manuel Ruiz-Dominguez, J., Mengual, L., Alcaraz, A., Pow-Sang, J., Herkommer, K., Vlahova, A., Dikov, T., Christova, S., Carracedo, A., Tretarre, B., Rebillard, X., Mulot, C., Adolfsson, J., Stattin, P., Johansson, J., Martin, R. M., Thompson, I. M., Chambers, S., Aitken, J., Horvath, L., Haynes, A., Tilley, W., Risbridger, G., Aly, M., Nordstrom, T., Pharoah, P., Tammela, T. J., Murtola, T., Auvinen, A., Burnet, N., Barnett, G., Andriole, G., Klim, A., Drake, B. F., Borre, M., Kerns, S., Ostrer, H., Zhang, H., Cao, G., Lin, J., Ling, J., Li, M., Feng, N., Li, J., He, W., Guo, X., Sun, Z., Wang, G., Guo, J., Southey, M. C., FitzGerald, L. M., Marsden, G., Gomez-Caamano, A., Carballo, A., Peleteiro, P., Calvo, P., Szulkin, R., Llorca, J., Dierssen-Sotos, T., Gomez-Acebo, I., Lin, H., Ostrander, E. A., Bisbjerg, R., Klarskov, P., Roder, M., Iversen, P., Holleczek, B., Stegmaier, C., Schnoeller, T., Bohnert, P., John, E. M., Ost, P., Teo, S., Gamulin, M., Kulis, T., Kastelan, Z., Slavov, C., Popov, E., Van den Broeck, T., Joniau, S., Larkin, S., Esteban Castelao, J., Martinez, M., van Schaik, R. N., Xu, J., Lindstrom, S., Riboli, E., Berry, C., Siddiq, A., Canzian, F., Kolonel, L. N., Le Marchand, L., Freedman, M., Cenee, S., Sanchez, M., PRACTICAL Consortium 2019; 10: 382

  Abstract

  The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

  View details for PubMedID 30655571

• Identification of novel common breast cancer risk variants at the 6q25 locusamong Latinas. Breast cancer research : BCR Hoffman, J., Fejerman, L., Hu, D., Huntsman, S., Li, M., John, E. M., Torres-Mejia, G., Kushi, L., Ding, Y. C., Weitzel, J., Neuhausen, S. L., Lott, P., COLUMBUS Consortium, Echeverry, M., Carvajal-Carmona, L., Burchard, E., Eng, C., Long, J., Zheng, W., Olopade, O., Huo, D., Haiman, C., Ziv, E. 2019; 21 (1): 3

  Abstract

  BACKGROUND: Breast cancer is a partially heritable trait and genome-wide association studies (GWAS) have identified over 180 common genetic variants associated with breast cancer. We have previously performed breast cancer GWAS in Latinas and identified a strongly protective single nucleotide polymorphism (SNP) at 6q25, with the protective minor allele originating from indigenous American ancestry. Here we report on fine mapping of the 6q25 locus in an expanded sample of Latinas.METHODS: We performed GWAS in 2385 cases and 6416 controls who were either US Latinas or Mexican women. We replicated the top SNPsin 2412 cases and 1620 controls of US Latina, Mexican, and Colombian women. In addition, we validated the top novel variants in studies of African, Asian and European ancestry. In each dataset we used logistic regression models to test the association between SNPs and breast cancer risk and corrected for genetic ancestry using either principal components or genetic ancestry inferred from ancestry informative markers using a model-based approach.RESULTS: We identified a novel set of SNPs at the 6q25 locus associated with genome-wide levels of significance (p=3.3*10-8 - 6.0*10-9) not in linkage disequilibrium (LD) with variants previously reported at this locus. These SNPs were in high LD (r2>0.9) with each other, with the top SNP, rs3778609, associated with breast cancer with an odds ratio (OR) and 95% confidence interval (95% CI) of 0.76 (0.70-0.84). In a replication in women of Latin American origin, we also observed a consistent effect (OR 0.88; 95% CI 0.78-0.99; p=0.037). We also performed a meta-analysis of these SNPs in East Asians, African ancestry and European ancestry populations and also observed a consistent effect (rs3778609, OR 0.95; 95% CI 0.91-0.97; p=0.0017).CONCLUSION: Our study adds to evidence about the importance of the 6q25 locus for breast cancer susceptibility. Our finding also highlights the utility of performing additional searches for genetic variants for breast cancer in non-European populations.

  View details for PubMedID 30642363

• Identification of novel common breast cancer risk variants at the 6q25 locusamong Latinas BREAST CANCER RESEARCH Hoffman, J., Fejerman, L., Hu, D., Huntsman, S., Li, M., John, E. M., Torres-Mejia, G., Kushi, L., Ding, Y., Weitzel, J., Neuhausen, S. L., Lott, P., Echeverry, M., Carvajal-Carmona, L., Burchard, E., Eng, C., Long, J., Zheng, W., Olopade, O., Huo, D., Haiman, C., Ziv, E., COLUMBUS Consortium 2019; 21

  View details for DOI 10.1186/s13058-018-1085-9

  View details for Web of Science ID 000455592400003

• Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma (vol 9, 3707, 2018) NATURE COMMUNICATIONS Went, M., Sud, A., Foersti, A., Halvarsson, B., Weinhold, N., Kimber, S., van Duin, M., Thorleifsson, G., Holroyd, A., Johnson, D. C., Li, N., Orlando, G., Law, P. J., Ali, M., Chen, B., Mitchell, J. S., Gudbjartsson, D. F., Kuiper, R., Stephens, O. W., Bertsch, U., Broderick, P., Campo, C., Bandapalli, O. R., Einsele, H., Gregory, W. A., Gullberg, U., Hillengass, J., Hoffmann, P., Jackson, G. H., Joeckel, K., Johnsson, E., Kristinsson, S. Y., Mellqvist, U., Nahi, H., Easton, D., Pharoah, P., Dunning, A., Peto, J., Canzian, F., Swerdlow, A., Eeles, R. A., Kote-Jarai, Z., Muir, K., Pashayan, N., Henderson, B. E., Haiman, C. A., Benlloch, S., Schumacher, F. R., Al Olama, A., Berndt, S. I., Conti, D. V., Wiklund, F., Chanock, S., Stevens, V. L., Tangen, C. M., Batra, J., Clements, J., Gronberg, H., Schleutker, J., Albanes, D., Weinstein, S., Wolk, A., West, C., Mucci, L., Cancel-Tassin, G., Koutros, S., Sorensen, K., Grindedal, E., Neal, D. E., Hamdy, F. C., Donovan, J. L., Travis, R. C., Hamilton, R. J., Ingles, S., Rosenstein, B., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., John, E. M., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R., Usmani, N., Claessens, F., Townsend, P. A., Gago-Dominguez, M., Roobol, M. J., Menegaux, F., Khaw, K., Cannon-Albright, L., Pandha, H., Thibodeau, S. N., Nickel, J., Noethen, M. M., Rafnar, T., Ross, F. M., Filho, M., Thomsen, H., Turesson, I., Vangsted, A., Andersen, N., Waage, A., Walker, B. A., Wihlborg, A., Broyl, A., Davies, F. E., Thorsteinsdottir, U., Langer, C., Hansson, M., Goldschmidt, H., Kaiser, M., Sonneveld, P., Stefansson, K., Morgan, G. J., Hemminki, K., Nilsson, B., Houlston, R. S., PRACTICAL Consortium 2019; 10: 213

  Abstract

  The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

  View details for DOI 10.1038/s41467-018-08107-8

  View details for Web of Science ID 000455355200001

  View details for PubMedID 30631080

  View details for PubMedCentralID PMC6328616

• Large-scale transcriptome-wide association study identifies new prostate cancer risk regions (vol 9, 4079, 2018) NATURE COMMUNICATIONS Mancuso, N., Gayther, S., Gusev, A., Zheng, W., Penney, K. L., Kote-Jarai, Z., Eeles, R., Freedman, M., Haiman, C., Pasaniuc, B., Henderson, B. E., Benlloch, S., Schumacher, F. R., Al Olama, A., Muir, K., Berndt, S. I., Conti, D. V., Wiklund, F., Chanock, S., Stevens, V. L., Tangen, C. M., Batra, J., Clements, J., Gronberg, H., Pashayan, N., Schleutker, J., Albanes, D., Weinstein, S., Wolk, A., West, C., Mucci, L., Cancel-Tassin, G., Koutros, S., Sorensen, K., Maehle, L., Neal, D. E., Hamdy, F. C., Donovan, J. L., Travis, R. C., Hamilton, R. J., Ingles, S., Rosenstein, B., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Kogevinas, M., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., John, E. M., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R., Usmani, N., Claessens, F., Townsend, P. A., Gago-Dominguez, M., Roobol, M. J., Menegaux, F., Khaw, K., Cannon-Albright, L., Pandha, H., Thibodeau, S. N., Hunter, D. J., Kraft, P., PRACTICAL Consortium 2019; 10: 171

  Abstract

  The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, In the original HTML version of this Article, the order of authors within the author list was incorrect. The consortium PRACTICAL consortium was incorrectly listed after Bogdan Pasaniuc and should have been listed after Kathryn L. Penney. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

  View details for DOI 10.1038/s41467-018-08108-7

  View details for Web of Science ID 000455104600002

  View details for PubMedID 30622272

  View details for PubMedCentralID PMC6325152

• Author Correction: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. Nature genetics Schumacher, F. R., Olama, A. A., Berndt, S. I., Benlloch, S., Ahmed, M., Saunders, E. J., Dadaev, T., Leongamornlert, D., Anokian, E., Cieza-Borrella, C., Goh, C., Brook, M. N., Sheng, X., Fachal, L., Dennis, J., Tyrer, J., Muir, K., Lophatananon, A., Stevens, V. L., Gapstur, S. M., Carter, B. D., Tangen, C. M., Goodman, P. J., Thompson, I. M., Batra, J., Chambers, S., Moya, L., Clements, J., Horvath, L., Tilley, W., Risbridger, G. P., Gronberg, H., Aly, M., Nordstrom, T., Pharoah, P., Pashayan, N., Schleutker, J., Tammela, T. L., Sipeky, C., Auvinen, A., Albanes, D., Weinstein, S., Wolk, A., Hakansson, N., West, C. M., Dunning, A. M., Burnet, N., Mucci, L. A., Giovannucci, E., Andriole, G. L., Cussenot, O., Cancel-Tassin, G., Koutros, S., Beane Freeman, L. E., Sorensen, K. D., Orntoft, T. F., Borre, M., Maehle, L., Grindedal, E. M., Neal, D. E., Donovan, J. L., Hamdy, F. C., Martin, R. M., Travis, R. C., Key, T. J., Hamilton, R. J., Fleshner, N. E., Finelli, A., Ingles, S. A., Stern, M. C., Rosenstein, B. S., Kerns, S. L., Ostrer, H., Lu, Y., Zhang, H., Feng, N., Mao, X., Guo, X., Wang, G., Sun, Z., Giles, G. G., Southey, M. C., MacInnis, R. J., FitzGerald, L. M., Kibel, A. S., Drake, B. F., Vega, A., Gomez-Caamano, A., Szulkin, R., Eklund, M., Kogevinas, M., Llorca, J., Castano-Vinyals, G., Penney, K. L., Stampfer, M., Park, J. Y., Sellers, T. A., Lin, H., Stanford, J. L., Cybulski, C., Wokolorczyk, D., Lubinski, J., Ostrander, E. A., Geybels, M. S., Nordestgaard, B. G., Nielsen, S. F., Weischer, M., Bisbjerg, R., Roder, M. A., Iversen, P., Brenner, H., Cuk, K., Holleczek, B., Maier, C., Luedeke, M., Schnoeller, T., Kim, J., Logothetis, C. J., John, E. M., Teixeira, M. R., Paulo, P., Cardoso, M., Neuhausen, S. L., Steele, L., Ding, Y. C., De Ruyck, K., De Meerleer, G., Ost, P., Razack, A., Lim, J., Teo, S., Lin, D. W., Newcomb, L. F., Lessel, D., Gamulin, M., Kulis, T., Kaneva, R., Usmani, N., Singhal, S., Slavov, C., Mitev, V., Parliament, M., Claessens, F., Joniau, S., Van den Broeck, T., Larkin, S., Townsend, P. A., Aukim-Hastie, C., Gago-Dominguez, M., Castelao, J. E., Martinez, M. E., Roobol, M. J., Jenster, G., van Schaik, R. H., Menegaux, F., Truong, T., Koudou, Y. A., Xu, J., Khaw, K., Cannon-Albright, L., Pandha, H., Michael, A., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., Lindstrom, S., Turman, C., Ma, J., Hunter, D. J., Riboli, E., Siddiq, A., Canzian, F., Kolonel, L. N., Le Marchand, L., Hoover, R. N., Machiela, M. J., Cui, Z., Kraft, P., Amos, C. I., Conti, D. V., Easton, D. F., Wiklund, F., Chanock, S. J., Henderson, B. E., Kote-Jarai, Z., Haiman, C. A., Eeles, R. A., Profile Study, Australian Prostate Cancer BioResource (APCB), IMPACT Study, Canary PASS Investigators, Breast and Prostate Cancer Cohort Consortium (BPC3), PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, Cancer of the Prostate in Sweden (CAPS), Prostate Cancer Genome-wide Association Study of Uncommon Susceptibility Loci (PEGASUS), Genetic Associations and Mechanisms in Oncology (GAME-ON)/Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium 2019

  Abstract

  In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.

  View details for PubMedID 30622367

• Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility (vol 8, 1892, 2017) NATURE COMMUNICATIONS Sud, A., Thomsen, H., Law, P. J., Foersti, A., Filho, M., Holroyd, A., Broderick, P., Orlando, G., Lenive, O., Wright, L., Cooke, R., Easton, D., Pharoah, P., Dunning, A., Peto, J., Canzian, F., Eeles, R., Kote-Jarai, Z., Muir, K., Pashayan, N., Hoffmann, P., Noethen, M. M., Joeckel, K., von Strandmann, E., Lightfoot, T., Kane, E., Roman, E., Lake, A., Montgomery, D., Jarrett, R. F., Swerdlow, A. J., Engert, A., Orr, N., Hemminki, K., Houlston, R. S., Henderson, B. E., Haiman, C. A., Benlloch, S., Schumacher, F. R., Al Olama, A., Berndt, S. I., Conti, D. V., Wiklund, F., Chanock, S., Stevens, V. L., Tangen, C. M., Batra, J., Clements, J., Gronberg, H., Schleutker, J., Albanes, D., Weinstein, S., Wolk, A., West, C., Mucci, L., Cancel-Tassin, G., Koutros, S., Sorensen, K., Maehle, L., Neal, D. E., Travis, R. C., Hamilton, R. J., Ingles, S., Rosenstein, B., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., John, E. M., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R., Usmani, N., Claessens, F., Townsend, P. A., Gago-Dominguez, M., Roobol, M. J., Menegaux, F., PRACTICAL Consortium 2019; 10: 157

  Abstract

  The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

  View details for DOI 10.1038/s41467-018-08105-w

  View details for Web of Science ID 000455103700001

  View details for PubMedID 30622283

  View details for PubMedCentralID PMC6325156

• Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes AMERICAN JOURNAL OF HUMAN GENETICS Mavaddat, N., Michailidou, K., Dennis, J., Lush, M., Fachal, L., Lee, A., Tyrer, J. P., Chen, T., Wang, Q., Bolla, M. K., Yang, X., Adank, M. A., Ahearn, T., Aittomaki, K., Allen, J., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Arndt, V., Aronson, K. J., Auer, P. L., Auvinen, P., Barrdahl, M., Freeman, L., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bernstein, L., Blomqvist, C., Bogdanova, N., Bojesen, S. E., Bonanni, B., Borresen-Dale, A., Brauch, H., Bremer, M., Brenner, H., Brentnall, A., Brock, I. W., Brooks-Wilson, A., Brucker, S. Y., Bruening, T., Burwinkel, B., Campa, D., Carter, B. D., Castelao, J. E., Chanock, S. J., Chlebowski, R., Christiansen, H., Clarke, C. L., Collee, J., Cordina-Duverger, E., Cornelissen, S., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Daly, M. B., Devilee, P., Doerk, T., dos-Santos-Silva, I., Dumont, M., Durcan, L., Dwek, M., Eccles, D. M., Ekici, A. B., Eliassen, A., Ellberg, C., Engel, C., Eriksson, M., Evans, D., Fasching, P. A., Figueroa, J., Fletcher, O., Flyger, H., Foersti, A., Fritschi, L., Gabrielson, M., Gago-Dominguez, M., Gapstur, S. M., Garcia-Saenz, J. A., Gaudet, M. M., Georgoulias, V., Giles, G. G., Gilyazova, I. R., Glendon, G., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Alnaes, G., Grip, M., Gronwald, J., Grundy, A., Guenel, P., Haeberle, L., Hahnen, E., Haiman, C. A., Hakansson, N., Hamann, U., Hankinson, S. E., Harkness, E. F., Hart, S. N., He, W., Hein, A., Heyworth, J., Hillemanns, P., Hollestelle, A., Hooning, M. J., Hoover, R. N., Hopper, J. L., Howell, A., Huang, G., Humphreys, K., Hunter, D. J., Jakimovska, M., Jakubowska, A., Janni, W., John, E. M., Johnson, N., Jones, M. E., Jukkola-Vuorinen, A., Jung, A., Kaaks, R., Kaczmarek, K., Kataja, V., Keeman, R., Kerin, M. J., Khusnutdinova, E., Kiiski, J., Knight, J. A., Ko, Y., Kosma, V., Koutros, S., Kristensen, V. N., Kruger, U., Kuehl, T., Lambrechts, D., Le Marchand, L., Lee, E., Lejbkowicz, F., Lilyquist, J., Lindblom, A., Lindstrom, S., Lissowska, J., Lo, W., Loibl, S., Long, J., Lubinski, J., Lux, M. P., MacInnis, R. J., Maishman, T., Makalic, E., Kostovska, I., Mannermaa, A., Manoukian, S., Margolin, S., Martens, J. M., Martinez, M., Mavroudis, D., McLean, C., Meindl, A., Menon, U., Middha, P., Miller, N., Moreno, F., Mulligan, A., Mulot, C., Munoz-Garzon, V. M., Neuhausen, S. L., Nevanlinna, H., Neven, P., Newman, W. G., Nielsen, S. F., Nordestgaard, B. G., Norman, A., Offit, K., Olson, J. E., Olsson, H., Orr, N., Pankratz, V., Park-Simon, T., Perez, J. A., Perez-Barrios, C., Peterlongo, P., Peto, J., Pinchev, M., Plaseska-Karanfilska, D., Polley, E. C., Prentice, R., Presneau, N., Prokofyeva, D., Purrington, K., Pylkas, K., Rack, B., Radice, P., Rau-Murthy, R., Rennert, G., Rennert, H. S., Rhenius, V., Robson, M., Romero, A., Ruddy, K. J., Ruebner, M., Saloustros, E., Sandler, D. P., Sawyer, E. J., Schmidt, D. F., Schmutzler, R. K., Schneeweiss, A., Schoemaker, M. J., Schumacher, F., Schuermann, P., Schwentner, L., Scott, C., Scott, R. J., Seynaeve, C., Shah, M., Sherman, M. E., Shrubsole, M. J., Shu, X., Slager, S., Smeets, A., Sohn, C., Soucy, P., Southey, M. C., Spinelli, J. J., Stegmaier, C., Stone, J., Swerdlow, A. J., Tamimi, R. M., Tapper, W. J., Taylor, J. A., Terry, M., Thoene, K., Tollenaar, R. M., Tomlinson, I., Truong, T., Tzardi, M., Ulmer, H., Untch, M., Vachon, C. M., van Veen, E. M., Vijai, J., Weinberg, C. R., Wendt, C., Whittemore, A. S., Wildiers, H., Willett, W., Winqvist, R., Wolk, A., Yang, X. R., Yannoukakos, D., Zhang, Y., Zheng, W., Ziogas, A., Clarke, C., Balleine, R., Baxter, R., Braye, S., Carpenter, J., Dahlstrom, J., Forbes, J., Lee, C., Marsh, D., Morey, A., Pathmanathan, N., Scott, R., Simpson, P., Spigelman, A., Wilcken, N., Yip, D., Zeps, N., Sexton, A., Dobrovic, A., Christian, A., Trainer, A., Fellows, A., Shelling, A., De Fazio, A., Blackburn, A., Crook, A., Meiser, B., Patterson, B., Clarke, C., Saunders, C., Hunt, C., Scott, C., Amor, D., Ortega, D., Marsh, D., Edkins, E., Salisbury, E., Haan, E., Macrea, F., Farshid, G., Lindeman, G., Trench, G., Mann, G., Giles, G., Gill, G., Thorne, H., Campbell, I., Hickie, I., Caldon, L., Winship, I., Cui, J., Flanagan, J., Kollias, J., Visvader, J., Taylor, J., Burke, J., Saunus, J., Forbs, J., Hopper, J., Beesley, J., Kirk, J., French, J., Tucker, K., Wu, K., Phillips, K., Forrest, L., Lipton, L., Andrews, L., Lobb, L., Walker, L., Kentwell, M., Spurdle, M., Cummings, M., Gleeson, M., Harris, M., Jenkins, M., Young, M., Delatycki, M., Wallis, M., Burgess, M., Brown, M., Southey, M., Bogwitz, M., Field, M., Friedlander, M., Gattas, M., Saleh, M., Aghmesheh, M., Hayward, N., Pachter, N., Cohen, P., Duijf, P., James, P., Simpson, P., Fong, P., Butow, P., Williams, R., Kefford, R., Simard, J., Balleine, R., Dawson, S., Lok, S., O'connell, S., Greening, S., Nightingale, S., Edwards, S., Fox, S., McLachlan, S., Lakhani, S., Dudding, T., Antill, Y., Sahlberg, K. K., Ottestad, L., Karesen, R., Schlichting, E., Holmen, M., Sauer, T., Haakensen, V., Engebraten, O., Naume, B., Fossa, A., Kiserud, C. E., Reinertsen, K., Helland, A., Riis, M., Geisler, J., Dunning, A. M., Thompson, D. J., Chenevix-Trench, G., Chang-Claude, J., Schmidt, M. K., Hall, P., Milne, R. L., Pharoah, P. P., Antoniou, A. C., Chatterjee, N., Kraft, P., Garcia-Closas, M., Easton, D. F., ABCTB Investigators, kConFab AOCS Investigators, NBCS Collaborators 2019; 104 (1): 21–34

  View details for DOI 10.1016/j.ajhg.2018.11.002

  View details for Web of Science ID 000454775500005

• Identification of novel susceptibility loci and genes for prostate cancer risk: A transcriptome-wide association study in over 140,000 European descendants. Cancer research Wu, L. n., Wang, J. n., Cai, Q. n., Cavazos, T. B., Emami, N. C., Long, J. n., Shu, X. O., Lu, Y. n., Guo, X. n., Bauer, J. A., Pasaniuc, B. n., Penney, K. L., Freedman, M. L., Kote-Jarai, Z. n., Witte, J. S., Haiman, C. A., Eeles, R. A., Zheng, W. n. 2019

  Abstract

  Genome-wide association studies have identified genetic variants associated with prostate cancer risk. However, these variants explain only a small fraction of the heritable component of prostate cancer risk, and the genes responsible for many of the identified associations remain unknown. To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, we performed a transcriptome-wide association study in 79,194 cases and 61,112 controls of European ancestry. Using data from the Genotype-Tissue Expression Project, we established genetic models to predict gene expression across the transcriptome for both prostate models and cross-tissue models and evaluated model performance using two independent datasets. We identified significant associations for 137 genes at P < 2.61×10-6, a Bonferroni-corrected threshold, including nine genes that remained significant at P < 2.61×10-6 after adjusting for all known prostate cancer risk variants in nearby regions. Of the 128 remaining associated genes, 94 have not yet been reported as potential target genes at known loci. We silenced 14 genes and many showed a consistent effect on viability and colony-forming efficiency in three cell lines. Our study provides substantial new information to advance our understanding of prostate cancer genetics and biology.

  View details for DOI 10.1158/0008-5472.CAN-18-3536

  View details for PubMedID 31101764

• Two truncating variants in FANCC and breast cancer risk. Scientific reports Dörk, T. n., Peterlongo, P. n., Mannermaa, A. n., Bolla, M. K., Wang, Q. n., Dennis, J. n., Ahearn, T. n., Andrulis, I. L., Anton-Culver, H. n., Arndt, V. n., Aronson, K. J., Augustinsson, A. n., Freeman, L. E., Beckmann, M. W., Beeghly-Fadiel, A. n., Behrens, S. n., Bermisheva, M. n., Blomqvist, C. n., Bogdanova, N. V., Bojesen, S. E., Brauch, H. n., Brenner, H. n., Burwinkel, B. n., Canzian, F. n., Chan, T. L., Chang-Claude, J. n., Chanock, S. J., Choi, J. Y., Christiansen, H. n., Clarke, C. L., Couch, F. J., Czene, K. n., Daly, M. B., Dos-Santos-Silva, I. n., Dwek, M. n., Eccles, D. M., Ekici, A. B., Eriksson, M. n., Evans, D. G., Fasching, P. A., Figueroa, J. n., Flyger, H. n., Fritschi, L. n., Gabrielson, M. n., Gago-Dominguez, M. n., Gao, C. n., Gapstur, S. M., García-Closas, M. n., García-Sáenz, J. A., Gaudet, M. M., Giles, G. G., Goldberg, M. S., Goldgar, D. E., Guénel, P. n., Haeberle, L. n., Haiman, C. A., Håkansson, N. n., Hall, P. n., Hamann, U. n., Hartman, M. n., Hauke, J. n., Hein, A. n., Hillemanns, P. n., Hogervorst, F. B., Hooning, M. J., Hopper, J. L., Howell, T. n., Huo, D. n., Ito, H. n., Iwasaki, M. n., Jakubowska, A. n., Janni, W. n., John, E. M., Jung, A. n., Kaaks, R. n., Kang, D. n., Kapoor, P. M., Khusnutdinova, E. n., Kim, S. W., Kitahara, C. M., Koutros, S. n., Kraft, P. n., Kristensen, V. N., Kwong, A. n., Lambrechts, D. n., Marchand, L. L., Li, J. n., Lindström, S. n., Linet, M. n., Lo, W. Y., Long, J. n., Lophatananon, A. n., Lubiński, J. n., Manoochehri, M. n., Manoukian, S. n., Margolin, S. n., Martinez, E. n., Matsuo, K. n., Mavroudis, D. n., Meindl, A. n., Menon, U. n., Milne, R. L., Mohd Taib, N. A., Muir, K. n., Mulligan, A. M., Neuhausen, S. L., Nevanlinna, H. n., Neven, P. n., Newman, W. G., Offit, K. n., Olopade, O. I., Olshan, A. F., Olson, J. E., Olsson, H. n., Park, S. K., Park-Simon, T. W., Peto, J. n., Plaseska-Karanfilska, D. n., Pohl-Rescigno, E. n., Presneau, N. n., Rack, B. n., Radice, P. n., Rashid, M. U., Rennert, G. n., Rennert, H. S., Romero, A. n., Ruebner, M. n., Saloustros, E. n., Schmidt, M. K., Schmutzler, R. K., Schneider, M. O., Schoemaker, M. J., Scott, C. n., Shen, C. Y., Shu, X. O., Simard, J. n., Slager, S. n., Smichkoska, S. n., Southey, M. C., Spinelli, J. J., Stone, J. n., Surowy, H. n., Swerdlow, A. J., Tamimi, R. M., Tapper, W. J., Teo, S. H., Terry, M. B., Toland, A. E., Tollenaar, R. A., Torres, D. n., Torres-Mejía, G. n., Troester, M. A., Truong, T. n., Tsugane, S. n., Untch, M. n., Vachon, C. M., Ouweland, A. M., Veen, E. M., Vijai, J. n., Wendt, C. n., Wolk, A. n., Yu, J. C., Zheng, W. n., Ziogas, A. n., Ziv, E. n., Dunning, A. M., Pharoah, P. D., Schindler, D. n., Devilee, P. n., Easton, D. F. 2019; 9 (1): 12524

  Abstract

  Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.

  View details for DOI 10.1038/s41598-019-48804-y

  View details for PubMedID 31467304

• The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer. NPJ breast cancer Figlioli, G., Bogliolo, M., Catucci, I., Caleca, L., Lasheras, S. V., Pujol, R., Kiiski, J. I., Muranen, T. A., Barnes, D. R., Dennis, J., Michailidou, K., Bolla, M. K., Leslie, G., Aalfs, C. M., ABCTB Investigators, Adank, M. A., Adlard, J., Agata, S., Cadoo, K., Agnarsson, B. A., Ahearn, T., Aittomaki, K., Ambrosone, C. B., Andrews, L., Anton-Culver, H., Antonenkova, N. N., Arndt, V., Arnold, N., Aronson, K. J., Arun, B. K., Asseryanis, E., Auber, B., Auvinen, P., Azzollini, J., Balmana, J., Barkardottir, R. B., Barrowdale, D., Barwell, J., Beane Freeman, L. E., Beauparlant, C. J., Beckmann, M. W., Behrens, S., Benitez, J., Berger, R., Bermisheva, M., Blanco, A. M., Blomqvist, C., Bogdanova, N. V., Bojesen, A., Bojesen, S. E., Bonanni, B., Borg, A., Brady, A. F., Brauch, H., Brenner, H., Bruning, T., Burwinkel, B., Buys, S. S., Caldes, T., Caliebe, A., Caligo, M. A., Campa, D., Campbell, I. G., Canzian, F., Castelao, J. E., Chang-Claude, J., Chanock, S. J., Claes, K. B., Clarke, C. L., Collavoli, A., Conner, T. A., Cox, D. G., Cybulski, C., Czene, K., Daly, M. B., de la Hoya, M., Devilee, P., Diez, O., Ding, Y. C., Dite, G. S., Ditsch, N., Domchek, S. M., Dorfling, C. M., Dos-Santos-Silva, I., Durda, K., Dwek, M., Eccles, D. M., Ekici, A. B., Eliassen, A. H., Ellberg, C., Eriksson, M., Evans, D. G., Fasching, P. A., Figueroa, J., Flyger, H., Foulkes, W. D., Friebel, T. M., Friedman, E., Gabrielson, M., Gaddam, P., Gago-Dominguez, M., Gao, C., Gapstur, S. M., Garber, J., Garcia-Closas, M., Garcia-Saenz, J. A., Gaudet, M. M., Gayther, S. A., GEMO Study Collaborators, Giles, G. G., Glendon, G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Guenel, P., Gutierrez-Barrera, A. M., Haeberle, L., Haiman, C. A., Hakansson, N., Hall, P., Hamann, U., Harrington, P. A., Hein, A., Heyworth, J., Hillemanns, P., Hollestelle, A., Hopper, J. L., Hosgood, H. D., Howell, A., Hu, C., Hulick, P. J., Hunter, D. J., Imyanitov, E. N., KConFab, Isaacs, C., Jakimovska, M., Jakubowska, A., James, P., Janavicius, R., Janni, W., John, E. M., Jones, M. E., Jung, A., Kaaks, R., Karlan, B. Y., Khusnutdinova, E., Kitahara, C. M., Konstantopoulou, I., Koutros, S., Kraft, P., Lambrechts, D., Lazaro, C., Le Marchand, L., Lester, J., Lesueur, F., Lilyquist, J., Loud, J. T., Lu, K. H., Luben, R. N., Lubinski, J., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martens, J. W., Maurer, T., Mavroudis, D., Mebirouk, N., Meindl, A., Menon, U., Miller, A., Montagna, M., Nathanson, K. L., Neuhausen, S. L., Newman, W. G., Nguyen-Dumont, T., Nielsen, F. C., Nielsen, S., Nikitina-Zake, L., Offit, K., Olah, E., Olopade, O. I., Olshan, A. F., Olson, J. E., Olsson, H., Osorio, A., Ottini, L., Peissel, B., Peixoto, A., Peto, J., Plaseska-Karanfilska, D., Pocza, T., Presneau, N., Pujana, M. A., Punie, K., Rack, B., Rantala, J., Rashid, M. U., Rau-Murthy, R., Rennert, G., Lejbkowicz, F., Rhenius, V., Romero, A., Rookus, M. A., Ross, E. A., Rossing, M., Rudaitis, V., Ruebner, M., Saloustros, E., Sanden, K., Santamarina, M., Scheuner, M. T., Schmutzler, R. K., Schneider, M., Scott, C., Senter, L., Shah, M., Sharma, P., Shu, X., Simard, J., Singer, C. F., Sohn, C., Soucy, P., Southey, M. C., Spinelli, J. J., Steele, L., Stoppa-Lyonnet, D., Tapper, W. J., Teixeira, M. R., Terry, M. B., Thomassen, M., Thompson, J., Thull, D. L., Tischkowitz, M., Tollenaar, R. A., Torres, D., Troester, M. A., Truong, T., Tung, N., Untch, M., Vachon, C. M., van Rensburg, E. J., van Veen, E. M., Vega, A., Viel, A., Wappenschmidt, B., Weitzel, J. N., Wendt, C., Wieme, G., Wolk, A., Yang, X. R., Zheng, W., Ziogas, A., Zorn, K. K., Dunning, A. M., Lush, M., Wang, Q., McGuffog, L., Parsons, M. T., Pharoah, P. D., Fostira, F., Toland, A. E., Andrulis, I. L., Ramus, S. J., Swerdlow, A. J., Greene, M. H., Chung, W. K., Milne, R. L., Chenevix-Trench, G., Dork, T., Schmidt, M. K., Easton, D. F., Radice, P., Hahnen, E., Antoniou, A. C., Couch, F. J., Nevanlinna, H., Surralles, J., Peterlongo, P., Balleine, R., Baxter, R., Braye, S., Carpenter, J., Dahlstrom, J., Forbes, J., Lee, C. S., Marsh, D., Morey, A., Pathmanathan, N., Scott, R., Simpson, P., Spigelman, A., Wilcken, N., Yip, D., Zeps, N., Belotti, M., Bertrand, O., Birot, A., Buecher, B., Caputo, S., Dupre, A., Fourme, E., Gauthier-Villars, M., Golmard, L., Le Mentec, M., Moncoutier, V., de Pauw, A., Saule, C., Boutry-Kryza, N., Calender, A., Giraud, S., Leone, M., Bressac-de-Paillerets, B., Caron, O., Guillaud-Bataille, M., Bignon, Y., Uhrhammer, N., Bonadona, V., Lasset, C., Berthet, P., Castera, L., Vaur, D., Bourdon, V., Nogues, C., Noguchi, T., Popovici, C., Remenieras, A., Sobol, H., Coupier, I., Pujol, P., Adenis, C., Dumont, A., Revillion, F., Muller, D., Barouk-Simonet, E., Bonnet, F., Bubien, V., Longy, M., Sevenet, N., Gladieff, L., Guimbaud, R., Feillel, V., Toulas, C., Dreyfus, H., Leroux, C. D., Peysselon, M., Rebischung, C., Legrand, C., Baurand, A., Bertolone, G., Coron, F., Faivre, L., Jacquot, C., Lizard, S., Kientz, C., Lebrun, M., Prieur, F., Fert-Ferrer, S., Mari, V., Venat-Bouvet, L., Bezieau, S., Delnatte, C., Mortemousque, I., Colas, C., Coulet, F., Soubrier, F., Warcoin, M., Bronner, M., Sokolowska, J., Collonge-Rame, M., Damette, A., Gesta, P., Lallaoui, H., Chiesa, J., Molina-Gomes, D., Ingster, O., Manouvrier-Hanu, S., Lejeune, S., Aghmesheh, M., Greening, S., Amor, D., Gattas, M., Botes, L., Buckley, M., Friedlander, M., Koehler, J., Meiser, B., Saleh, M., Salisbury, E., Trainer, A., Tucker, K., Antill, Y., Dobrovic, A., Fellows, A., Fox, S., Harris, M., Nightingale, S., Phillips, K., Sambrook, J., Thorne, H., Armitage, S., Arnold, L., Balleine, R., Kefford, R., Kirk, J., Rickard, E., Bastick, P., Beesley, J., Hayward, N., Spurdle, A., Walker, L., Beilby, J., Saunders, C., Bennett, I., Blackburn, A., Bogwitz, M., Gaff, C., Lindeman, G., Pachter, N., Scott, C., Sexton, A., Visvader, J., Taylor, J., Winship, I., Brennan, M., Brown, M., French, J., Edwards, S., Burgess, M., Burke, J., Patterson, B., Butow, P., Culling, B., Caldon, L., Callen, D., Chauhan, D., Eisenbruch, M., Heiniger, L., Chauhan, M., Christian, A., Dixon, J., Kidd, A., Cohen, P., Colley, A., Fenton, G., Crook, A., Dickson, R., Field, M., Marsh, D., Cui, J., Cummings, M., Dawson, S., DeFazio, A., Delatycki, M., Dudding, T., Edkins, T., Farshid, G., Flanagan, J., Fong, P., Forrest, L., Gallego-Ortega, D., George, P., Gill, G., Kollias, J., Haan, E., Hart, S., Jenkins, M., Hunt, C., Lakhani, S., Lipton, L., Lobb, L., Mann, G., McLachlan, S. A., O'Connell, S., O'Sullivan, S., Pieper, E., Robinson, B., Saunus, J., Scott, E., Scott, R., Shelling, A., Simpson, P., Williams, R., Young, M. A. 2019; 5: 38

  Abstract

  Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR=2.44, P=0.034 and OR=3.79; P=0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR=1.96; P=0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.

  View details for DOI 10.1038/s41523-019-0127-5

  View details for PubMedID 31700994

• Association of a Pathway-Specific Genetic Risk Score With Risk of Radiation-Associated Contralateral Breast Cancer. JAMA network open Watt, G. P., Reiner, A. S., Smith, S. A., Stram, D. O., Capanu, M. n., Malone, K. E., Lynch, C. F., John, E. M., Knight, J. A., Mellemkjær, L. n., Bernstein, L. n., Brooks, J. D., Woods, M. n., Liang, X. n., Haile, R. W., Riaz, N. n., Conti, D. V., Robson, M. n., Duggan, D. n., Boice, J. D., Shore, R. E., Tischkowitz, M. n., Orlow, I. n., Thomas, D. C., Concannon, P. n., Bernstein, J. L. 2019; 2 (9): e1912259

  Abstract

  Radiation therapy for breast cancer is associated with increased risk of a second primary contralateral breast cancer, but the genetic factors modifying this association are not well understood.To determine whether a genetic risk score comprising single nucleotide polymorphisms in the nonhomologous end-joining DNA repair pathway is associated with radiation-associated contralateral breast cancer.This case-control study included a case group of women with contralateral breast cancer that was diagnosed at least 1 year after a first primary breast cancer who were individually matched to a control group of women with unilateral breast cancer. Inclusion criteria were receiving a first invasive breast cancer diagnosis prior to age 55 years between 1985 and 2008. Women were recruited through 8 population-based cancer registries in the United States, Canada, and Denmark as part of the Women's Environment, Cancer, and Radiation Epidemiology Studies I (November 2000 to August 2004) and II (March 2010 to December 2012). Data analysis was conducted from July 2017 to August 2019.Stray radiation dose to the contralateral breast during radiation therapy for the first breast cancer. A novel genetic risk score comprised of genetic variants in the nonhomologous end-joining DNA repair pathway was considered the potential effect modifier, dichotomized as high risk if the score was above the median of 74 and low risk if the score was at or below the median.The main outcome was risk of contralateral breast cancer associated with stray radiation dose stratified by genetic risk score, age, and latency.A total of 5953 women were approached for study participation, and 3732 women (62.7%) agreed to participate. The median (range) age at first diagnosis was 46 (23-54) years. After 5 years of latency or more, among women who received the first diagnosis when they were younger than 40 years, exposure to 1.0 Gy (to convert to rad, multiply by 100) or more of stray radiation was associated with a 2-fold increased risk of contralateral breast cancer compared with women who were not exposed (rate ratio, 2.0 [95% CI, 1.1-3.6]). The risk was higher among women with a genetic risk score above the median (rate ratio, 3.0 [95% CI, 1.1-8.1]), and there was no association among women with a genetic risk score below the median (rate ratio, 1.3 [95% CI, 0.5-3.7]). Among younger women with a high genetic risk score, the attributable increased risk for contralateral breast cancer associated with stray radiation dose was 28%.This study found an increased risk of contralateral breast cancer that was attributable to stray radiation exposure among women with a high genetic risk score and who received a first breast cancer diagnosis when they were younger than 40 years after 5 years or more of latency. This genetic risk score may help guide treatment and surveillance for women with breast cancer.

  View details for DOI 10.1001/jamanetworkopen.2019.12259

  View details for PubMedID 31560388

• Publisher Correction: Shared heritability and functional enrichment across six solid cancers. Nature communications Jiang, X. n., Finucane, H. K., Schumacher, F. R., Schmit, S. L., Tyrer, J. P., Han, Y. n., Michailidou, K. n., Lesseur, C. n., Kuchenbaecker, K. B., Dennis, J. n., Conti, D. V., Casey, G. n., Gaudet, M. M., Huyghe, J. R., Albanes, D. n., Aldrich, M. C., Andrew, A. S., Andrulis, I. L., Anton-Culver, H. n., Antoniou, A. C., Antonenkova, N. N., Arnold, S. M., Aronson, K. J., Arun, B. K., Bandera, E. V., Barkardottir, R. B., Barnes, D. R., Batra, J. n., Beckmann, M. W., Benitez, J. n., Benlloch, S. n., Berchuck, A. n., Berndt, S. I., Bickeböller, H. n., Bien, S. A., Blomqvist, C. n., Boccia, S. n., Bogdanova, N. V., Bojesen, S. E., Bolla, M. K., Brauch, H. n., Brenner, H. n., Brenton, J. D., Brook, M. N., Brunet, J. n., Brunnström, H. n., Buchanan, D. D., Burwinkel, B. n., Butzow, R. n., Cadoni, G. n., Caldés, T. n., Caligo, M. A., Campbell, I. n., Campbell, P. T., Cancel-Tassin, G. n., Cannon-Albright, L. n., Campa, D. n., Caporaso, N. n., Carvalho, A. L., Chan, A. T., Chang-Claude, J. n., Chanock, S. J., Chen, C. n., Christiani, D. C., Claes, K. B., Claessens, F. n., Clements, J. n., Collée, J. M., Correa, M. C., Couch, F. J., Cox, A. n., Cunningham, J. M., Cybulski, C. n., Czene, K. n., Daly, M. B., deFazio, A. n., Devilee, P. n., Diez, O. n., Gago-Dominguez, M. n., Donovan, J. L., Dörk, T. n., Duell, E. J., Dunning, A. M., Dwek, M. n., Eccles, D. M., Edlund, C. K., Edwards, D. R., Ellberg, C. n., Evans, D. G., Fasching, P. A., Ferris, R. L., Liloglou, T. n., Figueiredo, J. C., Fletcher, O. n., Fortner, R. T., Fostira, F. n., Franceschi, S. n., Friedman, E. n., Gallinger, S. J., Ganz, P. A., Garber, J. n., García-Sáenz, J. A., Gayther, S. A., Giles, G. G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Goode, E. L., Goodman, M. T., Goodman, G. n., Grankvist, K. n., Greene, M. H., Gronberg, H. n., Gronwald, J. n., Guénel, P. n., Håkansson, N. n., Hall, P. n., Hamann, U. n., Hamdy, F. C., Hamilton, R. J., Hampe, J. n., Haugen, A. n., Heitz, F. n., Herrero, R. n., Hillemanns, P. n., Hoffmeister, M. n., Høgdall, E. n., Hong, Y. C., Hopper, J. L., Houlston, R. n., Hulick, P. J., Hunter, D. J., Huntsman, D. G., Idos, G. n., Imyanitov, E. N., Ingles, S. A., Isaacs, C. n., Jakubowska, A. n., James, P. n., Jenkins, M. A., Johansson, M. n., Johansson, M. n., John, E. M., Joshi, A. D., Kaneva, R. n., Karlan, B. Y., Kelemen, L. E., Kühl, T. n., Khaw, K. T., Khusnutdinova, E. n., Kibel, A. S., Kiemeney, L. A., Kim, J. n., Kjaer, S. K., Knight, J. A., Kogevinas, M. n., Kote-Jarai, Z. n., Koutros, S. n., Kristensen, V. N., Kupryjanczyk, J. n., Lacko, M. n., Lam, S. n., Lambrechts, D. n., Landi, M. T., Lazarus, P. n., Le, N. D., Lee, E. n., Lejbkowicz, F. n., Lenz, H. J., Leslie, G. n., Lessel, D. n., Lester, J. n., Levine, D. A., Li, L. n., Li, C. I., Lindblom, A. n., Lindor, N. M., Liu, G. n., Loupakis, F. n., Lubiński, J. n., Maehle, L. n., Maier, C. n., Mannermaa, A. n., Marchand, L. L., Margolin, S. n., May, T. n., McGuffog, L. n., Meindl, A. n., Middha, P. n., Miller, A. n., Milne, R. L., MacInnis, R. J., Modugno, F. n., Montagna, M. n., Moreno, V. n., Moysich, K. B., Mucci, L. n., Muir, K. n., Mulligan, A. M., Nathanson, K. L., Neal, D. E., Ness, A. R., Neuhausen, S. L., Nevanlinna, H. n., Newcomb, P. A., Newcomb, L. F., Nielsen, F. C., Nikitina-Zake, L. n., Nordestgaard, B. G., Nussbaum, R. L., Offit, K. n., Olah, E. n., Olama, A. A., Olopade, O. I., Olshan, A. F., Olsson, H. n., Osorio, A. n., Pandha, H. n., Park, J. Y., Pashayan, N. n., Parsons, M. T., Pejovic, T. n., Penney, K. L., Peters, W. H., Phelan, C. M., Phipps, A. I., Plaseska-Karanfilska, D. n., Pring, M. n., Prokofyeva, D. n., Radice, P. n., Stefansson, K. n., Ramus, S. J., Raskin, L. n., Rennert, G. n., Rennert, H. S., van Rensburg, E. J., Riggan, M. J., Risch, H. A., Risch, A. n., Roobol, M. J., Rosenstein, B. S., Rossing, M. A., De Ruyck, K. n., Saloustros, E. n., Sandler, D. P., Sawyer, E. J., Schabath, M. B., Schleutker, J. n., Schmidt, M. K., Setiawan, V. W., Shen, H. n., Siegel, E. M., Sieh, W. n., Singer, C. F., Slattery, M. L., Sorensen, K. D., Southey, M. C., Spurdle, A. B., Stanford, J. L., Stevens, V. L., Stintzing, S. n., Stone, J. n., Sundfeldt, K. n., Sutphen, R. n., Swerdlow, A. J., Tajara, E. H., Tangen, C. M., Tardon, A. n., Taylor, J. A., Teare, M. D., Teixeira, M. R., Terry, M. B., Terry, K. L., Thibodeau, S. N., Thomassen, M. n., Bjørge, L. n., Tischkowitz, M. n., Toland, A. E., Torres, D. n., Townsend, P. A., Travis, R. C., Tung, N. n., Tworoger, S. S., Ulrich, C. M., Usmani, N. n., Vachon, C. M., Van Nieuwenhuysen, E. n., Vega, A. n., Aguado-Barrera, M. E., Wang, Q. n., Webb, P. M., Weinberg, C. R., Weinstein, S. n., Weissler, M. C., Weitzel, J. N., West, C. M., White, E. n., Whittemore, A. S., Wichmann, H. E., Wiklund, F. n., Winqvist, R. n., Wolk, A. n., Woll, P. n., Woods, M. n., Wu, A. H., Wu, X. n., Yannoukakos, D. n., Zheng, W. n., Zienolddiny, S. n., Ziogas, A. n., Zorn, K. K., Lane, J. M., Saxena, R. n., Thomas, D. n., Hung, R. J., Diergaarde, B. n., McKay, J. n., Peters, U. n., Hsu, L. n., García-Closas, M. n., Eeles, R. A., Chenevix-Trench, G. n., Brennan, P. J., Haiman, C. A., Simard, J. n., Easton, D. F., Gruber, S. B., Pharoah, P. D., Price, A. L., Pasaniuc, B. n., Amos, C. I., Kraft, P. n., Lindström, S. n. 2019; 10 (1): 4386

  Abstract

  An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  View details for DOI 10.1038/s41467-019-12095-8

  View details for PubMedID 31548585

• Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness. Cancer research Patel, V. L., Busch, E. L., Friebel, T. M., Cronin, A. n., Leslie, G. n., McGuffog, L. n., Adlard, J. n., Agata, S. n., Agnarsson, B. A., Ahmed, M. n., Aittomäki, K. n., Alducci, E. n., Andrulis, I. L., Arason, A. n., Arnold, N. n., Artioli, G. n., Arver, B. n., Auber, B. n., Azzollini, J. n., Balmaña, J. n., Barkardottir, R. B., Barnes, D. R., Barroso, A. n., Barrowdale, D. n., Belotti, M. n., Benitez, J. n., Bertelsen, B. n., Blok, M. J., Bodrogi, I. n., Bonadona, V. n., Bonanni, B. n., Bondavalli, D. n., Boonen, S. E., Borde, J. n., Borg, A. n., Bradbury, A. R., Brady, A. n., Brewer, C. n., Brunet, J. n., Buecher, B. n., Buys, S. S., Cabezas-Camarero, S. n., Caldés, T. n., Caliebe, A. n., Caligo, M. A., Calvello, M. n., Campbell, I. G., Carnevali, I. n., Carrasco, E. n., Chan, T. L., Chu, A. T., Chung, W. K., Claes, K. B., Collaborators, G. S., Collaborators, E. n., Cook, J. n., Cortesi, L. n., Couch, F. J., Daly, M. B., Damante, G. n., Darder, E. n., Davidson, R. n., de la Hoya, M. n., Della Puppa, L. n., Dennis, J. n., Díez, O. n., Ding, Y. C., Ditsch, N. n., Domchek, S. M., Donaldson, A. n., Dworniczak, B. n., Easton, D. F., Eccles, D. M., Eeles, R. A., Ehrencrona, H. n., Ejlertsen, B. n., Engel, C. n., Evans, D. G., Faivre, L. n., Faust, U. n., Feliubadaló, L. n., Foretova, L. n., Fostira, F. n., Fountzilas, G. n., Frost, D. n., García-Barberán, V. n., Garre, P. n., Gauthier-Villars, M. n., Géczi, L. n., Gehrig, A. n., Gerdes, A. M., Gesta, P. n., Giannini, G. n., Glendon, G. n., Godwin, A. K., Goldgar, D. E., Greene, M. H., Gutierrez-Barrera, A. M., Hahnen, E. n., Hamann, U. n., Hauke, J. n., Herold, N. n., Hogervorst, F. B., Honisch, E. n., Hopper, J. L., Hulick, P. J., Investigators, k. n., Investigators, H. n., Izatt, L. n., Jager, A. n., James, P. n., Janavicius, R. n., Jensen, U. B., Jensen, T. D., Johannsson, O. T., John, E. M., Joseph, V. n., Kang, E. n., Kast, K. n., Kiiski, J. I., Kim, S. W., Kim, Z. n., Ko, K. P., Konstantopoulou, I. n., Kramer, G. n., Krogh, L. n., Kruse, T. A., Kwong, A. n., Larsen, M. n., Lasset, C. n., Lautrup, C. n., Lázaro, C. n., Lee, J. n., Lee, J. W., Lee, M. H., Lemke, J. n., Lesueur, F. n., Liljegren, A. n., Lindblom, A. n., Llovet, P. n., Lopez-Fernández, A. n., Lopez-Perolio, I. n., Lorca, V. n., Loud, J. T., Ma, E. S., Mai, P. L., Manoukian, S. n., Mari, V. n., Martin, L. n., Matricardi, L. n., Mebirouk, N. n., Medici, V. n., Meijers-Heijboer, H. E., Meindl, A. n., Mensenkamp, A. R., Miller, C. n., Molina Gomes, D. n., Montagna, M. n., Mooij, T. M., Moserle, L. n., Mouret-Fourme, E. n., Mulligan, A. M., Nathanson, K. L., Navratilova, M. n., Nevanlinna, H. n., Niederacher, D. n., Cilius Nielsen, F. C., Nikitina-Zake, L. n., Offit, K. n., Olah, E. n., Olopade, O. I., Ong, K. R., Osorio, A. n., Ott, C. E., Palli, D. n., Park, S. K., Parsons, M. T., Pedersen, I. S., Peissel, B. n., Peixoto, A. n., Pérez-Segura, P. n., Peterlongo, P. n., Høgh Petersen, A. n., Porteous, M. E., Pujana, M. A., Radice, P. n., Ramser, J. n., Rantala, J. n., Rashid, M. U., Rhiem, K. n., Rizzolo, P. n., Robson, M. E., Rookus, M. A., Rossing, C. M., Ruddy, K. J., Santos, C. n., Saule, C. n., Scarpitta, R. n., Schmutzler, R. K., Schuster, H. n., Senter, L. n., Seynaeve, C. M., Shah, P. D., Sharma, P. n., Shin, V. Y., Silvestri, V. n., Simard, J. n., Singer, C. F., Skytte, A. B., Snape, K. n., Solano, A. R., Soucy, P. n., Southey, M. C., Spurdle, A. B., Steele, L. n., Steinemann, D. n., Stoppa-Lyonnet, D. n., Stradella, A. n., Sunde, L. n., Sutter, C. n., Tan, Y. Y., Teixeira, M. R., Teo, S. H., Thomassen, M. n., Tibiletti, M. G., Tischkowitz, M. n., Tognazzo, S. n., Toland, A. E., Tommasi, S. n., Torres, D. n., Toss, A. n., Trainer, A. H., Tung, N. n., van Asperen, C. J., van der Baan, F. H., van der Kolk, L. E., van der Luijt, R. B., van Hest, L. P., Varesco, L. n., Varon-Mateeva, R. n., Viel, A. n., Vierstraete, J. n., Villa, R. n., von Wachenfeldt, A. n., Wagner, P. n., Wang-Gohrke, S. n., Wappenschmidt, B. n., Weitzel, J. N., Wieme, G. n., Yadav, S. n., Yannoukakos, D. n., Yoon, S. Y., Zanzottera, C. n., Zorn, K. K., D'Amico, A. V., Freedman, M. L., Pomerantz, M. M., Chenevix-Trench, G. n., Antoniou, A. C., Neuhausen, S. L., Ottini, L. n., Nielsen, H. R., Rebbeck, T. R. 2019

  Abstract

  Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer (PCa). We evaluated whether PSVs in BRCA1/2 were associated with risk of overall PCa or high grade (Gleason 8+) PCa using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with PCa, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without PCa. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of PCa compared with reference bin c.1001-c.7913 (HR=1.78, 95%CI: 1.25-2.52, p=0.001), as well as elevated risk of Gleason 8+ PCa (HR=3.11, 95%CI: 1.63-5.95, p=0.001). c.756-c.1000 was also associated with elevated PCa risk (HR=2.83, 95%CI: 1.71-4.68, p=0.00004) and elevated risk of Gleason 8+ PCa (HR=4.95, 95%CI: 2.12-11.54, p=0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive PCa.

  View details for DOI 10.1158/0008-5472.CAN-19-1840

  View details for PubMedID 31723001

• Estrogenic activity, race/ethnicity, and Indigenous American ancestry among San Francisco Bay Area women. PloS one Sanchez, S. S., Tachachartvanich, P., Stanczyk, F. Z., Gomez, S. L., John, E. M., Smith, M. T., Fejerman, L. 2019; 14 (3): e0213809

  Abstract

  Estrogens play a significant role in breast cancer development and are not only produced endogenously, but are also mimicked by estrogen-like compounds from environmental exposures. We evaluated associations between estrogenic (E) activity, demographic factors and breast cancer risk factors in Non-Latina Black (NLB), Non-Latina White (NLW), and Latina women. We examined the association between E activity and Indigenous American (IA) ancestry in Latina women. Total E activity was measured with a bioassay in plasma samples of 503 women who served as controls in the San Francisco Bay Area Breast Cancer Study. In the univariate model that included all women with race/ethnicity as the independent predictor, Latinas had 13% lower E activity (p = 0.239) and NLBs had 35% higher activity (p = 0.04) compared to NLWs. In the multivariable model that adjusted for demographic factors, Latinas continued to show lower E activity levels (26%, p = 0.026), but the difference between NLBs and NLWs was no longer statistically significant (p = 0.431). An inverse association was observed between E activity and IA ancestry among Latina women (50% lower in 0% vs. 100% European ancestry, p = 0.027) consistent with our previously reported association between IA ancestry and breast cancer risk. These findings suggest that endogenous estrogens and exogenous estrogen-like compounds that act on the estrogen receptor and modulate E activity may partially explain racial/ethnic differences in breast cancer risk.

  View details for DOI 10.1371/journal.pone.0213809

  View details for PubMedID 30908519

• Considerations when using breast cancer risk models for women with negative BRCA1/BRCA2 mutation results. Journal of the National Cancer Institute MacInnis, R. J., Liao, Y. n., Knight, J. A., Milne, R. L., Whittemore, A. S., Chung, W. K., Leoce, N. n., Buchsbaum, R. n., Zeinomar, N. n., Dite, G. S., Southey, M. C., Goldgar, D. n., Giles, G. G., McLachlan, S. A., Weideman, P. C., Nesci, S. n., Friedlander, M. L., Glendon, G. n., Andrulis, I. L., John, E. M., Daly, M. B., Buys, S. S., Phillips, K. A., Hopper, J. L., Terry, M. B. 2019

  Abstract

  The performance of breast cancer risk models for women with a family history but negative BRCA1 and/or BRCA2 mutation test results is uncertain. We calculated the cumulative 10-year invasive breast cancer risk at cohort entry for 14,657 unaffected women (96.1% had an affected relative) not known to carry BRCA1 or BRCA2 mutations at baseline using three pedigree-based models (BOADICEA, BRCAPRO and IBIS). During follow-up, 482 women were diagnosed with invasive breast cancer. Mutation testing was conducted independent of incident cancers. All models under-predicted risk by 26.3-56.7% for women who tested negative but whose relatives had not been tested (N = 1,363; 63 breast cancers). While replication studies with larger sample sizes are needed, until these models are re-calibrated for women who test negative and have no relatives tested, caution should be used when considering changing the breast cancer risk management intensity of such women based on risk estimates from these models.

  View details for DOI 10.1093/jnci/djz194

  View details for PubMedID 31584660

• Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Adams, C. D., Richmond, R., Ferreira, D., Spiller, W., Tan, V., Zheng, J., Wurtz, P., Donovan, J., Hamdy, F., Neal, D., Lane, J., Smith, G., Relton, C., Eeles, R. A., Haiman, C. A., Kote-Jarai, Z. S., Schumacher, F. R., Al Olama, A., Benlloch, S., Muir, K., Berndt, S. I., Conti, D. V., Wiklund, F., Chanock, S. J., Gapstur, S., Stevens, V. L., Tangen, C. M., Batra, J., Clements, J. A., Gronberg, H., Pashayan, N., Schleutker, J., Albanes, D., Wolk, A., West, C. L., Mucci, L. A., Cancel-Tassin, G., Koutros, S., Sorensen, K., Maehle, L., Travis, R. C., Hamilton, R. J., Ingles, S., Rosenstein, B. S., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., John, E. M., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R. P., Usmani, N., Claessens, F., Townsend, P. A., Dominguez, M., Roobol, M. J., Menegaux, F., Khaw, K., Cannon-Albright, L. A., Pandha, H., Thibodeau, S. N., Martin, R. M., PRACTICAL Consortium 2019; 28 (1): 208–16

  View details for DOI 10.1158/1055-9965.EPI-18-0079

  View details for Web of Science ID 000465320400023

• Assessing patient readiness for personalized genomic medicine. Journal of community genetics Frost, C. J., Andrulis, I. L., Buys, S. S., Hopper, J. L., John, E. M., Terry, M. B., Bradbury, A., Chung, W. K., Colbath, K., Quintana, N., Gamarra, E., Egleston, B., Galpern, N., Bealin, L., Glendon, G., Miller, L. P., Daly, M. B. 2019; 10 (1): 109-120

  Abstract

  The Human Genome Project and the continuing advances in DNA sequencing technology have ushered in a new era in genomic medicine. Successful translation of genomic medicine into clinical care will require that providers of this information are aware of the level of understanding, attitudes, perceived risks, benefits, and concerns of their patients. We used a mixed methods approach to conduct in-depth interviews with participants in the NCI-funded Breast Cancer Family Registry (BCFR). Our goal was to gain a better understanding of attitudes towards different types and amounts of genomic information, current interest in pursuing genomic testing, and perceived risks and benefits. We interviewed 32 women from the six BCFR sites in the USA, Canada, and Australia. In this sample of women with a personal or family history of breast cancer, we found high acknowledgement of the potential of genetics/genomics to improve their own health and that of their family members through lifestyle changes or alterations in their medical management. Respondents were more familiar with cancer genetics than the genetics of other diseases. Concerns about the testing itself included a potential sense of loss of control over health, feelings of guilt on passing on a mutation to a child, loss of privacy and confidentiality, questions about the test accuracy, and the potential uncertainty of the significance of test results. These data provide important insights into attitudes about the introduction of increasingly complex genetic testing, to inform interventions to prepare individuals for the introduction of this new technology into their clinical care.

  View details for DOI 10.1007/s12687-018-0365-5

  View details for PubMedID 29804257

  View details for PubMedCentralID PMC6325047

• The functional ALDH2 polymorphism is associated with breast cancer risk: A pooled analysis from the Breast Cancer Association Consortium. Molecular genetics & genomic medicine Ugai, T. n., Milne, R. L., Ito, H. n., Aronson, K. J., Bolla, M. K., Chan, T. n., Chan, C. W., Choi, J. Y., Conroy, D. M., Dennis, J. n., Dunning, A. M., Easton, D. F., Gaborieau, V. n., Gonzalez-Neira, A. n., Hartman, M. n., Healey, C. S., Iwasaki, M. n., John, E. M., Kang, D. n., Kim, S. W., Kwong, A. n., Lophatananon, A. n., Michailidou, K. n., Taib, N. A., Muir, K. n., Park, S. K., Pharoah, P. D., Sangrajrang, S. n., Shen, C. Y., Shu, X. O., Spinelli, J. J., Teo, S. H., Tessier, D. C., Tseng, C. C., Tsugane, S. n., Vincent, D. n., Wang, Q. n., Wu, A. H., Wu, P. E., Zheng, W. n., Matsuo, K. n. 2019: e707

  Abstract

  Epidemiological studies consistently indicate that alcohol consumption is an independent risk factor for female breast cancer (BC). Although the aldehyde dehydrogenase 2 (ALDH2) polymorphism (rs671: Glu>Lys) has a strong effect on acetaldehyde metabolism, the association of rs671 with BC risk and its interaction with alcohol intake have not been fully elucidated. We conducted a pooled analysis of 14 case-control studies, with individual data on Asian ancestry women participating in the Breast Cancer Association Consortium.We included 12,595 invasive BC cases and 12,884 controls for the analysis of rs671 and BC risk, and 2,849 invasive BC cases and 3,680 controls for the analysis of the gene-environment interaction between rs671 and alcohol intake for BC risk. The pooled odds ratios (OR) with 95% confidence intervals (CI) associated with rs671 and its interaction with alcohol intake for BC risk were estimated using logistic regression models.The Lys/Lys genotype of rs671 was associated with increased BC risk (OR = 1.16, 95% CI 1.03-1.30, p = 0.014). According to tumor characteristics, the Lys/Lys genotype was associated with estrogen receptor (ER)-positive BC (OR = 1.19, 95% CI 1.05-1.36, p = 0.008), progesterone receptor (PR)-positive BC (OR = 1.19, 95% CI 1.03-1.36, p = 0.015), and human epidermal growth factor receptor 2 (HER2)-negative BC (OR = 1.25, 95% CI 1.05-1.48, p = 0.012). No evidence of a gene-environment interaction was observed between rs671 and alcohol intake (p = 0.537).This study suggests that the Lys/Lys genotype confers susceptibility to BC risk among women of Asian ancestry, particularly for ER-positive, PR-positive, and HER2-negative tumor types.

  View details for PubMedID 31066241

• Regular use of aspirin and other non-steroidal anti-inflammatory drugs and breast cancer risk for women at familial or genetic risk: a cohort study. Breast cancer research : BCR Kehm, R. D., Hopper, J. L., John, E. M., Phillips, K. A., MacInnis, R. J., Dite, G. S., Milne, R. L., Liao, Y. n., Zeinomar, N. n., Knight, J. A., Southey, M. C., Vahdat, L. n., Kornhauser, N. n., Cigler, T. n., Chung, W. K., Giles, G. G., McLachlan, S. A., Friedlander, M. L., Weideman, P. C., Glendon, G. n., Nesci, S. n., Andrulis, I. L., Buys, S. S., Daly, M. B., Terry, M. B. 2019; 21 (1): 52

  Abstract

  The use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced breast cancer risk, but it is not known if this association extends to women at familial or genetic risk. We examined the association between regular NSAID use and breast cancer risk using a large cohort of women selected for breast cancer family history, including 1054 BRCA1 or BRCA2 mutation carriers.We analyzed a prospective cohort (N = 5606) and a larger combined, retrospective and prospective, cohort (N = 8233) of women who were aged 18 to 79 years, enrolled before June 30, 2011, with follow-up questionnaire data on medication history. The prospective cohort was further restricted to women without breast cancer when medication history was asked by questionnaire. Women were recruited from seven study centers in the United States, Canada, and Australia. Associations were estimated using multivariable Cox proportional hazards regression models adjusted for demographics, lifestyle factors, family history, and other medication use. Women were classified as regular or non-regular users of aspirin, COX-2 inhibitors, ibuprofen and other NSAIDs, and acetaminophen (control) based on self-report at follow-up of ever using the medication for at least twice a week for ≥1 month prior to breast cancer diagnosis. The main outcome was incident invasive breast cancer, based on self- or relative-report (81% confirmed pathologically).From fully adjusted analyses, regular aspirin use was associated with a 39% and 37% reduced risk of breast cancer in the prospective (HR = 0.61; 95% CI = 0.33-1.14) and combined cohorts (HR = 0.63; 95% CI = 0.57-0.71), respectively. Regular use of COX-2 inhibitors was associated with a 61% and 71% reduced risk of breast cancer (prospective HR = 0.39; 95% CI = 0.15-0.97; combined HR = 0.29; 95% CI = 0.23-0.38). Other NSAIDs and acetaminophen were not associated with breast cancer risk in either cohort. Associations were not modified by familial risk, and consistent patterns were found by BRCA1 and BRCA2 carrier status, estrogen receptor status, and attained age.Regular use of aspirin and COX-2 inhibitors might reduce breast cancer risk for women at familial or genetic risk.

  View details for PubMedID 30999962

• Alcohol consumption, cigarette smoking, and familial breast cancer risk: findings from the Prospective Family Study Cohort (ProF-SC). Breast cancer research : BCR Zeinomar, N. n., Knight, J. A., Genkinger, J. M., Phillips, K. A., Daly, M. B., Milne, R. L., Dite, G. S., Kehm, R. D., Liao, Y. n., Southey, M. C., Chung, W. K., Giles, G. G., McLachlan, S. A., Friedlander, M. L., Weideman, P. C., Glendon, G. n., Nesci, S. n., Andrulis, I. L., Buys, S. S., John, E. M., MacInnis, R. J., Hopper, J. L., Terry, M. B. 2019; 21 (1): 128

  Abstract

  Alcohol consumption and cigarette smoking are associated with an increased risk of breast cancer (BC), but it is unclear whether these associations vary by a woman's familial BC risk.Using the Prospective Family Study Cohort, we evaluated associations between alcohol consumption, cigarette smoking, and BC risk. We used multivariable Cox proportional hazard models to estimate hazard ratios (HR) and 95% confidence intervals (CI). We examined whether associations were modified by familial risk profile (FRP), defined as the 1-year incidence of BC predicted by Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), a pedigree-based algorithm.We observed 1009 incident BC cases in 17,435 women during a median follow-up of 10.4 years. We found no overall association of smoking or alcohol consumption with BC risk (current smokers compared with never smokers HR 1.02, 95% CI 0.85-1.23; consuming ≥ 7 drinks/week compared with non-regular drinkers HR 1.10, 95% CI 0.92-1.32), but we did observe differences in associations based on FRP and by estrogen receptor (ER) status. Women with lower FRP had an increased risk of ER-positive BC associated with consuming ≥ 7 drinks/week (compared to non-regular drinkers), whereas there was no association for women with higher FRP. For example, women at the 10th percentile of FRP (5-year BOADICEA = 0.15%) had an estimated HR of 1.46 (95% CI 1.07-1.99), whereas there was no association for women at the 90th percentile (5-year BOADICEA = 4.2%) (HR 1.07, 95% CI 0.80-1.44). While the associations with smoking were not modified by FRP, we observed a positive multiplicative interaction by FRP (pinteraction = 0.01) for smoking status in women who also consumed alcohol, but not in women who were non-regular drinkers.Moderate alcohol intake was associated with increased BC risk, particularly for women with ER-positive BC, but only for those at lower predicted familial BC risk (5-year BOADICEA < 1.25). For women with a high FRP (5-year BOADICEA ≥ 6.5%) who also consumed alcohol, being a current smoker was associated with increased BC risk.

  View details for DOI 10.1186/s13058-019-1213-1

  View details for PubMedID 31779655

• Re-evaluating genetic variants identified in candidate gene studies of breast cancer risk using data from nearly 280,000 women of Asian and European ancestry. EBioMedicine Yang, Y. n., Shu, X. n., Shu, X. O., Bolla, M. K., Kweon, S. S., Cai, Q. n., Michailidou, K. n., Wang, Q. n., Dennis, J. n., Park, B. n., Matsuo, K. n., Kwong, A. n., Park, S. K., Wu, A. H., Teo, S. H., Iwasaki, M. n., Choi, J. Y., Li, J. n., Hartman, M. n., Shen, C. Y., Muir, K. n., Lophatananon, A. n., Li, B. n., Wen, W. n., Gao, Y. T., Xiang, Y. B., Aronson, K. J., Spinell, J. J., Gago-Dominguez, M. n., John, E. M., Kurian, A. W., Chang-Claude, J. n., Chen, S. T., Dörk, T. n., Evans, D. G., Schmidt, M. K., Shin, M. H., Giles, G. G., Milne, R. L., Simard, J. n., Kubo, M. n., Kraft, P. n., Kang, D. n., Easton, D. F., Zheng, W. n., Long, J. n. 2019

  Abstract

  We previously conducted a systematic field synopsis of 1059 breast cancer candidate gene studies and investigated 279 genetic variants, 51 of which showed associations. The major limitation of this work was the small sample size, even pooling data from all 1059 studies. Thereafter, genome-wide association studies (GWAS) have accumulated data for hundreds of thousands of subjects. It's necessary to re-evaluate these variants in large GWAS datasets.Of these 279 variants, data were obtained for 228 from GWAS conducted within the Asian Breast Cancer Consortium (24,206 cases and 24,775 controls) and the Breast Cancer Association Consortium (122,977 cases and 105,974 controls of European ancestry). Meta-analyses were conducted to combine the results from these two datasets.Of those 228 variants, an association was observed for 12 variants in 10 genes at a Bonferroni-corrected threshold of P < 2·19 × 10-4. The associations for four variants reached P < 5 × 10-8 and have been reported by previous GWAS, including rs6435074 and rs6723097 (CASP8), rs17879961 (CHEK2) and rs2853669 (TERT). The remaining eight variants were rs676387 (HSD17B1), rs762551 (CYP1A2), rs1045485 (CASP8), rs9340799 (ESR1), rs7931342 (CHR11), rs1050450 (GPX1), rs13010627 (CASP10) and rs9344 (CCND1). Further investigating these 10 genes identified associations for two additional variants at P < 5 × 10-8, including rs4793090 (near HSD17B1), and rs9210 (near CYP1A2), which have not been identified by previous GWAS.Though most candidate gene variants were not associated with breast cancer risk, we found 14 variants showing an association. Our findings warrant further functional investigation of these variants. FUND: National Institutes of Health.

  View details for DOI 10.1016/j.ebiom.2019.09.006

  View details for PubMedID 31629678

• Race/ethnicity and accuracy of self-reported female first-degree family history of breast and other cancers in the Northern California Breast Cancer Family Registry. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology John, E. M., Canchola, A. J., Sanagaramoorthy, M. n., Koo, J. n., Whittemore, A. S., West, D. W. 2019

  Abstract

  Few studies have evaluated accuracy of self-reported family history of breast and other cancers in racial/ethnic minorities.We assessed the accuracy of cancer family history reports by women with breast cancer (probands) from the Northern California Breast Cancer Family Registry compared to two reference standards: personal cancer history reports by female first-degree relatives and California Cancer Registry records.Probands reported breast cancer in first-degree relatives with high accuracy, but accuracy was lower for other cancers. Sensitivity (% correctly identifying relatives with cancer) was 93% (95% CI, 89.5-95.4) when compared to the relatives' self-report of breast cancer as the reference standard and varied little by proband race/ethnicity and other demographic factors, except for marginally lower sensitivity for Hispanic white probands (87.3%, 95% CI, 78.0-93.1, P=0.07) than non-Hispanic white probands (95.1%, 95% CI=88.9-98.0). Accuracy was also high when compared to cancer registry records as the reference standard, with a sensitivity of 95.5% (95% CI, 93.4-96.9) for breast cancer, but lower sensitivity for Hispanic white probands (91.2%, 95% CI, 84.4-95.2, P=0.05) and probands with low English language proficiency (80%, 95% CI, 52.8-93.5, P <0.01).Non-Hispanic white, African American, and Asian American probands reported first-degree breast cancer family history with high accuracy, although sensitivity was lower for Hispanic white probands and those with low English language proficiency.Self-reported family history of breast cancer in first-degree relatives is highly accurate and can be used as a reliable standard when other validation methods are not available.

  View details for DOI 10.1158/1055-9965.EPI-19-0444

  View details for PubMedID 31488412

• Surveillance of cancer among sexual and gender minority populations: Where are we and where do we need to go? Cancer Gomez, S. L., Duffy, C. n., Griggs, J. J., John, E. M. 2019

  View details for DOI 10.1002/cncr.32384

  View details for PubMedID 31593334

• CYP2D6 phenotype, tamoxifen, and risk of contralateral breast cancer in the WECARE Study. Breast cancer research : BCR Brooks, J. D., Comen, E. A., Reiner, A. S., Orlow, I., Leong, S. F., Liang, X., Mellemkjar, L., Knight, J. A., Lynch, C. F., John, E. M., Bernstein, L., Woods, M., Doody, D. R., WECARE Study collaborative group, Malone, K. E., Bernstein, J. L., Bernstein, J. L., Capanu, M., Liang, X., Orlow, I., Reiner, A. S., Robson, M., Woods, M., Bernstein, L., Boice, J. D., Brooks, J. D., Concannon, P., Conti, D. V., Duggan, D., Elena, J. W., Haile, R. W., John, E. M., Knight, J. A., Lynch, C. F., Malone, K. E., Mellemkjar, L., Olsen, J. H., Seminara, D., Shore, R. E., Stovall, M., Stram, D. O., Tischkowitz, M., Thomas, D. C., Blackmore, K., Diep, A. T., Goldstein, J., Harris, I., Langballe, R., O'Brien, C., Smith, S., Weathers, R., West, M. 2018; 20 (1): 149

  Abstract

  BACKGROUND: Tamoxifen treatment greatly reduces a woman's risk of developing a second primary breast cancer. There is, however, substantial variability in treatment response, some of which may be attributed to germline genetic variation. CYP2D6 is a key enzyme in the metabolism of tamoxifen to its active metabolites, and variants in this gene have been associated with reduced tamoxifen metabolism. The impact of variation on risk of contralateral breast cancer (CBC) is unknown.METHODS: Germline DNA from 1514 CBC cases and 2203 unilateral breast cancer controls was genotyped for seven single nucleotide polymorphisms, one three-nucleotide insertion-deletion, and a full gene deletion. Each variant has an expected impact on enzyme activity, which in combination allows for the classification of women as extensive, intermediate, and poor metabolizers (EM, IM, and PM respectively). Each woman was assigned one of six possible diplotypes and a corresponding CYP2D6 activity score (AS): EM/EM (AS=2), EM/IM (AS=1.5), EM/PM (AS=1), IM/IM (AS=0.75), IM/PM (AS=0.5), and PM/PM (AS=0). We also collapsed categories of the AS to generate an overall phenotype (EM, AS ≥ 1; IM, AS=0.5-0.75; PM, AS=0). Rate ratios (RRs) and 95% confidence intervals (CIs) for the association between tamoxifen treatment and risk of CBC in our study population were estimated using conditional logistic regression, stratified by AS.RESULTS: Among women with AS ≥ 1 (i.e., EM), tamoxifen treatment was associated with a 20-55% reduced RR of CBC (AS=2, RR=-0.81, 95% CI 0.62-1.06; AS=1.5, RR=0.45, 95% CI 0.30-0.68; and AS=1, RR=0.55, 95% CI 0.40-0.74). Among women with no EM alleles and at least one PM allele (i.e., IM and PM), tamoxifen did not appear to impact the RR of CBC in this population (AS=0.5, RR=1.08, 95% CI 0.59-1.96; and AS=0, RR=1.17, 95% CI 0.58-2.35) (p for homogeneity=-0.02).CONCLUSION: This study suggests that the CYP2D6 phenotype may contribute to some of the observed variability in the impact of tamoxifen treatment for a first breast cancer on risk of developing CBC.

  View details for PubMedID 30526633

• CYP2D6 phenotype, tamoxifen, and risk of contralateral breast cancer in the WECARE Study BREAST CANCER RESEARCH Brooks, J. D., Comen, E. A., Reiner, A. S., Orlow, I., Leong, S. F., Liang, X., Mellemkjaer, L., Knight, J. A., Lynch, C. F., John, E. M., Bernstein, L., Woods, M., Doody, D. R., Malone, K. E., Bernstein, J. L., WECARE Study Collaborative Grp 2018; 20

  View details for DOI 10.1186/s13058-018-1083-y

  View details for Web of Science ID 000452613900001

• Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes. American journal of human genetics Mavaddat, N., Michailidou, K., Dennis, J., Lush, M., Fachal, L., Lee, A., Tyrer, J. P., Chen, T., Wang, Q., Bolla, M. K., Yang, X., Adank, M. A., Ahearn, T., Aittomaki, K., Allen, J., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Arndt, V., Aronson, K. J., Auer, P. L., Auvinen, P., Barrdahl, M., Beane Freeman, L. E., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bernstein, L., Blomqvist, C., Bogdanova, N. V., Bojesen, S. E., Bonanni, B., Borresen-Dale, A., Brauch, H., Bremer, M., Brenner, H., Brentnall, A., Brock, I. W., Brooks-Wilson, A., Brucker, S. Y., Bruning, T., Burwinkel, B., Campa, D., Carter, B. D., Castelao, J. E., Chanock, S. J., Chlebowski, R., Christiansen, H., Clarke, C. L., Collee, J. M., Cordina-Duverger, E., Cornelissen, S., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Daly, M. B., Devilee, P., Dork, T., Dos-Santos-Silva, I., Dumont, M., Durcan, L., Dwek, M., Eccles, D. M., Ekici, A. B., Eliassen, A. H., Ellberg, C., Engel, C., Eriksson, M., Evans, D. G., Fasching, P. A., Figueroa, J., Fletcher, O., Flyger, H., Forsti, A., Fritschi, L., Gabrielson, M., Gago-Dominguez, M., Gapstur, S. M., Garcia-Saenz, J. A., Gaudet, M. M., Georgoulias, V., Giles, G. G., Gilyazova, I. R., Glendon, G., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Grenaker Alnas, G. I., Grip, M., Gronwald, J., Grundy, A., Guenel, P., Haeberle, L., Hahnen, E., Haiman, C. A., Hakansson, N., Hamann, U., Hankinson, S. E., Harkness, E. F., Hart, S. N., He, W., Hein, A., Heyworth, J., Hillemanns, P., Hollestelle, A., Hooning, M. J., Hoover, R. N., Hopper, J. L., Howell, A., Huang, G., Humphreys, K., Hunter, D. J., Jakimovska, M., Jakubowska, A., Janni, W., John, E. M., Johnson, N., Jones, M. E., Jukkola-Vuorinen, A., Jung, A., Kaaks, R., Kaczmarek, K., Kataja, V., Keeman, R., Kerin, M. J., Khusnutdinova, E., Kiiski, J. I., Knight, J. A., Ko, Y., Kosma, V., Koutros, S., Kristensen, V. N., Kruger, U., Kuhl, T., Lambrechts, D., Le Marchand, L., Lee, E., Lejbkowicz, F., Lilyquist, J., Lindblom, A., Lindstrom, S., Lissowska, J., Lo, W., Loibl, S., Long, J., Lubinski, J., Lux, M. P., MacInnis, R. J., Maishman, T., Makalic, E., Maleva Kostovska, I., Mannermaa, A., Manoukian, S., Margolin, S., Martens, J. W., Martinez, M. E., Mavroudis, D., McLean, C., Meindl, A., Menon, U., Middha, P., Miller, N., Moreno, F., Mulligan, A. M., Mulot, C., Munoz-Garzon, V. M., Neuhausen, S. L., Nevanlinna, H., Neven, P., Newman, W. G., Nielsen, S. F., Nordestgaard, B. G., Norman, A., Offit, K., Olson, J. E., Olsson, H., Orr, N., Pankratz, V. S., Park-Simon, T., Perez, J. I., Perez-Barrios, C., Peterlongo, P., Peto, J., Pinchev, M., Plaseska-Karanfilska, D., Polley, E. C., Prentice, R., Presneau, N., Prokofyeva, D., Purrington, K., Pylkas, K., Rack, B., Radice, P., Rau-Murthy, R., Rennert, G., Rennert, H. S., Rhenius, V., Robson, M., Romero, A., Ruddy, K. J., Ruebner, M., Saloustros, E., Sandler, D. P., Sawyer, E. J., Schmidt, D. F., Schmutzler, R. K., Schneeweiss, A., Schoemaker, M. J., Schumacher, F., Schurmann, P., Schwentner, L., Scott, C., Scott, R. J., Seynaeve, C., Shah, M., Sherman, M. E., Shrubsole, M. J., Shu, X., Slager, S., Smeets, A., Sohn, C., Soucy, P., Southey, M. C., Spinelli, J. J., Stegmaier, C., Stone, J., Swerdlow, A. J., Tamimi, R. M., Tapper, W. J., Taylor, J. A., Terry, M. B., Thone, K., Tollenaar, R. A., Tomlinson, I., Truong, T., Tzardi, M., Ulmer, H., Untch, M., Vachon, C. M., van Veen, E. M., Vijai, J., Weinberg, C. R., Wendt, C., Whittemore, A. S., Wildiers, H., Willett, W., Winqvist, R., Wolk, A., Yang, X. R., Yannoukakos, D., Zhang, Y., Zheng, W., Ziogas, A., ABCTB Investigators, kConFab/AOCS Investigators, NBCS Collaborators, Dunning, A. M., Thompson, D. J., Chenevix-Trench, G., Chang-Claude, J., Schmidt, M. K., Hall, P., Milne, R. L., Pharoah, P. D., Antoniou, A. C., Chatterjee, N., Kraft, P., Garcia-Closas, M., Simard, J., Easton, D. F. 2018

  Abstract

  Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

  View details for PubMedID 30554720

• Risk-Reducing Oophorectomy and Breast Cancer Risk Across the Spectrum of Familial Risk. Journal of the National Cancer Institute Terry, M. B., Daly, M. B., Phillips, K. A., Ma, X., Zeinomar, N., Leoce, N., Dite, G. S., MacInnis, R. J., Chung, W. K., Knight, J. A., Southey, M. C., Milne, R. L., Goldgar, D., Giles, G. G., Weideman, P. C., Glendon, G., kConFab Investigators, Buchsbaum, R., Andrulis, I. L., John, E. M., Buys, S. S., Hopper, J. L. 2018

  Abstract

  There remains debate about whether risk-reducing salpingo-oophorectomy (RRSO), which reduces ovarian cancer risk, also reduces breast cancer risk. We examined the association between RRSO and breast cancer risk using a prospective cohort of 17917 women unaffected with breast cancer at baseline (7.2% known carriers of BRCA1 or BRCA2 mutations). During a median follow-up of 10.7years, 1046 women were diagnosed with incident breast cancer. Modeling RRSO as a time-varying exposure, there was no association with breast cancer risk overall (hazard ratio [HR] = 1.04, 95% confidence interval [CI]=0.87 to 1.24) or by tertiles of predicted absolute risk based on family history (HR=0.68, 95% CI=0.32 to 1.47, HR=0.94, 95% CI=0.70 to 1.26, and HR=1.10, 95% CI=0.88 to 1.39, for lowest, middle, and highest tertile of risk, respectively) or for BRCA1 and BRCA2 mutation carriers when examined separately. There was also no association after accounting for hormone therapy use after RRSO. These findings suggest that RRSO should not be considered efficacious for reducing breast cancer risk.

  View details for PubMedID 30496449

• Germline variation at 8q24 and prostate cancer risk in men of European ancestry. Nature communications Matejcic, M., Saunders, E. J., Dadaev, T., Brook, M. N., Wang, K., Sheng, X., Olama, A. A., Schumacher, F. R., Ingles, S. A., Govindasami, K., Benlloch, S., Berndt, S. I., Albanes, D., Koutros, S., Muir, K., Stevens, V. L., Gapstur, S. M., Tangen, C. M., Batra, J., Clements, J., Gronberg, H., Pashayan, N., Schleutker, J., Wolk, A., West, C., Mucci, L., Kraft, P., Cancel-Tassin, G., Sorensen, K. D., Maehle, L., Grindedal, E. M., Strom, S. S., Neal, D. E., Hamdy, F. C., Donovan, J. L., Travis, R. C., Hamilton, R. J., Rosenstein, B., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Bensen, J. T., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R., Usmani, N., Claessens, F., Townsend, P. A., Dominguez, M. G., Roobol, M. J., Menegaux, F., Khaw, K., Cannon-Albright, L. A., Pandha, H., Thibodeau, S. N., Schaid, D. J., PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, Wiklund, F., Chanock, S. J., Easton, D. F., Eeles, R. A., Kote-Jarai, Z., Conti, D. V., Haiman, C. A., Henderson, B. E., Stern, M. C., Thwaites, A., Guy, M., Whitmore, I., Morgan, A., Fisher, C., Hazel, S., Livni, N., Cook, M., Fachal, L., Weinstein, S., Beane Freeman, L. E., Hoover, R. N., Machiela, M. J., Lophatananon, A., Carter, B. D., Goodman, P., Moya, L., Srinivasan, S., Kedda, M., Yeadon, T., Eckert, A., Eklund, M., Cavalli-Bjoerkman, C., Dunning, A. M., Sipeky, C., Hakansson, N., Elliott, R., Ranu, H., Giovannucci, E., Turman, C., Hunter, D. J., Cussenot, O., Orntoft, T. F., Lane, A., Lewis, S. J., Davis, M., Key, T. J., Brown, P., Kulkarni, G. S., Zlotta, A. R., Fleshner, N. E., Finelli, A., Mao, X., Marzec, J., MacInnis, R. J., Milne, R., Hopper, J. L., Aguado, M., Bustamante, M., Castano-Vinyals, G., Gracia-Lavedan, E., Cecchini, L., Stampfer, M., Ma, J., Sellers, T. A., Geybels, M. S., Park, H., Zachariah, B., Kolb, S., Wokolorczyk, D., Jan Lubinski, Kluzniak, W., Nielsen, S. F., Weisher, M., Cuk, K., Vogel, W., Luedeke, M., Logothetis, C. J., Paulo, P., Cardoso, M., Maia, S., Silva, M. P., Steele, L., Ding, Y. C., De Meerleer, G., De Langhe, S., Thierens, H., Lim, J., Tan, M. H., Ong, A. T., Lin, D. W., Kachakova, D., Mitkova, A., Mitev, V., Parliament, M., Jenster, G., Bangma, C., Schroder, F. H., Truong, T., Koudou, Y. A., Michael, A., Kierzek, A., Karlsson, A., Broms, M., Wu, H., Aukim-Hastie, C., Tillmans, L., Riska, S., McDonnell, S. K., Dearnaley, D., Spurdle, A., Gardiner, R., Hayes, V., Butler, L., Taylor, R., Papargiris, M., Saunders, P., Kujala, P., Talala, K., Taari, K., Bentzen, S., Hicks, B., Vogt, A., Hutchinson, A., Cox, A., George, A., Toi, A., Evans, A., van der Kwast, T. H., Imai, T., Saito, S., Zhao, S., Ren, G., Zhang, Y., Yu, Y., Wu, Y., Wu, J., Zhou, B., Pedersen, J., Lobato-Busto, R., Ruiz-Dominguez, J. M., Mengual, L., Alcaraz, A., Pow-Sang, J., Herkommer, K., Vlahova, A., Dikov, T., Christova, S., Carracedo, A., Tretarre, B., Rebillard, X., Mulot, C., Jan Adolfsson, Stattin, P., Johansson, J., Martin, R. M., Thompson, I. M., Chambers, S., Aitken, J., Horvath, L., Haynes, A., Tilley, W., Risbridger, G., Aly, M., Nordstrom, T., Pharoah, P., Tammela, T. L., Murtola, T., Auvinen, A., Burnet, N., Barnett, G., Andriole, G., Klim, A., Drake, B. F., Borre, M., Kerns, S., Ostrer, H., Zhang, H., Cao, G., Lin, J., Ling, J., Li, M., Feng, N., Li, J., He, W., Guo, X., Sun, Z., Wang, G., Guo, J., Southey, M. C., FitzGerald, L. M., Marsden, G., Gomez-Caamano, A., Carballo, A., Peleteiro, P., Calvo, P., Szulkin, R., Llorca, J., Dierssen-Sotos, T., Gomez-Acebo, I., Lin, H., Ostrander, E. A., Bisbjerg, R., Klarskov, P., Roder, M. A., Iversen, P., Holleczek, B., Stegmaier, C., Schnoeller, T., Bohnert, P., John, E. M., Ost, P., Teo, S., Gamulin, M., Kulis, T., Kastelan, Z., Slavov, C., Popov, E., Van den Broeck, T., Joniau, S., Larkin, S., Castelao, J. E., Martinez, M. E., van Schaik, R. H., Xu, J., Lindstrom, S., Riboli, E., Berry, C., Siddiq, A., Canzian, F., Kolonel, L. N., Le Marchand, L., Freedman, M., Cenee, S., Sanchez, M. 2018; 9 (1): 4616

  Abstract

  Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p<4.28*10-15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI=3.62-4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.

  View details for PubMedID 30397198

• Germline variation at 8q24 and prostate cancer risk in men of European ancestry NATURE COMMUNICATIONS Matejcic, M., Saunders, E. J., Dadaev, T., Brook, M. N., Wang, K., Sheng, X., Al Olama, A., Schumacher, F. R., Ingles, S. A., Govindasami, K., Benlloch, S., Berndt, S., Albanes, D., Koutros, S., Muir, K., Stevens, V. L., Gapstur, S. M., Tangen, C. M., Batra, J., Clements, J., Gronberg, H., Pashayan, N., Schleutker, J., Wolk, A., West, C., Mucci, L., Kraft, P., Cancel-Tassin, G., Sorensen, K. D., Maehle, L., Grindedal, E. M., Strom, S. S., Neal, D. E., Hamdy, F. C., Donovan, J. L., Travis, R. C., Hamilton, R. J., Rosenstein, B., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Bensen, J. T., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., Teixeira, M. R., Neuhausen, S. L., De Ruyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R., Usmani, N., Claessens, F., Townsend, P. A., Dominguez, M. G., Roobol, M. J., Menegaux, F., Khaw, K., Cannon-Albright, L. A., Pandha, H., Thibodeau, S. N., Schaid, D. J., Wiklund, F., Chanock, S. J., Easton, D. F., Eeles, R. A., Kote-Jarai, Z., Conti, D., Haiman, C. A., PRACTICAL Consortium 2018; 9

  View details for DOI 10.1038/s41467-018-06863-1

  View details for Web of Science ID 000449269700006

• Age-specific breast cancer risk by body mass index and familial risk: prospective family study cohort (ProF-SC). Breast cancer research : BCR Hopper, J. L., Dite, G. S., MacInnis, R. J., Liao, Y., Zeinomar, N., Knight, J. A., Southey, M. C., Milne, R. L., Chung, W. K., Giles, G. G., Genkinger, J. M., McLachlan, S., Friedlander, M. L., Antoniou, A. C., Weideman, P. C., Glendon, G., Nesci, S., kConFab Investigators, Andrulis, I. L., Buys, S. S., Daly, M. B., John, E. M., Phillips, K. A., Terry, M. B. 2018; 20 (1): 132

  Abstract

  BACKGROUND: The association between body mass index (BMI) and risk of breast cancer depends on time of life, but it is unknown whether this association depends on a woman's familial risk.METHODS: We conducted a prospective study of a cohort enriched for familial risk consisting of 16,035 women from 6701 families in the Breast Cancer Family Registry and the Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer followed for up to 20years (mean 10.5years). There were 896 incident breast cancers (mean age at diagnosis 55.7years). We used Cox regression to model BMI risk associations as a function of menopausal status, age, and underlying familial risk based on pedigree data using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), all measured at baseline.RESULTS: The strength and direction of the BMI risk association depended on baseline menopausal status (P<0.001); after adjusting for menopausal status, the association did not depend on age at baseline (P=0.6). In terms of absolute risk, the negative association with BMI for premenopausal women has a much smaller influence than the positive association with BMI for postmenopausal women. Women at higher familial risk have a much larger difference in absolute risk depending on their BMI than women at lower familial risk.CONCLUSIONS: The greater a woman's familial risk, the greater the influence of BMI on her absolute postmenopausal breast cancer risk. Given that age-adjusted BMI is correlated across adulthood, maintaining a healthy weight throughout adult life is particularly important for women with a family history of breast cancer.

  View details for PubMedID 30390716

• Age-specific breast cancer risk by body mass index and familial risk: prospective family study cohort (ProF-SC) BREAST CANCER RESEARCH Hopper, J. L., Dite, G. S., MacInnis, R. J., Liao, Y., Zeinomar, N., Knight, J. A., Southey, M. C., Milne, R. L., Chung, W. K., Giles, G. G., Genkinger, J. M., McLachlan, S., Friedlander, M. L., Antoniou, A. C., Weideman, P. C., Glendon, G., Nesci, S., Andrulis, I. L., Buys, S. S., Daly, M. B., John, E. M., Phillips, K., Terry, M., kConFab Investigators 2018; 20

  View details for DOI 10.1186/s13058-018-1056-1

  View details for Web of Science ID 000449279500001

• Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Adams, C., Richmond, R. C., Santos Ferreira, D. L., Spiller, W., Tan, V. Y., Zheng, J., Wurtz, P., Donovan, J. L., Hamdy, F. C., Neal, D. E., Lane, J. A., Davey Smith, G., Relton, C. L., Eeles, R. A., Henderson, B. E., Haiman, C. A., Kote-Jarai, Z., Schumacher, F. R., Amin Al Olama, A., Benlloch, S., Muir, K., Berndt, S. I., Conti, D. V., Wiklund, F., Chanock, S. J., Gapstur, S. M., Stevens, V. L., Tangen, C. M., Batra, J., Clements, J. A., Gronberg, H., Pashayan, N., Schleutker, J., Albanes, D., Wolk, A., West, C. M., Mucci, L. A., Cancel-Tassin, G., Koutros, S., Sorensen, K. D., Maehle, L., Travis, R. C., Hamilton, R., Ingles, S. A., Rosenstein, B. S., Lu, Y., Giles, G. G., Kibel, A. S., Vega, A., Kogevinas, M., Penney, K. L., Park, J. Y., Stanford, J. L., Cybulski, C., Nordestgaard, B. G., Brenner, H., Maier, C., Kim, J., John, E. M., Teixeira, M. R., Neuhausen, S. L., DeRuyck, K., Razack, A., Newcomb, L. F., Lessel, D., Kaneva, R. P., Usmani, N., Claessens, F., Townsend, P., Gago Dominguez, M., Roobol, M. J., Menegaux, F., Khaw, K., Cannon-Albright, L. A., Pandha, H., Thibodeau, S. N., Martin, R. M. 2018

  Abstract

  BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR).MATERIALS AND METHODS: The case-control portion of the study was conducted in nine UK centres with men aged 50-69 years who underwent prostate-specific antigen (PSA) screening for prostate cancer within the Prostate testing for cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (p <0.0014, multiple-testing threshold). These fell into four classes: i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); ii) fatty acids and ratios; iii) amino acids; iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.

  View details for PubMedID 30352818

• Large-scale transcriptome-wide association study identifies new prostate cancer risk regions. Nature communications Mancuso, N., Gayther, S., Gusev, A., Zheng, W., Penney, K. L., Kote-Jarai, Z., Eeles, R., Freedman, M., Haiman, C., Pasaniuc, B. 2018; 9 (1): 4079

  Abstract

  Although genome-wide association studies (GWAS) for prostate cancer (PrCa) have identified more than 100 risk regions, most of the risk genes at these regions remain largely unknown. Here we integrate the largest PrCa GWAS (N = 142,392) with gene expression measured in 45 tissues (N = 4458), including normal and tumor prostate, to perform a multi-tissue transcriptome-wide association study (TWAS) for PrCa. We identify 217 genes at 84 independent 1 Mb regions associated with PrCa risk, 9 of which are regions with no genome-wide significant SNP within 2 Mb. 23 genes are significant in TWAS only for alternative splicing models in prostate tumor thus supporting the hypothesis of splicing driving risk for continued oncogenesis. Finally, we use a Bayesian probabilistic approach to estimate credible sets of genes containing the causal gene at a pre-defined level; this reduced the list of 217 associations to 109 genes in the 90% credible set. Overall, our findings highlight the power of integrating expression with PrCa GWAS to identify novel risk loci and prioritize putative causal genes at known risk loci.

  View details for DOI 10.1038/s41467-018-06302-1

  View details for PubMedID 30287866

  View details for PubMedCentralID PMC6172280

• Impact of individual and neighborhood factors on socioeconomic disparities in localized and advanced prostate cancer risk CANCER CAUSES & CONTROL DeRouen, M. C., Schupp, C. W., Yang, J., Koo, J., Hertz, A., Shariff-Marco, S., Cockburn, M., Nelson, D. O., Ingles, S. A., Cheng, I., John, E. M., Gomez, S. L. 2018; 29 (10): 951–66

  Abstract

  The reasons behind socio-economic disparities in prostate cancer incidence remain unclear. We tested the hypothesis that individual-level factors act jointly with neighborhood-level social and built environment factors to influence prostate cancer risk and that specific social and built environment factors contribute to socio-econmic differences in risk.We used multi-level data, combining individual-level data (including education and known prostate cancer risk factors) for prostate cancer cases (n = 775) and controls (n = 542) from the San Francisco Bay Area Prostate Cancer Study, a population-based case-control study, with contextual-level data on neighborhood socio-economic status (nSES) and specific social and built environment factors from the California Neighborhoods Data System. Multivariable logistic regression models were used to compute adjusted odds ratios separately for localized and advanced stage prostate cancer while controlling for neighborhood clustering.We found a more than twofold increased risk of both localized and advanced prostate cancer with increasing levels of nSES, and decreased risk of advanced prostate cancer with increasing levels of education. For localized disease, the nSES association was largely explained by known prostate cancer risk factors and specific neighborhood environment factors; population density, crowding, and residential mobility. For advanced disease, associations with education and nSES were not fully explained by any available individual- or neighborhood-level factors.These results demonstrate the importance of specific neighborhood social and built environment factors in understanding risk of localized prostate cancer. Further research is needed to understand the factors underpinning the associations between individual- and neighborhood-level SES and risk of advanced prostate cancer.

  View details for PubMedID 30136012

• The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations JNCI CANCER SPECTRUM Terry, M., Liao, Y., Kast, K., Antoniou, A. C., McDonald, J. A., Mooij, T. M., Engel, C., Nogues, C., Buecher, B., Mari, V., Moretta-Serra, J., Gladieff, L., Luporsi, E., Barrowdale, D., Frost, D., Henderson, A., Brewer, C., Evans, D., Eccles, D., Cook, J., Ong, K., Izatt, L., Ahmed, M., Morrison, P. J., Dommering, C. J., Oosterwijk, J. C., Ausems, M. M., Kriege, M., Buys, S. S., Andrulis, I. L., John, E. M., Daly, M., Friedlander, M., McLachlan, S., Osorio, A., Caldes, T., Jakubowska, A., Simard, J., Singer, C. F., Tan, Y., Olah, E., Navratilova, M., Foretova, L., Gerdes, A., Roos-Blom, M., Arver, B., Olsson, H., Schmutzler, R. K., Hopper, J. L., van Leeuwen, F. E., Goldgar, D., Milne, R. L., Easton, D. F., Rookus, M. A., Andrieu, N., Evans, G., Adlard, J., Eeles, R., Davidson, R., Tischkowitz, M., Snape, K., Walker, L., Porteous, M., Donaldson, A., Morrison, P., Eason, J., Rogers, M., Miller, C., Brady, A., Kennedy, M., Barwell, J., Gregory, H., Pottinger, C., Murray, A., Angelakos, M., Dite, G., Tsimiklis, H., Breysse, E., Pontois, P., Laborde, L., Stoppa-Lyonnet, D., Gauthier-Villars, M., Caron, O., Fourme-Mouret, E., Fricker, J., Lasset, C., Bonadona, V., Fert-Ferrer, S., Berthet, P., Venat-Bouvet, L., Gilbert-Dussardier, B., Faivre, L., Gesta, P., Sobol, H., Eisinger, F., Longy, M., Dugast, C., Coupier, I., Colas, C., Soubrier, F., Pujol, P., Corsini, C., Lortholary, A., Vennin, P., Adenis, C., Tan Dat Nguyen, Penet, C., Delnatte, C., Tinat, J., Tennevet, I., Limacher, J., Maugard, C., Demange, L., Dreyfus, H., Cohen-Haguenauer, O., Leroux, D., Zattara-Cannoni, H., Bera, O., Hogervorst, F. L., Adank, M. A., Schmidt, M. K., Russell, N. S., Jenner, D. J., Collee, J. M., van den Ouweland, A. W., Hooning, M. J., Seynaeve, C. M., van Deurzen, C. M., Obdeijn, I. M., van Asperen, C. J., Devilee, P., Kets, C. M., Mensenkamp, A. R., Koudijs, M. J., Aalfs, C. M., van Engelen, K., Gille, J. P., Gomez-Garcia, E. B., Blok, M. J., van der Hout, A. H., Mourits, M. J., de Bock, G. H., Siesling, S., Verloop, J., van den Belt-Dusebout, A. W., EMBRACE, GENEPSO, BCFR, HEBON, KConFab, IBCCS 2018; 2 (4): pky078

  Abstract

  Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers.Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, Ptrend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort Ptrend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98).These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers.

  View details for DOI 10.1093/jncics/pky078

  View details for Web of Science ID 000495718900033

  View details for PubMedID 30873510

  View details for PubMedCentralID PMC6405439

• Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma NATURE COMMUNICATIONS Went, M., Sud, A., Forsti, A., Halvarsson, B., Weinhold, N., Kimber, S., van Duin, M., Thorleifsson, G., Holroydl, A., Johnson, D. C., Li, N., Orlando, G., Law, P. J., Ali, M., Chen, B., Mitchell, J. S., Gudbjartsson, D. F., Kuiper, R., Stephens, O. W., Bertsch, U., Broderick, P., Campo, C., Bandapalli, O. R., Einsele, H., Gregory, W. A., Gullberg, U., Hillengass, J., Hoffmann, P., Jackson, G. H., Joeckel, K., Johnsson, E., Kristinsson, S. Y., Mellqvist, U., Nahi, H., Easton, D., Pharoah, P., Dunning, A., Peto, J., Canzian, F., Swerdlow, A., Eeles, R. A., Kote-Jarai, Z. S., Muir, K., Pashayan, N., Nickel, J., Noethen, M. M., Rafnar, T., Ross, F. M., Filho, M., Thomsen, H., Turesson, I., Vangsted, A., Andersen, N., Waage, A., Walker, B. A., Wihlborg, A., Broyl, A., Davies, F. E., Thorsteinsdottir, U., Langer, C., Hansson, M., Goldschmidt, H., Kaiser, M., Sonneveld, P., Stefansson, K., Morgans, G. J., Hemminki, K., Nilsson, B., Houlston, R. S., PRACTICAL Consortium 2018; 9: 3707

  Abstract

  Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM.

  View details for DOI 10.1038/s41467-018-04989-w

  View details for Web of Science ID 000444493600001

  View details for PubMedID 30213928

  View details for PubMedCentralID PMC6137048

• Germline Variation and Breast Cancer Incidence: A Gene-Based Association Study and Whole-Genome Prediction of Early-Onset Breast Cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Bryan, M., Argos, M., Andrulis, I. L., Hopper, J. L., Chang-Claude, J., Malone, K. E., John, E. M., Gammon, M. D., Daly, M. B., Terry, M., Buys, S. S., Huo, D., Olopade, O. I., Genkinger, J. M., Whittemore, A. S., Jasmine, F., Kibriya, M. G., Chen, L. S., Ahsan, H. 2018; 27 (9): 1057–64

  Abstract

  Background: Although germline genetics influences breast cancer incidence, published research only explains approximately half of the expected association. Moreover, the accuracy of prediction models remains low. For women who develop breast cancer early, the genetic architecture is less established.Methods: To identify loci associated with early-onset breast cancer, gene-based tests were carried out using exome array data from 3,479 women with breast cancer diagnosed before age 50 and 973 age-matched controls. Replication was undertaken in a population that developed breast cancer at all ages of onset.Results: Three gene regions were associated with breast cancer incidence: FGFR2 (P = 1.23 × 10-5; replication P < 1.00 × 10-6), NEK10 (P = 3.57 × 10-4; replication P < 1.00 × 10-6), and SIVA1 (P = 5.49 × 10-4; replication P < 1.00 × 10-6). Of the 151 gene regions reported in previous literature, 19 (12.5%) showed evidence of association (P < 0.05) with the risk of early-onset breast cancer in the early-onset population. To predict incidence, whole-genome prediction was implemented on a subset of 3,076 participants who were additionally genotyped on a genome wide array. The whole-genome prediction outperformed a polygenic risk score [AUC, 0.636; 95% confidence interval (CI), 0.614-0.659 compared with 0.601; 95% CI, 0.578-0.623], and when combined with known epidemiologic risk factors, the AUC rose to 0.662 (95% CI, 0.640-0.684).Conclusions: This research supports a role for variation within FGFR2 and NEK10 in breast cancer incidence, and suggests SIVA1 as a novel risk locus.Impact: This analysis supports a shared genetic etiology between women with early- and late-onset breast cancer, and suggests whole-genome data can improve risk assessment. Cancer Epidemiol Biomarkers Prev; 27(9); 1057-64. ©2018 AACR.

  View details for PubMedID 29898891

• A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer NATURE GENETICS Wu, L., Shi, W., Long, J., Guo, X., Michailidou, K., Beesley, J., Bolla, M. K., Shu, X., Lu, Y., Cai, Q., Al-Ejeh, F., Rozali, E., Wang, Q., Dennis, J., Li, B., Zeng, C., Feng, H., Gusev, A., Barfield, R. T., Andrulis, I. L., Anton-Culver, H., Arndt, V., Aronson, K. J., Auer, P. L., Barrdahl, M., Baynes, C., Beckmann, M. W., Benitez, J., Bermisheva, M., Blomqvist, C., Bogdanova, N. V., Bojesen, S. E., Brauch, H., Brenner, H., Brinton, L., Broberg, P., Brucker, S. Y., Burwinkel, B., Caldes, T., Canzian, F., Carter, B. D., Castelao, J., Chang-Claude, J., Chen, X., Cheng, T., Christiansen, H., Clarke, C. L., Collee, M., Cornelissen, S., Couch, F. J., Cox, D., Cox, A., Cross, S. S., Cunningham, J. M., Czene, K., Daly, M. B., Devilee, P., Doheny, K. F., Dork, T., dos-Santos-Silva, I., Dumont, M., Dwek, M., Eccles, D. M., Eilber, U., Eliassen, A., Engel, C., Eriksson, M., Fachal, L., Fasching, P. A., Figueroa, J., Flesch-Janys, D., Fletcher, O., Flyger, H., Fritschi, L., Gabrielson, M., Gago-Dominguez, M., Gapstur, S. M., Garcia-Closas, M., Gaudet, M. M., Ghoussaini, M., Giles, G. G., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Guenel, P., Hahnen, E., Haiman, C. A., Hakansson, N., Hall, P., Hallberg, E., Hamann, U., Harrington, P., Hein, A., Hicks, B., Hillemanns, P., Hollestelle, A., Hoover, R. N., Hopper, J. L., Huang, G., Humphreys, K., Hunter, D. J., Jakubowska, A., Janni, W., John, E. M., Johnson, N., Jones, K., Jones, M. E., Jung, A., Kaaks, R., Kerin, M. J., Khusnutdinova, E., Kosma, V., Kristensen, V. N., Lambrechts, D., Le Marchand, L., Li, J., Lindstrom, S., Lissowska, J., Lo, W., Loibl, S., Lubinski, J., Luccarini, C., Lux, M. P., MacInnis, R. J., Maishman, T., Kostovska, I., Mannermaa, A., Manson, J. E., Margolin, S., Mavroudis, D., Meijers-Heijboer, H., Meindl, A., Menon, U., Meyer, J., Mulligan, A., Neuhausen, S. L., Nevanlinna, H., Neven, P., Nielsen, S. F., Nordestgaard, B. G., Olopade, O. I., Olson, J. E., Olsson, H., Peterlongo, P., Peto, J., Plaseska-Karanfilska, D., Prentice, R., Presneau, N., Pylkas, K., Rack, B., Radice, P., Rahman, N., Rennert, G., Rennert, H. S., Rhenius, V., Romero, A., Romm, J., Rudolph, A., Saloustros, E., Sandler, D. P., Sawyer, E. J., Schmidt, M. K., Schmutzler, R. K., Schneeweiss, A., Scott, R. J., Scott, C. G., Seal, S., Shah, M., Shrubsole, M. J., Smeets, A., Southey, M. C., Spinelli, J. J., Stone, J., Surowy, H., Swerdlow, A. J., Tamimi, R. M., Tapper, W., Taylor, J. A., Terry, M., Tessier, D. C., Thomas, A., Thone, K., Tollenaar, R. M., Torres, D., Truong, T., Untch, M., Vachon, C., Van den Berg, D., Vincent, D., Waisfisz, Q., Weinberg, C. R., Wendt, C., Whittemore, A. S., Wildiers, H., Willett, W. C., Winqvist, R., Wolk, A., Xia, L., Yang, X. R., Ziogas, A., Ziv, E., Dunning, A. M., Pharoah, P. P., Simard, J., Milne, R. L., Edwards, S. L., Kraft, P., Easton, D. F., Chenevix-Trench, G., Zheng, W., NBCS Collaborators, kConFab AOCS Investigators 2018; 50 (7): 968-+

  Abstract

  The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

  View details for PubMedID 29915430

• Racial/ethnic disparities in breast cancer risk associated with body size. John, E. M. AMER ASSOC CANCER RESEARCH. 2018: 41–42

  View details for Web of Science ID 000437526000031

• Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci NATURE GENETICS Schumacher, F. R., Al Olama, A., Berndt, S. I., Benlloch, S., Ahmed, M., Saunders, E. J., Dadaev, T., Leongamornlert, D., Anokian, E., Cieza-Borrella, C., Goh, C., Brook, M. N., Sheng, X., Fachal, L., Dennis, J., Tyrer, J., Muir, K., Lophatananon, A., Stevens, V. L., Gapstur, S. M., Carter, B. D., Tangen, C. M., Goodman, P. J., Thompson, I. M., Batra, J., Chambers, S., Moya, L., Clements, J., Horvath, L., Tilley, W., Risbridger, G. P., Gronberg, H., Aly, M., Nordstrom, T., Pharoah, P., Pashayan, N., Schleutker, J., Tammela, T. J., Sipeky, C., Auvinen, A., Albanes, D., Weinstein, S., Wolk, A., Hakansson, N., West, C. L., Dunning, A. M., Burnet, N., Mucci, L. A., Giovannucci, E., Andriole, G. L., Cussenot, O., Cancel-Tassin, G., Koutros, S., Freeman, L., Sorensen, K., Orntoft, T., Borre, M., Maehle, L., Grindedal, E., Neal, D. E., Donovan, J. L., Hamdy, F. C., Martin, R. M., Travis, R. C., Key, T. J., Hamilton, R. J., Fleshner, N. E., Finelli, A., Ingles, S., Stern, M. C., Rosenstein, B. S., Kerns, S. L., Ostrer, H., Lu, Y., Zhang, H., Feng, N., Mao, X., Guo, X., Wang, G., Sun, Z., Giles, G. G., Southey, M. C., MacInnis, R. J., FitzGerald, L. M., Kibel, A. S., Drake, B. F., Vega, A., Gomez-Caamano, A., Szulkin, R., Eklund, M., Kogevinas, M., Llorca, J., Castano-Vinyals, G., Penney, K. L., Stampfer, M., Park, J. Y., Sellers, T. A., Lin, H., Stanford, J. L., Cybulski, C., Wokolorczyk, D., Lubinski, J., Ostrander, E. A., Geybels, M. S., Nordestgaard, B. G., Nielsen, S. F., Weischer, M., Bisbjerg, R., Roder, M., Iversen, P., Brenner, H., Cuk, K., Holleczek, B., Maier, C., Luedeke, M., Schnoeller, T., Kim, J., Logothetis, C. J., John, E. M., Teixeira, M. R., Paulo, P., Cardoso, M., Neuhausen, S. L., Steele, L., Ding, Y., De Ruyck, K., De Meerleer, G., Ost, P., Razack, A., Lim, J., Teo, S., Lin, D. W., Newcomb, L. F., Lessel, D., Gamulin, M., Kulis, T., Kaneva, R., Usmani, N., Singhal, S., Slavov, C., Mitev, V., Parliament, M., Claessens, F., Joniau, S., Van den Broeck, T., Larkin, S., Townsend, P. A., Aukim-Hastie, C., Dominguez, M., Castelao, J., Martinez, M., Roobol, M. J., Jenster, G., van Schaik, R. N., Menegaux, F., Truong, T., Koudou, Y., Xu, J., Khaw, K., Cannon-Albright, L., Pandha, H., Michael, A., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., Lindstrom, S., Turman, C., Ma, J., Hunter, D. J., Riboli, E., Siddiq, A., Canzian, F., Kolonel, L. N., Le Marchand, L., Hoover, R. N., Machiela, M. J., Cui, Z., Kraft, P., Conti, D. V., Easton, D. F., Wiklund, F., Chanock, S. J., Henderson, B. E., Kote-Jarai, Z., Haiman, C. A., Eeles, R. A., Profile Study, APCB, IMPACT Study, Canary PASS Investigators, Breast Prostate Canc Cohort Consor, PRACTICAL Prostate Canc As, Canc Prostate Sweden CAPS, Prostate Canc Genome-wide As, Genetic Assoc Mech Oncology GAME- 2018; 50 (7): 928-+

  Abstract

  Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa 1 .

  View details for PubMedID 29892016

• Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants NATURE COMMUNICATIONS Dadaev, T., Saunders, E. J., Newcombe, P. J., Anokian, E., Leongamornlert, D. A., Brook, M. N., Cieza-Borrella, C., Mijuskovic, M., Wakerell, S., Al Olama, A., Schumacher, F. R., Berndt, S. I., Benlloch, S., Ahmed, M., Goh, C., Sheng, X., Zhang, Z., Muir, K., Govindasami, K., Lophatananon, A., Stevens, V. L., Gapstur, S. M., Carter, B. D., Tangen, C. M., Goodman, P., Thompson, I. M., Batra, J., Chambers, S., Moya, L., Clements, J., Horvath, L., Tilley, W., Risbridger, G., Gronberg, H., Aly, M., Nordstrom, T., Pharoah, P., Pashayan, N., Schleutker, J., Tammela, T. J., Sipeky, C., Auvinen, A., Albanes, D., Weinstein, S., Wolk, A., Hakansson, N., West, C., Dunning, A. M., Burnet, N., Mucci, L., Giovannucci, E., Andriole, G., Cussenot, O., Cancel-Tassin, G., Koutros, S., Freeman, L., Sorensen, K., Orntoft, T., Borre, M., Maehle, L., Grindedal, E., Neal, D. E., Donovan, J. L., Hamdy, F. C., Martin, R. M., Travis, R. C., Key, T. J., Hamilton, R. J., Fleshner, N. E., Finelli, A., Ingles, S., Stern, M. C., Rosenstein, B., Kerns, S., Ostrer, H., Lu, Y., Zhang, H., Feng, N., Mao, X., Guo, X., Wang, G., Sun, Z., Giles, G. G., Southey, M. C., MacInnis, R. J., FitzGerald, L. M., Kibel, A. S., Drake, B. F., Vega, A., Gomez-Caamano, A., Fachal, L., Szulkin, R., Eklund, M., Kogevinas, M., Llorca, J., Castano-Vinyals, G., Penney, K. L., Stampfer, M., Park, J. Y., Sellers, T. A., Lin, H., Stanford, J. L., Cybulski, C., Wokolorczyk, D., Lubinski, J., Ostrander, E. A., Geybels, M. S., Nordestgaard, B. G., Nielsen, S. F., Weisher, M., Bisbjerg, R., Roder, M., Iversen, P., Brenner, H., Cuk, K., Holleczek, B., Maier, C., Luedeke, M., Schnoeller, T., Kim, J., Logothetis, C. J., John, E. M., Teixeira, M. R., Paulo, P., Cardoso, M., Neuhausen, S. L., Steele, L., Ding, Y., De Ruyck, K., De Meerleer, G., Ost, P., Razack, A., Lim, J., Teo, S., Lin, D. W., Newcomb, L. F., Lessel, D., Gamulin, M., Kulis, T., Kaneva, R., Usmani, N., Slavov, C., Mitev, V., Parliament, M., Singhal, S., Claessens, F., Joniau, S., Van den Broeck, T., Larkin, S., Townsend, P. A., Aukim-Hastie, C., Gago-Dominguez, M., Castelao, J., Martinez, M., Roobol, M. J., Jenster, G., van Schaik, R. N., Menegaux, F., Truong, T., Koudou, Y., Xu, J., Khaw, K., Cannon-Albright, L., Pandha, H., Michael, A., Kierzek, A., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., Lindstrom, S., Turman, C., Ma, J., Hunter, D. J., Riboli, E., Siddiq, A., Canzian, F., Kolonel, L. N., Le Marchand, L., Hoover, R. N., Machiela, M. J., Kraft, P., Freedman, M., Wiklund, F., Chanock, S., Henderson, B. E., Easton, D. F., Haiman, C. A., Eeles, R. A., Conti, D. V., Kote-Jarai, Z., PRACTICAL Prostate Canc Assoc Grp 2018; 9: 2256

  Abstract

  Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

  View details for PubMedID 29892050

• Reproductive history, breast-feeding and risk of triple negative breast cancer: The Breast Cancer Etiology in Minorities (BEM) study INTERNATIONAL JOURNAL OF CANCER John, E. M., Hines, L. M., Phipps, A. I., Koo, J., Longacre, T. A., Ingles, S. A., Baumgartner, K. B., Slattery, M. L., Wu, A. H. 2018; 142 (11): 2273–85

  Abstract

  Few risk factors have been identified for triple negative breast cancer (TNBC) which lacks expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). This more aggressive subtype disproportionately affects some racial/ethnic minorities and is associated with lower survival. We pooled data from three population-based studies (558 TNBC and 5,111 controls) and examined associations of TNBC risk with reproductive history and breast-feeding. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression. For younger women, aged <50 years, TNBC risk was increased two-fold for parous women who never breast-fed compared to nulliparous women (OR = 2.02, 95% CI = 1.12-3.63). For younger parous women, longer duration of lifetime breast-feeding was associated with a borderline reduced risk (≥24 vs. 0 months: OR = 0.52, 95% CI = 0.26-1.04, Ptrend  = 0.06). Considering the joint effect of parity and breast-feeding, risk was increased two-fold for women with ≥3 full-term pregnancies (FTPs) and no or short-term (<12 months) breast-feeding compared to women with 1-2 FTPs and breast-feeding ≥12 months (OR = 2.56, 95% CI = 1.22-5.35). None of these associations were observed among older women (≥50 years). Differences in reproductive patterns possibly contribute to the ethnic differences in TNBC incidence. Among controls aged <50 years, the prevalence of no or short-term breast-feeding and ≥3 FTPs was highest for Hispanics (22%), followed by African Americans (18%), Asian Americans (15%) and non-Hispanic whites (6%). Breast-feeding is a modifiable behavioral factor that may lower TNBC risk and mitigate the effect of FTPs in women under age 50 years.

  View details for PubMedID 29330856

  View details for PubMedCentralID PMC5893409

• Obesity, Body Composition, and Breast Cancer An Evolving Science JAMA ONCOLOGY Bandera, E. V., John, E. M. 2018; 4 (6): 804–5

  View details for PubMedID 29621383

• Breast Cancer Family History and Contralateral Breast Cancer Risk in Young Women: An Update From the Women's Environmental Cancer and Radiation Epidemiology Study JOURNAL OF CLINICAL ONCOLOGY Reiner, A. S., Sisti, J., John, E. M., Lynch, C. F., Brooks, J. D., Mellemkjaer, L., Boice, J. D., Knight, J. A., Concannon, P., Capanu, M., Tischkowitz, M., Robson, M., Liang, X., Woods, M., Conti, D. V., Duggan, D., Shore, R., Stram, D. O., Thomas, D. C., Malone, K. E., Bernstein, L., Bernstein, J. L., WECARE Study Collaborative Grp 2018; 36 (15): 1513-+

  View details for DOI 10.1200/JCO.2017.77.3424

  View details for Web of Science ID 000433635100009

• Metabolomic profiles in breast cancer: a pilot case-control study in the breast cancer family registry BMC CANCER Dougan, M. M., Li, Y., Chu, L. W., Haile, R. W., Whittemore, A. S., Han, S. S., Moore, S. C., Sampson, J. N., Andrulis, I. L., John, E. M., Hsing, A. W. 2018; 18: 532

  Abstract

  Metabolomics is emerging as an important tool for detecting differences between diseased and non-diseased individuals. However, prospective studies are limited.We examined the detectability, reliability, and distribution of metabolites measured in pre-diagnostic plasma samples in a pilot study of women enrolled in the Northern California site of the Breast Cancer Family Registry. The study included 45 cases diagnosed with breast cancer at least one year after the blood draw, and 45 controls. Controls were matched on age (within 5 years), family status, BRCA status, and menopausal status. Duplicate samples were included for reliability assessment. We used a liquid chromatography/gas chromatography mass spectrometer platform to measure metabolites. We calculated intraclass correlations (ICCs) among duplicate samples, and coefficients of variation (CVs) across metabolites.Of the 661 named metabolites detected, 338 (51%) were found in all samples, and 490 (74%) in more than 80% of samples. The median ICC between duplicates was 0.96 (25th - 75th percentile: 0.82-0.99). We observed a greater than 20% case-control difference in 24 metabolites (p < 0.05), although these associations were not significant after adjusting for multiple comparisons.These data show that assays are reproducible for many metabolites, there is a minimal laboratory variation for the same sample, and a large between-person variation. Despite small sample size, differences between cases and controls in some metabolites suggest that a well-powered large-scale study is likely to detect biological meaningful differences to provide a better understanding of breast cancer etiology.

  View details for PubMedID 29728083

• Intake of bean fiber, beans, and grains and reduced risk of hormone receptor-negative breast cancer: the San Francisco Bay Area Breast Cancer Study CANCER MEDICINE Sangaramoorthy, M., Koo, J., John, E. M. 2018; 7 (5): 2131–44

  Abstract

  High dietary fiber intake has been associated with reduced breast cancer risk, but few studies considered tumor subtypes defined by estrogen receptor (ER) and progesterone receptor (PR) status or included racial/ethnic minority populations who vary in their fiber intake. We analyzed food frequency data from a population-based case-control study, including 2135 breast cancer cases (1070 Hispanics, 493 African Americans, and 572 non-Hispanic Whites (NHWs)) and 2571 controls (1391 Hispanics, 557 African Americans, and 623 NHWs). Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer associated with fiber intake were calculated using unconditional logistic regression. Breast cancer risk associated with high intake (high vs. low quartile) of bean fiber (p-trend = 0.01), total beans (p-trend = 0.03), or total grains (p-trend = 0.05) was reduced by 20%. Inverse associations were strongest for ER-PR- breast cancer, with risk reductions associated with high intake ranging from 28 to 36%. For bean fiber, risk was reduced among foreign-born Hispanics only, who had the highest fiber intake, whereas for grain intake, inverse associations were found among NHWs only. There was no evidence of association with fiber intake from vegetables and fruits or total intake of vegetables and fruits. A high dietary intake of bean fiber and fiber-rich foods such as beans and grains may lower the risk of ER-PR- breast cancer, an aggressive breast cancer subtype for which few risk factors have been identified.

  View details for PubMedID 29573201

• Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations HUMAN MUTATION Rebbeck, T. R., Friebel, T. M., Friedman, E., Hamann, U., Huo, D., Kwong, A., Olah, E., Olopade, O. I., Solano, A. R., Teo, S., Thomassen, M., Weitzel, J. N., Chan, T. L., Couch, F. J., Goldgar, D. E., Kruse, T. A., Palmero, E., Park, S., Torres, D., van Rensburg, E. J., McGuffog, L., Parsons, M. T., Leslie, G., Aalfs, C. M., Abugattas, J., Adlard, J., Agata, S., Aittomaki, K., Andrews, L., Andrulis, I. L., Arason, A., Arnold, N., Arun, B. K., Asseryanis, E., Auerbach, L., Azzollini, J., Balmana, J., Barile, M., Barkardottir, R. B., Barrowdale, D., Benitez, J., Berger, A., Berger, R., Blanco, A. M., Blazer, K. R., Blok, M. J., Bonadona, V., Bonanni, B., Bradbury, A. R., Brewer, C., Buecher, B., Buys, S. S., Caldes, T., Caliebe, A., Caligo, M. A., Campbell, I., Caputo, S. M., Chiquette, J., Chung, W. K., Claes, K. M., Collee, J., Cook, J., Davidson, R., de la Hoya, M., De Leeneer, K., de Pauw, A., Delnatte, C., Diez, O., Ding, Y., Ditsch, N., Domchek, S., Dorfling, C. M., Velazquez, C., Dworniczak, B., Eason, J., Easton, D. F., Eeles, R., Ehrencrona, H., Ejlertsen, B., Engel, C., Engert, S., Evans, D., Faivre, L., Feliubadalo, L., Ferrer, S., Foretova, L., Fowler, J., Frost, D., Galvao, H. R., Ganz, P. A., Garber, J., Gauthier-Villars, M., Gehrig, A., Gerdes, A., Gesta, P., Giannini, G., Giraud, S., Glendon, G., Godwin, A. K., Greene, M. H., Gronwald, J., Gutierrez-Barrera, A., Hahnen, E., Hauke, J., Henderson, A., Hentschel, J., Hogervorst, F. L., Honisch, E., Imyanitov, E. N., Isaacs, C., Izatt, L., Izquierdo, A., Jakubowska, A., James, P., Janavicius, R., Jensen, U., John, E. M., Vijai, J., Kaczmarek, K., Karlan, B. Y., Kast, K., Kim, S., Konstantopoulou, I., Korach, J., Laitman, Y., Lasa, A., Lasset, C., Lazaro, C., Lee, A., Lee, M., Lester, J., Lesueur, F., Liljegren, A., Lindor, N. M., Longy, M., Loud, J. T., Lu, K. H., Lubinski, J., Machackova, E., Manoukian, S., Mari, V., Martinez-Bouzas, C., Matrai, Z., Mebirouk, N., Meijers-Heijboer, H. J., Meindl, A., Mensenkamp, A. R., Mickys, U., Miller, A., Montagna, M., Moysich, K. B., Mulligan, A., Musinsky, J., Neuhausen, S. L., Nevanlinna, H., Ngeow, J., Nguyen, H., Niederacher, D., Nielsen, H., Nielsen, F., Nussbaum, R. L., Offit, K., Ofverholm, A., Ong, K., Osorio, A., Papi, L., Papp, J., Pasini, B., Pedersen, I., Peixoto, A., Peruga, N., Peterlongo, P., Pohl, E., Pradhan, N., Prajzendanc, K., Prieur, F., Pujol, P., Radice, P., Ramus, S. J., Rantala, J., Rashid, M., Rhiem, K., Robson, M., Rodriguez, G. C., Rogers, M. T., Rudaitis, V., Schmidt, A. Y., Schmutzler, R., Senter, L., Shah, P. D., Sharma, P., Side, L. E., Simard, J., Singer, C. F., Skytte, A., Slavin, T. P., Snape, K., Sobol, H., Southey, M., Steele, L., Steinemann, D., Sukiennicki, G., Sutter, C., Szabo, C. I., Tan, Y. Y., Teixeira, M. R., Terry, M., Teule, A., Thomas, A., Thull, D. L., Tischkowitz, M., Tognazzo, S., Toland, A., Topka, S., Trainer, A. H., Tung, N., van Asperen, C. J., van der Hout, A. H., van der Kolk, L. E., van der Luijt, R. B., Van Heetvelde, M., Varesco, L., Varon-Mateeva, R., Vega, A., Villarreal-Garza, C., von Wachenfeldt, A., Walker, L., Wang-Gohrke, S., Wappenschmidt, B., Weber, B. F., Yannoukakos, D., Yoon, S., Zanzottera, C., Zidan, J., Zorn, K. K., Selkirk, C., Hulick, P. J., Chenevix-Trench, G., Spurdle, A. B., Antoniou, A. C., Nathanson, K. L., EMBRACE, GEMO Study Collaborators, HEBON, KConFab Investigators 2018; 39 (5): 593–620

  Abstract

  The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

  View details for PubMedID 29446198

  View details for PubMedCentralID PMC5903938

• Genetic susceptibility markers for a breast-colorectal cancer phenotype: Exploratory results from genome-wide association studies PLOS ONE Pande, M., Joon, A., Brewster, A. M., Chen, W. V., Hoppers, J. L., Eng, C., Shete, S., Casey, G., Schumacher, F., Lin, Y., Harrison, T. A., White, E., Ahsan, H., Andrulis, I. L., Whittemore, A. S., John, E. M., Win, A., Makalic, E., Schmidt, D. F., Kapuscinski, M. K., Ochs-Balcom, H. M., Gallinger, S., Jenkins, M. A., Newcomb, P. A., Lindor, N. M., Peters, U., Amos, C. I., Lynch, P. M. 2018; 13 (4): e0196245

  Abstract

  Clustering of breast and colorectal cancer has been observed within some families and cannot be explained by chance or known high-risk mutations in major susceptibility genes. Potential shared genetic susceptibility between breast and colorectal cancer, not explained by high-penetrance genes, has been postulated. We hypothesized that yet undiscovered genetic variants predispose to a breast-colorectal cancer phenotype.To identify variants associated with a breast-colorectal cancer phenotype, we analyzed genome-wide association study (GWAS) data from cases and controls that met the following criteria: cases (n = 985) were women with breast cancer who had one or more first- or second-degree relatives with colorectal cancer, men/women with colorectal cancer who had one or more first- or second-degree relatives with breast cancer, and women diagnosed with both breast and colorectal cancer. Controls (n = 1769), were unrelated, breast and colorectal cancer-free, and age- and sex- frequency-matched to cases. After imputation, 6,220,060 variants were analyzed using the discovery set and variants associated with the breast-colorectal cancer phenotype at P<5.0E-04 (n = 549, at 60 loci) were analyzed for replication (n = 293 cases and 2,103 controls).Multiple correlated SNPs in intron 1 of the ROBO1 gene were suggestively associated with the breast-colorectal cancer phenotype in the discovery and replication data (most significant; rs7430339, Pdiscovery = 1.2E-04; rs7429100, Preplication = 2.8E-03). In meta-analysis of the discovery and replication data, the most significant association remained at rs7429100 (P = 1.84E-06).The results of this exploratory analysis did not find clear evidence for a susceptibility locus with a pleiotropic effect on hereditary breast and colorectal cancer risk, although the suggestive association of genetic variation in the region of ROBO1, a potential tumor suppressor gene, merits further investigation.

  View details for PubMedID 29698419

• Comparison of methods to assess onset of breast development in the LEGACY Girls Study: methodological considerations for studies of breast cancer BREAST CANCER RESEARCH Houghton, L. C., Knight, J. A., De Souza, M., Goldberg, M., White, M. L., O'Toole, K., Chung, W. K., Bradbury, A. R., Daly, M. B., Andrulis, I. L., John, E. M., Buys, S. S., Terry, M. 2018; 20: 33

  Abstract

  Younger age at onset of breast development, which has been declining in recent decades, is associated with increased breast cancer risk independent of age at menarche. Given the need to study the drivers of these trends, it is essential to validate methods to assess breast onset that can be used in large-scale studies when direct clinical assessment of breast onset is not feasible.Breast development is usually measured by Tanner stages (TSs), assessed either by physical examination or by mother's report using a picture-based Sexual Maturation Scale (SMS). As an alternative, a mother-reported Pubertal Development Scale (PDS) without pictures has been used in some studies. We compared agreement of SMS and PDS with each other (n = 1022) and the accuracy of PDS with clinical TS as a gold standard for the subset of girls with this measure (n = 282) using the LEGACY cohort. We further compared prediction of breast onset using ROC curves and tested whether adding urinary estrone 1-glucuronide (E1G) improved the AUC.The agreement of PDS with SMS was high (kappa = 0.80). The sensitivity of PDS vs clinical TS was 86.6%. The AUCs for PDS alone and SMS alone were 0.88 and 0.79, respectively. Including E1G concentrations improved the AUC for both methods (0.91 and 0.86 for PDS and SMS, respectively).The PDS without pictures is a highly accurate, sensitive, and specific method for assessing breast onset, especially in settings where clinical TS is not feasible. In addition, it is comparable to SMS methods with pictures and thus easier to implement in large-scale studies, particularly phone-based interviews where pictures may not be available. Urinary E1G can improve accuracy over than PDS or SMS alone.

  View details for PubMedID 29669587

  View details for PubMedCentralID PMC5907380

• Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia NATURE COMMUNICATIONS Vijayakrishnan, J., Studd, J., Broderick, P., Kinnersley, B., Holroyd, A., Law, P. J., Kumar, R., Allan, J. M., Harrison, C. J., Moorman, A. V., Vora, A., Roman, E., Rachakonda, S., Kinsey, S. E., Sheridan, E., Thompson, P. D., Irving, J. A., Koehler, R., Hoffmann, P., Noethen, M. M., Heilmann-Heimbach, S., Joeckel, K., Easton, D. F., Pharaoh, P. P., Dunning, A. M., Peto, J., Canzian, F., Swerdlow, A., Eeles, R. A., Kote-Jarai, Z. S., Muir, K., Pashayan, N., Greaves, M., Zimmerman, M., Bartram, C. R., Schrappe, M., Stanulla, M., Hemminki, K., Houlston, R. S., PRACTICAL Consortium 2018; 9: 1340

  Abstract

  Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10-9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10-8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology.

  View details for DOI 10.1038/s41467-018-03178-z

  View details for Web of Science ID 000429498100002

  View details for PubMedID 29632299

  View details for PubMedCentralID PMC5890276

• Breast Cancer Family History and Contralateral Breast Cancer Risk in Young Women: An Update From the Women's Environmental Cancer and Radiation Epidemiology Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Reiner, A. S., Sisti, J., John, E. M., Lynch, C. F., Brooks, J. D., Mellemkjar, L., Boice, J. D., Knight, J. A., Concannon, P., Capanu, M., Tischkowitz, M., Robson, M., Liang, X., Woods, M., Conti, D. V., Duggan, D., Shore, R., Stram, D. O., Thomas, D. C., Malone, K. E., Bernstein, L., WECARE Study Collaborative Group, Bernstein, J. L. 2018: JCO2017773424

  Abstract

  Purpose The Women's Environmental Cancer and Radiation Epidemiology (WECARE) study demonstrated the importance of breast cancer family history on contralateral breast cancer (CBC) risk, even for noncarriers of deleterious BRCA1/2 mutations. With the completion of WECARE II, updated risk estimates are reported. Additional analyses that exclude women negative for deleterious mutations in ATM, CHEK2*1100delC, and PALB2 were performed. Patients and Methods The WECARE Study is a population-based case-control study that compared 1,521 CBC cases with 2,212 individually matched unilateral breast cancer (UBC) controls. Participants were younger than age 55 years when diagnosed with a first invasive breast cancer between 1985 and 2008. Women were interviewed about breast cancer risk factors, including family history. A subset of women was screened for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2. Rate ratios (RRs) were estimated using multivariable conditional logistic regression. Cumulative absolute risks (ARs) were estimated by combining RRs from the WECARE Study and population-based SEER*Stat cancer incidence data. Results Women with any first-degree relative with breast cancer had a 10-year AR of 8.1% for CBC (95% CI, 6.7% to 9.8%). Risks also were increased if the relative was diagnosed at an age younger than 40 years (10-year AR, 13.5%; 95% CI, 8.8% to 20.8%) or with CBC (10-year AR, 14.1%; 95% CI, 9.5% to 20.7%). These risks are comparable with those seen in BRCA1/2 deleterious mutation carriers (10-year AR, 18.4%; 95% CI, 16.0% to 21.3%). In the subset of women who tested negative for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2, estimates were unchanged. Adjustment for known breast cancer single-nucleotide polymorphisms did not affect estimates. Conclusion Breast cancer family history confers a high CBC risk, even after excluding women with deleterious mutations. Clinicians are urged to use detailed family histories to guide treatment and future screening decisions for young women with breast cancer.

  View details for PubMedID 29620998

• Discovery of mutations in homologous recombination genes in African-American women with breast cancer FAMILIAL CANCER Ding, Y., Adamson, A. W., Steele, L., Bailis, A. M., John, E. M., Tomlinson, G., Neuhausen, S. L. 2018; 17 (2): 187–95

  Abstract

  African-American women are more likely to develop aggressive breast cancer at younger ages and experience poorer cancer prognoses than non-Hispanic Caucasians. Deficiency in repair of DNA by homologous recombination (HR) is associated with cancer development, suggesting that mutations in genes that affect this process may cause breast cancer. Inherited pathogenic mutations have been identified in genes involved in repairing DNA damage, but few studies have focused on African-Americans. We screened for germline mutations in seven HR repair pathway genes in DNA of 181 African-American women with breast cancer, evaluated the potential effects of identified missense variants using in silico prediction software, and functionally characterized a set of missense variants by yeast two-hybrid assays. We identified five likely-damaging variants, including two PALB2 truncating variants (Q151X and W1038X) and three novel missense variants (RAD51C C135R, and XRCC3 L297P and V337E) that abolish protein-protein interactions in yeast two-hybrid assays. Our results add to evidence that HR gene mutations account for a proportion of the genetic risk for developing breast cancer in African-Americans. Identifying additional mutations that diminish HR may provide a tool for better assessing breast cancer risk and improving approaches for targeted treatment.

  View details for PubMedID 28864920

  View details for PubMedCentralID PMC5834346

• Impact of individual and neighborhood factors on disparities in prostate cancer survival CANCER EPIDEMIOLOGY DeRouen, M. C., Schupp, C. W., Koo, J., Yang, J., Hertz, A., Shariff-Marco, S., Cockburn, M., Nelson, D. O., Ingles, S. A., John, E. M., Gomez, S. L. 2018; 53: 1–11

  Abstract

  We addressed the hypothesis that individual-level factors act jointly with social and built environment factors to influence overall survival for men with prostate cancer and contribute to racial/ethnic and socioeconomic (SES) survival disparities.We analyzed multi-level data, combining (1) individual-level data from the California Collaborative Prostate Cancer Study, a population-based study of non-Hispanic White (NHW), Hispanic, and African American prostate cancer cases (N = 1800) diagnosed from 1997 to 2003, with (2) data on neighborhood SES (nSES) and social and built environment factors from the California Neighborhoods Data System, and (3) data on tumor characteristics, treatment and follow-up through 2009 from the California Cancer Registry. Multivariable, stage-stratified Cox proportional hazards regression models with cluster adjustments were used to assess education and nSES main and joint effects on overall survival, before and after adjustment for social and built environment factors.African American men had worse survival than NHW men, which was attenuated by nSES. Increased risk of death was associated with residence in lower SES neighborhoods (quintile 1 (lowest nSES) vs. 5: HR = 1.56, 95% CI: 1.11-2.19) and lower education (

  View details for PubMedID 29328959

• Associations between ALDH1A1 polymorphisms, alcohol consumption, and mortality among Hispanic and non-Hispanic white women diagnosed with breast cancer: the Breast Cancer Health Disparities Study BREAST CANCER RESEARCH AND TREATMENT Xia, Z., Baumgartner, K. B., Baumgartner, R. N., Boone, S. D., Hines, L. M., John, E. M., Wolff, R., Slattery, M. L., Connor, A. E. 2018; 168 (2): 443–55

  Abstract

  ALDH1A1, one of the main isotopes of aldehyde dehydrogenase-1 is involved in the differentiation and protection of normal hematopoietic stem cells and functions in alcohol sensitivity and dependence. We evaluated the associations between ALDH1A1 polymorphisms, alcohol consumption, and mortality among Hispanic and non-Hispanic white (NHW) breast cancer (BC) cases from the Breast Cancer Health Disparities Study.Nine SNPs in ALDH1A1 were evaluated in 920 Hispanic and 1372 NHW women diagnosed with incident invasive BC. Adjusted Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Models were stratified by Native American (NA) ancestry and alcohol consumption.A total of 443 deaths occurred over a median follow-up time of 11 years. After adjusting all results for multiple comparisons, rs7027604 was significantly associated with all-cause mortality (HRAA = 1.40; 95% CI 1.13-1.73, P adj = 0.018). The rs1424482 CC genotype (HRCC = 1.69; 95% CI 1.20-2.37, P adj = 0.027) and the rs7027604 AA genotype (HRAA = 1.65; 95% CI 1.21-2.26, P adj = 0.018) were positively associated with non-BC mortality. Among long-term light drinkers, rs1888202 was associated with decreased all-cause mortality (HRCG/GG = 0.36; 95% CI 0.20-0.64), while associations were not significant among non-drinkers or moderate/heavy drinkers (P interation = 0.218). The increased risk of all-cause mortality associated with rs63319 was limited to women with low NA ancestry (HRAA = 1.53; 95% CI 1.19-1.97).Multiple SNPs in ALDH1A1 were associated with increased risk of mortality after BC. Future BC studies examining the relationship between ALDH1A1 and mortality should consider the modifying effects of alcohol consumption and NA ancestry.

  View details for PubMedID 29190005

• The association of mammographic density with risk of contralateral breast cancer and change in density with treatment in the WECARE study BREAST CANCER RESEARCH Knight, J. A., Blackmore, K. M., Fan, J., Malone, K. E., John, E. M., Lynch, C. F., Vachon, C. M., Bernstein, L., Brooks, J. D., Reiner, A. S., Liang, X., Woods, M., Bernstein, J. L., WECARE Study Collaborative Grp 2018; 20

  View details for DOI 10.1186/s13058-018-0948-4

  View details for Web of Science ID 000428632700005

• The association of mammographic density with risk of contralateral breast cancer and change in density with treatment in the WECARE study. Breast cancer research : BCR Knight, J. A., Blackmore, K. M., Fan, J., Malone, K. E., John, E. M., Lynch, C. F., Vachon, C. M., Bernstein, L., Brooks, J. D., Reiner, A. S., Liang, X., Woods, M., Bernstein, J. L. 2018; 20 (1): 23

  Abstract

  Mammographic density (MD) is an established predictor of risk of a first breast cancer, but the relationship of MD to contralateral breast cancer (CBC) risk is not clear, including the roles of age, mammogram timing, and change with treatment. Multivariable prediction models for CBC risk are needed and MD could contribute to these.We conducted a case-control study of MD and CBC risk in phase II of the WECARE study where cases had a CBC diagnosed ≥ 2 years after first diagnosis at age <55 years and controls had unilateral breast cancer (UBC) with similar follow-up time. We retrieved film mammograms of the unaffected breast from two time points, prior to/at the time of the first diagnosis (253 CBC cases, 269 UBC controls) and ≥ 6 months up to 48 months following the first diagnosis (333 CBC cases, 377 UBC controls). Mammograms were digitized and percent MD (%MD) was measured using the thresholding program Cumulus. Odds ratios (OR) and 95% confidence intervals (CI) for association between %MD and CBC, adjusted for age, treatment, and other factors related to CBC, were estimated using logistic regression. Linear regression was used to estimate the association between treatment modality and change in %MD in 467 women with mammograms at both time points.For %MD assessed following diagnosis, there was a statistically significant trend of increasing CBC with increasing %MD (p = 0.03). Lower density (<25%) was associated with reduced risk of CBC compared to 25 to < 50% density (OR 0.69, 95% CI 0.49, 0.98). Similar, but weaker, associations were noted for %MD measurements prior to/at diagnosis. The relationship appeared strongest in women aged < 45 years and non-existent in women aged 50 to 54 years. A decrease of ≥ 10% in %MD between first and second mammogram was associated marginally with reduced risk of CBC (OR 0.63, 95% CI 0.40, 1.01) compared to change of <10%. Both tamoxifen and chemotherapy were associated with statistically significant 3% decreases in %MD (p < 0.01).Post-diagnosis measures of %MD may be useful to include in CBC risk prediction models with consideration of age at diagnosis. Chemotherapy is associated with reductions in %MD, similar to tamoxifen.

  View details for DOI 10.1186/s13058-018-0948-4

  View details for PubMedID 29566728

  View details for PubMedCentralID PMC5863854

• Benign breast disease and breast cancer risk across the spectrum of familial risk using a prospective family study cohort (ProF-SC) Zeinomar, N., Phillips, K. A., Liao, Y., MacInnis, R. J., Dite, G. S., Daly, M. B., John, E. M., Andrulis, I. L., Buys, S. S., Hopper, J. L., Terry, M. B. AMER ASSOC CANCER RESEARCH. 2018

  View details for Web of Science ID 000425489402152

• Risk-reducing oophorectomy and breast cancer risk across the spectrum of familial risk using a prospective family study cohort (ProF-SC) Terry, M. B., Phillips, K. A., Daly, M. B., Andrulis, I. L., Liao, Y., Ma, X., Zeinomar, N., MacInnis, R. J., Dite, G. S., John, E. M., Buys, S. S., Hopper, J. L. AMER ASSOC CANCER RESEARCH. 2018

  View details for Web of Science ID 000425489402149

• Agreement between self-reported and register-based cardiovascular events among Danish breast cancer survivors JOURNAL OF CANCER SURVIVORSHIP Langballe, R., John, E. M., Malone, K. E., Bernstein, L., Knight, J. A., Lynch, C. F., Howell, R. M., Shore, R., Woods, M., Concannon, P., Bernstein, J. L., Mellemkjaer, L., WECARE Study Collaborative Grp 2018; 12 (1): 95–100

  Abstract

  We examined the degree of over- and under-reporting of cardiovascular diseases (CVDs) among female breast cancer survivors comparing self-reports to diagnostic codes from the Danish National Patient Register (NPR).The study comprised 357 Danish breast cancer patients from the WECARE study who completed a telephone interview concerning CVDs. Disease diagnoses for these women were obtained from the NPR. Agreement was calculated as the number of diagnoses that were both self-reported and in the NPR divided by (1) number of self-reported diagnoses (over-reporting) or (2) number of diagnoses in the NPR (under-reporting).In total, 68 women reported 96 specific cardiovascular outcomes of which 56 (58%) were found in the NPR. Ninety cardiovascular diagnoses were found in the NPR of which 56 (62%) were specifically reported at the interview. There was 80% agreement as to the occurrence of a cardiovascular diagnosis overall. Of 289 women reporting no CVD, 273 (94%) had no diagnoses in the NPR.Breast cancer survivors seem to report absence of CVD accurately, but they both over-report and under-report specific cardiovascular diagnoses. Using a broader definition of CVDs improves the agreement between self-reported and NPR data.Determining how cancer treatments affect the risk of cardiovascular morbidities is essential, and the development of high-quality methods for collecting such data is critical. While self-reported data are adequate for assessing the presence of any CVD condition, medical record review will yield higher quality data on specific CVD conditions.

  View details for PubMedID 28963606

  View details for PubMedCentralID PMC5790612

• Breast cancer family history and allele-specific DNA methylation in the legacy girls study EPIGENETICS Wu, H., Do, C., Andrulis, I. L., John, E. M., Daly, M. B., Buys, S. S., Chung, W. K., Knight, J. A., Bradbury, A. R., Keegan, T. M., Schwartz, L., Krupska, I., Miller, R. L., Santella, R. M., Tycko, B., Terry, M. 2018; 13 (3): 240–50

  Abstract

  Family history, a well-established risk factor for breast cancer, can have both genetic and environmental contributions. Shared environment in families as well as epigenetic changes that also may be influenced by shared genetics and environment may also explain familial clustering of cancers. Epigenetic regulation, such as DNA methylation, can change the activity of a DNA segment without a change in the sequence; environmental exposures experienced across the life course can induce such changes. However, genetic-epigenetic interactions, detected as methylation quantitative trait loci (mQTLs; a.k.a. meQTLs) and haplotype-dependent allele-specific methylation (hap-ASM), can also contribute to inter-individual differences in DNA methylation patterns. To identify differentially methylated regions (DMRs) associated with breast cancer susceptibility, we examined differences in white blood cell DNA methylation in 29 candidate genes in 426 girls (ages 6-13 years) from the LEGACY Girls Study, 239 with and 187 without a breast cancer family history (BCFH). We measured methylation by targeted massively parallel bisulfite sequencing (bis-seq) and observed BCFH DMRs in two genes: ESR1 (Δ4.9%, P = 0.003) and SEC16B (Δ3.6%, P = 0.026), each of which has been previously implicated in breast cancer susceptibility and pubertal development. These DMRs showed high inter-individual variability in methylation, suggesting the presence of mQTLs/hap-ASM. Using single nucleotide polymorphisms data in the bis-seq amplicon, we found strong hap-ASM in SEC16B (with allele specific-differences ranging from 42% to 74%). These findings suggest that differential methylation in genes relevant to breast cancer susceptibility may be present early in life, and that inherited genetic factors underlie some of these epigenetic differences.

  View details for PubMedID 29436922

  View details for PubMedCentralID PMC5997170

• Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis. International journal of epidemiology Shu, X. n., Wu, L. n., Khankari, N. K., Shu, X. O., Wang, T. J., Michailidou, K. n., Bolla, M. K., Wang, Q. n., Dennis, J. n., Milne, R. L., Schmidt, M. K., Pharoah, P. D., Andrulis, I. L., Hunter, D. J., Simard, J. n., Easton, D. F., Zheng, W. n. 2018

  Abstract

  In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear.We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium.All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p  =  5.09  ×  10-4], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p  =  4.02  ×  10-4), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p  =  5.05  ×  10-19) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p  =  9.22  ×  10-6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer.We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.

  View details for DOI 10.1093/ije/dyy201

  View details for PubMedID 30277539

• Oral Contraceptive Use and Breast Cancer Risk: Retrospective and Prospective Analyses From a BRCA1 and BRCA2 Mutation Carrier Cohort Study. JNCI cancer spectrum Schrijver, L. H., Olsson, H. n., Phillips, K. A., Terry, M. B., Goldgar, D. E., Kast, K. n., Engel, C. n., Mooij, T. M., Adlard, J. n., Barrowdale, D. n., Davidson, R. n., Eeles, R. n., Ellis, S. n., Evans, D. G., Frost, D. n., Izatt, L. n., Porteous, M. E., Side, L. E., Walker, L. n., Berthet, P. n., Bonadona, V. n., Leroux, D. n., Mouret-Fourme, E. n., Venat-Bouvet, L. n., Buys, S. S., Southey, M. C., John, E. M., Chung, W. K., Daly, M. B., Bane, A. n., van Asperen, C. J., Gómez Garcia, E. B., Mourits, M. J., van Os, T. A., Roos-Blom, M. J., Friedlander, M. L., McLachlan, S. A., Singer, C. F., Tan, Y. Y., Foretova, L. n., Navratilova, M. n., Gerdes, A. M., Caldes, T. n., Simard, J. n., Olah, E. n., Jakubowska, A. n., Arver, B. n., Osorio, A. n., Noguès, C. n., Andrieu, N. n., Easton, D. F., van Leeuwen, F. E., Hopper, J. L., Milne, R. L., Antoniou, A. C., Rookus, M. A. 2018; 2 (2): pky023

  Abstract

  For BRCA1 and BRCA2 mutation carriers, the association between oral contraceptive preparation (OCP) use and breast cancer (BC) risk is still unclear.Breast camcer risk associations were estimated from OCP data on 6030 BRCA1 and 3809 BRCA2 mutation carriers using age-dependent Cox regression, stratified by study and birth cohort. Prospective, left-truncated retrospective and full-cohort retrospective analyses were performed.For BRCA1 mutation carriers, OCP use was not associated with BC risk in prospective analyses (hazard ratio [HR] = 1.08, 95% confidence interval [CI] = 0.75 to 1.56), but in the left-truncated and full-cohort retrospective analyses, risks were increased by 26% (95% CI = 6% to 51%) and 39% (95% CI = 23% to 58%), respectively. For BRCA2 mutation carriers, OCP use was associated with BC risk in prospective analyses (HR = 1.75, 95% CI = 1.03 to 2.97), but retrospective analyses were inconsistent (left-truncated: HR = 1.06, 95% CI = 0.85 to 1.33; full cohort: HR = 1.52, 95% CI = 1.28 to 1.81). There was evidence of increasing risk with duration of use, especially before the first full-term pregnancy (BRCA1: both retrospective analyses, P < .001 and P = .001, respectively; BRCA2: full retrospective analysis, P = .002).Prospective analyses did not show that past use of OCP is associated with an increased BC risk for BRCA1 mutation carriers in young middle-aged women (40-50 years). For BRCA2 mutation carriers, a causal association is also not likely at those ages. Findings between retrospective and prospective analyses were inconsistent and could be due to survival bias or a true association for younger women who were underrepresented in the prospective cohort. Given the uncertain safety of long-term OCP use for BRCA1/2 mutation carriers, indications other than contraception should be avoided and nonhormonal contraceptive methods should be discussed.

  View details for DOI 10.1093/jncics/pky023

  View details for PubMedID 31360853

  View details for PubMedCentralID PMC6649757

• Measuring serum melatonin in postmenopausal women: Implications for epidemiologic studies and breast cancer studies. PloS one Chu, L. W., John, E. M., Yang, B. n., Kurian, A. W., Zia, Y. n., Yu, K. n., Ingles, S. A., Stanczyk, F. Z., Hsing, A. W. 2018; 13 (4): e0195666

  Abstract

  Circulating melatonin is a good candidate biomarker for studies of circadian rhythms and circadian disruption. However, epidemiologic studies on circulating melatonin are limited because melatonin is secreted at night, yet most epidemiologic studies collect blood during the day when melatonin levels are very low, and assays are lacking that are ultrasensitive to detect low levels of melatonin reliably.To assess the performance of a refined radioimmunoassay in measuring morning melatonin among women.We used morning serum samples from 47 postmenopausal women ages 48-80 years without a history of breast cancer who participated in the San Francisco Bay Area Breast Cancer Study, including 19 women who had duplicate measurements. The coefficient of variation (CV) and intraclass coefficient (ICC) were estimated using the random effect model.Reproducibility for the assay was satisfactory, with a CV of 11.2% and an ICC of 98.9%; correlation between the replicate samples was also high (R = 0.96). In the 47 women, serum melatonin levels ranged from 0.6 to 62.6 pg/ml, with a median of 7.0 pg/ml.Our results suggest that it is possible to reliably measure melatonin in postmenopausal women in morning serum samples in large epidemiologic studies to evaluate the role of melatonin in cancer etiology or prognosis.

  View details for PubMedID 29641614

• Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility NATURE COMMUNICATIONS Sud, A., Thomsen, H., Law, P. J., Foersti, A., da Silva Filho, M., Holroyd, A., Broderick, P., Orlando, G., Lenive, O., Wright, L., Cooke, R., Easton, D., Pharoah, P., Dunning, A., Peto, J., Canzian, F., Eeles, R., Kote-Jarai, Z. S., Muir, K., Pashayan, N., Hoffmann, P., Noethen, M. M., Joeckel, K., von Strandmann, E., Lightfoot, T., Kane, E., Roman, E., Lake, A., Montgomery, D., Jarrett, R. F., Swerdlow, A. J., Engert, A., Orr, N., Hemminki, K., Houlston, R. S., PRACTICAL Consortium 2017; 8: 1892

  Abstract

  Several susceptibility loci for classical Hodgkin lymphoma have been reported. However, much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies, a new genome-wide association study, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all classical Hodgkin lymphoma at 6q22.33 (rs9482849, P = 1.52 × 10-8) and for nodular sclerosis Hodgkin lymphoma at 3q28 (rs4459895, P = 9.43 × 10-17), 6q23.3 (rs6928977, P = 4.62 × 10-11), 10p14 (rs3781093, P = 9.49 × 10-13), 13q34 (rs112998813, P = 4.58 × 10-8) and 16p13.13 (rs34972832, P = 2.12 × 10-8). Additionally, independent loci within the HLA region are observed for nodular sclerosis Hodgkin lymphoma (rs9269081, HLA-DPB1*03:01, Val86 in HLA-DRB1) and mixed cellularity Hodgkin lymphoma (rs1633096, rs13196329, Val86 in HLA-DRB1). The new and established risk loci localise to areas of active chromatin and show an over-representation of transcription factor binding for determinants of B-cell development and immune response.

  View details for DOI 10.1038/s41467-017-00320-1

  View details for Web of Science ID 000416933400014

  View details for PubMedID 29196614

  View details for PubMedCentralID PMC5711884

• Panel sequencing of 264 candidate susceptibility genes and segregation analysis in a cohort of non-BRCA1, non-BRCA2 breast cancer families BREAST CANCER RESEARCH AND TREATMENT Li, J., Li, H., Makunin, I., Thompson, B. A., Tao, K., Young, E. L., Lopez, J., Camp, N. J., Tavtigian, S. V., John, E. M., Andrulis, I. L., Khanna, K., Goldgar, D., Chenevix-Trench, G., KConFab Investigators 2017; 166 (3): 937–49

  Abstract

  The main aim of this study was to screen epigenetic modifier genes and known breast cancer driver genes for germline mutations in non-BRCA1/2 (BRCAx) breast cancer families in order to identify novel susceptibility genes of moderate-high penetrance.We screened 264 candidate susceptibility genes in 656 index cases from non-BRCA1/2 families. Potentially pathogenic candidate mutations were then genotyped in all available family members for the assessment of co-segregation of the variant with disease in the family in order to estimate the breast cancer risks associated with these mutations. For 11 of the candidate susceptibility genes, we screened an additional 800 non-BRCA1/2 breast cancer cases and 787 controls.Only two genes, CHD8 and USH2A showed any evidence of an increased risk of breast cancer (RR = 2.40 (95% CI 1.0-7.32) and 2.48 (95% CI 1.11-6.67), respectively).We found no convincing evidence that epigenetic modifier and known breast cancer driver genes carry germline mutations that increase breast cancer risk. USH2A is no longer regarded as a breast cancer driver gene and seems an implausible candidate given its association with Usher syndrome. However, somatic mutations in CHD8 have been recently reported, making it an even more promising candidate, but further analysis of CHD8 in very large cohorts of families or case-control studies would be required to determine if it is a moderate-risk breast cancer susceptibility gene.

  View details for PubMedID 28840378

• Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer NATURE GENETICS Milne, R. L., Kuchenbaecker, K. B., Michailidou, K., Beesley, J., Kar, S., Lindstrom, S., Hui, S., Lemacon, A., Soucy, P., Dennis, J., Jiang, X., Rostamianfar, A., Finucane, H., Bolla, M. K., McGuffog, L., Wang, Q., Aalfs, C. M., Adams, M., Adlard, J., Agata, S., Ahmed, S., Ahsan, H., Aittomaki, K., Al-Ejeh, F., Allen, J., Ambrosone, C. B., Amos, C. I., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Arndt, V., Arnold, N., Aronson, K. J., Auber, B., Auer, P. L., Ausems, M. M., Azzollini, J., Bacot, F., Balmana, J., Barile, M., Barjhoux, L., Barkardottir, R. B., Barrdahl, M., Barnes, D., Barrowdale, D., Baynes, C., Beckmann, M. W., Benitez, J., Bermisheva, M., Bernstein, L., Bignon, Y., Blazer, K. R., Blok, M. J., Blomqvist, C., Blot, W., Bobolis, K., Boeckx, B., Bogdanova, N. V., Bojesen, A., Bojesen, S. E., Bonanni, B., Borresen-Dale, A., Bozsik, A., Bradbury, A. R., Brand, J. S., Brauch, H., Brenner, H., Bressac-de Paillerets, B., Brewer, C., Brinton, L., Broberg, P., Brooks-Wilson, A., Brunet, J., Bruening, T., Burwinkel, B., Buys, S. S., Byun, J., Cai, Q., Caldes, T., Caligo, M. A., Campbell, I., Canzian, F., Caron, O., Carracedo, A., Carter, B. D., Esteban Castelao, J., Castera, L., Caux-Moncoutier, V., Chan, S. B., Chang-Claude, J., Chanock, S. J., Chen, X., Cheng, T., Chiquette, J., Christiansen, H., Claes, K. M., Clarke, C. L., Conner, T., Conroy, D. M., Cook, J., Cordina-Duverger, E., Cornelissen, S., Coupier, I., Cox, A., Cox, D. G., Cross, S. S., Cuk, K., Cunningham, J. M., Czene, K., Daly, M. B., Damiola, F., Darabi, H., Davidson, R., De Leeneer, K., Devilee, P., Dicks, E., Diez, O., Ding, Y., Ditsch, N., Doheny, K. F., Domchek, S. M., Dorfling, C. M., Doerk, T., dos-Santos-Silva, I., Dubois, S., Dugue, P., Dumont, M., Dunning, A. M., Durcan, L., Dwek, M., Dworniczak, B., Eccles, D., Eeles, R., Ehrencrona, H., Eilber, U., Ejlertsen, B., Ekici, A. B., Eliassen, A., Engel, C., Eriksson, M., Fachal, L., Faivre, L., Fasching, P. A., Faust, U., Figueroa, J., Flesch-Janys, D., Fletcher, O., Flyger, H., Foulkes, W. D., Friedman, E., Fritschi, L., Frost, D., Gabrielson, M., Gaddam, P., Gammon, M. D., Ganz, P. A., Gapstur, S. M., Garber, J., Garcia-Barberan, V., Garcia-Saenz, J. A., Gaudet, M. M., Gauthier-Villars, M., Gehrig, A., Georgoulias, V., Gerdes, A., Giles, G. G., Glendon, G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Goodfellow, P., Greene, M. H., Alnaes, G., Grip, M., Gronwald, J., Grundy, A., Gschwantler-Kaulich, D., Guenel, P., Guo, Q., Haeberle, L., Hahnen, E., Haiman, C. A., Hakansson, N., Hallberg, E., Hamann, U., Hamel, N., Hankinson, S., Hansen, T. O., Harrington, P., Hart, S. N., Hartikainen, J. M., Healey, C. S., Hein, A., Helbig, S., Henderson, A., Heyworth, J., Hicks, B., Hillemanns, P., Hodgson, S., Hogervorst, F. B., Hollestelle, A., Hooning, M. J., Hoover, B., Hopper, J. L., Hu, C., Huang, G., Hulick, P. J., Humphreys, K., Hunter, D. J., Imyanitov, E. N., Isaacs, C., Iwasaki, M., Izatt, L., Jakubowska, A., James, P., Janavicius, R., Janni, W., Jensen, U., John, E. M., Johnson, N., Jones, K., Jones, M., Jukkola-Vuorinen, A., Kaaks, R., Kabisch, M., Kaczmarek, K., Kang, D., Kast, K., Keeman, R., Kerin, M. J., Kets, C. M., Keupers, M., Khan, S., Khusnutdinova, E., Kiiski, J. I., Kim, S., Knight, J. A., Konstantopoulou, I., Kosma, V., Kristensen, V. N., Kruse, T. A., Kwong, A., Laenkholm, A., Laitman, Y., Lalloo, F., Lambrechts, D., Landsman, K., Lasset, C., Lazaro, C., Le Marchand, L., Lecarpentier, J., Lee, A., Lee, E., Lee, J., Lee, M., Lejbkowicz, F., Lesueur, F., Li, J., Lilyquist, J., Lincoln, A., Lindblom, A., Lissowska, J., Lo, W., Loibl, S., Long, J., Loud, J. T., Lubinski, J., Luccarini, C., Lush, M., MacInnis, R. J., Maishman, T., Makalic, E., Kostovska, I., Malone, K. E., Manoukian, S., Manson, J. E., Margolin, S., Martens, J. M., Martinez, M., Matsuo, K., Mavroudis, D., Mazoyer, S., McLean, C., Meijers-Heijboer, H., Menendez, P., Meyer, J., Miao, H., Miller, A., Miller, N., Mitchell, G., Montagna, M., Muir, K., Mulligan, A., Mulot, C., Nadesan, S., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Nevelsteen, I., Niederacher, D., Nielsen, S. F., Nordestgaard, B. G., Norman, A., Nussbaum, R. L., Olah, E., Olopade, O. I., Olson, J. E., Olswold, C., Ong, K., Oosterwijk, J. C., Orr, N., Osorio, A., Pankratz, V., Papi, L., Park-Simon, T., Paulsson-Karlsson, Y., Lloyd, R., Pedersen, I., Peissel, B., Peixoto, A., Perez, J. A., Peterlongo, P., Peto, J., Pfeiler, G., Phelan, C. M., Pinchev, M., Plaseska-Karanfilska, D., Poppe, B., Porteous, M. E., Prentice, R., Presneau, N., Prokofieva, D., Pugh, E., Angel Pujana, M., Pylkas, K., Rack, B., Radice, P., Rahman, N., Rantala, J., Rappaport-Fuerhauser, C., Rennert, G., Rennert, H. S., Rhenius, V., Rhiem, K., Richardson, A., Rodriguez, G. C., Romero, A., Romm, J., Rookus, M. A., Rudolph, A., Ruediger, T., Saloustros, E., Sanders, J., Sandler, D. P., Sangrajrang, S., Sawyer, E. J., Schmidt, D. F., Schoemaker, M. J., Schumacher, F., Schuermann, P., Schwentner, L., Scott, C., Scott, R. J., Seal, S., Senter, L., Seynaeve, C., Shah, M., Sharma, P., Shen, C., Sheng, X., Shimelis, H., Shrubsole, M. J., Shu, X., Side, L. E., Singer, C. F., Sohn, C., Southey, M. C., Spinelli, J. J., Spurdle, A. B., Stegmaier, C., Stoppa-Lyonnet, D., Sukiennicki, G., Surowy, H., Sutter, C., Swerdlow, A., Szabo, C. I., Tamimi, R. M., Tan, Y. Y., Taylor, J. A., Tejada, M., Tengstrom, M., Teo, S. H., Terry, M. B., Tessier, D. C., Teule, A., Thoene, K., Thull, D. L., Tibiletti, M., Tihomirova, L., Tischkowitz, M., Toland, A. E., Tollenaar, R. M., Tomlinson, I., Tong, L., Torres, D., Tranchant, M., Truong, T., Tucker, K., Tung, N., Tyrer, J., Ulmer, H., Vachon, C., van Asperen, C. J., Van Den Berg, D., van den Ouweland, A. W., van Rensburg, E. J., Varesco, L., Varon-Mateeva, R., Vega, A., Viel, A., Vijai, J., Vincent, D., Vollenweider, J., Walker, L., Wang, Z., Wang-Gohrke, S., Wappenschmidt, B., Weinberg, C. R., Weitzel, J. N., Wendt, C., Wesseling, J., Whittemore, A. S., Wijnen, J. T., Willett, W., Winqvist, R., Wolk, A., Wu, A. H., Xia, L., Yang, X. R., Yannoukakos, D., Zaffaroni, D., Zheng, W., Zhu, B., Ziogas, A., Ziv, E., Zorn, K. K., Gago-Dominguez, M., Mannermaa, A., Olsson, H., Teixeira, M. R., Stone, J., Offit, K., Ottini, L., Park, S. K., Thomassen, M., Hall, P., Meindl, A., Schmutzler, R. K., Droit, A., Bader, G. D., Pharoah, P. P., Couch, F. J., Easton, D. F., Kraft, P., Chenevix-Trench, G., Garcia-Closas, M., Schmidt, M. K., Antoniou, A. C., Simard, J., ABCTB Investigators, EMBRACE, GEMO Study Collaborators, HEBON, kConFab AOCS Investigators, NBSC Collaborators 2017; 49 (12): 1767–78

  Abstract

  Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

  View details for PubMedID 29058716

  View details for PubMedCentralID PMC5808456

• Association analysis identifies 65 new breast cancer risk loci NATURE Michailidou, K., Lindstrom, S., Dennis, J., Beesley, J., Hui, S., Kar, S., Lemacon, A., Soucy, P., Glubb, D., Rostamianfar, A., Bolla, M. K., Wang, Q., Tyrer, J., Dicks, E., Lee, A., Wang, Z., Allen, J., Keeman, R., Eilber, U., French, J. D., Chen, X., Fachal, L., McCue, K., McCart, A. E., Reed, A., Ghoussaini, M., Carroll, J. S., Jiang, X., Finucane, H., Adams, M., Adank, M. A., Ahsan, H., Aittomaki, K., Anton-Culver, H., Antonenkova, N. N., Arndt, V., Aronson, K. J., Arun, B., Auer, P. L., Bacot, F., Barrdahl, M., Baynes, C., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bernstein, L., Blomqvist, C., Bogdanova, N. V., Bojesen, S. E., Bonanni, B., Borresen-Dale, A., Brand, J. S., Brauch, H., Brennan, P., Brenner, H., Brinton, L., Broberg, P., Brock, I. W., Broeks, A., Brooks-Wilson, A., Brucker, S. Y., Bruening, T., Burwinkel, B., Butterbach, K., Cai, Q., Cai, H., Caldes, T., Canzian, F., Carracedo, A., Carter, B. D., Castelao, J. E., Chan, T. L., Cheng, T., Chia, K., Choi, J., Christiansen, H., Clarke, C. L., Collee, M., Conroy, D. M., Cordina-Duverger, E., Cornelissen, S., Cox, D. G., Cox, A., Cross, S. S., Cunningham, J. M., Czene, K., Daly, M. B., Devilee, P., Doheny, K. F., Doerk, T., dos-Santos-Silva, I., Dumont, M., Durcan, L., Dwek, M., Eccles, D. M., Ekici, A. B., Eliassen, A., Ellberg, C., Elvira, M., Engel, C., Eriksson, M., Fasching, P. A., Figueroa, J., Flesch-Janys, D., Fletcher, O., Flyger, H., Fritschi, L., Gaborieau, V., Gabrielson, M., Gago-Dominguez, M., Gao, Y., Gapstur, S. M., Garcia-Saenz, J. A., Gaudet, M. M., Georgoulias, V., Giles, G. G., Glendon, G., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Alnaes, G., Grip, M., Gronwald, J., Grundy, A., Guenel, P., Haeberle, L., Hahnen, E., Haiman, C. A., Hakansson, N., Hamann, U., Hamel, N., Hankinson, S., Harrington, P., Hart, S. N., Hartikainen, J. M., Hartman, M., Hein, A., Heyworth, J., Hicks, B., Hillemanns, P., Ho, D. N., Hollestelle, A., Hooning, M. J., Hoover, R. N., Hopper, J. L., Hou, M., Hsiung, C., Huang, G., Humphreys, K., Ishiguro, J., Ito, H., Iwasaki, M., Iwata, H., Jakubowska, A., Janni, W., John, E. M., Johnson, N., Jones, K., Jones, M., Jukkola-Vuorinen, A., Kaaks, R., Kabisch, M., Kaczmarek, K., Kang, D., Kasuga, Y., Kerin, M. J., Khan, S., Khusnutdinova, E., Kiiski, J. I., Kim, S., Knight, J. A., Kosma, V., Kristensen, V. N., Kruger, U., Kwong, A., Lambrechts, D., Le Marchand, L., Lee, E., Lee, M., Lee, J., Lee, C., Lejbkowicz, F., Li, J., Lilyquist, J., Lindblom, A., Lissowska, J., Lo, W., Loibl, S., Long, J., Lophatananon, A., Lubinski, J., Luccarini, C., Lux, M. P., Ma, E. K., MacInnis, R. J., Maishman, T., Makalic, E., Malone, K. E., Kostovska, I., Mannermaa, A., Manoukian, S., Manson, J. E., Margolin, S., Mariapun, S., Martinez, M., Matsuo, K., Mavroudis, D., McKay, J., McLean, C., Meijers-Heijboer, H., Meindl, A., Menendez, P., Menon, U., Meyer, J., Miao, H., Miller, N., Taib, N., Muir, K., Mulligan, A., Mulot, C., Neuhausen, S. L., Nevanlinna, H., Neven, P., Nielsen, S. F., Noh, D., Nordestgaard, B. G., Norman, A., Olopade, O. I., Olson, J. E., Olsson, H., Olswold, C., Orr, N., Pankratz, V., Park, S. K., Park-Simon, T., Lloyd, R., Perez, J. A., Peterlongo, P., Peto, J., Phillips, K., Pinchev, M., Plaseska-Karanfilska, D., Prentice, R., Presneau, N., Prokofyeva, D., Pugh, E., Pylkas, K., Rack, B., Radice, P., Rahman, N., Rennert, G., Rennert, H. S., Rhenius, V., Romero, A., Romm, J., Ruddy, K. J., Ruediger, T., Rudolph, A., Ruebner, M., Rutgers, E. T., Saloustros, E., Sandler, D. P., Sangrajrang, S., Sawyer, E. J., Schmidt, D. F., Schmutzler, R. K., Schneeweiss, A., Schoemaker, M. J., Schumacher, F., Schuermann, P., Scott, R. J., Scott, C., Seal, S., Seynaeve, C., Shah, M., Sharma, P., Shen, C., Sheng, G., Sherman, M. E., Shrubsole, M. J., Shu, X., Smeets, A., Sohn, C., Southey, M. C., Spinelli, J. J., Stegmaier, C., Stewart-Brown, S., Stone, J., Stram, D. O., Surowy, H., Swerdlow, A., Tamimi, R., Taylor, J. A., Tengstrom, M., Teo, S. H., Terry, M., Tessier, D. C., Thanasitthichai, S., Thoene, K., Tollenaar, R. M., Tomlinson, I., Tong, L., Torres, D., Truong, T., Tseng, C., Tsugane, S., Ulmer, H., Ursin, G., Untch, M., Vachon, C., van Asperen, C. J., Van Den Berg, D., van den Ouweland, A. W., van der Kolk, L., van der Luijt, R. B., Vincent, D., Vollenweider, J., Waisfisz, Q., Wang-Gohrke, S., Weinberg, C. R., Wendt, C., Whittemore, A. S., Wildiers, H., Willett, W., Winqvist, R., Wolk, A., Wu, A. H., Xia, L., Yamaji, T., Yang, X. R., Yip, C., Yoo, K., Yu, J., Zheng, W., Zheng, Y., Zhu, B., Ziogas, A., Ziv, E., Lakhani, S. R., Antoniou, A. C., Droit, A., Andrulis, I. L., Amos, C. I., Couch, F. J., Pharoah, P. P., Chang-Claude, J., Hall, P., Hunter, D. J., Milne, R. L., Garcia-Closas, M., Schmidt, M. K., Chanock, S. J., Dunning, A. M., Edwards, S. L., Bader, G. D., Chenevix-Trench, G., Simard, J., Kraft, P., Easton, D. F., NBCS Collaborators, ABCTB Investigators, KConFab AOCS Investigators 2017; 551 (7678): 92-+

  Abstract

  Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

  View details for PubMedID 29059683

  View details for PubMedCentralID PMC5798588

• Assessing biological and technological variability in protein levels measured in pre-diagnostic plasma samples of women with breast cancer. Biomarker research Yeh, C. Y., Adusumilli, R., Kullolli, M., Mallick, P., John, E. M., Pitteri, S. J. 2017; 5: 30

  Abstract

  Quantitative proteomics allows for the discovery and functional investigation of blood-based pre-diagnostic biomarkers for early cancer detection. However, a major limitation of proteomic investigations in biomarker studies remains the biological and technical variability in the analysis of complex clinical samples. Moreover, unlike 'omics analogues such as genomics and transcriptomics, proteomics has yet to achieve reproducibility and long-term stability on a unified technological platform. Few studies have thoroughly investigated protein variability in pre-diagnostic samples of cancer patients across multiple platforms.We obtained ten blood plasma "case" samples collected up to 2 years prior to breast cancer diagnosis. Each case sample was paired with a matched control plasma from a full biological sister without breast cancer. We measured protein levels using both mass-spectrometry and antibody-based technologies to: (1) assess the technical considerations in different protein assays when analyzing limited clinical samples, and (2) evaluate the statistical power of potential diagnostic analytes.Although we found inherent technical variation in the three assays used, we detected protein dependent biological signal from the limited samples. The three assay types yielded 32 proteins with statistically significantly (p < 1E-01) altered expression levels between cases and controls, with no proteins retaining statistical significance after false discovery correction.Technical, practical, and study design considerations are essential to maximize information obtained in limited pre-diagnostic samples of cancer patients. This study provides a framework that estimates biological effect sizes critical for consideration in designing studies for pre-diagnostic blood-based biomarker detection.

  View details for DOI 10.1186/s40364-017-0110-y

  View details for PubMedID 29075496

  View details for PubMedCentralID PMC5645980

• A pilot study on the utility of reduced urine collection frequency protocols for the assessment of reproductive hormones in adolescent girls JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM Allaway, H. M., John, E. M., Keegan, T. H., De Souza, M. 2017; 30 (10): 1083–93

  Abstract

  The objectives of this study were to assess the feasibility of and compliance to collecting urine samples in pre- and postmenarcheal girls and to determine if a less than daily collection frequency was sufficient for assessing ovarian function.Twenty-five postmenarcheal girls (11-17 years) collected samples using either a two or a three samples/week protocol during one menstrual cycle. Exposure and mean estrone-1-glucuronide (E1G) and pregnanediol glucuronide concentrations were calculated, and evidence of luteal activity (ELA) was evaluated. Sixteen premenarcheal girls (8-11 years) collected one sample/month for six consecutive months. Samples were analyzed for E1G concentration. Participant compliance was calculated using dates on the urine samples and paper calendars.Participants collecting three samples/week were more compliant to the protocol than those collecting two samples/week (83.6%±2.6% vs. 66.8%±6.6%; p=0.034). There were no differences (p>0.10) regarding paper calendar return (81.8%±12.2% vs. 92.9%±7.1%), recording menses (55.6%±17.6% vs. 92.3%±7.7%) or sample collection (88.9%±11.1% vs. 84.6%±10.4%) between the two protocols. The average cycle length was 30.5±1.3 days and 32% of cycles had ELA. The premenarcheal girls were 100% compliant to the protocol. Only 68.8% of participants returned the paper calendar and 81.8% of those participants recorded sample collection. The average E1G concentration was 15.9±3.8 ng/mL.Use of a less than daily collection frequency during one menstrual cycle in postmenarcheal, adolescent girls is feasible and provides informative data about ovarian function. Collection of one sample/month in premenarcheal girls is feasible and detects the expected low E1G concentrations. Alternate strategies to the use of a paper calendar should be considered.

  View details for DOI 10.1515/jpem-2017-0050

  View details for Web of Science ID 000412132400010

  View details for PubMedID 28949930

• Association of Common Genetic Variants With Contralateral Breast Cancer Risk in the WECARE Study. Journal of the National Cancer Institute Robson, M. E., Reiner, A. S., Brooks, J. D., Concannon, P. J., John, E. M., Mellemkjaer, L., Bernstein, L., Malone, K. E., Knight, J. A., Lynch, C. F., Woods, M., Liang, X., Haile, R. W., Duggan, D. J., Shore, R. E., Smith, S. A., Thomas, D. C., Stram, D. O., Bernstein, J. L. 2017; 109 (10)

  Abstract

  Women with unilateral breast cancer (UBC) are at risk of developing a subsequent contralateral breast cancer (CBC). Common variants are associated with breast cancer risk. Whether these influence CBC risk is unknown.Participants were breast cancer cases from the population-based Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study. Sixty-seven established breast cancer risk loci were genotyped directly or by imputation in 1459 case subjects with CBC and 2126 UBC control subjects. An unweighted polygenic risk score (PRS) was created by summing the number of risk alleles for each directly genotyped single nucleotide polymorphism (SNP), or for imputed loci, the imputed dosage. A weighted PRS was calculated similarly, but where each SNP's contribution was weighted by the published per-allele log odds ratio. Unweighted and weighted polygenic risk scores and CBC risk were modeled using conditional logistic regression. Cumulative CBC risk was estimated and benchmarked using Surveillance, Epidemiology, and End Results population incidence rates.Both unweighted and weighted PRS were statistically significantly associated with CBC risk. The adjusted risk ratio of CBC in women in the upper quartile of unweighted PRS compared with the lowest quartile was 1.63 (95% confidence interval [CI] = 1.33 to 2.00). The estimated 10-year cumulative risk for women in the upper quartile of the unweighted PRS was 7.4% (95% CI = 6.0% to 9.1%). For women in the upper quartile of the weighted PRS, the risk ratio for CBC was 1.75 (95% CI = 1.41 to 2.18) compared with women in the lowest quartile. There was no statistically significant heterogeneity by age, treatment (radiation therapy dose, tamoxifen, chemotherapy), estrogen receptor status of the first primary, histology of the first primary, length of at-risk period for CBC, or breast cancer family history.Common genomic variants associated with the development of first primary breast cancer are also associated with the development of CBC; the risk is strongest among those who carry more risk alleles.

  View details for DOI 10.1093/jnci/djx051

  View details for PubMedID 28521362

• Reply to Dietary isoflavone intake and all-cause mortality in breast cancer survivors: The Breast Cancer Family Registry-methodological issues CANCER Zhang, F., John, E. M. 2017; 123 (18): 3639

  View details for PubMedID 28621796

• Alcohol consumption and cigarette smoking in combination: A predictor of contralateral breast cancer risk in the WECARE study INTERNATIONAL JOURNAL OF CANCER Knight, J. A., Fan, J., Malone, K. E., John, E. M., Lynch, C. F., Langballe, R., Bernstein, L., Shore, R. E., Brooks, J. D., Reiner, A. S., Woods, M., Liang, X., Bernstein, J. L., WECARE Study Collaborative Grp 2017; 141 (5): 916–24

  Abstract

  Alcohol drinking and, to a lesser extent, cigarette smoking are risk factors for a first primary breast cancer. Information on these behaviours at diagnosis may contribute to risk prediction of contralateral breast cancer (CBC) and they are potentially modifiable. The WECARE Study is a large population-based case-control study of women with breast cancer where cases (N = 1,521) had asynchronous CBC and controls (N = 2,212), matched on survival time and other factors, had unilateral breast cancer (UBC). Using multivariable conditional logistic regression to estimate rate ratios (RR) and 95% confidence intervals (CI), we examined the risk of CBC in relation to drinking and smoking history at and following first diagnosis. We adjusted for treatment, disease characteristics and other factors. There was some evidence for an association between CBC risk and current drinking or current smoking at the time of first breast cancer diagnosis, but the increased risk occurred primarily among women exposed to both (RR = 1.62, 95% CI 1.24-2.11). CBC risk was also elevated in women who both smoked and drank alcohol after diagnosis (RR = 1.54, 95% CI 1.18-1.99). In the subset of women with detailed information on amount consumed, smoking an average of ≥10 cigarettes per day following diagnosis was also associated with increased CBC risk (RR = 1.50, 95% CI 1.08-2.08; p-trend = 0.03). Among women with a diagnosis of breast cancer, information on current drinking and smoking could contribute to the prediction of CBC risk. Women who both drink and smoke may represent a group who merit targeted lifestyle intervention to modify their risk of CBC.

  View details for PubMedID 28524234

  View details for PubMedCentralID PMC5518236

• Two Novel Susceptibility Loci for Prostate Cancer in Men of African Ancestry JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Conti, D. V., Wang, K., Sheng, X., Bensen, J. T., Hazelett, D. J., Cook, M. B., Ingles, S. A., Kittles, R. A., Strom, S. S., Rybicki, B. A., Nemesure, B., Isaacs, W. B., Stanford, J. L., Zheng, W., Sanderson, M., John, E. M., Park, J. Y., Xu, J., Stevens, V. L., Berndt, S. I., Haiman, C. A., PRACTICAL ELLIPSE Consortium 2017; 109 (8)

  Abstract

  Prostate cancer incidence is 1.6-fold higher in African Americans than in other populations. The risk factors that drive this disparity are unknown and potentially consist of social, environmental, and genetic influences. To investigate the genetic basis of prostate cancer in men of African ancestry, we performed a genome-wide association meta-analysis using two-sided statistical tests in 10 202 case subjects and 10 810 control subjects. We identified novel signals on chromosomes 13q34 and 22q12, with the risk-associated alleles found only in men of African ancestry (13q34: rs75823044, risk allele frequency = 2.2%, odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.37 to 1.76, P = 6.10 × 10-12; 22q12.1: rs78554043, risk allele frequency = 1.5%, OR = 1.62, 95% CI = 1.39 to 1.89, P = 7.50 × 10-10). At 13q34, the signal is located 5' of the gene IRS2 and 3' of a long noncoding RNA, while at 22q12 the candidate functional allele is a missense variant in the CHEK2 gene. These findings provide further support for the role of ancestry-specific germline variation in contributing to population differences in prostate cancer risk.

  View details for PubMedID 29117387

  View details for PubMedCentralID PMC5448553

• Hormone receptor status of a first primary breast cancer predicts contralateral breast cancer risk in the WECARE study population BREAST CANCER RESEARCH Reiner, A. S., Lynch, C. F., Sisti, J. S., John, E. M., Brooks, J. D., Bernstein, L., Knight, J. A., Hsu, L., Concannon, P., Mellemkjaer, L., Tischkowitz, M., Haile, R. W., Shen, R., Malone, K. E., Woods, M., Liang, X., Morrow, M., Bernstein, J. L., WECARE Study Collaborative Grp 2017; 19

  View details for DOI 10.1186/s13058-017-0874-x

  View details for Web of Science ID 000405798500001

• Hormone receptor status of a first primary breast cancer predicts contralateral breast cancer risk in the WECARE study population. Breast cancer research : BCR Reiner, A. S., Lynch, C. F., Sisti, J. S., John, E. M., Brooks, J. D., Bernstein, L., Knight, J. A., Hsu, L., Concannon, P., Mellemkjær, L., Tischkowitz, M., Haile, R. W., Shen, R., Malone, K. E., Woods, M., Liang, X., Morrow, M., Bernstein, J. L. 2017; 19 (1): 83

  Abstract

  Previous population-based studies have described first primary breast cancer tumor characteristics and their association with contralateral breast cancer (CBC) risk. However, information on influential covariates such as treatment, family history of breast cancer, and BRCA1/2 mutation carrier status was not available. In a large, population-based, case-control study, we evaluated whether tumor characteristics of the first primary breast cancer are associated with risk of developing second primary asynchronous CBC, overall and in subgroups of interest, including among BRCA1/2 mutation non-carriers, women who are not treated with tamoxifen, and women without a breast cancer family history.The Women's Environmental Cancer and Radiation Epidemiology Study is a population-based case-control study of 1521 CBC cases and 2212 individually-matched controls with unilateral breast cancer. Detailed information about breast cancer risk factors, treatment for and characteristics of first tumors, including estrogen receptor (ER) and progesterone receptor (PR) status, was obtained by telephone interview and medical record abstraction. Multivariable risk ratios (RRs) and 95% confidence intervals (CIs) were estimated in conditional logistic regression models, adjusting for demographics, treatment, and personal medical and family history. A subset of women was screened for BRCA1/2 mutations.Lobular histology of the first tumor was associated with a 30% increase in CBC risk (95% CI 1.0-1.6). Compared to women with ER+/PR+ first tumors, those with ER-/PR- tumors had increased risk of CBC (RR = 1.4, 95% CI 1.1-1.7). Notably, women with ER-/PR- first tumors were more likely to develop CBC with the ER-/PR- phenotype (RR = 5.4, 95% CI 3.0-9.5), and risk remained elevated in multiple subgroups: BRCA1/2 mutation non-carriers, women younger than 45 years of age, women without a breast cancer family history, and women who were not treated with tamoxifen.Having a hormone receptor negative first primary breast cancer is associated with increased risk of CBC. Women with ER-/PR- primary tumors were more likely to develop ER-/PR- CBC, even after excluding BRCA1/2 mutation carriers. Hormone receptor status, which is routinely evaluated in breast tumors, may be used clinically to determine treatment protocols and identify patients who may benefit from increased surveillance for CBC.

  View details for DOI 10.1186/s13058-017-0874-x

  View details for PubMedID 28724391

  View details for PubMedCentralID PMC5517810

• Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores JOURNAL OF CLINICAL ONCOLOGY Lecarpentier, J., Silvestri, V., Kuchenbaecker, K. B., Barrowdale, D., Dennis, J., McGuffog, L., Soucy, P., Leslie, G., Rizzolo, P., Navazio, A., Valentini, V., Zelli, V., Lee, A., Al Olama, A., Tyrer, J. P., Southey, M., John, E. M., Conner, T. A., Goldgar, D. E., Buys, S. S., Janavicius, R., Steele, L., Ding, Y., Neuhausen, S. L., Hansen, T. O., Osorio, A., Weitzel, J. N., Toss, A., Medici, V., Cortesi, L., Zanna, I., Palli, D., Radice, P., Manoukian, S., Peissel, B., Azzollini, J., Viel, A., Cini, G., Damante, G., Tommasi, S., Peterlongo, P., Fostira, F., Hamann, U., Evans, D., Henderson, A., Brewer, C., Eccles, D., Cook, J., Ong, K., Walker, L., Side, L. E., Porteous, M. E., Davidson, R., Hodgson, S., Frost, D., Adlard, J., Izatt, L., Eeles, R., Ellis, S., Tischkowitz, M., Godwin, A. K., Meindl, A., Gehrig, A., Dworniczak, B., Sutter, C., Engel, C., Niederacher, D., Steinemann, D., Hahnen, E., Hauke, J., Rhiem, K., Kast, K., Arnold, N., Ditsch, N., Wang-Gohrke, S., Wappenschmidt, B., Wand, D., Lasset, C., Stoppa-Lyonnet, D., Belotti, M., Damiola, F., Barjhoux, L., Mazoyer, S., Van Heetvelde, M., Poppe, B., De Leeneer, K., Claes, K. M., de la Hoya, M., Garcia-Barberan, V., Caldes, T., Perez Segura, P., Kiiski, J. I., Aittomaeki, K., Khan, S., Nevanlinna, H., van Asperen, C. J., Vaszko, T., Kasler, M., Olah, E., Balmana, J., Gutierrez-Enriquez, S., Diez, O., Teule, A., Izquierdo, A., Darder, E., Brunet, J., Del Valle, J., Feliubadalo, L., Pujana, M., Lazaro, C., Arason, A., Agnarsson, B. A., Johannsson, O., Barkardottir, R. B., Alducci, E., Tognazzo, S., Montagna, M., Teixeira, M. R., Pinto, P., Spurdle, A. B., Holland, H., Lee, J., Lee, M., Lee, J., Kim, S., Kang, E., Kim, Z., Sharma, P., Rebbeck, T. R., Vijai, J., Robson, M., Lincoln, A., Musinsky, J., Gaddam, P., Tan, Y. Y., Berger, A., Singer, C. F., Loud, J. T., Greene, M. H., Mulligan, A., Glendon, G., Andrulis, I. L., Toland, A., Senter, L., Bojesen, A., Nielsen, H., Skytte, A., Sunde, L., Jensen, U., Pedersen, I., Krogh, L., Kruse, T. A., Caligo, M. A., Yoon, S., Teo, S., von Wachenfeldt, A., Huo, D., Nielsen, S. M., Olopade, O. I., Nathanson, K. L., Domchek, S. M., Lorenchick, C., Jankowitz, R. C., Campbell, I., James, P., Mitchell, G., Orr, N., Park, S., Thomassen, M., Offit, K., Couch, F. J., Simard, J., Easton, D. F., Chenevix-Trench, G., Schmutzler, R. K., Antoniou, A. C., Ottini, L., EMBRACE, GEMO Study Collaborators, HEBON, KConFab Investigators 2017; 35 (20): 2240-+

  Abstract

  Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.

  View details for PubMedID 28448241

  View details for PubMedCentralID PMC5501359

• Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Kuchenbaecker, K. B., McGuffog, L., Barrowdale, D., Lee, A., Soucy, P., Dennis, J., Domchek, S. M., Robson, M., Spurdle, A. B., Ramus, S. J., Mavaddat, N., Terry, M., Neuhausen, S. L., Schmutzler, R., Simard, J., Pharoah, P. P., Offit, K., Couch, F. J., Chenevix-Trench, G., Easton, D. F., Antoniou, A. C. 2017; 109 (7)

  Abstract

  Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates.We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS.The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P =  8.2×10 -53 ). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P =  7.2×10 -20 ). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS.BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.

  View details for DOI 10.1093/jnci/djw302

  View details for Web of Science ID 000405496200004

  View details for PubMedID 28376175

  View details for PubMedCentralID PMC5408990

• Characterizing Genetic Susceptibility to Breast Cancer in Women of African Ancestry CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Feng, Y., Rhie, S., Huo, D., Ruiz-Narvaez, E. A., Haddad, S. A., Ambrosone, C. B., John, E. M., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Zheng, Y., Yao, S., Han, Y., Ogundiran, T. O., Rebbeck, T. R., Adebamowo, C., Ojengbede, O., Falusi, A. G., Hennis, A., Nemesure, B., Ambs, S., Blot, W., Cai, Q., Signorello, L., Nathanson, K. L., Lunetta, K. L., Sucheston-Campbell, L. E., Bensen, J. T., Chanock, S. J., Le Marchand, L., Olshan, A. F., Kolonel, L. N., Conti, D. V., Coetzee, G. A., Stram, D. O., Olopade, O. I., Palmer, J. R., Haiman, C. A. 2017; 26 (7): 1016–26

  Abstract

  Background: Genome-wide association studies have identified approximately 100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Because of different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry.Methods: We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER, and ROOT).Results: Fifty-four of the 74 variants (73%) were found to have ORs that were directionally consistent with those previously reported, of which 12 were nominally statistically significant (P < 0.05). Through fine-mapping, in six regions (3p24, 12p11, 14q13, 16q12/FTO, 16q23, 19p13), we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions (11q13, 16q12/TOX3), we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality.Conclusions: Through fine-mapping of known susceptibility regions, we have revealed alleles that better characterize breast cancer risk in women of African ancestry.Impact: The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry. Cancer Epidemiol Biomarkers Prev; 26(7); 1016-26. ©2017 AACR.

  View details for PubMedID 28377418

  View details for PubMedCentralID PMC5500414

• Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Kuchenbaecker, K. B., Hopper, J. L., Barnes, D. R., Phillips, K., Mooij, T. M., Roos-Blom, M., Jervis, S., van Leeuwen, F. E., Milne, R. L., Andrieu, N., Goldgar, D. E., Terry, M., Rookus, M. A., Easton, D. F., Antoniou, A. C., BRCA1 BRCA2 Cohort Consortium 2017; 317 (23): 2402–16

  Abstract

  The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates.To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location.Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years.BRCA1/2 mutations, family cancer history, and mutation location.Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer.Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001).These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.

  View details for PubMedID 28632866

• Pubertal development in girls by breast cancer family history: the LEGACY girls cohort BREAST CANCER RESEARCH Terry, M., Keegan, T. M., Houghton, L. C., Goldberg, M., Andrulis, I. L., Daly, M. B., Buys, S. S., Wei, Y., Whittemore, A. S., Protacio, A., Bradbury, A. R., Chung, W. K., Knight, J. A., John, E. M. 2017; 19: 69

  Abstract

  Pubertal milestones, such as onset of breast development and menstruation, play an important role in breast cancer etiology. It is unclear if these milestones are different in girls with a first- or second-degree breast cancer family history (BCFH).In the LEGACY Girls Study (n = 1040), we examined whether three mother/guardian-reported pubertal milestones (having reached Tanner Stage 2 or higher (T2+) for breast and pubic hair development, and having started menstruation) differed by BCFH. We also examined whether associations between body size and race/ethnicity and pubertal milestones were modified by BCFH. We used mother/guardian reports as the primary measure of pubertal milestones, but also conducted sensitivity analyses using clinical Tanner measurements available for a subcohort (n = 204). We analyzed cross-sectional baseline data with logistic regression models for the entire cohort, and longitudinal data with Weibull survival models for the subcohort of girls that were aged 5-7 years at baseline (n = 258).BCFH was modestly, but not statistically significantly, associated with Breast T2+ (odds ratio (OR) = 1.36, 95% confidence interval (CI) = 0.88-2.10), with a stronger association seen in the subcohort of girls with clinical breast Tanner staging (OR = 2.20, 95% CI = 0.91-5.32). In a longitudinal analysis of girls who were aged 5-7 years at baseline, BCFH was associated with a 50% increased rate of having early breast development (hazard ratio (HR) = 1.49, 95% CI = 1.0-2.21). This association increased to twofold in girls who were not overweight at baseline (HR = 2.04, 95% CI = 1.29-3.21). BCFH was not associated with pubic hair development and post-menarche status. The median interval between onset of breast development and menarche was longer for BCFH+ than BCFH- girls (2.3 versus 1.7 years), suggesting a slower developmental tempo for BCFH+ girls. Associations between pubertal milestones and body size and race/ethnicity were similar in girls with or without a BCFH. For example, weight was positively associated with Breast T2+ in both girls with (OR = 1.06 per 1 kg, 95% CI = 1.03-1.10) and without (OR = 1.14 per 1 kg, 95% CI = 1.04-1.24) a BCFH.These results suggest that BCFH may be related to earlier breast development and slower pubertal tempo independent of body size and race/ethnicity.

  View details for PubMedID 28595647

  View details for PubMedCentralID PMC5465536

• Dietary isoflavone intake and all-cause mortality in breast cancer survivors: The Breast Cancer Family Registry. Cancer Zhang, F. F., Haslam, D. E., Terry, M. B., Knight, J. A., Andrulis, I. L., Daly, M. B., Buys, S. S., John, E. M. 2017; 123 (11): 2070-2079

  Abstract

  Soy foods possess both antiestrogenic and estrogen-like properties. It remains controversial whether women diagnosed with breast cancer should be advised to eat more or less soy foods, especially for those who receive hormone therapies as part of cancer treatment.The association of dietary intake of isoflavone, the major phytoestrogen in soy, with all-cause mortality was examined in 6235 women with breast cancer enrolled in the Breast Cancer Family Registry. Dietary intake was assessed using a Food Frequency Questionnaire developed for the Hawaii-Los Angeles Multiethnic Cohort among 5178 women who reported prediagnosis diet and 1664 women who reported postdiagnosis diet. Cox proportional-hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).During a median follow-up of 113 months (approximately 9.4 years), 1224 deaths were documented. A 21% decrease was observed in all-cause mortality for women who had the highest versus lowest quartile of dietary isoflavone intake (≥1.5 vs < 0.3 mg daily: HR, 0.79; 95% confidence interval CI, 0.64-0.97; Ptrend  = .01). Lower mortality associated with higher intake was limited to women who had tumors that were negative for hormone receptors (HR, 0.49; 95% CI, 0.29-0.83; Ptrend  = .005) and those who did not receive hormone therapy for their breast cancer (HR, 0.68; 95% CI, 0.51-0.91; Ptrend  = .02). Interactions, however, did not reach statistical significance.In this large, ethnically diverse cohort of women with breast cancer living in North America, a higher dietary intake of isoflavone was associated with reduced all-cause mortality. Cancer 2017;123:2070-2079. © 2017 American Cancer Society.

  View details for DOI 10.1002/cncr.30615

  View details for PubMedID 28263368

• Limited influence of germline genetic variation on all-cause mortality in women with early onset breast cancer: evidence from gene-based tests, single-marker regression, and whole-genome prediction. Breast cancer research and treatment Scannell Bryan, M., Argos, M., Andrulis, I. L., Hopper, J. L., Chang-Claude, J., Malone, K., John, E. M., Gammon, M. D., Daly, M., Terry, M. B., Buys, S. S., Huo, D., Olopade, O., Genkinger, J. M., Jasmine, F., Kibriya, M. G., Chen, L., Ahsan, H. 2017

  Abstract

  Women diagnosed with breast cancer have heterogeneous survival outcomes that cannot be fully explained by known prognostic factors, and germline variation is a plausible but unconfirmed risk factor.We used three approaches to test the hypothesis that germline variation drives some differences in survival: mortality loci identification, tumor aggressiveness loci identification, and whole-genome prediction. The 2954 study participants were women diagnosed with breast cancer before age 50, with a median follow-up of 15 years who were genotyped on an exome array. We first searched for loci in gene regions that were associated with all-cause mortality. We next searched for loci in gene regions associated with five histopathological characteristics related to tumor aggressiveness. Last, we also predicted 10-year all-cause mortality on a subset of 1903 participants (3,245,343 variants after imputation) using whole-genome prediction methods.No risk loci for mortality or tumor aggressiveness were identified. This null result persisted when restricting to women with estrogen receptor-positive tumors, when examining suggestive loci in an independent study, and when restricting to previously published risk loci. Additionally, the whole-genome prediction model also found no evidence to support an association.Despite multiple complementary approaches, our study found no evidence that mortality in women with early onset breast cancer is influenced by germline variation.

  View details for DOI 10.1007/s10549-017-4287-4

  View details for PubMedID 28503721

• Genetic modifiers of CHEK2*1100delC-associated breast cancer risk GENETICS IN MEDICINE Muranen, T. A., Greco, D., Blomqvist, C., Aittomaki, K., Khan, S., Hogervorst, F., Verhoef, S., Pharoah, P. D., Dunning, A. M., Shah, M., Luben, R., Bojesen, S. E., Nordestgaard, B. G., Schoemaker, M., Swerdlow, A., Garcia-Closas, M., Figueroa, J., Doerk, T., Bogdanova, N. V., Hall, P., Li, J., Khusnutdinova, E., Bermisheva, M., Kristensen, V., Borresen-Dale, A., Peto, J., Silva, I. d., Couch, F. J., Olson, J. E., Hillemans, P., Park-Simon, T., Brauch, H., Hamann, U., Burwinkel, B., Marme, F., Meindl, A., Schmutzler, R. K., Cox, A., Cross, S. S., Sawyer, E. J., Tomlinson, I., Lambrechts, D., Moisse, M., Lindblom, A., Margolin, S., Hollestelle, A., Martens, J. W., Fasching, P. A., Beckmann, M. W., Andrulis, I. L., Knight, J. A., Anton-Culver, H., Ziogas, A., Giles, G. G., Milne, R. L., Brenner, H., Arndt, V., Mannermaa, A., Kosma, V., Chang-Claude, J., Rudolph, A., Devilee, P., Seynaeve, C., Hopper, J. L., Southey, M. C., John, E. M., Whittemore, A. S., Bolla, M. K., Wang, Q., Michailidou, K., Dennis, J., Easton, D. F., Schmidt, M. K., Nevanlinna, H. 2017; 19 (5): 599-603

  Abstract

  CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction.The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average.Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.

  View details for DOI 10.1038/gim.2016.147

  View details for Web of Science ID 000401247400017

  View details for PubMedCentralID PMC5382131

• Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer NATURE GENETICS Phelan, C. M., Kuchenbaecker, K. B., Tyrer, J. P., Kar, S. P., Lawrenson, K., Winham, S. J., Dennis, J., Pirie, A., Riggan, M. J., Chornokur, G., Earp, M. A., Lyra, P. C., Lee, J. M., Coetzee, S., Beesley, J., McGuffog, L., Soucy, P., Dicks, E., Lee, A., Barrowdale, D., Lecarpentier, J., Leslie, G., Aalfs, C. M., Aben, K. K., Adams, M., Adlard, J., Andrulis, I. L., Anton-Culver, H., Antonenkova, N., Aravantinos, G., Arnold, N., Arun, B. K., Arver, B., Azzollini, J., Balmana, J., Banerjee, S. N., Barjhoux, L., Barkardottir, R. B., Bean, Y., Beckmann, M. W., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Bernardini, M. Q., Birrer, M. J., Bjorge, L., Black, A., Blankstein, K., Blok, M. J., Bodelon, C., Bogdanova, N., Bojesen, A., Bonanni, B., Borg, A., Bradbury, A. R., Brenton, J. D., Brewer, C., Brinton, L., Broberg, P., Brooks-Wilson, A., Bruinsma, F., Brunet, J., Buecher, B., Butzow, R., Buys, S. S., Caldes, T., Caligo, M. A., Campbell, I., Cannioto, R., Carney, M. E., Cescon, T., Chan, S. B., Chang-Claude, J., Chanock, S., Chen, X. Q., Chiew, Y., Chiquette, J., Chung, W. K., Claes, K. B., Conner, T., Cook, L. S., Cook, J., Cramer, D. W., Cunningham, J. M., D'Aloisio, A. A., Daly, M. B., Damiola, F., Damirovna, S. D., Dansonka-Mieszkowska, A., Dao, F., Davidson, R., deFazio, A., Delnatte, C., Doheny, K. F., Diez, O., Ding, Y. C., Doherty, J. A., Domchek, S. M., Dorfling, C. M., Dork, T., Dossus, L., Duran, M., Durst, M., Dworniczak, B., Eccles, D., Edwards, T., Eeles, R., Eilber, U., Ejlertsen, B., Ekici, A. B., Ellis, S., Elvira, M., Eng, K. H., Engel, C., Evans, D. G., Fasching, P. A., Ferguson, S., Ferrer, S. F., Flanagan, J. M., Fogarty, Z. C., Fortner, R. T., Fostira, F., Foulkes, W. D., Fountzilas, G., Fridley, B. L., Friebel, T. M., friedman, e., Frost, D., Ganz, P. A., Garber, J., Garcia, M. J., Garcia-Barberan, V., Gehrig, A., Gentry-Maharaj, A., Gerdes, A., Giles, G. G., Glasspool, R., Glendon, G., Godwin, A. K., Goldgar, D. E., Goranova, T., Gore, M., Greene, M. H., Gronwald, J., Gruber, S., Hahnen, E., Haiman, C. A., Hakansson, N., Hamann, U., Hansen, T. v., Harrington, P. A., Harris, H. R., Hauke, J., Hein, A., Henderson, A., Hildebrandt, M. A., Hillemanns, P., Hodgson, S., Hogdall, C. K., Hogdall, E., Hogervorst, F. B., Holland, H., Hooning, M. J., Hosking, K., Huang, R., Hulick, P. J., Hung, J., Hunter, D. J., Huntsman, D. G., Huzarski, T., Imyanitov, E. N., Isaacs, C., Iversen, E. S., Izatt, L., Izquierdo, A., Jakubowska, A., James, P., Janavicius, R., Jernetz, M., Jensen, A., Jensen, U. B., John, E. M., Johnatty, S., Jones, M. E., Kannisto, P., Karlan, B. Y., Karnezis, A., Kast, K., Kennedy, C. J., Khusnutdinova, E., Kiemeney, L. A., Kiiski, J. I., Kim, S., Kjaer, S. K., Kobel, M., Kopperud, R. K., Kruse, T. A., Kupryjanczyk, J., Kwong, A., Laitman, Y., Lambrechts, D., Larranaga, N., Larson, M. C., Lazaro, C., Le, N. D., Le Marchand, L., Lee, J. W., Lele, S. B., Leminen, A., Leroux, D., Lester, J., Lesueur, F., Levine, D. A., Liang, D., Liebrich, C., Lilyquist, J., Lipworth, L., Lissowska, J., Lu, K. H., Lubinski, J., Luccarini, C., Lundvall, L., Mai, P. L., Mendoza-Fandino, G., Manoukian, S., Massuger, L. F., May, T., Mazoyer, S., McAlpine, J. N., McGuire, V., McLaughlin, J. R., McNeish, I., Meijers-Heijboer, H., Meindl, A., Menon, U., Mensenkamp, A. R., Merritt, M. A., Milne, R. L., Mitchell, G., Modugno, F., Moes-Sosnowska, J., Moffitt, M., Montagna, M., Moysich, K. B., Mulligan, A. M., Musinsky, J., Nathanson, K. L., Nedergaard, L., Ness, R. B., Neuhausen, S. L., Nevanlinna, H., Niederacher, D., Nussbaum, R. L., Odunsi, K., Olah, E., Olopade, O. I., Olsson, H., Olswold, C., O'Malley, D. M., Ong, K., Onland-Moret, N. C., Orr, N., Orsulic, S., Osorio, A., Palli, D., Papi, L., Park-Simon, T., Paul, J., Pearce, C. L., Pedersen, I. S., Peeters, P. H., Peissel, B., Peixoto, A., Pejovic, T., Pelttari, L. M., Permuth, J. B., Peterlongo, P., Pezzani, L., Pfeiler, G., Phillips, K., Piedmonte, M., Pike, M. C., Piskorz, A. M., Poblete, S. R., Pocza, T., Poole, E. M., Poppe, B., Porteous, M. E., Prieur, F., Prokofyeva, D., Pugh, E., Pujana, M. A., Pujol, P., Radice, P., Rantala, J., Rappaport-Fuerhauser, C., Rennert, G., Rhiem, K., Rice, P., Richardson, A., Robson, M., Rodriguez, G. C., Rodriguez-Antona, C., Romm, J., Rookus, M. A., Rossing, M. A., Rothstein, J. H., Rudolph, A., Runnebaum, I. B., Salvesen, H. B., Sandler, D. P., Schoemaker, M. J., Senter, L., Setiawan, V. W., Severi, G., Sharma, P., Shelford, T., Siddiqui, N., Side, L. E., Sieh, W., Singer, C. F., Sobol, H., Song, H., Southey, M. C., Spurdle, A. B., Stadler, Z., Steinemann, D., Stoppa-Lyonnet, D., Sucheston-Campbell, L. E., Sukiennicki, G., Sutphen, R., Sutter, C., Swerdlow, A. J., Szabo, C. I., Szafron, L., Tan, Y. Y., Taylor, J. A., Tea, M., Teixeira, M. R., Teo, S., Terry, K. L., Thompson, P. J., Thomsen, L. C., Thull, D. L., Tihomirova, L., Tinker, A. V., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tone, A., Trabert, B., Travis, R. C., Trichopoulou, A., Tung, N., Tworoger, S. S., van Altena, A. M., Van Den Berg, D., van der Hout, A. H., van der Luijt, R. B., Van Heetvelde, M., van Nieuwenhuysen, E., Van Rensburg, E. J., Vanderstichele, A., Varon-Mateeva, R., Vega, A., Edwards, D. V., Vergote, I., Vierkant, R. A., Vijai, J., Vratimos, A., Walker, L., Walsh, C., Wand, D., Wang-Gohrke, S., Wappenschmidt, B., Webb, P. M., Weinberg, C. R., Weitzel, J. N., Wentzensen, N., Whittemore, A. S., Wijnen, J. T., Wilkens, L. R., Wolk, A., Woo, M., Wu, X., Wu, A. H., Yang, H., Yannoukakos, D., Ziogas, A., Zorn, K. K., Narod, S. A., Easton, D. F., Amos, C. I., Schildkraut, J. M., Ramus, S. J., Ottini, L., Goodman, M. T., Park-, S. K., Kelemen, L. E., Risch, H. A., Thomassen, M., Offit, K., Simard, J., Schmutzler, R. K., Hazelett, D., Monteiro, A. N., Couch, F. J., Berchuck, A., Chenevix-Trench, G., Goode, E. L., Sellers, T. A., Gayther, S. A., Antoniou, A. C., Pharoah, P. D. 2017; 49 (5): 680-?

  Abstract

  To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

  View details for DOI 10.1038/ng.3826

  View details for PubMedID 28346442

• The Interaction between Genetic Ancestry and Breast Cancer Risk Factors among Hispanic Women: The Breast Cancer Health Disparities Study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Hines, L. M., Sedjo, R. L., Byers, T., John, E. M., Fejerman, L., Stern, M. C., Baumgartner, K. B., Giuliano, A. R., Torres-Mejia, G., Wolff, R. K., Harrall, K. K., Slattery, M. L. 2017; 26 (5): 692–701

  Abstract

  Background: Hispanic women have lower breast cancer incidence rates than non-Hispanic white (NHW) women. To what extent genetic versus nongenetic factors account for this difference is unknown.Methods: Using logistic regression, we evaluated the interactive influences of established risk factors and ethnicity (self-identified and identified by ancestral informative markers) on breast cancer risk among 2,326 Hispanic and 1,854 NHW postmenopausal women from the United States and Mexico in the Breast Cancer Health Disparities Study.Results: The inverse association between the percentage of Native American (NA) ancestry and breast cancer risk was only slightly attenuated after adjusting for known risk factors [lowest versus highest quartile: odds ratio (OR) =1.39, 95% confidence interval (CI) = 1.00-1.92 among U.S. Hispanics; OR = 1.92 (95% CI, 1.29-2.86) among Mexican women]. The prevalence of several risk factors, as well as the associations with certain factors and breast cancer risk, differed according to genetic admixture. For example, higher body mass index (BMI) was associated with reduced risk among women with lower NA ancestry only [BMI <25 versus >30: OR = 0.65 (95% CI, 0.44-0.98) among U.S. Hispanics; OR = 0.53 (95% CI, 0.29-0.97) among Mexicans]. The average number of risk factors among cases was inversely related to the percentage of NA ancestry.Conclusions: The lower NA ancestry groups were more likely to have the established risk factors, with the exception of BMI. Although the majority of factors were associated with risk in the expected directions among all women, BMI had an inverse association among Hispanics with lower NA ancestry.Impact: These data suggest that the established risk factors are less relevant for breast cancer development among women with more NA ancestry. Cancer Epidemiol Biomarkers Prev; 26(5); 692-701. ©2016 AACR.

  View details for PubMedID 27932594

  View details for PubMedCentralID PMC5413419

• Racial/Ethnic Differences in the Impact of Neighborhood Social and Built Environment on Breast Cancer Risk: The Neighborhoods and Breast Cancer Study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Conroy, S. M., Shariff-Marco, S., Koo, J., Yang, J., Keegan, T. M., Sangaramoorthy, M., Hertz, A., Nelson, D. O., Cockburn, M., Satariano, W. A., Yen, I. H., Ponce, N. A., John, E. M., Gomez, S. 2017; 26 (4): 541–52

  Abstract

  Background: Neighborhood socioeconomic status (nSES) has been found to be associated with breast cancer risk. It remains unclear whether this association applies across racial/ethnic groups independent of individual-level factors and is attributable to other neighborhood characteristics.Methods: We examined the independent and joint associations of education and nSES with odds of breast cancer. Residential addresses were geocoded for 2,838 cases and 3,117 controls and linked to nSES and social and built environment characteristics. We estimated ORs and 95% confidence intervals (CI) using multilevel logistic regression controlling for individual-level breast cancer risk factors and assessed the extent to which nSES associations were due to neighborhood characteristics.Results: Women living in the highest versus lowest nSES quintile had a nearly 2-fold greater odds of breast cancer, with elevated odds (adjusted ORs, 95% CI) for non-Hispanic whites (NHWs; 2.27; 1.45-3.56), African Americans (1.74; 1.07-2.83), U.S.-born Hispanics (1.82; 1.19-2.79), and foreign-born Hispanics (1.83; 1.06-3.17). Considering education and nSES jointly, ORs were increased for low education/high nSES NHWs (1.83; 1.14-2.95), high education/high nSES NHWs (1.64; 1.06-2.54), and high education/high nSES foreign-born Hispanics (2.17; 1.52-3.09) relative to their race/ethnicity/nativity-specific low education/low nSES counterparts. Adjustment for urban and mixed-land use characteristics attenuated the nSES associations for most racial/ethnic/nativity groups except NHWs.Conclusions: Our study provides empirical evidence for a role of neighborhood environments in breast cancer risk, specifically social and built environment attributes.Impact: Considering the role of neighborhood characteristics among diverse populations may offer insights to understand racial/ethnic disparities in breast cancer risk. Cancer Epidemiol Biomarkers Prev; 26(4); 541-52. ©2017 AACR.

  View details for PubMedID 28196846

  View details for PubMedCentralID PMC5380527

• Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium PLOS GENETICS Ng, M. Y., Graff, M., Lu, Y., Justice, A. E., Mudgal, P., Liu, C., Young, K., Yanek, L. R., Feitosa, M. F., Wojczynski, M. K., Rand, K., Brody, J. A., Cade, B. E., Dimitrov, L., Duan, Q., Guo, X., Lange, L. A., Nalls, M. A., Okut, H., Tajuddin, S. M., Tayo, B. O., Vedantam, S., Bradfield, J. P., Chen, G., Chen, W., Chesi, A., Irvin, M. R., Padhukasahasram, B., Smith, J. A., Zheng, W., Allison, M. A., Ambrosone, C. B., Bandera, E. V., Bartz, T. M., Berndt, S. I., Bernstein, L., Blot, W. J., Bottinger, E. P., Carpten, J., Chanock, S. J., Chen, Y., Conti, D. V., Cooper, R. S., Fornage, M., Freedman, B. I., Garcia, M., Goodman, P. J., Hsu, Y. H., Hu, J., Huff, C. D., Ingles, S. A., John, E. M., Kittles, R., Klein, E., Li, J., McKnight, B., Nayak, U., Nemesure, B., Ogunniyi, A., Olshan, A., Press, M. F., Rohde, R., Rybicki, B. A., Salako, B., Sanderson, M., Shao, Y., Siscovick, D. S., Stanford, J. L., Stevens, V. L., Stram, A., Strom, S. S., Vaidya, D., Witte, J. S., Yao, J., Zhu, X., Ziegler, R. G., Zonderman, A. B., Adeyemo, A., Ambs, S., Cushman, M., Faul, J. D., Hakonarson, H., Levin, A. M., Nathanson, K. L., Ware, E. B., Weir, D. R., Zhao, W., Zhi, D., Arnett, D. K., Grant, S. A., Kardia, S. R., Oloapde, O. I., Rao, D. C., Rotimi, C. N., Sale, M. M., Williams, L., Zemel, B. S., Becker, D. M., Borecki, I. B., Evans, M. K., Harris, T. B., Hirschhorn, J. N., Li, Y., Patel, S. R., Psaty, B. M., Rotter, J. I., Wilson, J. G., Bowden, D. W., Cupples, L., Haiman, C. A., Loos, R. F., North, K. E., Bone Mineral Density Childhood Stu 2017; 13 (4): e1006719

  Abstract

  Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

  View details for PubMedID 28430825

• Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers EUROPEAN JOURNAL OF HUMAN GENETICS Walker, L., Marquart, L., Pearson, J., Wiggins, G., O'Mara, T., Parsons, M. T., Barrowdale, D., McGuffog, L., Dennis, J., Benitez, J., Slavin, T. P., Radice, P., Frost, D., Godwin, A. K., Meindl, A., Schmutzler, R., Isaacs, C., Peshkin, B. N., Caldes, T., Hogervorst, F. L., Lazaro, C., Jakubowska, A., Montagna, M., Chen, X., Offit, K., Hulick, P. J., Andrulis, I. L., Lindblom, A., Nussbaum, R. L., Nathanson, K. L., Chenevix-Trench, G., Antoniou, A. C., Couch, F. J., Spurdle, A. B., BCFR, EMBRACE, GEMO Study Collaborators, HEBON, KConFAB Investigators 2017; 25 (4): 432–38

  Abstract

  Genome-wide studies of patients carrying pathogenic variants (mutations) in BRCA1 or BRCA2 have reported strong associations between single-nucleotide polymorphisms (SNPs) and cancer risk. To conduct the first genome-wide association analysis of copy-number variants (CNVs) with breast or ovarian cancer risk in a cohort of 2500 BRCA1 pathogenic variant carriers, CNV discovery was performed using multiple calling algorithms and Illumina 610k SNP array data from a previously published genome-wide association study. Our analysis, which focused on functionally disruptive genomic deletions overlapping gene regions, identified a number of loci associated with risk of breast or ovarian cancer for BRCA1 pathogenic variant carriers. Despite only including putative deletions called by at least two or more algorithms, detection of selected CNVs by ancillary molecular technologies only confirmed 40% of predicted common (>1% allele frequency) variants. These include four loci that were associated (unadjusted P<0.05) with breast cancer (GTF2H2, ZNF385B, NAALADL2 and PSG5), and two loci associated with ovarian cancer (CYP2A7 and OR2A1). An interesting finding from this study was an association of a validated CNV deletion at the CYP2A7 locus (19q13.2) with decreased ovarian cancer risk (relative risk=0.50, P=0.007). Genomic analysis found this deletion coincides with a region displaying strong regulatory potential in ovarian tissue, but not in breast epithelial cells. This study highlighted the need to verify CNVs in vitro, but also provides evidence that experimentally validated CNVs (with plausible biological consequences) can modify risk of breast or ovarian cancer in BRCA1 pathogenic variant carriers.

  View details for DOI 10.1038/ejhg.2016.203

  View details for Web of Science ID 000395996200010

  View details for PubMedID 28145423

  View details for PubMedCentralID PMC5386423

• A functionally significant SNP in TP53 and breast cancer risk in African-American women NPJ BREAST CANCER Murphy, M. E., Liu, S., Yao, S., Huo, D., Liu, Q., Dolfi, S. C., Hirshfield, K. M., Hong, C., Hu, Q., Olshan, A. F., Ogundiran, T. O., Adebamowo, C., Domchek, S. M., Nathanson, K. L., Nemesure, B., Ambs, S., Blot, W. J., Feng, Y., John, E. M., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Nyante, S., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Haiman, C. A., Olopade, O. I., Lunetta, K. L., Palmer, J. R., Ambrosone, C. B. 2017; 3: 5

  Abstract

  A coding region polymorphism exists in the TP53 gene (Pro47Ser; rs1800371) in individuals of African descent, which reduces p53 tumor suppressor function in a mouse model. It has been unclear whether this functionally significant polymorphism alters cancer risk in humans. This analysis included 6907 women with breast cancer and 7644 controls from the AMBER, ROOT, and AABC consortia. We used multivariable logistic regression to estimate associations between the TP53 Pro47Ser allele and overall breast cancer risk. Because polymorphisms in TP53 tend to be associated with cancer risk in pre-menopausal women, we also limited our analyses to this population in the AMBER and ROOT consortia, where menopausal status was known, and conducted a fixed effects meta-analysis. In an analysis of all women in the AMBER, ROOT, and AABC consortia, we found no evidence for association of the Pro47Ser variant with breast cancer risk. However, when we restricted our analysis to only pre-menopausal women from the AMBER and ROOT consortia, there was a per allele odds ratio of 1.72 (95% confidence interval 1.08-2.76; p-value = 0.023). Although the Pro47Ser variant was not associated with overall breast cancer risk, it may increase risk among pre-menopausal women of African ancestry. Following up on more studies in human populations may better elucidate the role of this variant in breast cancer etiology. However, because of the low frequency of the polymorphism in women of African ancestry, its impact at a population level may be minimal.

  View details for PubMedID 28649645

• Non-invasive optical spectroscopic monitoring of breast development during puberty BREAST CANCER RESEARCH Lilge, L., Terry, M. B., Walter, J., Pinnaduwage, D., Glendon, G., Hanna, D., Tammemagi, M., Bradbury, A., Buys, S., Daly, M., John, E. M., Knight, J. A., Andrulis, I. L. 2017; 19

  Abstract

  Tanner staging (TS), a five-stage classification indicating no breast tissue (TS1) to full breast development (TS5), is used both in health research and clinical care to assess the onset of breast development (TS2) and duration in each stage. Currently, TS is measured both visually and through palpation but non-invasive methods will improve comparisons across settings.We used optical spectroscopy (OS) measures from 102 girls at the Ontario site of the LEGACY girls study (average age 12 years, range 10.0-15.4 years) to determine whether breast tissue optical properties map to each TS. We further examined whether these properties differed by age, body mass index (BMI), and breast cancer risk score (BCRS) by examining the major principal components (PC).Age and BMI increased linearly with increasing TS. Eight PCs explained 99.9% of the variation in OS data. Unlike the linear increase with age and BMI, OS components had distinct patterns by TS: the onset of breast development (TS1 to TS2) was marked by elevation of PC3 scores indicating an increase in adipose tissue and decrease in signal from the pectoral muscle; transition to TS3 was marked by elevation of PC6 and PC7 and decline of PC2 scores indicating an increase in glandular or dense tissue; and transition to TS4+ by decline of PC2 scores representing a further increase in glandular tissue relative to adipose tissue. Of the eight PCs, three component scores (PC4, PC5, and PC8) remained in the best-fitting model of BCRS, suggesting different levels of collagen in the breast tissue by BCRS.Our results suggest that serial measures of OS, a non-invasive assessment of breast tissue characteristics, can be used as an objective outcome that does not rely on visual inspection or palpation, for studying drivers of breast development.

  View details for DOI 10.1186/s13058-017-0805-x

  View details for Web of Science ID 000393623100001

  View details for PubMedID 28166807

• Projecting Individualized Absolute Invasive Breast Cancer Risk in US Hispanic Women JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Banegas, M. P., John, E. M., Slattery, M. L., Gomez, S. L., Yu, M., LaCroix, A. Z., Pee, D., Chlebowski, R. T., Hines, L. M., Thompson, C. A., Gail, M. H. 2017; 109 (2)

  Abstract

  There is no model to estimate absolute invasive breast cancer risk for Hispanic women.The San Francisco Bay Area Breast Cancer Study (SFBCS) provided data on Hispanic breast cancer case patients (533 US-born, 553 foreign-born) and control participants (464 US-born, 947 foreign-born). These data yielded estimates of relative risk (RR) and attributable risk (AR) separately for US-born and foreign-born women. Nativity-specific absolute risks were estimated by combining RR and AR information with nativity-specific invasive breast cancer incidence and competing mortality rates from the California Cancer Registry and Surveillance, Epidemiology, and End Results program to develop the Hispanic risk model (HRM). In independent data, we assessed model calibration through observed/expected (O/E) ratios, and we estimated discriminatory accuracy with the area under the receiver operating characteristic curve (AUC) statistic.The US-born HRM included age at first full-term pregnancy, biopsy for benign breast disease, and family history of breast cancer; the foreign-born HRM also included age at menarche. The HRM estimated lower risks than the National Cancer Institute's Breast Cancer Risk Assessment Tool (BCRAT) for US-born Hispanic women, but higher risks in foreign-born women. In independent data from the Women's Health Initiative, the HRM was well calibrated for US-born women (observed/expected [O/E] ratio = 1.07, 95% confidence interval [CI] = 0.81 to 1.40), but seemed to overestimate risk in foreign-born women (O/E ratio = 0.66, 95% CI = 0.41 to 1.07). The AUC was 0.564 (95% CI = 0.485 to 0.644) for US-born and 0.625 (95% CI = 0.487 to 0.764) for foreign-born women.The HRM is the first absolute risk model that is based entirely on data specific to Hispanic women by nativity. Further studies in Hispanic women are warranted to evaluate its validity.

  View details for DOI 10.1093/jnci/djw215

  View details for Web of Science ID 000396507600006

  View details for PubMedID 28003316

• Breast cancer risk prediction using a polygenic risk score in the familial setting: a prospective study from the Breast Cancer Family Registry and kConFab GENETICS IN MEDICINE Li, H., Feng, B., Miron, A., Chen, X., Beesley, J., Bimeh, E., Barrowdale, D., John, E. M., Daly, M. B., Andrulis, I. L., Buys, S. S., Kraft, P., Thorne, H., Chenevix-Trench, G., Southey, M. C., Antoniou, A. C., James, P. A., Terry, M. B., Phillips, K., Hopper, J. L., Mitchell, G., Goldgar, D. E. 2017; 19 (1): 30-35

  Abstract

  This study examined the utility of sets of single-nucleotide polymorphisms (SNPs) in familial but non-BRCA-associated breast cancer (BC).We derived a polygenic risk score (PRS) based on 24 known BC risk SNPs for 4,365 women from the Breast Cancer Family Registry and Kathleen Cuningham Consortium Foundation for Research into Familial Breast Cancer familial BC cohorts. We compared scores for women based on cancer status at baseline; 2,599 women unaffected at enrollment were followed-up for an average of 7.4 years. Cox proportional hazards regression was used to analyze the association of PRS with BC risk. The BOADICEA risk prediction algorithm was used to measure risk based on family history alone.The mean PRS at baseline was 2.25 (SD, 0.35) for affected women and was 2.17 (SD, 0.35) for unaffected women from combined cohorts (P < 10(-6)). During follow-up, 205 BC cases occurred. The hazard ratios for continuous PRS (per SD) and upper versus lower quintiles were 1.38 (95% confidence interval: 1.22-1.56) and 3.18 (95% confidence interval: 1.84-5.23) respectively. Based on their PRS-based predicted risk, management for up to 23% of women could be altered.Including BC-associated SNPs in risk assessment can provide more accurate risk prediction than family history alone and can influence recommendations for cancer screening and prevention modalities for high-risk women.Genet Med 19 1, 30-35.

  View details for DOI 10.1038/gim.2016.43

  View details for Web of Science ID 000391911100005

  View details for PubMedCentralID PMC5107177

• Response to Conner et al. Re: "Cigarette Smoking and Breast Cancer Risk in Hispanic and Non-Hispanic White Women: The Breast Cancer Health Disparities Study". Journal of women's health (2002) Connor, A. E., Baumgartner, K. B., Pinkston, C. M., Boone, S. D., Baumgartner, R. N., Hines, L. M., Stern, M. C., Torres-Mejía, G., John, E. M., Slattery, M. L. 2017; 26 (1): 92-93

  View details for DOI 10.1089/jwh.2016.6292

  View details for PubMedID 28051904

  View details for PubMedCentralID PMC5278810

• Breast cancer risk prediction using a polygenic risk score in the familial setting: a prospective study from the Breast Cancer Family Registry and kConFab. Genetics in medicine Li, H., Feng, B., Miron, A., Chen, X., Beesley, J., Bimeh, E., Barrowdale, D., John, E. M., Daly, M. B., Andrulis, I. L., Buys, S. S., Kraft, P., Thorne, H., Chenevix-Trench, G., Southey, M. C., Antoniou, A. C., James, P. A., Terry, M. B., Phillips, K., Hopper, J. L., Mitchell, G., Goldgar, D. E. 2017; 19 (1): 30-35

  Abstract

  This study examined the utility of sets of single-nucleotide polymorphisms (SNPs) in familial but non-BRCA-associated breast cancer (BC).We derived a polygenic risk score (PRS) based on 24 known BC risk SNPs for 4,365 women from the Breast Cancer Family Registry and Kathleen Cuningham Consortium Foundation for Research into Familial Breast Cancer familial BC cohorts. We compared scores for women based on cancer status at baseline; 2,599 women unaffected at enrollment were followed-up for an average of 7.4 years. Cox proportional hazards regression was used to analyze the association of PRS with BC risk. The BOADICEA risk prediction algorithm was used to measure risk based on family history alone.The mean PRS at baseline was 2.25 (SD, 0.35) for affected women and was 2.17 (SD, 0.35) for unaffected women from combined cohorts (P < 10(-6)). During follow-up, 205 BC cases occurred. The hazard ratios for continuous PRS (per SD) and upper versus lower quintiles were 1.38 (95% confidence interval: 1.22-1.56) and 3.18 (95% confidence interval: 1.84-5.23) respectively. Based on their PRS-based predicted risk, management for up to 23% of women could be altered.Including BC-associated SNPs in risk assessment can provide more accurate risk prediction than family history alone and can influence recommendations for cancer screening and prevention modalities for high-risk women.Genet Med 19 1, 30-35.

  View details for DOI 10.1038/gim.2016.43

  View details for PubMedID 27171545

• Assessing biological and technological variability in protein levels measured in pre-diagnostic plasma samples of women with breast cancer Biomarker Research Yeh, C. Y., Adusumilli, R., Kullolli, M., Mallick, P., John, E. M., Pitteri, S. J. 2017; 5: 30

  Abstract

  Quantitative proteomics allows for the discovery and functional investigation of blood-based pre-diagnostic biomarkers for early cancer detection. However, a major limitation of proteomic investigations in biomarker studies remains the biological and technical variability in the analysis of complex clinical samples. Moreover, unlike 'omics analogues such as genomics and transcriptomics, proteomics has yet to achieve reproducibility and long-term stability on a unified technological platform. Few studies have thoroughly investigated protein variability in pre-diagnostic samples of cancer patients across multiple platforms.We obtained ten blood plasma "case" samples collected up to 2 years prior to breast cancer diagnosis. Each case sample was paired with a matched control plasma from a full biological sister without breast cancer. We measured protein levels using both mass-spectrometry and antibody-based technologies to: (1) assess the technical considerations in different protein assays when analyzing limited clinical samples, and (2) evaluate the statistical power of potential diagnostic analytes.Although we found inherent technical variation in the three assays used, we detected protein dependent biological signal from the limited samples. The three assay types yielded 32 proteins with statistically significantly (p < 1E-01) altered expression levels between cases and controls, with no proteins retaining statistical significance after false discovery correction.Technical, practical, and study design considerations are essential to maximize information obtained in limited pre-diagnostic samples of cancer patients. This study provides a framework that estimates biological effect sizes critical for consideration in designing studies for pre-diagnostic blood-based biomarker detection.

  View details for DOI 10.1186/s40364-017-0110-y

  View details for PubMedCentralID PMC5645980

• Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3 BREAST CANCER RESEARCH AND TREATMENT Hamdi, Y., Soucy, P., Kuchenbaeker, K. B., Pastinen, T., Droit, A., Lemacon, A., Adlard, J., Aittomaki, K., Andrulis, I. L., Arason, A., Arnold, N., Arun, B. K., Azzollini, J., Bane, A., Barjhoux, L., Barrowdale, D., Benitez, J., Berthet, P., Blok, M. J., Bobolis, K., Bonadona, V., Bonanni, B., Bradbury, A. R., Brewer, C., Buecher, B., Buys, S. S., Caligo, M. A., Chiquette, J., Chung, W. K., Claes, K. B., Daly, M. B., Damiola, F., Davidson, R., de la Hoya, M., De Leeneer, K., Diez, O., Ding, Y. C., Dolcetti, R., Domchek, S. M., Dorfling, C. M., Eccles, D., Eeles, R., Einbeigi, Z., Ejlertsen, B., Engel, C., Evans, D. G., Feliubadalo, L., Foretova, L., Fostira, F., Foulkes, W. D., Fountzilas, G., friedman, e., Frost, D., Ganschow, P., Ganz, P. A., Garber, J., Gayther, S. A., Gerdes, A., Glendon, G., Godwin, A. K., Goldgar, D. E., Greene, M. H., Gronwald, J., Hahnen, E., Hamann, U., Hansen, T. v., Hart, S., Hays, J. L., Hogervorst, F. B., Hulick, P. J., Imyanitov, E. N., Isaacs, C., Izatt, L., Jakubowska, A., James, P., Janavicius, R., Jensen, U. B., John, E. M., Joseph, V., Just, W., Kaczmarek, K., Karlan, B. Y., Kets, C. M., Kirk, J., Kriege, M., Laitman, Y., Laurent, M., Lazaro, C., Leslie, G., Lester, J., Lesueur, F., Liljegren, A., Loman, N., Loud, J. T., Manoukian, S., Mariani, M., Mazoyer, S., McGuffog, L., Meijers-Heijboer, H. E., Meindl, A., Miller, A., Montagna, M., Mulligan, A. M., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Nussbaum, R. L., Olah, E., Olopade, O. I., Ong, K., Oosterwijk, J. C., Osorio, A., Papi, L., Park, S. K., Pedersen, I. S., Peissel, B., Segura, P. P., Peterlongo, P., Phelan, C. M., Radice, P., Rantala, J., Rappaport-Fuerhauser, C., Rennert, G., Richardson, A., Robson, M., Rodriguez, G. C., Rookus, M. A., Schmutzler, R. K., Sevenet, N., Shah, P. D., Singer, C. F., Slavin, T. P., Snape, K., Sokolowska, J., Sonderstrup, I. M., Southey, M., Spurdle, A. B., Stadler, Z., Stoppa-Lyonnet, D., Sukiennicki, G., Sutter, C., Tan, Y., Tea, M., Teixeira, M. R., Teule, A., Teo, S., Terry, M. B., Thomassen, M., Tihomirova, L., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tung, N., van den Ouweland, A. M., van der Luijt, R. B., van Engelen, K., Van Rensburg, E. J., Varon-Mateeva, R., Wappenschmidt, B., Wijnen, J. T., Rebbeck, T., Chenevix-Trench, G., Offit, K., Couch, F. J., Nord, S., Easton, D. F., Antoniou, A. C., Simard, J. 2017; 161 (1): 117-134

  Abstract

  Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways.Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2.We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10(-6)). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance.We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

  View details for DOI 10.1007/s10549-016-4018-2

  View details for Web of Science ID 000392188500012

  View details for PubMedCentralID PMC5222911

• Pre-diagnostic breastfeeding, adiposity, and mortality among parous Hispanic and non-Hispanic white women with invasive breast cancer: the Breast Cancer Health Disparities Study BREAST CANCER RESEARCH AND TREATMENT Connor, A. E., Visvanathan, K., Baumgartner, K. B., Baumgartner, R. N., Boone, S. D., Hines, L. M., Wolff, R. K., John, E. M., Slattery, M. L. 2017; 161 (2): 321-331

  Abstract

  U.S. Hispanic women have high rates of parity, breastfeeding, and obesity. It is unclear whether these reproductive factors are associated with breast cancer (BC) mortality. We examined the associations between breastfeeding, parity, adiposity and BC-specific and overall mortality in Hispanic and non-Hispanic white (NHW) BC cases.The study population included 2921 parous women (1477 Hispanics, 1444 NHWs) from the Breast Cancer Health Disparities Study with invasive BC diagnosed between 1995 and 2004. Information on reproductive history and lifestyle factors was collected by in-person interview. Overall and stratified Cox proportional hazard regression models by ethnicity, parity, and body mass index (BMI) at age 30 years were used to calculate hazard ratios (HR) and 95% confidence intervals (CI).After a median follow-up time of 11.2 years, a total of 679 deaths occurred. Pre-diagnostic breastfeeding was associated with a 16% reduction in mortality (HR 0.84; 95% 0.72-0.99) irrespective of ethnicity. Parity significantly modified the association between breastfeeding duration and mortality (p interaction = 0.05), with longer breastfeeding duration associated with lower risk among women who had ≤2 births (p trend = 0.02). Breastfeeding duration was associated with reduced risk of both BC-specific and overall mortality among women with BMI <25 kg/m2, while positive associations were observed among women with BMI ≥25 kg/m2 (p interactions <0.01).Pre-diagnostic breastfeeding was inversely associated with risk of mortality after BC, particularly in women of low parity or normal BMI. These results provide another reason to encourage breastfeeding and weight management among young women.

  View details for DOI 10.1007/s10549-016-4048-9

  View details for Web of Science ID 000392385100013

  View details for PubMedID 27837379

• A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Rand, K. A., Song, C., Dean, E., Serie, D. J., Curtin, K., Sheng, X., Hu, D., Huff, C. A., Bernal-Mizrachi, L., Tomasson, M. H., Ailawadhi, S., Singhal, S., Pawlish, K., Peters, E. S., Bock, C. H., Stram, A., Van den Berg, D. J., Edlund, C. K., Conti, D. V., Zimmerman, T., Hwang, A. E., Huntsman, S., Graff, J., Nooka, A., Kong, Y., Pregja, S. L., Berndt, S. I., Blot, W. J., Carpten, J., Casey, G., Chu, L., Diver, W. R., Stevens, V. L., Lieber, M. R., Goodman, P. J., Hennis, A. J., Hsing, A. W., Mehta, J., Kittles, R. A., Kolb, S., Klein, E. A., Leske, C., Murphy, A. B., Nemesure, B., Neslund-Dudas, C., Strom, S. S., Vij, R., Rybicki, B. A., Stanford, J. L., Signorello, L. B., Witte, J. S., Ambrosone, C. B., Bhatti, P., John, E. M., Bernstein, L., Zheng, W., Olshan, A. F., Hu, J. J., Ziegler, R. G., Nyante, S. J., Bandera, E. V., Birmann, B. M., Ingles, S. A., Press, M. F., Atanackovic, D., Glenn, M. J., Cannon-Albright, L. A., Jones, B., Tricot, G., Martin, T. G., Kumar, S. K., Wolf, J. L., Halverson, S. L., Rothman, N., Brooks-Wilson, A. R., Rajkumar, S. V., Kolonel, L. N., Chanock, S. J., Slager, S. L., Severson, R. K., Janakiraman, N., Terebelo, H. R., Brown, E. E., De Roos, A. J., Mohrbacher, A. F., Colditz, G. A., Giles, G. G., Spinelli, J. J., Chiu, B. C., Munshi, N. C., Anderson, K. C., Levy, J., Zonder, J. A., Orlowski, R. Z., Lonial, S., Camp, N. J., Vachon, C. M., Ziv, E., Stram, D. O., Hazelett, D. J., Haiman, C. A., Cozen, W. 2016; 25 (12): 1609-1618

  Abstract

  Genome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma.We performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality.We found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4 Correlated variants in 7p15.3 clustered around an enhancer at the 3' end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10(-7)) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7 CONCLUSIONS: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles.A subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR.

  View details for PubMedID 27587788

• Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women BREAST CANCER RESEARCH Rebbeck, T. R., Friebel, T. M., Mitra, N., Wan, F., Chen, S., Andrulis, I. L., Apostolou, P., Arnold, N., Arun, B. K., Barrowdale, D., Benitez, J., Berger, R., Berthet, P., Borg, A., Buys, S. S., Caldes, T., Carter, J., Chiquette, J., Claes, K. M., Couch, F. J., Cybulski, C., Daly, M. B., de la Hoya, M., Diez, O., Domchek, S. M., Nathanson, K. L., Durda, K., Ellis, S., Evans, D., Foretova, L., Friedman, E., Frost, D., Ganz, P. A., Garber, J., Glendon, G., Godwin, A. K., Greene, M. H., Gronwald, J., Hahnen, E., Hallberg, E., Hamann, U., Hansen, T. O., Imyanitov, E. N., Isaacs, C., Jakubowska, A., Janavicius, R., Jaworska-Bieniek, K., John, E. M., Karlan, B. Y., Kaufman, B., Kwong, A., Laitman, Y., Lasset, C., Lazaro, C., Lester, J., Loman, N., Lubinski, J., Manoukian, S., Mitchell, G., Montagna, M., Neuhausen, S. L., Nevanlinna, H., Niederacher, D., Nussbaum, R. L., Offit, K., Olah, E., Olopade, O. I., Park, S., Piedmonte, M., Radice, P., Rappaport-Fuerhauser, C., Rookus, M. A., Seynaeve, C., Simard, J., Singer, C. F., Soucy, P., Southey, M., Stoppa-Lyonnet, D., Sukiennicki, G., Szabo, C. I., Tancredi, M., Teixeira, M. R., Teo, S., Terry, M., Thomassen, M., Tihomirova, L., Tischkowitz, M., Toland, A., Toloczko-Grabarek, A., Tung, N., van Rensburg, E. J., Villano, D., Wang-Gohrke, S., Wappenschmidt, B., Weitzel, J. N., Zidan, J., Zorn, K. K., McGuffog, L., Easton, D., Chenevix-Trench, G., Antoniou, A. C., Ramus, S. J., EMBRACE, HEBON, KConFab Investigators 2016; 18: 112

  Abstract

  Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood.From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2.The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC.Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.

  View details for PubMedID 27836010

  View details for PubMedCentralID PMC5106833

• Body mass index, weight change, and risk of second primary breast cancer in the WECARE study: influence of estrogen receptor status of the first breast cancer CANCER MEDICINE Brooks, J. D., John, E. M., Mellemkjaer, L., Lynch, C. F., Knight, J. A., Malone, K. E., Reiner, A. S., Bernstein, L., Liang, X., Shore, R. E., Stovall, M., Bernstein, J. L., WECARE Study Collaborative Grp 2016; 5 (11): 3282–91

  View details for DOI 10.1002/cam4.890

  View details for Web of Science ID 000388370000028

• Body mass index, weight change, and risk of second primary breast cancer in the WECARE study: influence of estrogen receptor status of the first breast cancer. Cancer medicine Brooks, J. D., John, E. M., Mellemkjaer, L., Lynch, C. F., Knight, J. A., Malone, K. E., Reiner, A. S., Bernstein, L., Liang, X., Shore, R. E., Stovall, M., Bernstein, J. L. 2016; 5 (11): 3282-3291

  Abstract

  Studies examining the relationship between body mass index (BMI) and risk of contralateral breast cancer (CBC) have reported mixed findings. We previously showed that obese postmenopausal women with estrogen receptor (ER)-negative breast cancer have a fivefold higher risk of CBC compared with normal weight women. In the current analysis, we reexamined this relationship in the expanded Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study, focusing on the impact of menopausal status and ER status of the first breast cancer. The WECARE Study is a population-based case-control study of young women with CBC (cases, N = 1386) and with unilateral breast cancer (controls, N = 2045). Rate ratios (RR) and 95% confidence intervals (CI) were calculated to assess the relationship between BMI and risk of CBC stratified by menopausal and ER status. Positive associations with obesity and weight gain were limited to women who became postmenopausal following their first primary breast cancer. Among those with an ER-negative first breast cancer, obesity (vs. normal weight) at first diagnosis was associated with an increased risk of CBC (RR = 1.9, 95% CI: 1.02, 3.4). Also, weight gain of ≥10 kg after first diagnosis was associated with an almost twofold increased risk of CBC (RR = 1.9, 95% CI: 0.99, 3.8). These results suggest that women with an ER-negative first primary cancer who are obese at first primary diagnosis or who experience a large weight gain afterward may benefit from heightened surveillance. Future studies are needed to address the impact of weight loss interventions on risk of CBC.

  View details for DOI 10.1002/cam4.890

  View details for PubMedID 27700016

  View details for PubMedCentralID PMC5119984

• Genome-wide association studies in women of African ancestry identified 3q26.21 as a novel susceptibility locus for oestrogen receptor negative breast cancer HUMAN MOLECULAR GENETICS Huo, D., Feng, Y., Haddad, S., Zheng, Y., Yao, S., Han, Y., Ogundiran, T. O., Adebamowo, C., Ojengbede, O., Falusi, A. G., Zheng, W., Blot, W., Cai, Q., Signorello, L., John, E. M., Bernstein, L., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Nathanson, K. L., Domchek, S. M., Rebbeck, T. R., Ruiz-Narvaez, E. A., Sucheston-Campbell, L. E., Bensen, J. T., Simon, M. S., Hennis, A., Nemesure, B., Leske, M., Ambs, S., Chen, L. S., Qian, F., Gamazon, E. R., Lunetta, K. L., Cox, N. J., Chanock, S. J., Kolonel, L. N., Olshan, A. F., Ambrosone, C. B., Olopade, O. I., Palmer, J. R., Haiman, C. A. 2016; 25 (21): 4835–46

  Abstract

  Multiple breast cancer loci have been identified in previous genome-wide association studies, but they were mainly conducted in populations of European ancestry. Women of African ancestry are more likely to have young-onset and oestrogen receptor (ER) negative breast cancer for reasons that are unknown and understudied. To identify genetic risk factors for breast cancer in women of African descent, we conducted a meta-analysis of two genome-wide association studies of breast cancer; one study consists of 1,657 cases and 2,029 controls genotyped with Illumina’s HumanOmni2.5 BeadChip and the other study included 3,016 cases and 2,745 controls genotyped using Illumina Human1M-Duo BeadChip. The top 18,376 single nucleotide polymorphisms (SNP) from the meta-analysis were replicated in the third study that consists of 1,984 African Americans cases and 2,939 controls. We found that SNP rs13074711, 26.5 Kb upstream of TNFSF10 at 3q26.21, was significantly associated with risk of oestrogen receptor (ER)-negative breast cancer (odds ratio [OR]=1.29, 95% CI: 1.18-1.40; P = 1.8 × 10 − 8). Functional annotations suggest that the TNFSF10 gene may be involved in breast cancer aetiology, but further functional experiments are needed. In addition, we confirmed SNP rs10069690 was the best indicator for ER-negative breast cancer at 5p15.33 (OR = 1.30; P = 2.4 × 10 − 10) and identified rs12998806 as the best indicator for ER-positive breast cancer at 2q35 (OR = 1.34; P = 2.2 × 10 − 8) for women of African ancestry. These findings demonstrated additional susceptibility alleles for breast cancer can be revealed in diverse populations and have important public health implications in building race/ethnicity-specific risk prediction model for breast cancer.

  View details for PubMedID 28171663

  View details for PubMedCentralID PMC5975608

• Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3. Breast cancer research and treatment Hamdi, Y., Soucy, P., Kuchenbaeker, K. B., Pastinen, T., Droit, A., Lemaçon, A., Adlard, J., Aittomäki, K., Andrulis, I. L., Arason, A., Arnold, N., Arun, B. K., Azzollini, J., Bane, A., Barjhoux, L., Barrowdale, D., Benitez, J., Berthet, P., Blok, M. J., Bobolis, K., Bonadona, V., Bonanni, B., Bradbury, A. R., Brewer, C., Buecher, B., Buys, S. S., Caligo, M. A., Chiquette, J., Chung, W. K., Claes, K. B., Daly, M. B., Damiola, F., Davidson, R., de la Hoya, M., De Leeneer, K., Diez, O., Ding, Y. C., Dolcetti, R., Domchek, S. M., Dorfling, C. M., Eccles, D., Eeles, R., Einbeigi, Z., Ejlertsen, B., Engel, C., Gareth Evans, D., Feliubadalo, L., Foretova, L., Fostira, F., Foulkes, W. D., Fountzilas, G., friedman, e., Frost, D., Ganschow, P., Ganz, P. A., Garber, J., Gayther, S. A., Gerdes, A., Glendon, G., Godwin, A. K., Goldgar, D. E., Greene, M. H., Gronwald, J., Hahnen, E., Hamann, U., Hansen, T. v., Hart, S., Hays, J. L., Hogervorst, F. B., Hulick, P. J., Imyanitov, E. N., Isaacs, C., Izatt, L., Jakubowska, A., James, P., Janavicius, R., Jensen, U. B., John, E. M., Joseph, V., Just, W., Kaczmarek, K., Karlan, B. Y., Kets, C. M., Kirk, J., Kriege, M., Laitman, Y., Laurent, M., Lazaro, C., Leslie, G., Lester, J., Lesueur, F., Liljegren, A., Loman, N., Loud, J. T., Manoukian, S., Mariani, M., Mazoyer, S., McGuffog, L., Meijers-Heijboer, H. E., Meindl, A., Miller, A., Montagna, M., Mulligan, A. M., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Nussbaum, R. L., Olah, E., Olopade, O. I., Ong, K., Oosterwijk, J. C., Osorio, A., Papi, L., Park, S. K., Pedersen, I. S., Peissel, B., Segura, P. P., Peterlongo, P., Phelan, C. M., Radice, P., Rantala, J., Rappaport-Fuerhauser, C., Rennert, G., Richardson, A., Robson, M., Rodriguez, G. C., Rookus, M. A., Schmutzler, R. K., Sevenet, N., Shah, P. D., Singer, C. F., Slavin, T. P., Snape, K., Sokolowska, J., Sønderstrup, I. M., Southey, M., Spurdle, A. B., Stadler, Z., Stoppa-Lyonnet, D., Sukiennicki, G., Sutter, C., Tan, Y., Tea, M., Teixeira, M. R., Teulé, A., Teo, S., Terry, M. B., Thomassen, M., Tihomirova, L., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tung, N., van den Ouweland, A. M., van der Luijt, R. B., van Engelen, K., Van Rensburg, E. J., Varon-Mateeva, R., Wappenschmidt, B., Wijnen, J. T., Rebbeck, T., Chenevix-Trench, G., Offit, K., Couch, F. J., Nord, S., Easton, D. F., Antoniou, A. C., Simard, J. 2016: -?

  Abstract

  Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways.Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2.We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10(-6)). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance.We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

  View details for PubMedID 27796716

• Genetic modifiers of CHEK2*1100delC-associated breast cancer risk. Genetics in medicine Muranen, T. A., Greco, D., Blomqvist, C., Aittomäki, K., Khan, S., Hogervorst, F., Verhoef, S., Pharoah, P. D., Dunning, A. M., Shah, M., Luben, R., Bojesen, S. E., Nordestgaard, B. G., Schoemaker, M., Swerdlow, A., García-Closas, M., Figueroa, J., Dörk, T., Bogdanova, N. V., Hall, P., Li, J., Khusnutdinova, E., Bermisheva, M., Kristensen, V., Borresen-Dale, A., Investigators, N., Peto, J., dos Santos Silva, I., Couch, F. J., Olson, J. E., Hillemans, P., Park-Simon, T., Brauch, H., Hamann, U., Burwinkel, B., Marme, F., Meindl, A., Schmutzler, R. K., Cox, A., Cross, S. S., Sawyer, E. J., Tomlinson, I., Lambrechts, D., Moisse, M., Lindblom, A., Margolin, S., Hollestelle, A., Martens, J. W., Fasching, P. A., Beckmann, M. W., Andrulis, I. L., Knight, J. A., Investigators, k., Anton-Culver, H., Ziogas, A., Giles, G. G., Milne, R. L., Brenner, H., Arndt, V., Mannermaa, A., Kosma, V., Chang-Claude, J., Rudolph, A., Devilee, P., Seynaeve, C., Hopper, J. L., Southey, M. C., John, E. M., Whittemore, A. S., Bolla, M. K., Wang, Q., Michailidou, K., Dennis, J., Easton, D. F., Schmidt, M. K., Nevanlinna, H. 2016

  Abstract

  CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction.The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average.Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.

  View details for DOI 10.1038/gim.2016.147

  View details for PubMedID 27711073

• Genetic variants in microRNA and microRNA biogenesis pathway genes and breast cancer risk among women of African ancestry. Human genetics Qian, F., Feng, Y., Zheng, Y., Ogundiran, T. O., Ojengbede, O., Zheng, W., Blot, W., Ambrosone, C. B., John, E. M., Bernstein, L., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Nathanson, K. L., Hennis, A., Nemesure, B., Ambs, S., Kolonel, L. N., Olopade, O. I., Haiman, C. A., Huo, D. 2016; 135 (10): 1145-1159

  Abstract

  MicroRNAs (miRNA) regulate breast biology by binding to specific RNA sequences, leading to RNA degradation and inhibition of translation of their target genes. While germline genetic variations may disrupt some of these interactions between miRNAs and their targets, studies assessing the relationship between genetic variations in the miRNA network and breast cancer risk are still limited, particularly among women of African ancestry. We systematically put together a list of 822 and 10,468 genetic variants among primary miRNA sequences and 38 genes in the miRNA biogenesis pathway, respectively; and examined their association with breast cancer risk in the ROOT consortium which includes women of African ancestry. Findings were replicated in an independent consortium. Logistic regression was used to estimate the odds ratio (OR) and 95 % confidence intervals (CI). For overall breast cancer risk, three single-nucleotide polymorphisms (SNPs) in miRNA biogenesis genes DROSHA rs78393591 (OR = 0.69, 95 % CI: 0.55-0.88, P = 0.003), ESR1 rs523736 (OR = 0.88, 95 % CI: 0.82-0.95, P = 3.99 × 10(-4)), and ZCCHC11 rs114101502 (OR = 1.33, 95 % CI: 1.11-1.59, P = 0.002), and one SNP in primary miRNA sequence (rs116159732 in miR-6826, OR = 0.74, 95 % CI: 0.63-0.89, P = 0.001) were found to have significant associations in both discovery and validation phases. In a subgroup analysis, two SNPs were associated with risk of estrogen receptor (ER)-negative breast cancer, and three SNPs were associated with risk of ER-positive breast cancer. Several variants in miRNA and miRNA biogenesis pathway genes were associated with breast cancer risk. Risk associations varied by ER status, suggesting potential new mechanisms in etiology.

  View details for DOI 10.1007/s00439-016-1707-1

  View details for PubMedID 27380242

  View details for PubMedCentralID PMC5021583

• Admixture Mapping of African-American Women in the AMBER Consortium Identifies New Loci for Breast Cancer and Estrogen-Receptor Subtypes FRONTIERS IN GENETICS Ruiz-Narvaez, E. A., Sucheston-Campbell, L., Bensen, J. T., Yao, S., Haddad, S., Haiman, C. A., Bandera, E. V., John, E. M., Bernstein, L., Hu, J. J., Ziegler, R. G., Deming, S. L., Olshan, A. F., Ambrosone, C. B., Palmer, J. R., Lunetta, K. L. 2016; 7: 170

  Abstract

  Recent genetic admixture coupled with striking differences in incidence of estrogen receptor (ER) breast cancer subtypes, as well as severity, between women of African and European ancestry, provides an excellent rationale for performing admixture mapping in African American women with breast cancer risk. We performed the largest breast cancer admixture mapping study with in African American women to identify novel genomic regions associated with the disease. We conducted a genome-wide admixture scan using 2,624 autosomal ancestry informative markers (AIMs) in 3,629 breast cancer cases (including 1,968 ER-positive, 1093 ER-negative, and 601 triple-negative) and 4,658 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, a collaborative study of four large geographically different epidemiological studies of breast cancer in African American women. We used an independent case-control study to test for SNP association in regions with genome-wide significant admixture signals. We found two novel genome-wide significant regions of excess African ancestry, 4p16.1 and 17q25.1, associated with ER-positive breast cancer. Two regions known to harbor breast cancer variants, 10q26 and 11q13, were also identified with excess of African ancestry. Fine-mapping of the identified genome-wide significant regions suggests the presence of significant genetic associations with ER-positive breast cancer in 4p16.1 and 11q13. In summary, we identified three novel genomic regions associated with breast cancer risk by ER status, suggesting that additional previously unidentified variants may contribute to the racial differences in breast cancer risk in the African American population.

  View details for PubMedID 27708667

• Association of lifestyle and demographic factors with estrogenic and glucocorticogenic activity in Mexican American women CARCINOGENESIS Fejerman, L., Sanchez, S. S., Thomas, R., Tachachartvanich, P., Riby, J., Gomez, S. L., John, E. M., Smith, M. T. 2016; 37 (9): 904–11

  Abstract

  Breast cancer risk is higher in US-born than in foreign-born Hispanics/Latinas and also increases with greater length of US residency. It is only partially known what factors contribute to these patterns of risk. To gain new insights, we tested the association between lifestyle and demographic variables and breast cancer status, with measures of estrogenic (E) and glucocorticogenic (G) activity in Mexican American women. We used Chemical-Activated LUciferase gene eXpression assays to measure E and G activity in total plasma from 90 Mexican American women, without a history of breast cancer at the time of recruitment, from the San Francisco Bay Area Breast Cancer Study. We tested associations of nativity, lifestyle and sociodemographic factors with E and G activity using linear regression models. We did not find a statistically significant difference in E or G activity by nativity. However, in multivariable models, E activity was associated with Indigenous American ancestry (19% decrease in E activity per 10% increase in ancestry, P = 0.014) and with length of US residency (28% increase in E activity for every 10 years, P = 0.035). G activity was associated with breast cancer status (women who have developed breast cancer since recruitment into the study had 21% lower G activity than those who have not, P = 0.054) and alcohol intake (drinkers had 25% higher G activity than non-drinkers, P = 0.015). These associations suggest that previously reported breast cancer risk factors such as genetic ancestry and alcohol intake might in part be associated with breast cancer risk through mechanisms linked to the endocrine system.

  View details for PubMedID 27412823

  View details for PubMedCentralID PMC5008251

• Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers. Journal of clinical oncology Schmidt, M. K., Hogervorst, F., van Hien, R., Cornelissen, S., Broeks, A., Adank, M. A., Meijers, H., Waisfisz, Q., Hollestelle, A., Schutte, M., van den Ouweland, A., Hooning, M., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Antoniou, A. C., Arndt, V., Bermisheva, M., Bogdanova, N. V., Bolla, M. K., Brauch, H., Brenner, H., Brüning, T., Burwinkel, B., Chang-Claude, J., Chenevix-Trench, G., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Dunning, A. M., Fasching, P. A., Figueroa, J., Fletcher, O., Flyger, H., Galle, E., García-Closas, M., Giles, G. G., Haeberle, L., Hall, P., Hillemanns, P., Hopper, J. L., Jakubowska, A., John, E. M., Jones, M., Khusnutdinova, E., Knight, J. A., Kosma, V., Kristensen, V., Lee, A., Lindblom, A., Lubinski, J., Mannermaa, A., Margolin, S., Meindl, A., Milne, R. L., Muranen, T. A., Newcomb, P. A., Offit, K., Park-Simon, T., Peto, J., Pharoah, P. D., Robson, M., Rudolph, A., Sawyer, E. J., Schmutzler, R. K., Seynaeve, C., Soens, J., Southey, M. C., Spurdle, A. B., Surowy, H., Swerdlow, A., Tollenaar, R. A., Tomlinson, I., Trentham-Dietz, A., Vachon, C., Wang, Q., Whittemore, A. S., Ziogas, A., van der Kolk, L., Nevanlinna, H., Dörk, T., Bojesen, S., Easton, D. F. 2016; 34 (23): 2750-2760

  Abstract

  CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC.CHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies.Proportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center-based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10(-20)). The OR was higher for estrogen receptor (ER)-positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10(-21)]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10(-4)). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom.These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up.

  View details for DOI 10.1200/JCO.2016.66.5844

  View details for PubMedID 27269948

• Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent PLOS MEDICINE Guo, Y., Andersen, S. W., Shu, X., Michailidou, K., Bolla, M. K., Wang, Q., Garcia-Closas, M., Milne, R. L., Schmidt, M. K., Chang-Claude, J., Dunning, A., Bojesen, S. E., Ahsan, H., Aittomaki, K., Andrulis, I. L., Anton-Culver, H., Arndt, V., Beckmann, M. W., Beeghly-Fadiel, A., Benitez, J., Bogdanova, N. V., Bonanni, B., Borresen-Dale, A., Brand, J., Brauch, H., Brenner, H., Bruening, T., Burwinkel, B., Casey, G., Chenevix-Trench, G., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Devilee, P., Doerk, T., Dumont, M., Fasching, P. A., Figueroa, J., Flesch-Janys, D., Fletcher, O., Flyger, H., Fostira, F., Gammon, M., Giles, G. G., Guenel, P., Haiman, C. A., Hamann, U., Hooning, M. J., Hopper, J. L., Jakubowska, A., Jasmine, F., Jenkins, M., John, E. M., Johnson, N., Jones, M. E., Kabisch, M., Kibriya, M., Knight, J. A., Koppert, L. B., Kosma, V., Kristensen, V., Le Marchand, L., Lee, E., Li, J., Lindblom, A., Luben, R., Lubinski, J., Malone, K. E., Mannermaa, A., Margolin, S., Marme, F., McLean, C., Meijers-Heijboer, H., Meindl, A., Neuhausen, S. L., Nevanlinna, H., Neven, P., Olson, J. E., Perez, J. I., Perkins, B., Peterlongo, P., Phillips, K., Pylkas, K., Rudolph, A., Santella, R., Sawyer, E. J., Schmutzler, R. K., Seynaeve, C., Shah, M., Shrubsole, M. J., Southey, M. C., Swerdlow, A. J., Toland, A. E., Tomlinson, I., Torres, D., Truong, T., Ursin, G., van der Luijt, R. B., Verhoef, S., Whittemore, A. S., Winqvist, R., Zhao, H., Zhao, S., Hall, P., Simard, J., Kraft, P., Pharoah, P., Hunter, D., Easton, D. F., Zheng, W. 2016; 13 (8)

  Abstract

  Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases  =  46,325, controls  =  42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]  =  0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10). The associations were similar for both premenopausal (OR   =   0.44, 95% CI:0.31-0.62, p  =  9.91 × 10-8) and postmenopausal breast cancer (OR  =  0.57, 95% CI: 0.46-0.71, p  =  1.88 × 10-8). This association was replicated in the data from the DRIVE consortium (OR  =  0.72, 95% CI: 0.60-0.84, p   =   1.64 × 10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk.BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.

  View details for DOI 10.1371/journal.pmed.1002105

  View details for Web of Science ID 000383357400022

  View details for PubMedCentralID PMC4995025

• Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent. PLoS medicine Guo, Y., Warren Andersen, S., Shu, X., Michailidou, K., Bolla, M. K., Wang, Q., Garcia-Closas, M., Milne, R. L., Schmidt, M. K., Chang-Claude, J., Dunning, A., Bojesen, S. E., Ahsan, H., Aittomäki, K., Andrulis, I. L., Anton-Culver, H., Arndt, V., Beckmann, M. W., Beeghly-Fadiel, A., Benitez, J., Bogdanova, N. V., Bonanni, B., Børresen-Dale, A., Brand, J., Brauch, H., Brenner, H., Brüning, T., Burwinkel, B., Casey, G., Chenevix-Trench, G., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Devilee, P., Dörk, T., Dumont, M., Fasching, P. A., Figueroa, J., Flesch-Janys, D., Fletcher, O., Flyger, H., Fostira, F., Gammon, M., Giles, G. G., Guénel, P., Haiman, C. A., Hamann, U., Hooning, M. J., Hopper, J. L., Jakubowska, A., Jasmine, F., Jenkins, M., John, E. M., Johnson, N., Jones, M. E., Kabisch, M., Kibriya, M., Knight, J. A., Koppert, L. B., Kosma, V., Kristensen, V., Le Marchand, L., Lee, E., Li, J., Lindblom, A., Luben, R., Lubinski, J., Malone, K. E., Mannermaa, A., Margolin, S., Marme, F., McLean, C., Meijers-Heijboer, H., Meindl, A., Neuhausen, S. L., Nevanlinna, H., Neven, P., Olson, J. E., Perez, J. I., Perkins, B., Peterlongo, P., Phillips, K., Pylkäs, K., Rudolph, A., Santella, R., Sawyer, E. J., Schmutzler, R. K., Seynaeve, C., Shah, M., Shrubsole, M. J., Southey, M. C., Swerdlow, A. J., Toland, A. E., Tomlinson, I., Torres, D., Truong, T., Ursin, G., van der Luijt, R. B., Verhoef, S., Whittemore, A. S., Winqvist, R., Zhao, H., Zhao, S., Hall, P., Simard, J., Kraft, P., Pharoah, P., Hunter, D., Easton, D. F., Zheng, W. 2016; 13 (8)

  Abstract

  Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases  =  46,325, controls  =  42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]  =  0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10). The associations were similar for both premenopausal (OR   =   0.44, 95% CI:0.31-0.62, p  =  9.91 × 10-8) and postmenopausal breast cancer (OR  =  0.57, 95% CI: 0.46-0.71, p  =  1.88 × 10-8). This association was replicated in the data from the DRIVE consortium (OR  =  0.72, 95% CI: 0.60-0.84, p   =   1.64 × 10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk.BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.

  View details for DOI 10.1371/journal.pmed.1002105

  View details for PubMedID 27551723

• Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers PLOS ONE Vigorito, E., Kuchenbaecker, K. B., Beesley, J., Adlard, J., Agnarsson, B. A., Andrulis, I. L., Arun, B. K., Barjhoux, L., Belotti, M., Benitez, J., Berger, A., Bojesen, A., Bonanni, B., Brewer, C., Caldes, T., Caligo, M. A., Campbell, I., Chan, S. B., Claes, K. M., Cohn, D. E., Cook, J., Daly, M. B., Damiola, F., Davidson, R., de Pauw, A., Delnatte, C., Diez, O., Domchek, S. M., Dumont, M., Durda, K., Dworniczak, B., Easton, D. F., Eccles, D., Ardnor, C., Eeles, R., Ejlertsen, B., Ellis, S., Evans, D., Feliubadalo, L., Fostira, F., Foulkes, W. D., Friedman, E., Frost, D., Gaddam, P., Ganz, P. A., Garber, J., Garcia-Barberan, V., Gauthier-Villars, M., Gehrig, A., Gerdes, A., Giraud, S., Godwin, A. K., Goldgar, D. E., Hake, C. R., Hansen, T. O., Healey, S., Hodgson, S., Hogervorst, F. L., Houdayer, C., Hulick, P. J., Imyanitov, E. N., Isaacs, C., Izatt, L., Izquierdo, A., Jacobs, L., Jakubowska, A., Janavicius, R., Jaworska-Bieniek, K., Jensen, U., John, E. M., Vijai, J., Karlan, B. Y., Kast, K., Khan, S., Kwong, A., Laitman, Y., Lester, J., Lesueur, F., Liljegren, A., Lubinski, J., Mai, P. L., Manoukian, S., Mazoyer, S., Meindl, A., Mensenkamp, A. R., Montagna, M., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Niederacher, D., Olah, E., Olopade, O. I., Ong, K., Osorio, A., Park, S., Paulsson-Karlsson, Y., Pedersen, I., Peissel, B., Peterlongo, P., Pfeiler, G., Phelan, C. M., Piedmonte, M., Poppe, B., Angel Pujana, M., Radice, P., Rennert, G., Rodriguez, G. C., Rookus, M. A., Ross, E. A., Schmutzler, R., Simard, J., Singer, C. F., Slavin, T. P., Soucy, P., Southey, M., Steinemann, D., Stoppa-Lyonnet, D., Sukiennicki, G., Sutter, C., Szabo, C. I., Tea, M., Teixeira, M. R., Teo, S., Terry, M., Thomassen, M., Tibiletti, M., Tihomirova, L., Tognazzo, S., van Rensburg, E. J., Varesco, L., Varon-Mateeva, R., Vratimos, A., Weitzel, J. N., McGuffog, L., Kirk, J., Toland, A., Hamann, U., Lindor, N., Ramus, S. J., Greene, M. H., Couch, F. J., Offit, K., Pharoah, P. P., Chenevix-Trench, G., Antoniou, A. C., Kconfab Investigators 2016; 11 (7): e0158801

  Abstract

  Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.

  View details for PubMedID 27463617

• Systemic therapy for breast cancer and risk of subsequent contralateral breast cancer in the WECARE Study BREAST CANCER RESEARCH Langballe, R., Mellemkjaer, L., Malone, K. E., Lynch, C. F., John, E. M., Knight, J. A., Bernstein, L., Brooks, J., Andersson, M., Reiner, A. S., Liang, X., Woods, M., Concannon, P. J., Bernstein, J. L., WECARE Study Collaborative Grp 2016; 18

  View details for DOI 10.1186/s13058-016-0726-0

  View details for Web of Science ID 000379313900001

• Systemic therapy for breast cancer and risk of subsequent contralateral breast cancer in the WECARE Study. Breast cancer research : BCR Langballe, R., Mellemkjær, L., Malone, K. E., Lynch, C. F., John, E. M., Knight, J. A., Bernstein, L., Brooks, J., Andersson, M., Reiner, A. S., Liang, X., Woods, M., Concannon, P. J., Bernstein, J. L. 2016; 18 (1): 65

  Abstract

  Treatment with tamoxifen or chemotherapy reduces the risk of contralateral breast cancer (CBC). However, it is uncertain how long the protection lasts and whether the protective effect is modified by patient, tumor, or treatment characteristics.The population-based WECARE Study included 1521 cases with CBC and 2212 age- and year of first diagnosis-matched controls with unilateral breast cancer recruited during two phases in the USA, Canada, and Denmark. Women were diagnosed with a first breast cancer before age 55 years during 1985-2008. Abstraction of medical records provided detailed treatment information, while information on risk factors was obtained during telephone interviews. Risk ratios (RRs) and 95 % confidence intervals (CIs) for CBC were obtained from multivariable conditional logistic regression models.Compared with never users of tamoxifen, the RR of CBC was lower for current users of tamoxifen (RR = 0.73; 95 % CI = 0.55-0.97) and for past users within 3 years of last use (RR = 0.73; 95 % CI = 0.53-1.00). There was no evidence of an increased risk of estrogen receptor-negative CBC associated with ever use of tamoxifen or use for 4.5 or more years. Use of chemotherapy (ever versus never use) was associated with a significantly reduced RR of developing CBC 1-4 years (RR = 0.59; 95 % CI = 0.45-0.77) and 5-9 years (RR = 0.73; 95 % CI = 0.56-0.95) after first breast cancer diagnosis. RRs of CBC associated with tamoxifen or with chemotherapy use were independent of age, family history of breast cancer, body mass index and tumor characteristics of the first breast cancer with the exception that the RR of CBC was lower for lobular histology compared with other histologies.Our findings are consistent with previous studies showing that treatment with tamoxifen or chemotherapy is associated with a lower risk of CBC although the risk reduction appears to last for a limited time period after treatment is completed.

  View details for DOI 10.1186/s13058-016-0726-0

  View details for PubMedID 27400983

  View details for PubMedCentralID PMC4940926

• The Effect of Patient and Contextual Characteristics on Racial/Ethnic Disparity in Breast Cancer Mortality CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Sposto, R., Keegan, T. H., Vigen, C., Kwan, M. L., Bernstein, L., John, E. M., Cheng, I., Yang, J., Koo, J., Kurian, A. W., Caan, B. J., Lu, Y., Monroe, K. R., Shariff-Marco, S., Gomez, S. L., Wu, A. H. 2016; 25 (7): 1064-1072

  Abstract

  Racial/ethnic disparity in breast cancer-specific mortality in the U.S. is well documented. We examined whether accounting for racial/ethnic differences in the prevalence of clinical, patient, and lifestyle and contextual factors that are associated with breast cancer-specific mortality can explain this disparity.The California Breast Cancer Survivorship Consortium combined interview data from six California-based breast cancer studies with cancer registry data to create a large racially diverse cohort of women with primary invasive breast cancer. We examined the contribution of variables in a previously reported Cox regression baseline model plus additional contextual, physical activity, body size, and comorbidity variables to the racial/ethnic disparity in breast cancer-specific mortality.The cohort comprised 12,098 women. Fifty-four percent were non-Latina Whites, 17% African Americans, 17% Latinas, and 12% Asian Americans. In a model adjusting only for age and study, breast cancer-specific hazard ratios relative to Whites were 1.69 (95% CI 1.46 - 1.96), 1.00 (0.84 - 1.19), and 0.52 (0.33 - 0.85) for African Americans, Latinas, and Asian Americans respectively. Adjusting for baseline-model variables decreased disparity primarily by reducing the hazard ratio for African Americans to 1.13 (0.96 - 1.33). The most influential variables were related to disease characteristics, neighborhood socioeconomic status, and smoking status at diagnosis. Other variables had negligible impact on disparity.While contextual, physical activity, body size, and comorbidity variables may influence breast cancer-specific mortality, they do not explain racial/ethnic mortality disparity.Other factors besides those investigated here may explain the existing racial/ethnic disparity in mortality.

  View details for DOI 10.1158/1055-9965.EPI-15-1326

  View details for PubMedID 27197297

• Comparison of Clinical, Maternal, and Self Pubertal Assessments: Implications for Health Studies PEDIATRICS Terry, M. B., Goldberg, M., Schechter, S., Houghton, L. C., White, M. L., O'Toole, K., Chung, W. K., Daly, M. B., Keegan, T. H., Andrulis, I. L., Bradbury, A. R., Schwartz, L., Knight, J. A., John, E. M., Buys, S. S. 2016; 138 (1)

  Abstract

  Most epidemiologic studies of puberty have only 1 source of pubertal development information (maternal, self or clinical). Interpretation of results across studies requires data on reliability and validity across sources.The LEGACY Girls Study, a 5-site prospective study of girls aged 6 to 13 years (n = 1040) collected information on breast and pubic hair development from mothers (for all daughters) and daughters (if ≥10 years) according to Tanner stage (T1-5) drawings. At 2 LEGACY sites, girls (n = 282) were also examined in the clinic by trained professionals. We assessed agreement (κ) and validity (sensitivity and specificity) with the clinical assessment (gold standard) for both the mothers' and daughters' assessment in the subcohort of 282. In the entire cohort, we examined the agreement between mothers and daughters.Compared with clinical assessment, sensitivity of maternal assessment for breast development was 77.2 and specificity was 94.3. In girls aged ≥11 years, self-assessment had higher sensitivity and specificity than maternal report. Specificity for both mothers and self, but not sensitivity, was significantly lower for overweight girls. In the overall cohort, maternal and daughter agreement for breast development and pubic hair development (T2+ vs T1) were similar (0.66, [95% confidence interval 0.58-0.75] and 0.69 [95% confidence interval 0.61-0.77], respectively), but declined with age. Mothers were more likely to report a lower Tanner stage for both breast and pubic hair compared with self-assessments.These differences in validity should be considered in studies measuring pubertal changes longitudinally when they do not have access to clinical assessments.

  View details for DOI 10.1542/peds.2015-4571

  View details for Web of Science ID 000378853100029

  View details for PubMedID 27279647

• Prostate Cancer Susceptibility in Men of African Ancestry at 8q24. Journal of the National Cancer Institute Han, Y., Rand, K. A., Hazelett, D. J., Ingles, S. A., Kittles, R. A., Strom, S. S., Rybicki, B. A., Nemesure, B., Isaacs, W. B., Stanford, J. L., Zheng, W., Schumacher, F. R., Berndt, S. I., Wang, Z., Xu, J., Rohland, N., Reich, D., Tandon, A., Pasaniuc, B., Allen, A., Quinque, D., Mallick, S., Notani, D., Rosenfeld, M. G., Jayani, R. S., Kolb, S., Gapstur, S. M., Stevens, V. L., Pettaway, C. A., Yeboah, E. D., Tettey, Y., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Chokkalingam, A. P., John, E. M., Murphy, A. B., Signorello, L. B., Carpten, J., Leske, M. C., Wu, S., Hennis, A. J., Neslund-Dudas, C., Hsing, A. W., Chu, L., Goodman, P. J., Klein, E. A., Zheng, S. L., Witte, J. S., Casey, G., Lubwama, A., Pooler, L. C., Sheng, X., Coetzee, G. A., Cook, M. B., Chanock, S. J., Stram, D. O., Watya, S., Blot, W. J., Conti, D. V., Henderson, B. E., Haiman, C. A. 2016; 108 (7)

  Abstract

  The 8q24 region harbors multiple risk variants for distinct cancers, including >8 for prostate cancer. In this study, we conducted fine mapping of the 8q24 risk region (127.8-128.8Mb) in search of novel associations with common and rare variation in 4853 prostate cancer case patients and 4678 control subjects of African ancestry. All statistical tests were two-sided. We identified three independent associations at P values of less than 5.00×10(-8), all of which were replicated in studies from Ghana and Uganda (combined sample = 5869 case patients, 5615 control subjects; rs114798100: risk allele frequency [RAF] = 0.04, per-allele odds ratio [OR] = 2.31, 95% confidence interval [CI] = 2.04 to 2.61, P = 2.38×10(-40); rs72725879: RAF = 0.33, OR = 1.37, 95% CI = 1.30 to 1.45, P = 3.04×10(-27); and rs111906932: RAF = 0.03, OR = 1.79, 95% CI = 1.53 to 2.08, P = 1.39×10(-13)). Risk variants rs114798100 and rs111906923 are only found in men of African ancestry, with rs111906923 representing a novel association signal. The three variants are located within or near a number of prostate cancer-associated long noncoding RNAs (lncRNAs), including PRNCR1, PCAT1, and PCAT2. These findings highlight ancestry-specific risk variation and implicate prostate-specific lncRNAs at the 8q24 prostate cancer susceptibility region.

  View details for DOI 10.1093/jnci/djv431

  View details for PubMedID 26823525

• ABRAXAS (FAM175A) and Breast Cancer Susceptibility: No Evidence of Association in the Breast Cancer Family Registry PLOS ONE Renault, A., Lesueur, F., Coulombe, Y., Gobeil, S., Soucy, P., Hamdi, Y., Desjardins, S., Le Calvez-Kelm, F., Vallee, M., Voegele, C., Hopper, J. L., Andrulis, I. L., Southey, M. C., John, E. M., Masson, J., Tavtigian, S. V., Simard, J. 2016; 11 (6)

  Abstract

  Approximately half of the familial aggregation of breast cancer remains unexplained. This proportion is less for early-onset disease where familial aggregation is greater, suggesting that other susceptibility genes remain to be discovered. The majority of known breast cancer susceptibility genes are involved in the DNA double-strand break repair pathway. ABRAXAS is involved in this pathway and mutations in this gene impair BRCA1 recruitment to DNA damage foci and increase cell sensitivity to ionizing radiation. Moreover, a recurrent germline mutation was reported in Finnish high-risk breast cancer families. To determine if ABRAXAS could be a breast cancer susceptibility gene in other populations, we conducted a population-based case-control mutation screening study of the coding exons and exon/intron boundaries of ABRAXAS in the Breast Cancer Family Registry. In addition to the common variant p.Asp373Asn, sixteen distinct rare variants were identified. Although no significant difference in allele frequencies between cases and controls was observed for the identified variants, two variants, p.Gly39Val and p.Thr141Ile, were shown to diminish phosphorylation of gamma-H2AX in MCF7 human breast adenocarcinoma cells, an important biomarker of DNA double-strand breaks. Overall, likely damaging or neutral variants were evenly represented among cases and controls suggesting that rare variants in ABRAXAS may explain only a small proportion of hereditary breast cancer.

  View details for DOI 10.1371/journal.pone.0156820

  View details for Web of Science ID 000377561000040

  View details for PubMedID 27270457

  View details for PubMedCentralID PMC4896418

• Cohort Profile: The Breast Cancer Prospective Family Study Cohort (ProF-SC) INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Terry, M. B., Phillips, K., Daly, M. B., John, E. M., Andrulis, I. L., Buys, S. S., Goldgar, D. E., Knight, J. A., Whittemore, A. S., Chung, W. K., Apicella, C., Hopper, J. L. 2016; 45 (3): 683-692

  View details for DOI 10.1093/ije/dyv118

  View details for PubMedID 26174520

• Multigene testing of moderate-risk genes: be mindful of the missense JOURNAL OF MEDICAL GENETICS Young, E. L., Feng, B. J., Stark, A. W., Damiola, F., Durand, G., Forey, N., Francy, T. C., Gammon, A., Kohlmann, W. K., Kaphingst, K. A., McKay-Chopin, S., Nguyen-Dumont, T., Oliver, J., Paquette, A. M., Pertesi, M., Robinot, N., Rosenthal, J. S., Vallee, M., Voegele, C., Hopper, J. L., Southey, M. C., Andrulis, I. L., John, E. M., Hashibe, M., Gertz, J., Le Calvez-Kelm, F., Lesueur, F., Goldgar, D. E., Tavtigian, S. V., Breast Canc Family Registry 2016; 53 (6): 366–76

  Abstract

  Moderate-risk genes have not been extensively studied, and missense substitutions in them are generally returned to patients as variants of uncertain significance lacking clearly defined risk estimates. The fraction of early-onset breast cancer cases carrying moderate-risk genotypes and quantitative methods for flagging variants for further analysis have not been established.We evaluated rare missense substitutions identified from a mutation screen of ATM, CHEK2, MRE11A, RAD50, NBN, RAD51, RINT1, XRCC2 and BARD1 in 1297 cases of early-onset breast cancer and 1121 controls via scores from Align-Grantham Variation Grantham Deviation (GVGD), combined annotation dependent depletion (CADD), multivariate analysis of protein polymorphism (MAPP) and PolyPhen-2. We also evaluated subjects by polygenotype from 18 breast cancer risk SNPs. From these analyses, we estimated the fraction of cases and controls that reach a breast cancer OR≥2.5 threshold.Analysis of mutation screening data from the nine genes revealed that 7.5% of cases and 2.4% of controls were carriers of at least one rare variant with an average OR≥2.5. 2.1% of cases and 1.2% of controls had a polygenotype with an average OR≥2.5.Among early-onset breast cancer cases, 9.6% had a genotype associated with an increased risk sufficient to affect clinical management recommendations. Over two-thirds of variants conferring this level of risk were rare missense substitutions in moderate-risk genes. Placement in the estimated OR≥2.5 group by at least two of these missense analysis programs should be used to prioritise variants for further study. Panel testing often creates more heat than light; quantitative approaches to variant prioritisation and classification may facilitate more efficient clinical classification of variants.

  View details for PubMedID 26787654

  View details for PubMedCentralID PMC4893078

• The LEGACY Girls Study: Growth and Development in the Context of Breast Cancer Family History. Epidemiology John, E. M., Terry, M. B., Keegan, T. H., Bradbury, A. R., Knight, J. A., Chung, W. K., Frost, C. J., Lilge, L., Patrick-Miller, L., Schwartz, L. A., Whittemore, A. S., Buys, S. S., Daly, M. B., Andrulis, I. L. 2016; 27 (3): 438-448

  Abstract

  Although the timing of pubertal milestones has been associated with breast cancer risk, few studies of girls' development include girls at increased breast cancer risk due to their family history.The Lessons in Epidemiology and Genetics of Adult Cancer from Youth (LEGACY) Girls Study was initiated in 2011 in the USA and Canada to assess the relation between early life exposures and intermediate markers of breast cancer risk (e.g., pubertal development, breast tissue characteristics) and to investigate psychosocial well being and health behaviors in the context of family history. We describe the methods used to establish and follow a cohort of 1,040 girls ages 6-13 years at baseline, half with a breast cancer family history, and the collection of questionnaire data (family history, early life exposures, growth and development, psychosocial and behavioral), anthropometry, biospecimens, and breast tissue characteristics using optical spectroscopy.During this initial 5-year phase of the study, follow-up visits are conducted every 6 months for repeated data and biospecimen collection. Participation in baseline components was high (98% for urine, 97.5% for blood or saliva, and 98% for anthropometry). At enrollment, 77% of girls were premenarcheal and 49% were at breast Tanner stage T1.This study design allows thorough examination of events affecting girls' growth and development and how they differ across the spectrum of breast cancer risk. A better understanding of early life breast cancer risk factors will be essential to enhance prevention across the lifespan for those with and without a family history of the disease.

  View details for DOI 10.1097/EDE.0000000000000456

  View details for PubMedID 26829160

• Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry CANCER CAUSES & CONTROL Zhao, Z., Wen, W., Michailidou, K., Bolla, M. K., Wang, Q., Zhang, B., Long, J., Shu, X., Schmidt, M. K., Milne, R. L., Garcia-Closas, M., Chang-Claude, J., Lindstrom, S., Bojesen, S. E., Ahsan, H., Aittomaki, K., Andrulis, I. L., Anton-Culver, H., Arndt, V., Beckmann, M. W., Beeghly-Fadiel, A., Benitez, J., Blomqvist, C., Bogdanova, N. V., Borresen-Dale, A., Brand, J., Brauch, H., Brenner, H., Burwinkel, B., Cai, Q., Casey, G., Chenevix-Trench, G., Couch, F. J., Cox, A., Cross, S. S., Czene, K., Doerk, T., Dumont, M., Fasching, P. A., Figueroa, J., Flesch-Janys, D., Fletcher, O., Flyger, H., Fostira, F., Gammon, M., Giles, G. G., Guenel, P., Haiman, C. A., Hamann, U., Harrington, P., Hartman, M., Hooning, M. J., Hopper, J. L., Jakubowska, A., Jasmine, F., John, E. M., Johnson, N., Kabisch, M., Khan, S., Kibriya, M., Knight, J. A., Kosma, V., Kriege, M., Kristensen, V., Le Marchand, L., Lee, E., Li, J., Lindblom, A., Lophatananon, A., Luben, R., Lubinski, J., Malone, K. E., Mannermaa, A., Manoukian, S., Margolin, S., Marme, F., McLean, C., Meijers-Heijboer, H., Meindl, A., Miao, H., Muir, K., Neuhausen, S. L., Nevanlinna, H., Neven, P., Olson, J. E., Perkins, B., Peterlongo, P., Phillips, K., Pylkas, K., Rudolph, A., Santella, R., Sawyer, E. J., Schmutzler, R. K., Schoemaker, M., Shah, M., Shrubsole, M., Southey, M. C., Swerdlow, A. J., Toland, A. E., Tomlinson, I., Torres, D., Therese Truong, T., Ursin, G., van der Luijt, R. B., Verhoef, S., Wang-Gohrke, S., Whittemore, A. S., Winqvist, R., Zamora, M. P., Zhao, H., Dunning, A. M., Simard, J., Hall, P., Kraft, P., Pharoah, P., Hunter, D., Easton, D. F., Zheng, W. 2016; 27 (5): 679-693

  Abstract

  Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors.We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies.The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92-0.95, p = 4.13E-13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02-1.06, p = 1.26E-05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95-0.99, p = 8.05E-04).We have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.

  View details for DOI 10.1007/s10552-016-0741-6

  View details for PubMedID 27053251

• Ethnic differences in the relationships between diabetes, early age adiposity and mortality among breast cancer survivors: the Breast Cancer Health Disparities Study BREAST CANCER RESEARCH AND TREATMENT Connor, A. E., Visvanathan, K., Baumgartner, K. B., Baumgartner, R. N., Boone, S. D., Hines, L. M., Wolff, R. K., John, E. M., Slattery, M. L. 2016; 157 (1): 167-178

  Abstract

  The contribution of type 2 diabetes and obesity on mortality in breast cancer (BC) patients has not been well studied among Hispanic women, in whom these exposures are highly prevalent. In a multi-center population-based study, we examined the associations between diabetes, multiple obesity measures, and mortality in 1180 Hispanic and 1298 non-Hispanic white (NHW) women who were diagnosed with incident invasive BC from the San Francisco Bay Area, New Mexico, Utah, Colorado, and Arizona. Adjusted hazard ratios (HR) and 95 % confidence intervals (CI) were calculated using Cox proportional hazards regression models. The median follow-up time from BC diagnosis to death was 10.8 years. In ethnic-stratified results, the association for BC-specific mortality among Hispanics was significantly increased (HR 1.85 95 % CI 1.11, 3.09), but the ethnic interaction was not statistically significant. In contrast, obesity at age 30 increased BC-specific mortality risk in NHW women (HR 2.33 95 % CI 1.36, 3.97) but not Hispanics (p-interaction = 0.045). Although there were no ethnic differences for all-cause mortality, diabetes, obesity at age 30, and post-diagnostic waist-hip ratio were significantly associated with all-cause mortality in all women. This study provides evidence that diabetes and adiposity, both modifiable, are prognostic factors among Hispanic and NHW BC patients.

  View details for DOI 10.1007/s10549-016-3810-3

  View details for Web of Science ID 000376303100016

  View details for PubMedID 27116186

• No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing JOURNAL OF MEDICAL GENETICS Easton, D. F., Lesueur, F., Decker, B., Michailidou, K., Li, J., Allen, J., Luccarini, C., Pooley, K. A., Shah, M., Bolla, M. K., Wang, Q., Dennis, J., Ahmad, J., Thompson, E. R., Damiola, F., Pertesi, M., Voegele, C., Mebirouk, N., Robinot, N., Durand, G., Forey, N., Luben, R. N., Ahmed, S., Aittomaki, K., Anton-Culver, H., Arndt, V., Baynes, C., Beckman, M. W., Benitez, J., Van Den Berg, D., Blot, W. J., Bogdanova, N. V., Bojesen, S. E., Brenner, H., Chang-Claude, J., Chia, K. S., Choi, J., Conroy, D. M., Cox, A., Cross, S. S., Czene, K., Darabi, H., Devilee, P., Eriksson, M., Fasching, P. A., Figueroa, J., Flyger, H., Fostira, F., Garcia-Closas, M., Giles, G. G., Glendon, G., Gonzalez-Neira, A., Guenel, P., Haiman, C. A., Hall, P., Hart, S. N., Hartman, M., Hooning, M. J., Hsiung, C., Ito, H., Jakubowska, A., James, P. A., John, E. M., Johnson, N., Jones, M., Kabisch, M., Kang, D., Kosma, V., Kristensen, V., Lambrechts, D., Li, N., Lindblom, A., Long, J., Lophatananon, A., Lubinski, J., Mannermaa, A., Manoukian, S., Margolin, S., Matsuo, K., Meindl, A., Mitchell, G., Muir, K., Nevelsteen, I., van den Ouweland, A., Peterlongo, P., Phuah, S. Y., Pylkas, K., Rowley, S. M., Sangrajrang, S., Schmutzler, R. K., Shen, C., Shu, X., Southey, M. C., Surowy, H., Swerdlow, A., Teo, S. H., Tollenaar, R. A., Tomlinson, I., Torres, D., Truong, T., Vachon, C., Verhoef, S., Wong-Brown, M., Zheng, W., Zheng, Y., Nevanlinna, H., Scott, R. J., Andrulis, I. L., Wu, A. H., Hopper, J. L., Couch, F. J., Winqvist, R., Burwinkel, B., Sawyer, E. J., Schmidt, M. K., Rudolph, A., Doerk, T., Brauch, H., Hamann, U., Neuhausen, S. L., Milne, R. L., Fletcher, O., Pharoah, P. D., Campbell, I. G., Dunning, A. M., Le Calvez-Kelm, F., Goldgar, D. E., Tavtigian, S. V., Chenevix-Trench, G. 2016; 53 (5): 298-309

  Abstract

  BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction.We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia.The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75).These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

  View details for DOI 10.1136/jmedgenet-2015-103529

  View details for Web of Science ID 000375274900003

  View details for PubMedID 26921362

  View details for PubMedCentralID PMC4938802

• Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170 NATURE GENETICS Dunning, A. M., Michailidou, K., Kuchenbaecker, K. B., Thompson, D., French, J. D., Beesley, J., Healey, C. S., Kar, S., Pooley, K. A., Lopez-Knowles, E., Dicks, E., Barrowdale, D., Sinnott-Armstrong, N. A., Sallari, R. C., Hillman, K. M., Kaufmann, S., Sivakumaran, H., Marjaneh, M. M., Lee, J. S., Hills, M., Jarosz, M., Drury, S., Canisius, S., Bolla, M. K., Dennis, J., Wang, Q., Hopper, J. L., Southey, M. C., Broeks, A., Schmidt, M. K., Lophatananon, A., Muir, K., Beckmann, M. W., Fasching, P. A., Dos-Santos-Silva, I., Peto, J., Sawyer, E. J., Tomlinson, I., Burwinkel, B., Marme, F., Guenel, P., Truong, T., Bojesen, S. E., Flyger, H., Gonzalez-Neira, A., Perez, J. I., Anton-Culver, H., Eunjung, L., Arndt, V., Brenner, H., Meindl, A., Schmutzler, R. K., Brauch, H., Hamann, U., Aittomaki, K., Blomqvist, C., Ito, H., Matsuo, K., Bogdanova, N., Dork, T., Lindblom, A., Margolin, S., Kosma, V., Mannermaa, A., Tseng, C., Wu, A. H., Lambrechts, D., Wildiers, H., Chang-Claude, J., Rudolph, A., Peterlongo, P., Radice, P., Olson, J. E., Giles, G. G., Milne, R. L., Haiman, C. A., Henderson, B. E., Goldberg, M. S., Teo, S. H., Yip, C. H., Nord, S., Borresen-Dale, A., Kristensen, V., Long, J., Zheng, W., Pylkas, K., Winqvist, R., Andrulis, I. L., Knight, J. A., Devilee, P., Seynaeve, C., Figueroa, J., Sherman, M. E., Czene, K., Darabi, H., Hollestelle, A., van den Ouweland, A. M., Humphreys, K., Gao, Y., Shu, X., Cox, A., Cross, S. S., Blot, W., Cai, Q., Ghoussaini, M., Perkins, B. J., Shah, M., Choi, J., Kang, D., Lee, S. C., Hartman, M., Kabisch, M., Torres, D., Jakubowska, A., Lubinski, J., Brennan, P., Sangrajrang, S., Ambrosone, C. B., Toland, A. E., Shen, C., Wu, P., Orr, N., Swerdlow, A., McGuffog, L., Healey, S., Lee, A., Kapuscinski, M., John, E. M., Terry, M. B., Daly, M. B., Goldgar, D. E., Buys, S. S., Janavicius, R., Tihomirova, L., Tung, N., Dorfling, C. M., Van Rensburg, E. J., Neuhausen, S. L., Ejlertsen, B., Hansen, T. v., Osorio, A., Benitez, J., Rando, R., Weitzel, J. N., Bonanni, B., Peissel, B., Manoukian, S., Papi, L., Ottini, L., Konstantopoulou, I., Apostolou, P., Garber, J., Rashid, M. U., Frost, D., Izatt, L., Ellis, S., Godwin, A. K., Arnold, N., Niederacher, D., Rhiem, K., Bogdanova-Markov, N., Sagne, C., Stoppa-Lyonnet, D., Damiola, F., Sinilnikova, O. M., Mazoyer, S., Isaacs, C., Claes, K. B., De Leeneer, K., de la Hoya, M., Caldes, T., Nevanlinna, H., Khan, S., Mensenkamp, A. R., Hooning, M. J., Rookus, M. A., Kwong, A., Olah, E., Diez, O., Brunet, J., Pujana, M. A., Gronwald, J., Huzarski, T., Barkardottir, R. B., Laframboise, R., Soucy, P., Montagna, M., Agata, S., Teixeira, M. R., Park, S. K., Lindor, N., Couch, F. J., Tischkowitz, M., Foretova, L., Vijai, J., Offit, K., Singer, C. F., Rappaport, C., Phelan, C. M., Greene, M. H., Mai, P. L., Rennert, G., Imyanitov, E. N., Hulick, P. J., Phillips, K., Piedmonte, M., Mulligan, A. M., Glendon, G., Bojesen, A., Thomassen, M., Caligo, M. A., Yoon, S., friedman, e., Laitman, Y., Borg, A., von Wachenfeldt, A., Ehrencrona, H., Rantala, J., Olopade, O. I., Ganz, P. A., Nussbaum, R. L., Gayther, S. A., Nathanson, K. L., Domchek, S. M., Arun, B. K., Mitchell, G., Karlan, B. Y., Lester, J., Maskarinec, G., Woolcott, C., Scott, C., Stone, J., Apicella, C., Tamimi, R., Luben, R., Khaw, K., Helland, A., Haakensen, V., Dowsett, M., Pharoah, P. D., Simard, J., Hall, P., Garcia-Closas, M., Vachon, C., Chenevix-Trench, G., Antoniou, A. C., Easton, D. F., Edwards, S. L. 2016; 48 (4): 374-?

  Abstract

  We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.

  View details for DOI 10.1038/ng.3521

  View details for Web of Science ID 000372908800009

  View details for PubMedCentralID PMC4938803

• Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170. Nature genetics Dunning, A. M., Michailidou, K., Kuchenbaecker, K. B., Thompson, D., French, J. D., Beesley, J., Healey, C. S., Kar, S., Pooley, K. A., Lopez-Knowles, E., Dicks, E., Barrowdale, D., Sinnott-Armstrong, N. A., Sallari, R. C., Hillman, K. M., Kaufmann, S., Sivakumaran, H., Moradi Marjaneh, M., Lee, J. S., Hills, M., Jarosz, M., Drury, S., Canisius, S., Bolla, M. K., Dennis, J., Wang, Q., Hopper, J. L., Southey, M. C., Broeks, A., Schmidt, M. K., Lophatananon, A., Muir, K., Beckmann, M. W., Fasching, P. A., Dos-Santos-Silva, I., Peto, J., Sawyer, E. J., Tomlinson, I., Burwinkel, B., Marme, F., Guénel, P., Truong, T., Bojesen, S. E., Flyger, H., González-Neira, A., Perez, J. I., Anton-Culver, H., Eunjung, L., Arndt, V., Brenner, H., Meindl, A., Schmutzler, R. K., Brauch, H., Hamann, U., Aittomäki, K., Blomqvist, C., Ito, H., Matsuo, K., Bogdanova, N., Dörk, T., Lindblom, A., Margolin, S., Kosma, V., Mannermaa, A., Tseng, C., Wu, A. H., Lambrechts, D., Wildiers, H., Chang-Claude, J., Rudolph, A., Peterlongo, P., Radice, P., Olson, J. E., Giles, G. G., Milne, R. L., Haiman, C. A., Henderson, B. E., Goldberg, M. S., Teo, S. H., Yip, C. H., Nord, S., Borresen-Dale, A., Kristensen, V., Long, J., Zheng, W., Pylkäs, K., Winqvist, R., Andrulis, I. L., Knight, J. A., Devilee, P., Seynaeve, C., Figueroa, J., Sherman, M. E., Czene, K., Darabi, H., Hollestelle, A., van den Ouweland, A. M., Humphreys, K., Gao, Y., Shu, X., Cox, A., Cross, S. S., Blot, W., Cai, Q., Ghoussaini, M., Perkins, B. J., Shah, M., Choi, J., Kang, D., Lee, S. C., Hartman, M., Kabisch, M., Torres, D., Jakubowska, A., Lubinski, J., Brennan, P., Sangrajrang, S., Ambrosone, C. B., Toland, A. E., Shen, C., Wu, P., Orr, N., Swerdlow, A., McGuffog, L., Healey, S., Lee, A., Kapuscinski, M., John, E. M., Terry, M. B., Daly, M. B., Goldgar, D. E., Buys, S. S., Janavicius, R., Tihomirova, L., Tung, N., Dorfling, C. M., Van Rensburg, E. J., Neuhausen, S. L., Ejlertsen, B., Hansen, T. v., Osorio, A., Benitez, J., Rando, R., Weitzel, J. N., Bonanni, B., Peissel, B., Manoukian, S., Papi, L., Ottini, L., Konstantopoulou, I., Apostolou, P., Garber, J., Rashid, M. U., Frost, D., Izatt, L., Ellis, S., Godwin, A. K., Arnold, N., Niederacher, D., Rhiem, K., Bogdanova-Markov, N., Sagne, C., Stoppa-Lyonnet, D., Damiola, F., Sinilnikova, O. M., Mazoyer, S., Isaacs, C., Claes, K. B., De Leeneer, K., de la Hoya, M., Caldes, T., Nevanlinna, H., Khan, S., Mensenkamp, A. R., Hooning, M. J., Rookus, M. A., Kwong, A., Olah, E., Diez, O., Brunet, J., Pujana, M. A., Gronwald, J., Huzarski, T., Barkardottir, R. B., Laframboise, R., Soucy, P., Montagna, M., Agata, S., Teixeira, M. R., Park, S. K., Lindor, N., Couch, F. J., Tischkowitz, M., Foretova, L., Vijai, J., Offit, K., Singer, C. F., Rappaport, C., Phelan, C. M., Greene, M. H., Mai, P. L., Rennert, G., Imyanitov, E. N., Hulick, P. J., Phillips, K., Piedmonte, M., Mulligan, A. M., Glendon, G., Bojesen, A., Thomassen, M., Caligo, M. A., Yoon, S., friedman, e., Laitman, Y., Borg, A., von Wachenfeldt, A., Ehrencrona, H., Rantala, J., Olopade, O. I., Ganz, P. A., Nussbaum, R. L., Gayther, S. A., Nathanson, K. L., Domchek, S. M., Arun, B. K., Mitchell, G., Karlan, B. Y., Lester, J., Maskarinec, G., Woolcott, C., Scott, C., Stone, J., Apicella, C., Tamimi, R., Luben, R., Khaw, K., Helland, Å., Haakensen, V., Dowsett, M., Pharoah, P. D., Simard, J., Hall, P., García-Closas, M., Vachon, C., Chenevix-Trench, G., Antoniou, A. C., Easton, D. F., Edwards, S. L. 2016; 48 (4): 374-386

  Abstract

  We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.

  View details for DOI 10.1038/ng.3521

  View details for PubMedID 26928228

• Red meat, poultry, and fish intake and breast cancer risk among Hispanic and Non-Hispanic white women: The Breast Cancer Health Disparities Study. Cancer causes & control Kim, A. E., Lundgreen, A., Wolff, R. K., Fejerman, L., John, E. M., Torres-Mejía, G., Ingles, S. A., Boone, S. D., Connor, A. E., Hines, L. M., Baumgartner, K. B., Giuliano, A., Joshi, A. D., Slattery, M. L., Stern, M. C. 2016; 27 (4): 527-543

  Abstract

  There is suggestive but limited evidence for a relationship between meat intake and breast cancer (BC) risk. Few studies included Hispanic women. We investigated the association between meats and fish intake and BC risk among Hispanic and NHW women.The study included NHW (1,982 cases and 2,218 controls) and the US Hispanics (1,777 cases and 2,218 controls) from two population-based case-control studies. Analyses considered menopausal status and percent Native American ancestry. We estimated pooled ORs combining harmonized data from both studies, and study- and race-/ethnicity-specific ORs that were combined using fixed or random effects models, depending on heterogeneity levels.When comparing highest versus lowest tertile of intake, among NHW we observed an association between tuna intake and BC risk (pooled OR 1.25; 95 % CI 1.05-1.50; trend p = 0.006). Among Hispanics, we observed an association between BC risk and processed meat intake (pooled OR 1.42; 95 % CI 1.18-1.71; trend p < 0.001), and between white meat (OR 0.80; 95 % CI 0.67-0.95; trend p = 0.01) and BC risk, driven by poultry. All these findings were supported by meta-analysis using fixed or random effect models and were restricted to estrogen receptor-positive tumors. Processed meats and poultry were not associated with BC risk among NHW women; red meat and fish were not associated with BC risk in either race/ethnic groups.Our results suggest the presence of ethnic differences in associations between meat and BC risk that may contribute to BC disparities.

  View details for DOI 10.1007/s10552-016-0727-4

  View details for PubMedID 26898200

  View details for PubMedCentralID PMC4821634

• Red meat, poultry, and fish intake and breast cancer risk among Hispanic and Non-Hispanic white women: The Breast Cancer Health Disparities Study CANCER CAUSES & CONTROL Kim, A. E., Lundgreen, A., Wolff, R. K., Fejerman, L., John, E. M., Torres-Mejia, G., Ingles, S. A., Boone, S. D., Connor, A. E., Hines, L. M., Baumgartner, K. B., Giuliano, A., Joshi, A. D., Slattery, M. L., Stern, M. C. 2016; 27 (4): 527-543

  Abstract

  There is suggestive but limited evidence for a relationship between meat intake and breast cancer (BC) risk. Few studies included Hispanic women. We investigated the association between meats and fish intake and BC risk among Hispanic and NHW women.The study included NHW (1,982 cases and 2,218 controls) and the US Hispanics (1,777 cases and 2,218 controls) from two population-based case-control studies. Analyses considered menopausal status and percent Native American ancestry. We estimated pooled ORs combining harmonized data from both studies, and study- and race-/ethnicity-specific ORs that were combined using fixed or random effects models, depending on heterogeneity levels.When comparing highest versus lowest tertile of intake, among NHW we observed an association between tuna intake and BC risk (pooled OR 1.25; 95 % CI 1.05-1.50; trend p = 0.006). Among Hispanics, we observed an association between BC risk and processed meat intake (pooled OR 1.42; 95 % CI 1.18-1.71; trend p < 0.001), and between white meat (OR 0.80; 95 % CI 0.67-0.95; trend p = 0.01) and BC risk, driven by poultry. All these findings were supported by meta-analysis using fixed or random effect models and were restricted to estrogen receptor-positive tumors. Processed meats and poultry were not associated with BC risk among NHW women; red meat and fish were not associated with BC risk in either race/ethnic groups.Our results suggest the presence of ethnic differences in associations between meat and BC risk that may contribute to BC disparities.

  View details for DOI 10.1007/s10552-016-0727-4

  View details for Web of Science ID 000372554500007

  View details for PubMedCentralID PMC4821634

• Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer NATURE COMMUNICATIONS Couch, F. J., Kuchenbaecker, K. B., Michailidou, K., Mendoza-Fandino, G. A., Nord, S., Lilyquist, J., Olswold, C., Hallberg, E., Agata, S., Ahsan, H., Aittomaeki, K., Ambrosone, C., Andrulis, I. L., Anton-Culver, H., Arndt, V., Arun, B. K., Arver, B., Barile, M., Barkardottir, R. B., Barrowdale, D., Beckmann, L., Beckmann, M. W., Benitez, J., Blank, S. V., Blomqvist, C., Bogdanova, N. V., Bojesen, S. E., Bolla, M. K., Bonanni, B., Brauch, H., Brenner, H., Burwinkel, B., Buys, S. S., Caldes, T., Caligo, M. A., Canzian, F., Carpenter, J., Chang-Claude, J., Chanock, S. J., Chung, W. K., Claes, K. B., Cox, A., Cross, S. S., Cunningham, J. M., Czene, K., Daly, M. B., Damiola, F., Darabi, H., de la Hoya, M., Devilee, P., Diez, O., Ding, Y. C., Dolcetti, R., Domchek, S. M., Dorfling, C. M., Dos-Santos-Silva, I., Dumont, M., Dunning, A. M., Eccles, D. M., Ehrencrona, H., Ekici, A. B., Eliassen, H., Ellis, S., Fasching, P. A., Figueroa, J., Flesch-Janys, D., Foersti, A., Fostira, F., Foulkes, W. D., Friebel, T., friedman, e., Frost, D., Gabrielson, M., Gammon, M. D., Ganz, P. A., Gapstur, S. M., Garber, J., Gaudet, M. M., Gayther, S. A., Gerdes, A., Ghoussaini, M., Giles, G. G., Glendon, G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Greene, M. H., Gronwald, J., Guenel, P., Gunter, M., Haeberle, L., Haiman, C. A., Hamann, U., Hansen, T. v., Hart, S., Healey, S., Heikkinen, T., Henderson, B. E., Herzog, J., Hogervorst, F. B., Hollestelle, A., Hooning, M. J., Hoover, R. N., Hopper, J. L., Humphreys, K., Hunter, D. J., Huzarski, T., Imyanitov, E. N., Isaacs, C., Jakubowska, A., James, P., Janavicius, R., Jensen, U. B., John, E. M., Jones, M., Kabisch, M., Kar, S., Karlan, B. Y., Khan, S., Khaw, K., Kibriya, M. G., Knight, J. A., Ko, Y., Konstantopoulou, I., Kosma, V., Kristensen, V., Kwong, A., Laitman, Y., Lambrechts, D., Lazaro, C., Lee, E., Le Marchand, L., Lester, J., Lindblom, A., Lindor, N., Lindstrom, S., Liu, J., Long, J., Lubinski, J., Mai, P. L., Makalic, E., Malone, K. E., Mannermaa, A., Manoukian, S., Margolin, S., Marme, F., Martens, J. W., McGuffog, L., Meindl, A., Miller, A., Milne, R. L., Miron, P., Montagna, M., Mazoyer, S., Mulligan, A. M., Muranen, T. A., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Nordestgaard, B. G., Nussbaum, R. L., Offit, K., Olah, E., Olopade, O. I., Olson, J. E., Osorio, A., Park, S. K., Peeters, P. H., Peissel, B., Peterlongo, P., Peto, J., Phelan, C. M., Pilarski, R., Poppe, B., Pylkaes, K., Radice, P., Rahman, N., Rantala, J., Rappaport, C., Rennert, G., Richardson, A., Robson, M., Romieu, I., Rudolph, A., Rutgers, E. J., Sanchez, M., Santella, R. M., Sawyer, E. J., Schmidt, D. F., Schmidt, M. K., Schmutzler, R. K., Schumacher, F., Scott, R., Senter, L., Sharma, P., Simard, J., Singer, C. F., Sinilnikova, O. M., Soucy, P., Southey, M., Steinemann, D., Stenmark-Askmalm, M., Stoppa-Lyonnet, D., Swerdlow, A., Szabo, C. I., Tamimi, R., Tapper, W., Teixeira, M. R., Teo, S., Terry, M. B., Thomassen, M., Thompson, D., Tihomirova, L., Toland, A. E., Tollenaar, R. A., Tomlinson, I., Truong, T., Tsimiklis, H., Teule, A., Tumino, R., Tung, N., Turnbull, C., Ursin, G., van Deurzen, C. H., Van Rensburg, E. J., Varon-Mateeva, R., Wang, Z., Wang-Gohrke, S., Weiderpass, E., Weitzel, J. N., Whittemore, A., Wildiers, H., Winqvist, R., Yang, X. R., Yannoukakos, D., Yao, S., Zamora, M. P., Zheng, W., Hall, P., Kraft, P., Vachon, C., Slager, S., Chenevix-Trench, G., Pharoah, P. D., Monteiro, A. A., Garcia-Closas, M., Easton, D. F., Antoniou, A. C. 2016; 7

  Abstract

  Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.

  View details for DOI 10.1038/ncomms11375

  View details for Web of Science ID 000374894400001

  View details for PubMedCentralID PMC4853421

• Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation NATURE COMMUNICATIONS Gusev, A., Shi, H., Kichaev, G., Pomerantz, M., Li, F., Long, H. W., Ingles, S. A., Kittles, R. A., Strom, S. S., Rybicki, B. A., Nemesure, B., Isaacs, W. B., Zheng, W., Pettaway, C. A., Yeboah, E. D., Tettey, Y., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Chokkalingam, A. P., John, E. M., Murphy, A. B., Signorello, L. B., Carpten, J., Leske, M. C., Wu, S., Hennis, A. J., Neslund-Dudas, C., Hsing, A. W., Chu, L., Goodman, P. J., Klein, E. A., Witte, J. S., Casey, G., Kaggwa, S., Cook, M. B., Stram, D. O., Blot, W. J., Eeles, R. A., Easton, D., Kote-Jarai, Z., Al Olama, A. A., Benlloch, S., Muir, K., Giles, G. G., Southey, M. C., FitzGerald, L. M., Gronberg, H., Wiklund, F., Aly, M., Henderson, B. E., Schleutker, J., Wahlfors, T., Tammela, T. L., Nordestgaard, B. G., Key, T. J., Travis, R. C., Neal, D. E., Donovan, J. L., Hamdy, F. C., Pharoah, P., Pashayan, N., Khaw, K., Stanford, J. L., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., Maier, C., Vogel, W., Luedeke, M., Herkommer, K., Kibel, A. S., Cybulski, C., Wokolorczyk, D., Kluzniak, W., Cannon-Albright, L., Teerlink, C., Brenner, H., Dieffenbach, A. K., Arndt, V., Park, J. Y., Sellers, T. A., Lin, H., Slavov, C., Kaneva, R., Mitev, V., Batra, J., Spurdle, A., Clements, J. A., Teixeira, M. R., Pandha, H., Michael, A., Paulo, P., Maia, S., Kierzek, A., Conti, D. V., Albanes, D., Berg, C., Berndt, S. I., Campa, D., Crawford, E. D., Diver, W. R., Gapstur, S. M., Gaziano, J. M., Giovannucci, E., Hoover, R., Hunter, D. J., Johansson, M., Kraft, P., Le Marchand, L., Lindstrom, S., Navarro, C., Overvad, K., Riboli, E., Siddiq, A., Stevens, V. L., Trichopoulos, D., Vineis, P., Yeager, M., Trynka, G., Raychaudhuri, S., Schumacher, F. R., Price, A. L., Freedman, M. L., Haiman, C. A., Pasaniuc, B., Cook, M., Guy, M., Govindasami, K., Leongamornlert, D., Sawyer, E. J., Wilkinson, R., Saunders, E. J., Tymrakiewicz, M., Dadaev, T., Morgan, A., Fisher, C., Hazel, S., Livni, N., Lophatananon, A., Pedersen, J., Hopper, J. L., Adolfson, J., Stattin, P., Johansson, J., Cavalli-Bjoerkman, C., Karlsson, A., Broms, M., Auvinen, A., Kujala, P., Maeaettaenen, L., Murtola, T., Taari, K., Weischer, M., Nielsen, S. F., Klarskov, P., Roder, A., Iversen, P., Wallinder, H., Gustafsson, S., Cox, A., Brown, P., George, A., Marsden, G., Lane, A., Davis, M., Zheng, W., Signorello, L. B., Blot, W. J., Tillmans, L., Riska, S., Wang, L., Rinckleb, A., Lubiski, J., Stegmaier, C., Pow-Sang, J., Park, H., Radlein, S., Rincon, M., Haley, J., Zachariah, B., Kachakova, D., Popov, E., Mitkova, A., Vlahova, A., Dikov, T., Christova, S., Heathcote, P., Wood, G., Malone, G., Saunders, P., Eckert, A., Yeadon, T., Kerr, K., Collins, A., Turner, M., Srinivasan, S., Kedda, M., Alexander, K., Omara, T., Wu, H., Henrique, R., Pinto, P., Santos, J., Barros-Silva, J. 2016; 7

  Abstract

  Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

  View details for DOI 10.1038/ncomms10979

  View details for PubMedID 27052111

• Validation of self-reported comorbidity status of breast cancer patients with medical records: the California Breast Cancer Survivorship Consortium (CBCSC). Cancer causes & control Vigen, C., Kwan, M. L., John, E. M., Gomez, S. L., Keegan, T. H., Lu, Y., Shariff-Marco, S., Monroe, K. R., Kurian, A. W., Cheng, I., Caan, B. J., Lee, V. S., Roh, J. M., Bernstein, L., Sposto, R., Wu, A. H. 2016; 27 (3): 391-401

  Abstract

  To compare information from self-report and electronic medical records for four common comorbidities (diabetes, hypertension, myocardial infarction, and other heart diseases).We pooled data from two multiethnic studies (one case-control and one survivor cohort) enrolling 1,936 women diagnosed with breast cancer, who were members of Kaiser Permanente Northern California.Concordance varied by comorbidity; kappa values ranged from 0.50 for other heart diseases to 0.87 for diabetes. Sensitivities for comorbidities from self-report versus medical record were similar for racial/ethnic minorities and non-Hispanic Whites, and did not vary by age, neighborhood socioeconomic status, or education. Women with a longer history of comorbidity or who took medications for the comorbidity were more likely to report the condition. Hazard ratios for all-cause mortality were not consistently affected by source of comorbidity information; the hazard ratio was lower for diabetes, but higher for the other comorbidities when medical record versus self-report was used. Model fit was better when the medical record versus self-reported data were used.Comorbidities are increasingly recognized to influence the survival of patients with breast or other cancers. Potential effects of misclassification of comorbidity status should be considered in the interpretation of research results.

  View details for DOI 10.1007/s10552-016-0715-8

  View details for PubMedID 26797455

• Cigarette Smoking and Breast Cancer Risk in Hispanic and Non-Hispanic White Women: The Breast Cancer Health Disparities Study. Journal of women's health (2002) Connor, A. E., Baumgartner, K. B., Baumgartner, R. N., Pinkston, C. M., Boone, S. D., John, E. M., Torres-Mejía, G., Hines, L. M., Giuliano, A. R., Wolff, R. K., Slattery, M. L. 2016; 25 (3): 299-310

  Abstract

  Few epidemiological studies have included Hispanics with the evaluation of the effects of cigarette smoking and breast cancer. We examined the relationship between cigarette smoking, ethnicity, and breast cancer risk using data from the Breast Cancer Health Disparities Study (BCHDS).The BCHDS is a consortium of three population-based case-control studies, including U.S. non-Hispanic whites (NHWs) (1,525 cases; 1,593 controls), U.S. Hispanics/Native Americans (1,265 cases; 1,495 controls), and Mexican women (990 cases; 1,049 controls). Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs).Breast cancer risk was elevated among Mexican former smokers (OR 1.43, 95% CI 1.04-1.96) and among those who smoked ≥31 years (OR 1.95, 95% CI 1.13-3.35), compared to never smokers. In addition, Mexican former smokers with a history of alcohol consumption had increased breast cancer risk (OR 2.30, 95% CI 1.01-5.21). Among NHW premenopausal women, breast cancer risk was increased for smoking ≥20 cigarettes per day (OR 1.61, 95% CI 1.07-2.41).Our findings suggest the possibility of ethnic differences with the associations between cigarette smoking and breast cancer risk.

  View details for DOI 10.1089/jwh.2015.5502

  View details for PubMedID 26682495

  View details for PubMedCentralID PMC4790199

• Cigarette Smoking and Breast Cancer Risk in Hispanic and Non-Hispanic White Women: The Breast Cancer Health Disparities Study JOURNAL OF WOMENS HEALTH Connor, A. E., Baumgartner, K. B., Baumgartner, R. N., Pinkston, C. M., Boone, S. D., John, E. M., Torres-Mejia, G., Hines, L. M., Giuliano, A. R., Wolff, R. K., Slattery, M. L. 2016; 25 (3): 299-310

  Abstract

  Few epidemiological studies have included Hispanics with the evaluation of the effects of cigarette smoking and breast cancer. We examined the relationship between cigarette smoking, ethnicity, and breast cancer risk using data from the Breast Cancer Health Disparities Study (BCHDS).The BCHDS is a consortium of three population-based case-control studies, including U.S. non-Hispanic whites (NHWs) (1,525 cases; 1,593 controls), U.S. Hispanics/Native Americans (1,265 cases; 1,495 controls), and Mexican women (990 cases; 1,049 controls). Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs).Breast cancer risk was elevated among Mexican former smokers (OR 1.43, 95% CI 1.04-1.96) and among those who smoked ≥31 years (OR 1.95, 95% CI 1.13-3.35), compared to never smokers. In addition, Mexican former smokers with a history of alcohol consumption had increased breast cancer risk (OR 2.30, 95% CI 1.01-5.21). Among NHW premenopausal women, breast cancer risk was increased for smoking ≥20 cigarettes per day (OR 1.61, 95% CI 1.07-2.41).Our findings suggest the possibility of ethnic differences with the associations between cigarette smoking and breast cancer risk.

  View details for DOI 10.1089/jwh.2015.5502

  View details for Web of Science ID 000372173200015

  View details for PubMedCentralID PMC4790199

• Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2 BREAST CANCER RESEARCH Silvestri, V., Barrowdale, D., Mulligan, A., Neuhausen, S. L., Fox, S., Karlan, B. Y., Mitchell, G., James, P., Thull, D. L., Zorn, K. K., Carter, N. J., Nathanson, K. L., Dornchek, S. M., Rebbeck, T. R., Ramus, S. J., Nussbaum, R. L., Olopade, O. I., Rantala, J., Yoon, S., Caligo, M. A., Spugnesi, L., Bojesen, A., Pedersen, I., Thomassen, M., Jensen, U., Toland, A., Senter, L., Andrulis, I. L., Glendon, G., Hulick, P. J., Irnyanitov, E. N., Greene, M. H., Mai, P. L., Singer, C. F., Rappaport-Fuerhauser, C., Kramer, G., Vijai, J., Offit, K., Robson, M., Lincoln, A., Jacobs, L., Machackova, E., Foretova, L., Navratilova, M., Vasickova, P., Couch, F. J., Hallberg, E., Ruddy, K. J., Sharma, P., Kim, S., Teixeira, M. R., Pinte, P., Montagna, M., Matricardi, L., Arason, A., Johannsson, O., Barkardottir, R. B., Jakubowska, A., Lubinski, J., Izquierdo, A., Angel Pujana, M., Balmana, J., Diez, O., Ivady, G., Papp, J., Olah, E., Kwong, A., Nevanlinna, H., Aittomaki, K., Perez Segura, P., Caldes, T., Van Maerken, T., Poppe, B., Claes, K. M., Isaacs, C., Elan, C., Lasset, C., Stoppa-Lyonnet, D., Barjhoux, L., Belotti, M., Meindl, A., Gehrig, A., Sutter, C., Enger, C., Niederacher, D., Steinemann, D., Hahnen, E., Kast, K., Arnold, N., Varon-Mateeva, R., Wand, D., Godwin, A. K., Evans, D., Frost, D., Perkins, J., Adlard, J., Izatt, L., Platte, R., Eeles, R., Ellis, S., Hamann, U., Garber, J., Fostira, F., Fountzilas, G., Pasini, B., Giannini, G., Rizzolo, P., Russo, A., Cortesi, L., Papi, L., Varesco, L., Palli, D., Zanna, I., Savarese, A., Radice, P., Manoukian, S., Peissel, B., Barile, M., Bonanni, B., Viel, A., Pensotti, V., Tommasi, S., Peterlongo, P., Weitzel, J. N., Osorio, A., Benitez, J., McGuffog, L., Healey, S., Gerdes, A., Ejlertsen, B., Hansen, T. O., Steele, L., Ding, Y., Tung, N., Janavicius, R., Goldgar, D. E., Buys, S. S., Daly, M. B., Bane, A., Terry, M., John, E. M., Southey, M., Easton, D. F., Chenevix-Trench, G., Antoniou, A. C., Ottini, L., kConFab Investigators, Hereditary Breast Ovarian Canc Res, EMBRACE 2016; 18: 15

  Abstract

  BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs).We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database.Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10(-12)).On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.

  View details for PubMedID 26857456

  View details for PubMedCentralID PMC4746828

• BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Meeks, H. D., Song, H., Michailidou, K., Bolla, M. K., Dennis, J., Wang, Q., Barrowdale, D., Frost, D., McGuffog, L., Ellis, S., Feng, B., Buys, S. S., Hopper, J. L., Southey, M. C., Tesoriero, A., James, P. A., Bruinsma, F., Campbell, I. G., Broeks, A., Schmidt, M. K., Hogervorst, F. B., Beckman, M. W., Fasching, P. A., Fletcher, O., Johnson, N., Sawyer, E. J., Riboli, E., Banerjee, S., Menon, U., Tomlinson, I., Burwinkel, B., Hamann, U., Marme, F., Rudolph, A., Janavicius, R., Tihomirova, L., Tung, N., Garber, J., Cramer, D., Terry, K. L., Poole, E. M., Tworoger, S. S., Dorfling, C. M., Van Rensburg, E. J., Godwin, A. K., Guenel, P., Truong, T., Stoppa-Lyonnet, D., Damiola, F., Mazoyer, S., Sinilnikova, O. M., Isaacs, C., Maugard, C., Bojesen, S. E., Flyger, H., Gerdes, A., Hansen, T. v., Jensen, A., Kjaer, S. K., Hogdall, C., Hogdall, E., Pedersen, I. S., Thomassen, M., Benitez, J., Gonzalez-Neira, A., Osorio, A., de la Hoya, M., Perez Segura, P., Diez, O., Lazaro, C., Brunet, J., Anton-Culver, H., Eunjung, L., John, E. M., Neuhausen, S. L., Ding, Y. C., Castillo, D., Weitzel, J. N., Ganz, P. A., Nussbaum, R. L., Chan, S. B., Karlan, B. Y., Lester, J., Wu, A., Gayther, S., Ramus, S. J., Sieh, W., Whittermore, A. S., Monteiro, A. N., Phelan, C. M., Terry, M. B., Piedmonte, M., Offit, K., Robson, M., Levine, D., Moysich, K. B., Cannioto, R., Olson, S. H., Daly, M. B., Nathanson, K. L., Domchek, S. M., Lu, K. H., Liang, D., Hildebrant, M. A., Ness, R., Modugno, F., Pearce, L., Goodman, M. T., Thompson, P. J., Brenner, H., Butterbach, K., Meindl, A., Hahnen, E., Wappenschmidt, B., Brauch, H., Bruening, T., Blomqvist, C., Khan, S., Nevanlinna, H., Pelttari, L. M., Aittomaeki, K., Butzow, R., Bogdanova, N. V., Doerk, T., Lindblom, A., Margolin, S., Rantala, J., Kosma, V., Mannermaa, A., Lambrechts, D., Neven, P., Claes, K. B., Van Maerken, T., Chang-Claude, J., Flesch-Janys, D., Heitz, F., Varon-Mateeva, R., Peterlongo, P., Radice, P., Viel, A., Barile, M., Peissel, B., Manoukian, S., Montagna, M., Oliani, C., Peixoto, A., Teixeira, M. R., Collavoli, A., Hallberg, E., Olson, J. E., Goode, E. L., Hart, S. N., Shimelis, H., Cunningham, J. M., Giles, G. G., Milne, R. L., Healey, S., Tucker, K., Haiman, C. A., Henderson, B. E., Goldberg, M. S., Tischkowitz, M., Simard, J., Soucy, P., Eccles, D. M., Le, N., Borresen-Dale, A., Kristensen, V., Salvesen, H. B., Bjorge, L., Bandera, E. V., Risch, H., Zheng, W., Beeghly-Fadiel, A., Cai, H., Pylkas, K., Tollenaar, R. A., van der Ouweland, A. M., Andrulis, I. L., Knight, J. A., Narod, S., Devilee, P., Winqvist, R., Figueroa, J., Greene, M. H., Mai, P. L., Loud, J. T., Garcia-Closas, M., Schoemaker, M. J., Czene, K., Darabi, H., McNeish, I., Siddiquil, N., Glasspool, R., Kwong, A., Park, S. K., Teo, S. H., Yoon, S., Matsuo, K., Hosono, S., Woo, Y. L., Gao, Y., Foretova, L., Singer, C. F., Rappaport-Feurhauser, C., friedman, e., Laitman, Y., Rennert, G., Imyanitov, E. N., Hulick, P. J., Olopade, O. I., Senter, L., Olah, E., Doherty, J. A., Schildkraut, J., Koppert, L. B., Kiemeney, L. A., Massuger, L. F., Cook, L. S., Pejovic, T., Li, J., Borg, A., Ofverholm, A., Rossing, M. A., Wentzensen, N., Henriksson, K., Cox, A., Cross, S. S., Pasini, B. J., Shah, M., Kabisch, M., Torres, D., Jakubowska, A., Lubinski, J., Gronwald, J., Agnarsson, B. A., Kupryjanczyk, J., Moes-Sosnowska, J., Fostira, F., Konstantopoulou, I., Slager, S., Jones, M., Antoniou, A. C., Berchuck, A., Swerdlow, A., Chenevix-Trench, G., Dunning, A. M., Pharoah, P. D., Hall, P., Easton, D. F., Couch, F. J., Spurdle, A. B., Goldgar, D. E. 2016; 108 (2)

  Abstract

  The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers.Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided.The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed.Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.

  View details for DOI 10.1093/jnci/djv315

  View details for Web of Science ID 000371153900007

  View details for PubMedID 26586665

  View details for PubMedCentralID PMC4907358

• Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. Nature communications Lawrenson, K., Kar, S., McCue, K., Kuchenbaeker, K., Michailidou, K., Tyrer, J., Beesley, J., Ramus, S. J., Li, Q., Delgado, M. K., Lee, J. M., Aittomäki, K., Andrulis, I. L., Anton-Culver, H., Arndt, V., Arun, B. K., Arver, B., Bandera, E. V., Barile, M., Barkardottir, R. B., Barrowdale, D., Beckmann, M. W., Benitez, J., Berchuck, A., Bisogna, M., Bjorge, L., Blomqvist, C., Blot, W., Bogdanova, N., Bojesen, A., Bojesen, S. E., Bolla, M. K., Bonanni, B., Børresen-Dale, A., Brauch, H., Brennan, P., Brenner, H., Bruinsma, F., Brunet, J., Buhari, S. A., Burwinkel, B., Butzow, R., Buys, S. S., Cai, Q., Caldes, T., Campbell, I., Canniotto, R., Chang-Claude, J., Chiquette, J., Choi, J., Claes, K. B., Cook, L. S., Cox, A., Cramer, D. W., Cross, S. S., Cybulski, C., Czene, K., Daly, M. B., Damiola, F., Dansonka-Mieszkowska, A., Darabi, H., Dennis, J., Devilee, P., Diez, O., Doherty, J. A., Domchek, S. M., Dorfling, C. M., Dörk, T., Dumont, M., Ehrencrona, H., Ejlertsen, B., Ellis, S., Engel, C., Lee, E., Evans, D. G., Fasching, P. A., Feliubadalo, L., Figueroa, J., Flesch-Janys, D., Fletcher, O., Flyger, H., Foretova, L., Fostira, F., Foulkes, W. D., Fridley, B. L., friedman, e., Frost, D., Gambino, G., Ganz, P. A., Garber, J., García-Closas, M., Gentry-Maharaj, A., Ghoussaini, M., Giles, G. G., Glasspool, R., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., González-Neira, A., Goode, E. L., Goodman, M. T., Greene, M. H., Gronwald, J., Guénel, P., Haiman, C. A., Hall, P., Hallberg, E., Hamann, U., Hansen, T. v., Harrington, P. A., Hartman, M., Hassan, N., Healey, S., Heitz, F., Herzog, J., Høgdall, E., Høgdall, C. K., Hogervorst, F. B., Hollestelle, A., Hopper, J. L., Hulick, P. J., Huzarski, T., Imyanitov, E. N., Isaacs, C., Ito, H., Jakubowska, A., Janavicius, R., Jensen, A., John, E. M., Johnson, N., Kabisch, M., Kang, D., Kapuscinski, M., Karlan, B. Y., Khan, S., Kiemeney, L. A., Kjaer, S. K., Knight, J. A., Konstantopoulou, I., Kosma, V., Kristensen, V., Kupryjanczyk, J., Kwong, A., de la Hoya, M., Laitman, Y., Lambrechts, D., Le, N., De Leeneer, K., Lester, J., Levine, D. A., Li, J., Lindblom, A., Long, J., Lophatananon, A., Loud, J. T., Lu, K., Lubinski, J., Mannermaa, A., Manoukian, S., Le Marchand, L., Margolin, S., Marme, F., Massuger, L. F., Matsuo, K., Mazoyer, S., McGuffog, L., McLean, C., McNeish, I., Meindl, A., Menon, U., Mensenkamp, A. R., Milne, R. L., Montagna, M., Moysich, K. B., Muir, K., Mulligan, A. M., Nathanson, K. L., Ness, R. B., Neuhausen, S. L., Nevanlinna, H., Nord, S., Nussbaum, R. L., Odunsi, K., Offit, K., Olah, E., Olopade, O. I., Olson, J. E., Olswold, C., O'Malley, D., Orlow, I., Orr, N., Osorio, A., Park, S. K., Pearce, C. L., Pejovic, T., Peterlongo, P., Pfeiler, G., Phelan, C. M., Poole, E. M., Pylkäs, K., Radice, P., Rantala, J., Rashid, M. U., Rennert, G., Rhenius, V., Rhiem, K., Risch, H. A., Rodriguez, G., Rossing, M. A., Rudolph, A., Salvesen, H. B., Sangrajrang, S., Sawyer, E. J., Schildkraut, J. M., Schmidt, M. K., Schmutzler, R. K., Sellers, T. A., Seynaeve, C., Shah, M., Shen, C., Shu, X., Sieh, W., Singer, C. F., Sinilnikova, O. M., Slager, S., Song, H., Soucy, P., Southey, M. C., Stenmark-Askmalm, M., Stoppa-Lyonnet, D., Sutter, C., Swerdlow, A., Tchatchou, S., Teixeira, M. R., Teo, S. H., Terry, K. L., Terry, M. B., Thomassen, M., Tibiletti, M. G., Tihomirova, L., Tognazzo, S., Toland, A. E., Tomlinson, I., Torres, D., Truong, T., Tseng, C., Tung, N., Tworoger, S. S., Vachon, C., van den Ouweland, A. M., van Doorn, H. C., Van Rensburg, E. J., van't Veer, L. J., Vanderstichele, A., Vergote, I., Vijai, J., Wang, Q., Wang-Gohrke, S., Weitzel, J. N., Wentzensen, N., Whittemore, A. S., Wildiers, H., Winqvist, R., Wu, A. H., Yannoukakos, D., Yoon, S., Yu, J., Zheng, W., Zheng, Y., Khanna, K. K., Simard, J., Monteiro, A. N., French, J. D., Couch, F. J., Freedman, M. L., Easton, D. F., Dunning, A. M., Pharoah, P. D., Edwards, S. L., Chenevix-Trench, G., Antoniou, A. C., Gayther, S. A. 2016; 7: 12675-?

  Abstract

  A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.

  View details for DOI 10.1038/ncomms12675

  View details for PubMedID 27601076

• Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer. Nature communications Couch, F. J., Kuchenbaecker, K. B., Michailidou, K., Mendoza-Fandino, G. A., Nord, S., Lilyquist, J., Olswold, C., Hallberg, E., Agata, S., Ahsan, H., Aittomäki, K., Ambrosone, C., Andrulis, I. L., Anton-Culver, H., Arndt, V., Arun, B. K., Arver, B., Barile, M., Barkardottir, R. B., Barrowdale, D., Beckmann, L., Beckmann, M. W., Benitez, J., Blank, S. V., Blomqvist, C., Bogdanova, N. V., Bojesen, S. E., Bolla, M. K., Bonanni, B., Brauch, H., Brenner, H., Burwinkel, B., Buys, S. S., Caldes, T., Caligo, M. A., Canzian, F., Carpenter, J., Chang-Claude, J., Chanock, S. J., Chung, W. K., Claes, K. B., Cox, A., Cross, S. S., Cunningham, J. M., Czene, K., Daly, M. B., Damiola, F., Darabi, H., de la Hoya, M., Devilee, P., Diez, O., Ding, Y. C., Dolcetti, R., Domchek, S. M., Dorfling, C. M., Dos-Santos-Silva, I., Dumont, M., Dunning, A. M., Eccles, D. M., Ehrencrona, H., Ekici, A. B., Eliassen, H., Ellis, S., Fasching, P. A., Figueroa, J., Flesch-Janys, D., Försti, A., Fostira, F., Foulkes, W. D., Friebel, T., friedman, e., Frost, D., Gabrielson, M., Gammon, M. D., Ganz, P. A., Gapstur, S. M., Garber, J., Gaudet, M. M., Gayther, S. A., Gerdes, A., Ghoussaini, M., Giles, G. G., Glendon, G., Godwin, A. K., Goldberg, M. S., Goldgar, D. E., González-Neira, A., Greene, M. H., Gronwald, J., Guénel, P., Gunter, M., Haeberle, L., Haiman, C. A., Hamann, U., Hansen, T. v., Hart, S., Healey, S., Heikkinen, T., Henderson, B. E., Herzog, J., Hogervorst, F. B., Hollestelle, A., Hooning, M. J., Hoover, R. N., Hopper, J. L., Humphreys, K., Hunter, D. J., Huzarski, T., Imyanitov, E. N., Isaacs, C., Jakubowska, A., James, P., Janavicius, R., Jensen, U. B., John, E. M., Jones, M., Kabisch, M., Kar, S., Karlan, B. Y., Khan, S., Khaw, K., Kibriya, M. G., Knight, J. A., Ko, Y., Konstantopoulou, I., Kosma, V., Kristensen, V., Kwong, A., Laitman, Y., Lambrechts, D., Lazaro, C., Lee, E., Le Marchand, L., Lester, J., Lindblom, A., Lindor, N., Lindstrom, S., Liu, J., Long, J., Lubinski, J., Mai, P. L., Makalic, E., Malone, K. E., Mannermaa, A., Manoukian, S., Margolin, S., Marme, F., Martens, J. W., McGuffog, L., Meindl, A., Miller, A., Milne, R. L., Miron, P., Montagna, M., Mazoyer, S., Mulligan, A. M., Muranen, T. A., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Nordestgaard, B. G., Nussbaum, R. L., Offit, K., Olah, E., Olopade, O. I., Olson, J. E., Osorio, A., Park, S. K., Peeters, P. H., Peissel, B., Peterlongo, P., Peto, J., Phelan, C. M., Pilarski, R., Poppe, B., Pylkäs, K., Radice, P., Rahman, N., Rantala, J., Rappaport, C., Rennert, G., Richardson, A., Robson, M., Romieu, I., Rudolph, A., Rutgers, E. J., Sanchez, M., Santella, R. M., Sawyer, E. J., Schmidt, D. F., Schmidt, M. K., Schmutzler, R. K., Schumacher, F., Scott, R., Senter, L., Sharma, P., Simard, J., Singer, C. F., Sinilnikova, O. M., Soucy, P., Southey, M., Steinemann, D., Stenmark-Askmalm, M., Stoppa-Lyonnet, D., Swerdlow, A., Szabo, C. I., Tamimi, R., Tapper, W., Teixeira, M. R., Teo, S., Terry, M. B., Thomassen, M., Thompson, D., Tihomirova, L., Toland, A. E., Tollenaar, R. A., Tomlinson, I., Truong, T., Tsimiklis, H., Teulé, A., Tumino, R., Tung, N., Turnbull, C., Ursin, G., van Deurzen, C. H., Van Rensburg, E. J., Varon-Mateeva, R., Wang, Z., Wang-Gohrke, S., Weiderpass, E., Weitzel, J. N., Whittemore, A., Wildiers, H., Winqvist, R., Yang, X. R., Yannoukakos, D., Yao, S., Zamora, M. P., Zheng, W., Hall, P., Kraft, P., Vachon, C., Slager, S., Chenevix-Trench, G., Pharoah, P. D., Monteiro, A. A., García-Closas, M., Easton, D. F., Antoniou, A. C. 2016; 7: 11375-?

  Abstract

  Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.

  View details for DOI 10.1038/ncomms11375

  View details for PubMedID 27117709

• Energy homeostasis genes and survival after breast cancer diagnosis: the Breast Cancer Health Disparities Study CANCER CAUSES & CONTROL Pellatt, A. J., Lundgreen, A., Wolff, R. K., Hines, L., John, E. M., Slattery, M. L. 2016; 27 (1): 47-57

  Abstract

  The leptin-signaling pathway and other genes involved in energy homeostasis (EH) have been examined in relation to breast cancer risk as well as to obesity. We test the hypothesis that genetic variation in EH genes influences survival after diagnosis with breast cancer and that body mass index (BMI) will modify that risk.We evaluated associations between 10 EH genes and survival among 1,186 non-Hispanic white and 1,155 Hispanic/Native American women diagnosed with breast cancer. Percent Native American (NA) ancestry was determined from 104 ancestry-informative markers. Adaptive rank truncation product (ARTP) was used to determine gene and pathway significance.The overall EH pathway was marginally significant for all-cause mortality among women with low NA ancestry (P(ARTP) = 0.057). Within the pathway, ghrelin(GHRL) and leptin receptor (LEPR) were significantly associated with all-cause mortality (P(ARTP) = 0.035 and 0.007, respectively). The EH pathway was significantly associated with breast cancer-specific mortality among women with low NA ancestry (P(ARTP) = 0.038). Three genes cholecystokinin (CCK), GHRL, and LEPR were significantly associated with breast cancer-specific mortality among women with low NA ancestry (P(ARTP) = 0.046,0.015, and 0.046, respectively), while neuropeptide Y (NPY) was significantly associated with breast cancer-specific mortality among women with higher NA ancestry(P(ARTP) = 0.038). BMI did not modify these associations.Our data support our hypothesis that certain EH genes influence survival after diagnosis with breast cancer; associations appear to be most important among women with low NA ancestry.

  View details for DOI 10.1007/s10552-015-0681-6

  View details for Web of Science ID 000368151600005

  View details for PubMedCentralID PMC4833710

• Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus. Breast cancer research Zeng, C., Guo, X., Long, J., Kuchenbaecker, K. B., Droit, A., Michailidou, K., Ghoussaini, M., Kar, S., Freeman, A., Hopper, J. L., Milne, R. L., Bolla, M. K., Wang, Q., Dennis, J., Agata, S., Ahmed, S., Aittomäki, K., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Arason, A., Arndt, V., Arun, B. K., Arver, B., Bacot, F., Barrowdale, D., Baynes, C., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Blomqvist, C., Blot, W. J., Bogdanova, N. V., Bojesen, S. E., Bonanni, B., Borresen-Dale, A., Brand, J. S., Brauch, H., Brennan, P., Brenner, H., Broeks, A., Brüning, T., Burwinkel, B., Buys, S. S., Cai, Q., Caldes, T., Campbell, I., Carpenter, J., Chang-Claude, J., Choi, J., Claes, K. B., Clarke, C., Cox, A., Cross, S. S., Czene, K., Daly, M. B., de la Hoya, M., De Leeneer, K., Devilee, P., Diez, O., Domchek, S. M., Doody, M., Dorfling, C. M., Dörk, T., Dos-Santos-Silva, I., Dumont, M., Dwek, M., Dworniczak, B., Egan, K., Eilber, U., Einbeigi, Z., Ejlertsen, B., Ellis, S., Frost, D., Lalloo, F., Fasching, P. A., Figueroa, J., Flyger, H., Friedlander, M., friedman, e., Gambino, G., Gao, Y., Garber, J., García-Closas, M., Gehrig, A., Damiola, F., Lesueur, F., Mazoyer, S., Stoppa-Lyonnet, D., Giles, G. G., Godwin, A. K., Goldgar, D. E., González-Neira, A., Greene, M. H., Guénel, P., Haeberle, L., Haiman, C. A., Hallberg, E., Hamann, U., Hansen, T. v., Hart, S., Hartikainen, J. M., Hartman, M., Hassan, N., Healey, S., Hogervorst, F. B., Verhoef, S., Hendricks, C. B., Hillemanns, P., Hollestelle, A., Hulick, P. J., Hunter, D. J., Imyanitov, E. N., Isaacs, C., Ito, H., Jakubowska, A., Janavicius, R., Jaworska-Bieniek, K., Jensen, U. B., John, E. M., Joly Beauparlant, C., Jones, M., Kabisch, M., Kang, D., Karlan, B. Y., Kauppila, S., Kerin, M. J., Khan, S., Khusnutdinova, E., Knight, J. A., Konstantopoulou, I., Kraft, P., Kwong, A., Laitman, Y., Lambrechts, D., Lazaro, C., Le Marchand, L., Lee, C. N., Lee, M. H., Lester, J., Li, J., Liljegren, A., Lindblom, A., Lophatananon, A., Lubinski, J., Mai, P. L., Mannermaa, A., Manoukian, S., Margolin, S., Marme, F., Matsuo, K., McGuffog, L., Meindl, A., Menegaux, F., Montagna, M., Muir, K., Mulligan, A. M., Nathanson, K. L., Neuhausen, S. L., Nevanlinna, H., Newcomb, P. A., Nord, S., Nussbaum, R. L., Offit, K., Olah, E., Olopade, O. I., Olswold, C., Osorio, A., Papi, L., Park-Simon, T., Paulsson-Karlsson, Y., Peeters, S., Peissel, B., Peterlongo, P., Peto, J., Pfeiler, G., Phelan, C. M., Presneau, N., Radice, P., Rahman, N., Ramus, S. J., Rashid, M. U., Rennert, G., Rhiem, K., Rudolph, A., Salani, R., Sangrajrang, S., Sawyer, E. J., Schmidt, M. K., Schmutzler, R. K., Schoemaker, M. J., Schürmann, P., Seynaeve, C., Shen, C., Shrubsole, M. J., Shu, X., Sigurdson, A., Singer, C. F., Slager, S., Soucy, P., Southey, M., Steinemann, D., Swerdlow, A., Szabo, C. I., Tchatchou, S., Teixeira, M. R., Teo, S. H., Terry, M. B., Tessier, D. C., Teulé, A., Thomassen, M., Tihomirova, L., Tischkowitz, M., Toland, A. E., Tung, N., Turnbull, C., van den Ouweland, A. M., Van Rensburg, E. J., Ven den Berg, D., Vijai, J., Wang-Gohrke, S., Weitzel, J. N., Whittemore, A. S., Winqvist, R., Wong, T. Y., Wu, A. H., Yannoukakos, D., Yu, J., Pharoah, P. D., Hall, P., Chenevix-Trench, G., Dunning, A. M., Simard, J., Couch, F. J., Antoniou, A. C., Easton, D. F., Zheng, W. 2016; 18 (1): 64-?

  Abstract

  Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05.This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.

  View details for DOI 10.1186/s13058-016-0718-0

  View details for PubMedID 27459855

• Reproductive factors, tumor estrogen receptor status and contralateral breast cancer risk: results from the WECARE study SPRINGERPLUS Sisti, J. S., Bernstein, J. L., Lynch, C. F., Reiner, A. S., Mellemkjaer, L., Brooks, J. D., Knight, J. A., Bernstein, L., Malone, K. E., Woods, M., Liang, X., John, E. M., WECARE Study Collaborative Grp 2015; 4

  View details for DOI 10.1186/s40064-015-1642-y

  View details for Web of Science ID 000368720800006

• Reproductive factors, tumor estrogen receptor status and contralateral breast cancer risk: results from the WECARE study. SpringerPlus Sisti, J. S., Bernstein, J. L., Lynch, C. F., Reiner, A. S., Mellemkjaer, L., Brooks, J. D., Knight, J. A., Bernstein, L., Malone, K. E., Woods, M., Liang, X., John, E. M. 2015; 4: 825

  Abstract

  Several reproductive factors are known to be associated with risk of breast cancer; however, relationships between these factors with risk of second primary asynchronous contralateral breast cancer (CBC) have not been widely studied. The Women's Environmental, Cancer, and Radiation Epidemiology (WECARE) Study is a population-based case-control study of 1521 CBC cases and 2212 individually matched controls with unilateral breast cancer. Using multivariable conditional logistic regression models, we examined associations between reproductive factors and CBC risk, and whether associations differed by estrogen receptor (ER) status and menopausal status of the first breast cancer. Older age at menarche was inversely associated with CBC risk (≥14 vs. ≤11 years risk ratio (RR) = 0.82, 95 % confidence interval (CI) 0.65-1.03, P trend = 0.02). Among parous women, an increasing number of full-term pregnancies (FTP) was inversely associated with risk (≥4 vs. 1 FTP RR = 0.60, 95 % CI 0.41-0.88, P trend = 0.005). Ever breast-feeding was inversely associated with CBC risk only among women with ER-negative first tumors (ever vs. never breast-fed RR = 0.69, 95 % CI 0.48-1.00, P heterogeneity = 0.05). Older age at first FTP was inversely associated with CBC risk among women with ER-negative first tumors (≥30 vs. <20 years old RR = 0.66, 95 % CI 0.35-1.27, P trend = 0.03), but suggestively positively associated with risk among women with ER-positive first tumors (P heterogeneity = 0.03). Young age at menarche and low parity, both risk factors for first primary breast cancer, were also associated with overall CBC risk. Reductions in risk associated with breast-feeding were limited to women with ER-negative first tumors, who are at higher CBC risk than women with ER-positive primaries.

  View details for DOI 10.1186/s40064-015-1642-y

  View details for PubMedID 26751177

  View details for PubMedCentralID PMC4695460

• Intersection of Race/Ethnicity and Socioeconomic Status in Mortality After Breast Cancer JOURNAL OF COMMUNITY HEALTH Shariff-Marco, S., Yang, J., John, E. M., Kurian, A. W., Cheng, I., Leung, R., Koo, J., Monroe, K. R., Henderson, B. E., Bernstein, L., Lu, Y., Kwan, M. L., Sposto, R., Vigen, C. L., Wu, A. H., Keegan, T. H., Gomez, S. L. 2015; 40 (6): 1287-1299

  Abstract

  We investigated social disparities in breast cancer (BC) mortality, leveraging data from the California Breast Cancer Survivorship Consortium. The associations of race/ethnicity, education, and neighborhood SES (nSES) with all-cause and BC-specific mortality were assessed among 9372 women with BC (diagnosed 1993-2007 in California with follow-up through 2010) from four racial/ethnic groups [African American, Asian American, Latina, and non-Latina (NL) White] using Cox proportional hazards models. Compared to NL White women with high-education/high-nSES, higher all-cause mortality was observed among NL White women with high-education/low-nSES [hazard ratio (HR) (95 % confidence interval) 1.24 (1.08-1.43)], and African American women with low-nSES, regardless of education [high education HR 1.24 (1.03-1.49); low-education HR 1.19 (0.99-1.44)]. Latina women with low-education/high-nSES had lower all-cause mortality [HR 0.70 (0.54-0.90)] and non-significant lower mortality was observed for Asian American women, regardless of their education and nSES. Similar patterns were seen for BC-specific mortality. Individual- and neighborhood-level measures of SES interact with race/ethnicity to impact mortality after BC diagnosis. Considering the joint impacts of these social factors may offer insights to understanding inequalities by multiple social determinants of health.

  View details for DOI 10.1007/s10900-015-0052-y

  View details for PubMedID 26072260

• Diet quality of cancer survivors and noncancer individuals: Results from a national survey CANCER Zhang, F., Liu, S., John, E. M., Must, A., Demark-Wahnefried, W. 2015; 121 (23): 4212–21

  Abstract

  Patterns of poor nutritional intake may exacerbate the elevated morbidity experienced by cancer survivors. It remains unclear whether cancer survivors adhere to existing dietary guidelines and whether survivors' diets differ from those of individuals without cancer over the long term.The authors evaluated dietary intake and quality in 1533 adult cancer survivors who participated in the National Health and Nutrition Examination Survey from 1999 to 2010 compared with dietary intake and quality in 3075 individuals who had no history of cancer and were matched to the cancer survivors by age, sex, and race/ethnicity. Dietary intake was assessed using 24-hour dietary recalls. The 2010 Healthy Eating Index (HEI-2010) was used to evaluate diet quality.The mean ± standard deviation HEI-2010 total score was 47.2 ± 0.5 in the cancer survivors and 48.3 ± 0.4 in the noncancer group (P = .03). Compared with the noncancer group, cancer survivors had a significantly lower score for empty calories (13.6 vs 14.4; P = .001), which corresponded to worse adherence to dietary intake of calories from solid fats, alcohol, and added sugars. Cancer survivors also had significantly lower dietary intake of fiber than the noncancer group (15.0 vs 15.9 g per day; P = .02). In relation to recommended intake, survivors' mean dietary intake of vitamin D, vitamin E, potassium, fiber, and calcium was 31%, 47%, 55%, 60%, and 73%, respectively; whereas their mean dietary intake of saturated fat and sodium was 112% and 133%, respectively, of the recommended intake.Cancer survivors had poor adherence to the US Department of Agriculture 2010 Dietary Guidelines for Americans, and their intake patterns were worse than those in the general population for empty calories and fiber.

  View details for PubMedID 26624564

  View details for PubMedCentralID PMC4667562

• Associations between ALOX, COX, and CRP polymorphisms and breast cancer among Hispanic and non-Hispanic white women: The breast cancer health disparities study MOLECULAR CARCINOGENESIS Connor, A. E., Baumgartner, R. N., Baumgartner, K. B., Pinkston, C. M., Boone, S. D., John, E. M., Torres-Mejia, G., Hines, L. M., Giuliano, A. R., Wolff, R. K., Slattery, M. L. 2015; 54 (12): 1541-1553

  Abstract

  Chronic inflammation is suggested to be associated with specific cancer sites, including breast cancer. Recent research has focused on the roles of genes involved in the leukotriene/lipoxygenase and prostaglandin/cyclooxygenase pathways in breast cancer etiology. We hypothesized that genes in ALOX/COX pathways and CRP polymorphisms would be associated with breast cancer risk and mortality in our sample of Hispanic/Native American (NA) (1430 cases, 1599 controls) and non-Hispanic white (NHW) (2093 cases, 2610 controls) women. A total of 104 Ancestral Informative Markers was used to distinguish European and NA ancestry. The adaptive rank truncated product (ARTP) method was used to determine the significance of associations for each gene and the inflammation pathway with breast cancer risk and by NA ancestry. Overall, the pathway was associated with breast cancer risk (PARTP = 0.01). Two-way interactions with NA ancestry (P(adj)  < 0.05) were observed for ALOX12 (rs2292350, rs2271316) and PTGS1 (rs10306194). We observed increases in breast cancer risk in stratified analyses by tertiles of polyunsaturated fat intake for ALOX12 polymorphisms; the largest increase in risk was among women in the highest tertile with ALOX12 rs9904779CC (Odds Ratio (OR), 1.49; 95% Confidence Interval (CI) 1.14-1.94, P(adj) = 0.01). In a sub-analysis stratified by NSAIDs use, two-way interactions with NSAIDs use were found for ALOX12 rs9904779 (P(adj)  = 0.02), rs434473 (P(adj ) = 0.02), and rs1126667 (P(adj)  =  0.01); ORs for ALOX12 polymorphisms ranged from 1.55 to 1.64 among regular users. Associations were not observed with breast cancer mortality. These findings could support advances in the discovery of new pathways related to inflammation for breast cancer treatment.

  View details for DOI 10.1002/mc.22228

  View details for Web of Science ID 000363480000002

  View details for PubMedID 25339205

• Energy homeostasis genes and breast cancer risk: The influence of ancestry, body size, and menopausal status, the breast cancer health disparities study CANCER EPIDEMIOLOGY Slattery, M. L., Lundgreen, A., Hines, L., Wolff, R. K., Torres-Mejia, G., Baumgartner, K. N., John, E. M. 2015; 39 (6): 1113–22

  Abstract

  Obesity and breast cancer risk is multifaceted and genes associated with energy homeostasis may modify this relationship.We evaluated 10 genes that have been associated with obesity and energy homeostasis to determine their association with breast cancer risk in Hispanic/Native American (2111 cases, 2597 controls) and non-Hispanic white (1481 cases, 1585 controls) women.Cholecystokinin (CCK) rs747455 and proopiomelanocortin (POMC) rs6713532 and rs7565877 (for low Indigenous American (IA) ancestry); CCK rs8192472 and neuropeptide Y (NYP) rs16141 and rs14129 (intermediate IA ancestry); and leptin receptor (LEPR) rs11585329 (high IA ancestry) were strongly associated with multiple indicators of body size. There were no significant associations with breast cancer risk between genes and SNPs overall. However, LEPR was significantly associated with breast cancer risk among women with low IA ancestry (PARTP=0.024); POMC was significantly associated with breast cancer risk among women with intermediate (PARTP=0.015) and high (PARTP=0.012) IA ancestry. The overall pathway was statistically significant for pre-menopausal women with low IA ancestry (PARTP=0.05), as was cocaine and amphetamine regulated transcript protein (CARTPT) (PARTP=0.014) and ghrelin (GHRL) (PARTP=0.007). POMC was significantly associated with breast cancer risk among post-menopausal women with higher IA ancestry (PARTP=0.005). Three SNPs in LEPR (rs6704167, rs17412175, and rs7626141), and adiponectin (ADIPOQ); rs822391) showed significant 4-way interactions (GxExMenopausexAncestry) for multiple indicators of body size among pre-menopausal women.Energy homeostasis genes were associated with breast cancer risk; menopausal status, body size, and genetic ancestry influenced this relationship.

  View details for PubMedID 26395295

  View details for PubMedCentralID PMC4679560

• Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Zhang, B., Shu, X., Delahanty, R. J., Zeng, C., Michailidou, K., Bolla, M. K., Wang, Q., Dennis, J., Wen, W., Long, J., Li, C., Dunning, A. M., Chang-Claude, J., Shah, M., Perkins, B. J., Czene, K., Darabi, H., Eriksson, M., Bojesen, S. E., Nordestgaard, B. G., Nielsen, S. F., Flyger, H., Lambrechts, D., Neven, P., Wildiers, H., Floris, G., Schmidt, M. K., Rookus, M. A., van den Hurk, K., de Kort, W. L., Couch, F. J., Olson, J. E., Hallberg, E., Vachon, C., Rudolph, A., Seibold, P., Flesch-Janys, D., Peto, J., Dos-Santos-Silva, I., Fletcher, O., Johnson, N., Nevanlinna, H., Muranen, T. A., Aittomaki, K., Blomqvist, C., Li, J., Humphreys, K., Brand, J., Guenel, P., Truong, T., Cordina-Duverger, E., Menegaux, F., Burwinkel, B., Marme, F., Yang, R., Surowy, H., Benitez, J., Pilar Zamora, M., Perez, J. I., Cox, A., Cross, S. S., Reed, M. W., Andrulis, I. L., Knight, J. A., Glendon, G., Tchatchou, S., Sawyer, E. J., Tomlinson, I., Kerin, M. J., Miller, N., Chenevix-Trench, G., Haiman, C. A., Henderson, B. E., Schumacher, F., Le Marchand, L., Lindblom, A., Margolin, S., Hooning, M. J., Martens, J. W., Tilanus-Linthorst, M. M., Collee, J. M., Hopper, J. L., Southey, M. C., Tsimiklis, H., Apicella, C., Slager, S., Toland, A. E., Ambrosone, C. B., Yannoukakos, D., Giles, G. G., Milne, R. L., McLean, C., Fasching, P. A., Haeberle, L., Ekici, A. B., Beckmann, M. W., Brenner, H., Dieffenbach, A. K., Arndt, V., Stegmaier, C., Swerdlow, A. J., Ashworth, A., Orr, N., Jones, M., Figueroa, J., Garcia-Closas, M., Brinton, L., Lissowska, J., Dumont, M., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Brauch, H., Bruening, T., Ko, Y., Peterlongo, P., Manoukian, S., Bonanni, B., Radice, P., Bogdanova, N., Antonenkova, N., Doerk, T., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Devilee, P., Seynaeve, C., van Asperen, C. J., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Hamann, U., Torres, D., Schmutzler, R. K., Neuhausen, S. L., Anton-Culver, H., Kristensen, V. N., Alnaes, G. I., Pierce, B. L., Kraft, P., Peters, U., Lindstrom, S., Seminara, D., Burgess, S., Ahsan, H., Whittemore, A. S., John, E. M., Gammon, M. D., Malone, K. E., Tessier, D. C., Vincent, D., Bacot, F., Luccarini, C., Baynes, C., Ahmed, S., Maranian, M., Healey, C. S., Gonzalez-Neira, A., Pita, G., Rosario Alonso, M., Alvarez, N., Herrero, D., Pharoah, P. D., Simard, J., Hall, P., Hunter, D. J., Easton, D. F., Zheng, W. 2015; 107 (11)

  Abstract

  Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear.We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5216302 women, including 113178 events. In a consortium with individual-level data from 46325 case patients and 42482 control patients, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16003 case patients and 41335 control patients.The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5×10(-8).Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.

  View details for DOI 10.1093/jnci/djv219

  View details for Web of Science ID 000366972300027

  View details for PubMedID 26296642

  View details for PubMedCentralID PMC4643630

• Psychosocial Adjustment in School-age Girls With a Family History of Breast Cancer. Pediatrics Bradbury, A. R., Patrick-Miller, L., Schwartz, L., Egleston, B., Sands, C. B., Chung, W. K., Glendon, G., McDonald, J. A., Moore, C., Rauch, P., Tuchman, L., Andrulis, I. L., Buys, S. S., Frost, C. J., Keegan, T. H., Knight, J. A., Terry, M. B., John, E. M., Daly, M. B. 2015; 136 (5): 927-37

  Abstract

  Understanding how young girls respond to growing up with breast cancer family histories is critical given expansion of genetic testing and breast cancer messaging. We examined the impact of breast cancer family history on psychosocial adjustment and health behaviors among >800 girls in the multicenter LEGACY Girls Study.Girls aged 6 to 13 years with a family history of breast cancer or familial BRCA1/2 mutation (BCFH+), peers without a family history (BCFH-), and their biological mothers completed assessments of psychosocial adjustment (maternal report for 6- to 13-year-olds, self-report for 10- to 13-year-olds), breast cancer-specific distress, perceived risk of breast cancer, and health behaviors (10- to 13-year-olds).BCFH+ girls had better general psychosocial adjustment than BCFH- peers by maternal report. Psychosocial adjustment and health behaviors did not differ significantly by self-report among 10- to 13-year-old girls. BCFH+ girls reported higher breast cancer-specific distress (P = .001) and were more likely to report themselves at increased breast cancer risk than BCFH- peers (38.4% vs 13.7%, P < .001), although many girls were unsure of their risk. In multivariable analyses, higher daughter anxiety was associated with higher maternal anxiety and poorer family communication. Higher daughter breast cancer-specific distress was associated with higher maternal breast cancer-specific distress.Although growing up in a family at risk for breast cancer does not negatively affect general psychosocial adjustment among preadolescent girls, those from breast cancer risk families experience greater breast cancer-specific distress. Interventions to address daughter and mother breast cancer concerns and responses to genetic or familial risk might improve psychosocial outcomes of teen daughters.

  View details for DOI 10.1542/peds.2015-0498

  View details for PubMedID 26482668

  View details for PubMedCentralID PMC4972044

• Active and passive cigarette smoking and mortality among Hispanic and non-Hispanic white women diagnosed with invasive breast cancer ANNALS OF EPIDEMIOLOGY Boone, S. D., Baumgartner, K. B., Baumgartner, R. N., Connor, A. E., John, E. M., Giuliano, A. R., Hines, L. M., Rai, S. N., Riley, E. C., Pinkston, C. M., Wolff, R. K., Slattery, M. L. 2015; 25 (11): 824-831

  Abstract

  Women who smoke at breast cancer diagnosis have higher risk of breast cancer-specific and all-cause mortality than nonsmokers; however, differences by ethnicity or prognostic factors and risk for noncancer mortality have not been evaluated.We examined associations of active and passive smoke exposure with mortality among Hispanic (n = 1020) and non-Hispanic white (n = 1198) women with invasive breast cancer in the Breast Cancer Health Disparities Study (median follow-up of 10.6 years).Risk of breast cancer-specific (HR = 1.55, 95% CI = 1.11-2.16) and all-cause (HR = 1.68, 95% CI = 1.30-2.17) mortality was increased for current smokers, with similar results stratified by ethnicity. Ever smokers had an increased risk of noncancer mortality (HR = 1.68, 95% CI = 1.12-2.51). Associations were strongest for current smokers who smoked for 20 years or more were postmenopausal, overweight and/or obese, or reported moderate and/or high alcohol consumption; however, interactions were not significant. Breast cancer-specific mortality was increased two fold for moderate and/or high recent passive smoke exposure among never smokers (HR = 2.12, 95% CI = 1.24-3.63).Findings support associations of active-smoking and passive-smoking diagnosis with risk of breast cancer-specific and all-cause mortality and ever smoking with noncancer mortality, regardless of ethnicity, and other factors. Smoking is a modifiable lifestyle factor and effective smoking cessation, and maintenance programs should be routinely recommended for women with breast cancer.

  View details for DOI 10.1016/j.annepidem.2015.08.007

  View details for Web of Science ID 000363602300004

  View details for PubMedID 26387598

• Racial and Ethnic Disparities in the Impact of Obesity on Breast Cancer Risk and Survival: A Global Perspective ADVANCES IN NUTRITION Bandera, E. V., Maskarinec, G., Romieu, I., John, E. M. 2015; 6 (6): 803–19

  Abstract

  Obesity is a global concern, affecting both developed and developing countries. Although there are large variations in obesity and breast cancer rates worldwide and across racial/ethnic groups, most studies evaluating the impact of obesity on breast cancer risk and survival have been conducted in non-Hispanic white women in the United States or Europe. Given the known racial/ethnic differences in tumor hormone receptor subtype distribution, obesity prevalence, and risk factor profiles, we reviewed published data for women of African, Hispanic, and Asian ancestry in the United States and their countries of origin. Although the data are limited, current evidence suggests a stronger adverse effect of obesity on breast cancer risk and survival in women of Asian ancestry. For African Americans and Hispanics, the strength of the associations appears to be more comparable to that of non-Hispanic whites, particularly when accounting for subtype and menopausal status. Central obesity seems to have a stronger impact in African-American women than general adiposity as measured by body mass index. International data from countries undergoing economic transition offer a unique opportunity to evaluate the impact of rapid weight gain on breast cancer. Such studies should take into account genetic ancestry, which may help elucidate differences in associations between ethnically admixed populations. Overall, additional large studies that use a variety of adiposity measures are needed, because the current evidence is based on few studies, most with limited statistical power. Future investigations of obesity biomarkers will be useful to understand possible racial/ethnic biological differences underlying the complex association between obesity and breast cancer development and progression.

  View details for PubMedID 26567202

  View details for PubMedCentralID PMC4642425

• Interaction between Common Breast Cancer Susceptibility Variants, Genetic Ancestry, and Nongenetic Risk Factors in Hispanic Women CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Fejerman, L., Stern, M. C., John, E. M., Torres-Meja, G., Hines, L. M., Wolff, R. K., Baumgartner, K. B., Giuliano, A. R., Ziv, E., Perez-Stable, E. J., Slattery, M. L. 2015; 24 (11): 1731–38

  Abstract

  Most genetic variants associated with breast cancer risk have been discovered in women of European ancestry, and only a few genome-wide association studies (GWAS) have been conducted in minority groups. This research disparity persists in post-GWAS gene-environment interaction analyses. We tested the interaction between hormonal and lifestyle risk factors for breast cancer, and ten GWAS-identified SNPs among 2,107 Hispanic women with breast cancer and 2,587 unaffected controls, to gain insight into a previously reported gene by ancestry interaction in this population.We estimated genetic ancestry with a set of 104 ancestry-informative markers selected to discriminate between Indigenous American and European ancestry. We used logistic regression models to evaluate main effects and interactions.We found that the rs13387042-2q35(G/A) SNP was associated with breast cancer risk only among postmenopausal women who never used hormone therapy [per A allele OR: 0.94 (95% confidence intervals, 0.74-1.20), 1.20 (0.94-1.53), and 1.49 (1.28-1.75) for current, former, and never hormone therapy users, respectively, Pinteraction 0.002] and premenopausal women who breastfed >12 months [OR: 1.01 (0.72-1.42), 1.19 (0.98-1.45), and 1.69 (1.26-2.26) for never, <12 months, and >12 months breastfeeding, respectively, Pinteraction 0.014].The correlation between genetic ancestry, hormone replacement therapy use, and breastfeeding behavior partially explained a previously reported interaction between a breast cancer risk variant and genetic ancestry in Hispanic women.These results highlight the importance of understanding the interplay between genetic ancestry, genetics, and nongenetic risk factors and their contribution to breast cancer risk.

  View details for PubMedID 26364163

  View details for PubMedCentralID PMC4633366

• Psychosocial Adjustment in School-age Girls With a Family History of Breast Cancer PEDIATRICS Bradbury, A. R., Patrick-Miller, L., Schwartz, L., Egleston, B., Sands, C. B., Chung, W. K., Glendon, G., McDonald, J. A., Moore, C., Rauch, P., Tuchman, L., Andrulis, I. L., Buys, S. S., Frost, C. J., Keegan, T. H., Knight, J. A., Terry, M. B., John, E. M., Daly, M. B. 2015; 136 (5): 927-937

  Abstract

  Understanding how young girls respond to growing up with breast cancer family histories is critical given expansion of genetic testing and breast cancer messaging. We examined the impact of breast cancer family history on psychosocial adjustment and health behaviors among >800 girls in the multicenter LEGACY Girls Study.Girls aged 6 to 13 years with a family history of breast cancer or familial BRCA1/2 mutation (BCFH+), peers without a family history (BCFH-), and their biological mothers completed assessments of psychosocial adjustment (maternal report for 6- to 13-year-olds, self-report for 10- to 13-year-olds), breast cancer-specific distress, perceived risk of breast cancer, and health behaviors (10- to 13-year-olds).BCFH+ girls had better general psychosocial adjustment than BCFH- peers by maternal report. Psychosocial adjustment and health behaviors did not differ significantly by self-report among 10- to 13-year-old girls. BCFH+ girls reported higher breast cancer-specific distress (P = .001) and were more likely to report themselves at increased breast cancer risk than BCFH- peers (38.4% vs 13.7%, P < .001), although many girls were unsure of their risk. In multivariable analyses, higher daughter anxiety was associated with higher maternal anxiety and poorer family communication. Higher daughter breast cancer-specific distress was associated with higher maternal breast cancer-specific distress.Although growing up in a family at risk for breast cancer does not negatively affect general psychosocial adjustment among preadolescent girls, those from breast cancer risk families experience greater breast cancer-specific distress. Interventions to address daughter and mother breast cancer concerns and responses to genetic or familial risk might improve psychosocial outcomes of teen daughters.

  View details for DOI 10.1542/peds.2015-0498

  View details for Web of Science ID 000363969600058

  View details for PubMedCentralID PMC4972044

• Impact of neighborhoods and body size on survival after breast cancer diagnosis HEALTH & PLACE Shariff-Marco, S., Gomez, S. L., Sangaramoorthy, M., Yang, J., Koo, J., Hertz, A., John, E. M., Cheng, I., Keegan, T. H. 2015; 36: 162-172

  Abstract

  With data from the Neighborhoods and Breast Cancer Study, we examined the associations between body size, social and built environments, and survival following breast cancer diagnosis among 4347 women in the San Francisco Bay Area. Lower neighborhood socioeconomic status and greater neighborhood crowding were associated with higher waist-to-hip ratio (WHR). After mutual adjustment, WHR, but not neighborhood characteristics, was positively associated with overall mortality and marginally with breast cancer-specific mortality. Our findings suggest that WHR is an important modifiable prognostic factor for breast cancer survivors. Future WHR interventions should account for neighborhood characteristics that may influence WHR.

  View details for DOI 10.1016/j.healthplace.2015.10.003

  View details for PubMedID 26606455

• Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions. Human molecular genetics Han, Y., Hazelett, D. J., Wiklund, F., Schumacher, F. R., Stram, D. O., Berndt, S. I., Wang, Z., Rand, K. A., Hoover, R. N., Machiela, M. J., Yeager, M., Burdette, L., Chung, C. C., Hutchinson, A., Yu, K., Xu, J., Travis, R. C., Key, T. J., Siddiq, A., Canzian, F., Takahashi, A., Kubo, M., Stanford, J. L., Kolb, S., Gapstur, S. M., Diver, W. R., Stevens, V. L., Strom, S. S., Pettaway, C. A., Al Olama, A. A., Kote-Jarai, Z., Eeles, R. A., Yeboah, E. D., Tettey, Y., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Chokkalingam, A. P., Isaacs, W. B., Chen, C., Lindstrom, S., Le Marchand, L., Giovannucci, E. L., Pomerantz, M., Long, H., Li, F., Ma, J., Stampfer, M., John, E. M., Ingles, S. A., Kittles, R. A., Murphy, A. B., Blot, W. J., Signorello, L. B., Zheng, W., Albanes, D., Virtamo, J., Weinstein, S., Nemesure, B., Carpten, J., Leske, M. C., Wu, S., Hennis, A. J., Rybicki, B. A., Neslund-Dudas, C., Hsing, A. W., Chu, L., Goodman, P. J., Klein, E. A., Zheng, S. L., Witte, J. S., Casey, G., Riboli, E., Li, Q., Freedman, M. L., Hunter, D. J., Gronberg, H., Cook, M. B., Nakagawa, H., Kraft, P., Chanock, S. J., Easton, D. F., Henderson, B. E., Coetzee, G. A., Conti, D. V., Haiman, C. A. 2015; 24 (19): 5603-5618

  Abstract

  Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genome-encoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10(-4)-5.6 × 10(-3)) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10(-6)) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.

  View details for DOI 10.1093/hmg/ddv269

  View details for PubMedID 26162851

• Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study HUMAN MOLECULAR GENETICS Zhang, C., Doherty, J. A., Burgess, S., Hung, R. J., Lindstroem, S., Kraft, P., Gong, J., Amos, C. I., Sellers, T. A., Monteiro, A. N., Chenevix-Trench, G., Bickeboeller, H., Risch, A., Brennan, P., McKay, J. D., Houlston, R. S., Landi, M. T., Timofeeva, M. N., Wang, Y., Heinrich, J., Kote-Jarai, Z., Eeles, R. A., Muir, K., Wiklund, F., Gronberg, H., Berndt, S. I., Chanock, S. J., Schumacher, F., Haiman, C. A., Henderson, B. E., Al Olama, A. A., Andrulis, I. L., Hopper, J. L., Chang-Claude, J., John, E. M., Malone, K. E., Gammon, M. D., Ursin, G., Whittemore, A. S., Hunter, D. J., Gruber, S. B., Knight, J. A., Hou, L., Le Marchand, L., Newcomb, P. A., Hudson, T. J., Chan, A. T., Li, L., Woods, M. O., Ahsan, H., Pierce, B. L. 2015; 24 (18): 5356-5366

  Abstract

  Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10(-6)). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk.

  View details for DOI 10.1093/hmg/ddv252

  View details for Web of Science ID 000361317200024

  View details for PubMedCentralID PMC4550826

• Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study. Human molecular genetics Zhang, C., Doherty, J. A., Burgess, S., Hung, R. J., Lindström, S., Kraft, P., Gong, J., Amos, C. I., Sellers, T. A., Monteiro, A. N., Chenevix-Trench, G., Bickeböller, H., Risch, A., Brennan, P., McKay, J. D., Houlston, R. S., Landi, M. T., Timofeeva, M. N., Wang, Y., Heinrich, J., Kote-Jarai, Z., Eeles, R. A., Muir, K., Wiklund, F., Grönberg, H., Berndt, S. I., Chanock, S. J., Schumacher, F., Haiman, C. A., Henderson, B. E., Amin Al Olama, A., Andrulis, I. L., Hopper, J. L., Chang-Claude, J., John, E. M., Malone, K. E., Gammon, M. D., Ursin, G., Whittemore, A. S., Hunter, D. J., Gruber, S. B., Knight, J. A., Hou, L., Le Marchand, L., Newcomb, P. A., Hudson, T. J., Chan, A. T., Li, L., Woods, M. O., Ahsan, H., Pierce, B. L. 2015; 24 (18): 5356-5366

  Abstract

  Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51 725 cases and 62 035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10(-6)). Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk.

  View details for DOI 10.1093/hmg/ddv252

  View details for PubMedID 26138067

• Contribution of the Neighborhood Environment and Obesity to Breast Cancer Survival: The California Breast Cancer Survivorship Consortium CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Cheng, I., Shariff-Marco, S., Koo, J., Monroe, K. R., Yang, J., John, E. M., Kurian, A. W., Kwan, M. L., Henderson, B. E., Bernstein, L., Lu, Y., Sposto, R., Vigen, C., Wu, A. H., Gomez, S. L., Keegan, T. H. 2015; 24 (8): 1282-1290

  Abstract

  Little is known about neighborhood attributes that may influence opportunities for healthy eating and physical activity in relation to breast cancer mortality. We used data from the California Breast Cancer Survivorship Consortium and the California Neighborhoods Data System to examine the neighborhood environment, body mass index, and mortality after breast cancer. We studied 8,995 African American, Asian American, Latina, and non-Latina White women with breast cancer. Residential addresses were linked to the CNDS to characterize neighborhoods. We used multinomial logistic regression to evaluate the associations between neighborhood factors and obesity, and Cox proportional hazards regression to examine associations between neighborhood factors and mortality. For Latinas, obesity was associated with more neighborhood crowding (Quartile 4 (Q4) vs. Q1: Odds Ratio (OR)=3.24; 95% Confidence Interval (CI): 1.50-7.00); breast cancer-specific mortality was inversely associated with neighborhood businesses (Q4 vs. Q1: Hazard Ratio (HR)=0.46; 95% CI: 0.25-0.85) and positively associated with multi-family housing (Q3 vs. Q1: HR=1.98; 95% CI: 1.20-3.26). For non-Latina Whites, lower neighborhood socioeconomic status (SES) was associated with obesity (Quintile 1 (Q1) vs. Q5: OR=2.52; 95% CI: 1.31-4.84), breast cancer-specific (Q1 vs. Q5: HR=2.75; 95% CI: 1.47-5.12), and all-cause (Q1 vs. Q5: HR=1.75; 95% CI: 1.17-2.62) mortality. For Asian Americans, no associations were seen. For African Americans, lower neighborhood SES was associated with lower mortality in a nonlinear fashion. Attributes of the neighborhood environment were associated with obesity and mortality following breast cancer diagnosis, but these associations differed across racial/ethnic groups.

  View details for DOI 10.1158/1055-9965.EPI-15-0055

  View details for PubMedID 26063477

• Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults PLOS ONE Chen, F., He, J., Zhang, J., Chen, G. K., Thomas, V., Ambrosone, C. B., Bandera, E. V., Berndt, S. I., Bernstein, L., Blot, W. J., Cai, Q., Carpten, J., Casey, G., Chanock, S. J., Cheng, I., Chu, L., Deming, S. L., Driver, W. R., Goodman, P., Hayes, R. B., Hennis, A. J., Hsing, A. W., Hu, J. J., Ingles, S. A., John, E. M., Kittles, R. A., Kolb, S., Leske, M. C., Millikan, R. C., Monroe, K. R., Murphy, A., Nemesure, B., Neslund-Dudas, C., Nyante, S., Ostrander, E. A., Press, M. F., Rodriguez-Gil, J. L., Rybicki, B. A., Schumacher, F., Stanford, J. L., Signorello, L. B., Strom, S. S., Stevens, V., Van Den Berg, D., Wang, Z., Witte, J. S., Wu, S., Yamamura, Y., Zheng, W., Ziegler, R. G., Stram, A. H., Kolonel, L. N., Le Marchand, L., Henderson, B. E., Haiman, C. A., Stram, D. O. 2015; 10 (6)

  Abstract

  Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.

  View details for DOI 10.1371/journal.pone.0131106

  View details for Web of Science ID 000358151300033

  View details for PubMedCentralID PMC4488332

• History of Recreational Physical Activity and Survival After Breast Cancer The California Breast Cancer Survivorship Consortium AMERICAN JOURNAL OF EPIDEMIOLOGY Lu, Y., John, E. M., Sullivan-Halley, J., Vigen, C., Gomez, S. L., Kwan, M. L., Caan, B. J., Lee, V. S., Roh, J. M., Shariff-Marco, S., Keegan, T. H., Kurian, A. W., Monroe, K. R., Cheng, I., Sposto, R., Wu, A. H., Bernstein, L. 2015; 181 (12): 944-955

  Abstract

  Recent epidemiologic evidence suggests that prediagnosis physical activity is associated with survival in women diagnosed with breast cancer. However, few data exist for racial/ethnic groups other than non-Latina whites. To examine the association between prediagnosis recreational physical activity and mortality by race/ethnicity, we pooled data from the California Breast Cancer Survivorship Consortium for 3 population-based case-control studies of breast cancer patients (n = 4,608) diagnosed from 1994 to 2002 and followed up through 2010. Cox proportional hazards models provided estimates of the relative hazard ratio for mortality from all causes, breast cancer, and causes other than breast cancer associated with recent recreational physical activity (i.e., in the 10 years before diagnosis). Among 1,347 ascertained deaths, 826 (61%) were from breast cancer. Compared with women with the lowest level of recent recreational physical activity, those with the highest level had a marginally decreased risk of all-cause mortality (hazard ratio = 0.88, 95% confidence interval: 0.76, 1.01) and a statistically significant decreased risk of mortality from causes other than breast cancer (hazard ratio = 0.63, 95% confidence interval: 0.49, 0.80), and particularly from cardiovascular disease. No association was observed for breast cancer-specific mortality. These risk patterns did not differ by race/ethnicity (non-Latina white, African American, Latina, and Asian American). Our findings suggest that physical activity is beneficial for overall survival regardless of race/ethnicity.

  View details for DOI 10.1093/aje/kwu466

  View details for Web of Science ID 000356180600004

  View details for PubMedID 25925388

• Second primary breast cancer in BRCA1 and BRCA2 mutation carriers: 10-year cumulative incidence in the Breast Cancer Family Registry BREAST CANCER RESEARCH AND TREATMENT Menes, T. S., Terry, M., Goldgar, D., Andrulis, I. L., Knight, J. A., John, E. M., Liao, Y., Southey, M., Miron, A., Chung, W., Buys, S. S. 2015; 151 (3): 653–60

  Abstract

  BReast CAncer genes 1 and 2 (BRCA1 and BRCA2) mutation carriers diagnosed with breast cancer are at increased risk of developing a second primary breast cancer. Data from high-risk clinics may be subject to different biases which can cause both over and underestimation of this risk. Using data from a large multi-institutional family registry we estimated the 10-year cumulative risk of second primary breast cancer including more complete testing information on family members. We prospectively followed 800 women diagnosed with breast cancer from the Breast Cancer Family Registry (BCFR) who were carriers of a BRCA1 or BRCA2 pathogenic mutation or a variant of unknown clinical significance. In order to limit survival and ascertainment bias, cases were limited to those diagnosed with a first primary breast cancer from 1994 to 2001 and enrolled in the BCFR within 3 years after their cancer diagnosis. We excluded women enrolled after being diagnosed with a second breast cancer. We calculated 10-year incidence of second primary breast cancers. The 10-year incidence of a second primary breast cancer was highest in BRCA1 mutation carriers (17 %; 95 % CI 11-25 %), with even higher estimates in those first diagnosed under the age of 40 (21 %; 95 % CI 13-34 %). Lower rates were found in BRCA2 mutation carriers (7 %; 95 % CI 3-15 %) and women with a variant of unknown clinical significance (6 %; 95 % CI 4-9 %). Whereas the cumulative 10-year incidence of second primary breast cancer is high in BRCA1 mutation carriers, the estimates in BRCA2 mutation carriers and women with variants of unknown clinical significance are similar to those reported in women with sporadic breast cancer.

  View details for DOI 10.1007/s10549-015-3419-y

  View details for Web of Science ID 000355658700016

  View details for PubMedID 25975955

  View details for PubMedCentralID PMC4545282

• Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Mavaddat, N., Pharoah, P. D., Michailidou, K., Tyrer, J., Brook, M. N., Bolla, M. K., Wang, Q., Dennis, J., Dunning, A. M., Shah, M., Luben, R., Brown, J., Bojesen, S. E., Nordestgaard, B. G., Nielsen, S. F., Flyger, H., Czene, K., Darabi, H., Eriksson, M., Peto, J., Dos-Santos-Silva, I., Dudbridge, F., Johnson, N., Schmidt, M. K., Broeks, A., Verhoef, S., Rutgers, E. J., Swerdlow, A., Ashworth, A., Orr, N., Schoemaker, M. J., Figueroa, J., Chanock, S. J., Brinton, L., Lissowska, J., Couch, F. J., Olson, J. E., Vachon, C., Pankratz, V. S., Lambrechts, D., Wildiers, H., van Ongeval, C., Van Limbergen, E., Kristensen, V., Alnaes, G. G., Nord, S., Borresen-Dale, A., Nevanlinna, H., Muranen, T. A., Aittomaeki, K., Blomqvist, C., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Fasching, P. A., Haeberle, L., Ekici, A. B., Beckmann, M. W., Burwinkel, B., Marme, F., Schneeweiss, A., Sohn, C., Trentham-Dietz, A., Newcomb, P., Titus, L., Egan, K. M., Hunter, D. J., Lindstrom, S., Tamimi, R. M., Kraft, P., Rahman, N., Turnbull, C., Renwick, A., Seal, S., Li, J., Liu, J., Humphreys, K., Benitez, J., Zamora, M. P., Perez, J. I., Menendez, P., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Bogdanova, N. V., Antonenkova, N. N., Doerk, T., Anton-Culver, H., Neuhausen, S. L., Ziogas, A., Bernstein, L., Devilee, P., Tollenaar, R. A., Seynaeve, C., van Asperen, C. J., Cox, A., Cross, S. S., Reed, M. W., Khusnutdinova, E., Bermisheva, M., Prokofyeva, D., Takhirova, Z., Meindl, A., Schmutzler, R. K., Sutter, C., Yang, R., Schuermann, P., Bremer, M., Christiansen, H., Park-Simon, T., Hillemanns, P., Guenel, P., Truong, T., Menegaux, F., Sanchez, M., Radice, P., Peterlongo, P., Manoukian, S., Pensotti, V., Hopper, J. L., Tsimiklis, H., Apicella, C., Southey, M. C., Brauch, H., Bruening, T., Ko, Y., Sigurdson, A. J., Doody, M. M., Hamann, U., Torres, D., Ulmer, H., Foersti, A., Sawyer, E. J., Tomlinson, I., Kerin, M. J., Miller, N., Andrulis, I. L., Knight, J. A., Glendon, G., Mulligan, A. M., Chenevix-Trench, G., Balleine, R., Giles, G. G., Milne, R. L., McLean, C., Lindblom, A., Margolin, S., Haiman, C. A., Henderson, B. E., Schumacher, F., Le Marchand, L., Eilber, U., Wang-Gohrke, S., Hooning, M. J., Hollestelle, A., van den Ouweland, A. M., Koppert, L. B., Carpenter, J., Clarke, C., Scott, R., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Brenner, H., Arndt, V., Stegmaier, C., Dieffenbach, A. K., Winqvist, R., Pylkaes, K., Jukkola-Vuorinen, A., Grip, M., Offit, K., Vijai, J., Robson, M., Rau-Murthy, R., Dwek, M., Swann, R., Perkins, K. A., Goldberg, M. S., Labreche, F., Dumont, M., Eccles, D. M., Tapper, W. J., Rafiq, S., John, E. M., Whittemore, A. S., Slager, S., Yannoukakos, D., Toland, A. E., Yao, S., Zheng, W., Halverson, S. L., Gonzalez-Neira, A., Pita, G., Alonso, M. R., Alvarez, N., Herrero, D., Tessier, D. C., Vincent, D., Bacot, F., Luccarini, C., Baynes, C., Ahmed, S., Maranian, M., Healey, C. S., Simard, J., Hall, P., Easton, D. F., Garcia-Closas, M. 2015; 107 (5)

  View details for DOI 10.1093/jnci/djv036

  View details for Web of Science ID 000355088600009

• Two susceptibility loci identified for prostate cancer aggressiveness NATURE COMMUNICATIONS Berndt, S. I., Wang, Z., Yeager, M., Alavanja, M. C., Albanes, D., Amundadottir, L., Andriole, G., Freeman, L. B., Campa, D., Cancel-Tassin, G., Canzian, F., Cornu, J., Cussenot, O., Diver, W. R., Gapstur, S. M., Gronberg, H., Haiman, C. A., Henderson, B., Hutchinson, A., Hunter, D. J., Key, T. J., Kolb, S., Koutros, S., Kraft, P., Le Marchand, L., Lindstroem, S., Machiela, M. J., Ostrander, E. A., Riboli, E., Schumacher, F., Siddiq, A., Stanford, J. L., Stevens, V. L., Travis, R. C., Tsilidis, K. K., Virtamo, J., Weinstein, S., Wilkund, F., Xu, J., Zheng, S. L., Yu, K., Wheeler, W., Zhang, H., Consortium, A. A., Sampson, J., Black, A., Jacobs, K., Hoover, R. N., Tucker, M., Chanock, S. J. 2015; 6

  Abstract

  Most men diagnosed with prostate cancer will experience indolent disease; hence, discovering genetic variants that distinguish aggressive from nonaggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, we identify two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49 × 10(-9)) and rs78943174 at 3q26.31 (NAALADL2, P=4.18 × 10(-8)). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P=8.85 × 10(-5)) with no association for nonaggressive prostate cancer compared with controls (P=0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation.

  View details for DOI 10.1038/ncomms7889

  View details for Web of Science ID 000355526400001

  View details for PubMedID 25939597

  View details for PubMedCentralID PMC4422072

• An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers BREAST CANCER RESEARCH Blein, S., Bardel, C., Danjean, V., McGuffog, L., Healey, S., Barrowdale, D., Lee, A., Dennis, J., Kuchenbaecker, K. B., Soucy, P., Terry, M., Chung, W. K., Goldgar, D. E., Buys, S. S., Janavicius, R., Tihomirova, L., Tung, N., Dorfling, C. M., van Rensburg, E. J., Neuhausen, S. L., Ding, Y., Gerdes, A., Ejlertsen, B., Nielsen, F. C., Hansen, T. O., Osorio, A., Benitez, J., Andres Conejero, R., Segota, E., Weitzel, J. N., Thelander, M., Peterlongo, P., Radice, P., Pensotti, V., Dolcetti, R., Bonanni, B., Peissel, B., Zaffaroni, D., Scuvera, G., Manoukian, S., Varesco, L., Capone, G. L., Papi, L., Ottini, L., Yannoukakos, D., Konstantopoulou, I., Garber, J., Hamann, U., Donaldson, A., Brady, A., Brewer, C., Foo, C., Evans, D., Frost, D., Eccles, D., Douglas, F., Cook, J., Adlard, J., Barwell, J., Walker, L., Izatt, L., Side, L. E., Kennedy, M., Tischkowitz, M., Rogers, M. T., Porteous, M. E., Morrison, P. J., Platte, R., Eeles, R., Davidson, R., Hodgson, S., Cole, T., Godwin, A. K., Isaacs, C., Claes, K., De Leeneer, K., Meindl, A., Gehrig, A., Wappenschmidt, B., Sutter, C., Engel, C., Niederacher, D., Steinemann, D., Plendl, H., Kast, K., Rhiem, K., Ditsch, N., Arnold, N., Varon-Mateeva, R., Schmutzler, R. K., Preisler-Adams, S., Markov, N., Wang-Gohrke, S., de Pauw, A., Lefol, C., Lasset, C., Leroux, D., Rouleau, E., Damiola, F., Dreyfus, H., Barjhoux, L., Golmard, L., Uhrhammer, N., Bonadona, V., Sornin, V., Bignon, Y., Carter, J., Van Le, L., Piedmonte, M., DiSilvestro, P. A., de la Hoya, M., Caldes, T., Nevanlinna, H., Aittomaki, K., Jager, A., van den Ouweland, A. W., Kets, C. M., Aalfs, C. M., van Leeuwen, F. E., Hogervorst, F. L., Meijers-Heijboer, H. J., Oosterwijk, J. C., van Roozendaal, K. P., Rookus, M. A., Devilee, P., van der Luijt, R. B., Olah, E., Diez, O., Teule, A., Lazaro, C., Blanco, I., Del Valle, J., Jakubowska, A., Sukiennicki, G., Gronwald, J., Lubinski, J., Durda, K., Jaworska-Bieniek, K., Agnarsson, B. A., Maugard, C., Amadori, A., Montagna, M., Teixeira, M. R., Spurdle, A. B., Foulkes, W., Olswold, C., Lindor, N. M., Pankratz, V. S., Szabo, C. I., Lincoln, A., Jacobs, L., Corines, M., Robson, M., Vijai, J., Berger, A., Fink-Retter, A., Singer, C. F., Rappaport, C., Kaulich, D., Pfeiler, G., Tea, M., Greene, M. H., Mai, P. L., Rennert, G., Imyanitov, E. N., Mulligan, A., Glendon, G., Andrulis, I. L., Tchatchou, S., Toland, A., Pedersen, I., Thomassen, M., Kruse, T. A., Jensen, U., Caligo, M. A., Friedman, E., Zidan, J., Laitman, Y., Lindblom, A., Melin, B., Arver, B., Loman, N., Rosenquist, R., Olopade, O. I., Nussbaum, R. L., Ramus, S. J., Nathanson, K. L., Domchek, S. M., Rebbeck, T. R., Arun, B. K., Mitchell, G., Karlan, B. Y., Lester, J., Orsulic, S., Stoppa-Lyonnet, D., Thomas, G., Simard, J., Couch, F. J., Offit, K., Easton, D. F., Chenevix-Trench, G., Antoniou, A. C., Mazoyer, S., Phelan, C. M., Sinilnikova, O. M., Cox, D. G., Breast Canc Family Registry, EMBRACE, GEMO Study Collaborators, HEBON 2015; 17: 61

  Abstract

  Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

  View details for PubMedID 25925750

• Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA Rebbeck, T. R., Mitra, N., Wan, F., Sinilnikova, O. M., Healey, S., McGuffog, L., Mazoyer, S., Chenevix-Trench, G., Easton, D. F., Antoniou, A. C., Nathanson, K. L., Laitman, Y., Kushnir, A., Paluch-Shimon, S., Berger, R., Zidan, J., friedman, e., Ehrencrona, H., Stenmark-Askmalm, M., Einbeigi, Z., Loman, N., Harbst, K., Rantala, J., Melin, B., Huo, D., Olopade, O. I., Seldon, J., Ganz, P. A., Nussbaum, R. L., Chan, S. B., Odunsi, K., Gayther, S. A., Domchek, S. M., Arun, B. K., Lu, K. H., Mitchell, G., Karlan, B. Y., Walsh, C., Lester, J., Godwin, A. K., Pathak, H., Ross, E., Daly, M. B., Whittemore, A. S., John, E. M., Miron, A., Terry, M. B., Chung, W. K., Goldgar, D. E., Buys, S. S., Janavicius, R., Tihomirova, L., Tung, N., Dorfling, C. M., Van Rensburg, E. J., Steele, L., Neuhausen, S. L., Ding, Y. C., Ejlertsen, B., Gerdes, A., Hansen, T. v., Ramón y Cajal, T., Osorio, A., Benitez, J., Godino, J., Tejada, M., Duran, M., Weitzel, J. N., Bobolis, K. A., Sand, S. R., Fontaine, A., Savarese, A., Pasini, B., Peissel, B., Bonanni, B., Zaffaroni, D., Vignolo-Lutati, F., Scuvera, G., Giannini, G., Bernard, L., Genuardi, M., Radice, P., Dolcetti, R., Manoukian, S., Pensotti, V., Gismondi, V., Yannoukakos, D., Fostira, F., Garber, J., Torres, D., Rashid, M. U., Hamann, U., Peock, S., Frost, D., Platte, R., Evans, D. G., Eeles, R., Davidson, R., Eccles, D., Cole, T., Cook, J., Brewer, C., Hodgson, S., Morrison, P. J., Walker, L., Porteous, M. E., Kennedy, M. J., Izatt, L., Adlard, J., Donaldson, A., Ellis, S., Sharma, P., Schmutzler, R. K., Wappenschmidt, B., Becker, A., Rhiem, K., Hahnen, E., Engel, C., Meindl, A., Engert, S., Ditsch, N., Arnold, N., Plendl, H. J., Mundhenke, C., Niederacher, D., Fleisch, M., Sutter, C., Bartram, C. R., Dikow, N., Wang-Gohrke, S., Gadzicki, D., Steinemann, D., Kast, K., Beer, M., Varon-Mateeva, R., Gehrig, A., Weber, B. H., Stoppa-Lyonnet, D., Sinilnikova, O. M., Mazoyer, S., Houdayer, C., Belotti, M., Gauthier-Villars, M., Damiola, F., Boutry-Kryza, N., Lasset, C., Sobol, H., Peyrat, J., Muller, D., Fricker, J., Collonge-Rame, M., Mortemousque, I., Nogues, C., Rouleau, E., Isaacs, C., De Paepe, A., Poppe, B., Claes, K., De Leeneer, K., Piedmonte, M., Rodriguez, G., Wakely, K., Boggess, J., Blank, S. V., Basil, J., Azodi, M., Phillips, K., Caldes, T., de la Hoya, M., Romero, A., Nevanlinna, H., Aittomäki, K., van der Hout, A. H., Hogervorst, F. B., Verhoef, S., Collée, J. M., Seynaeve, C., Oosterwijk, J. C., Gille, J. J., Wijnen, J. T., Garcia, E. B., Kets, C. M., Ausems, M. G., Aalfs, C. M., Devilee, P., Mensenkamp, A. R., Kwong, A., Olah, E., Papp, J., Diez, O., Lazaro, C., Darder, E., Blanco, I., Salinas, M., Jakubowska, A., Lubinski, J., Gronwald, J., Jaworska-Bieniek, K., Durda, K., Sukiennicki, G., Huzarski, T., Byrski, T., Cybulski, C., Toloczko-Grabarek, A., Zlowocka-Perlowska, E., Menkiszak, J., Arason, A., Barkardottir, R. B., Simard, J., Laframboise, R., Montagna, M., Agata, S., Alducci, E., Peixoto, A., Teixeira, M. R., Spurdle, A. B., Lee, M. H., Park, S. K., Kim, S., Friebel, T. M., Couch, F. J., Lindor, N. M., Pankratz, V. S., Guidugli, L., Wang, X., Tischkowitz, M., Foretova, L., Vijai, J., Offit, K., Robson, M., Rau-Murthy, R., Kauff, N., Fink-Retter, A., Singer, C. F., Rappaport, C., Gschwantler-Kaulich, D., Pfeiler, G., Tea, M., Berger, A., Greene, M. H., Mai, P. L., Imyanitov, E. N., Toland, A. E., Senter, L., Bojesen, A., Pedersen, I. S., Skytte, A., Sunde, L., Thomassen, M., Moeller, S. T., Kruse, T. A., Jensen, U. B., Caligo, M. A., Aretini, P., Teo, S., Selkirk, C. G., Hulick, P. J., Andrulis, I. 2015; 313 (13): 1347-1361

  Abstract

  Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.To identify mutation-specific cancer risks for carriers of BRCA1/2.Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.Mutations of BRCA1 or BRCA2.Breast and ovarian cancer risks.Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

  View details for DOI 10.1001/jama.2014.5985

  View details for PubMedID 25849179

• Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer NATURE GENETICS Michailidou, K., Beesley, J., Lindstrom, S., Canisius, S., Dennis, J., Lush, M. J., Maranian, M. J., Bolla, M. K., Wang, Q., Shah, M., Perkins, B. J., Czene, K., Eriksson, M., Darabi, H., Brand, J. S., Bojesen, S. E., Nordestgaard, B. G., Flyger, H., Nielsen, S. F., Rahman, N., Turnbull, C., Fletcher, O., Peto, J., Gibson, L., Dos-Santos-Silva, I., Chang-Claude, J., Flesch-Janys, D., Rudolph, A., Eilber, U., Behrens, S., Nevanlinna, H., Muranen, T. A., Aittomaki, K., Blomqvist, C., Khan, S., Aaltonen, K., Ahsan, H., Kibriya, M. G., Whittemore, A. S., John, E. M., Malone, K. E., Gammon, M. D., Santella, R. M., Ursin, G., Makalic, E., Schmidt, D. F., Casey, G., Hunter, D. J., Gapstur, S. M., Gaudet, M. M., Diver, W. R., Haiman, C. A., Schumacher, F., Henderson, B. E., Le Marchand, L., Berg, C. D., Chanock, S. J., Figueroa, J., Hoover, R. N., Lambrechts, D., Neven, P., Wildiers, H., Van Limbergen, E., Schmidt, M. K., Broeks, A., Verhoef, S., Cornelissen, S., Couch, F. J., Olson, J. E., Hallberg, E., Vachon, C., Waisfisz, Q., Meijers-Heijboer, H., Adank, M. A., van der Luijt, R. B., Li, J., Liu, J., Humphreys, K., Kang, D., Choi, J., Park, S. K., Yoo, K., Matsuo, K., Ito, H., Iwata, H., Tajima, K., Guenel, P., Truong, T., Mulot, C., Sanchez, M., Burwinkel, B., Marme, F., Surowy, H., Sohn, C., Wu, A. H., Tseng, C., Van Den Berg, D., Stram, D. O., Gonzalez-Neira, A., Benitez, J., Zamora, M. P., Arias Perez, J. I., Shu, X., Lu, W., Gao, Y., Cai, H., Cox, A., Cross, S. S., Reed, M. W., Andrulis, I. L., Knight, J. A., Glendon, G., Mulligan, A. M., Sawyer, E. J., Tomlinson, I., Kerin, M. J., Miller, N., Lindblom, A., Margolin, S., Teo, S. H., Yip, C. H., Taib, N. A., Tan, G., Hooning, M. J., Hollestelle, A., Martens, J. W., Collee, J. M., Blot, W., Signorello, L. B., Cai, Q., Hopper, J. L., Southey, M. C., Tsimiklis, H., Apicella, C., Shen, C., Hsiung, C., Wu, P., Hou, M., Kristensen, V. N., Nord, S., Alnaes, G. I., Giles, G. G., Milne, R. L., McLean, C., Canzian, F., Trichopoulos, D., Peeters, P., Lund, E., Sund, M., Khaw, K., Gunter, M. J., Palli, D., Mortensen, L. M., Dossus, L., Huerta, J., Meindl, A., Schmutzler, R. K., Sutter, C., Yang, R., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Hartman, M., Miao, H., Chia, K. S., Chan, C. W., Fasching, P. A., Hein, A., Beckmann, M. W., Haeberle, L., Brenner, H., Dieffenbach, A. K., Arndt, V., Stegmaier, C., Ashworth, A., Orr, N., Schoemaker, M. J., Swerdlow, A. J., Brinton, L., Garcia-Closas, M., Zheng, W., Halverson, S. L., Shrubsole, M., Long, J., Goldberg, M. S., Labreche, F., Dumont, M., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Brauch, H., Hamann, U., Bruening, T., Radice, P., Peterlongo, P., Manoukian, S., Bernard, L., Bogdanova, N. V., Doerk, T., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Devilee, P., Tollenaar, R. A., Seynaeve, C., van Asperen, C. J., Jakubowska, A., Lubinski, J., Jaworska, K., Huzarski, T., Sangrajrang, S., Gaborieau, V., Brennan, P., McKay, J., Slager, S., Toland, A. E., Ambrosone, C. B., Yannoukakos, D., Kabisch, M., Torres, D., Neuhausen, S. L., Anton-Culver, H., Luccarini, C., Baynes, C., Ahmed, S., Healey, C. S., Tessier, D. C., Vincent, D., Bacot, F., Pita, G., Rosario Alonso, M., Alvarez, N., Herrero, D., Simard, J., Pharoah, P. P., Kraft, P., Dunning, A. M., Chenevix-Trench, G., Hall, P., Easton, D. F. 2015; 47 (4): 373-U127

  Abstract

  Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.

  View details for DOI 10.1038/ng.3242

  View details for Web of Science ID 000351922900013

  View details for PubMedCentralID PMC4549775

• Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer. Nature genetics Michailidou, K., Beesley, J., Lindstrom, S., Canisius, S., Dennis, J., Lush, M. J., Maranian, M. J., Bolla, M. K., Wang, Q., Shah, M., Perkins, B. J., Czene, K., Eriksson, M., Darabi, H., Brand, J. S., Bojesen, S. E., Nordestgaard, B. G., Flyger, H., Nielsen, S. F., Rahman, N., Turnbull, C., Fletcher, O., Peto, J., Gibson, L., Dos-Santos-Silva, I., Chang-Claude, J., Flesch-Janys, D., Rudolph, A., Eilber, U., Behrens, S., Nevanlinna, H., Muranen, T. A., Aittomäki, K., Blomqvist, C., Khan, S., Aaltonen, K., Ahsan, H., Kibriya, M. G., Whittemore, A. S., John, E. M., Malone, K. E., Gammon, M. D., Santella, R. M., Ursin, G., Makalic, E., Schmidt, D. F., Casey, G., Hunter, D. J., Gapstur, S. M., Gaudet, M. M., Diver, W. R., Haiman, C. A., Schumacher, F., Henderson, B. E., Le Marchand, L., Berg, C. D., Chanock, S. J., Figueroa, J., Hoover, R. N., Lambrechts, D., Neven, P., Wildiers, H., Van Limbergen, E., Schmidt, M. K., Broeks, A., Verhoef, S., Cornelissen, S., Couch, F. J., Olson, J. E., Hallberg, E., Vachon, C., Waisfisz, Q., Meijers-Heijboer, H., Adank, M. A., van der Luijt, R. B., Li, J., Liu, J., Humphreys, K., Kang, D., Choi, J., Park, S. K., Yoo, K., Matsuo, K., Ito, H., Iwata, H., Tajima, K., Guénel, P., Truong, T., Mulot, C., Sanchez, M., Burwinkel, B., Marme, F., Surowy, H., Sohn, C., Wu, A. H., Tseng, C., Van Den Berg, D., Stram, D. O., González-Neira, A., Benitez, J., Zamora, M. P., Perez, J. I., Shu, X., Lu, W., Gao, Y., Cai, H., Cox, A., Cross, S. S., Reed, M. W., Andrulis, I. L., Knight, J. A., Glendon, G., Mulligan, A. M., Sawyer, E. J., Tomlinson, I., Kerin, M. J., Miller, N., Lindblom, A., Margolin, S., Teo, S. H., Yip, C. H., Taib, N. A., Tan, G., Hooning, M. J., Hollestelle, A., Martens, J. W., Collée, J. M., Blot, W., Signorello, L. B., Cai, Q., Hopper, J. L., Southey, M. C., Tsimiklis, H., Apicella, C., Shen, C., Hsiung, C., Wu, P., Hou, M., Kristensen, V. N., Nord, S., Alnaes, G. I., Giles, G. G., Milne, R. L., McLean, C., Canzian, F., Trichopoulos, D., Peeters, P., Lund, E., Sund, M., Khaw, K., Gunter, M. J., Palli, D., Mortensen, L. M., Dossus, L., Huerta, J., Meindl, A., Schmutzler, R. K., Sutter, C., Yang, R., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Hartman, M., Miao, H., Chia, K. S., Chan, C. W., Fasching, P. A., Hein, A., Beckmann, M. W., Haeberle, L., Brenner, H., Dieffenbach, A. K., Arndt, V., Stegmaier, C., Ashworth, A., Orr, N., Schoemaker, M. J., Swerdlow, A. J., Brinton, L., Garcia-Closas, M., Zheng, W., Halverson, S. L., Shrubsole, M., Long, J., Goldberg, M. S., Labrèche, F., Dumont, M., Winqvist, R., Pylkäs, K., Jukkola-Vuorinen, A., Grip, M., Brauch, H., Hamann, U., Brüning, T., Radice, P., Peterlongo, P., Manoukian, S., Bernard, L., Bogdanova, N. V., Dörk, T., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Devilee, P., Tollenaar, R. A., Seynaeve, C., van Asperen, C. J., Jakubowska, A., Lubinski, J., Jaworska, K., Huzarski, T., Sangrajrang, S., Gaborieau, V., Brennan, P., McKay, J., Slager, S., Toland, A. E., Ambrosone, C. B., Yannoukakos, D., Kabisch, M., Torres, D., Neuhausen, S. L., Anton-Culver, H., Luccarini, C., Baynes, C., Ahmed, S., Healey, C. S., Tessier, D. C., Vincent, D., Bacot, F., Pita, G., Alonso, M. R., Álvarez, N., Herrero, D., Simard, J., Pharoah, P. P., Kraft, P., Dunning, A. M., Chenevix-Trench, G., Hall, P., Easton, D. F. 2015; 47 (4): 373-380

  Abstract

  Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.

  View details for DOI 10.1038/ng.3242

  View details for PubMedID 25751625

• Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers PLOS ONE Blanco, I., Kuchenbaecker, K., Cuadras, D., Wang, X., Barrowdale, D., Ruiz de Garibay, G., Librado, P., Sanchez-Gracia, A., Rozas, J., Bonifaci, N., McGuffog, L., Pankratz, V. S., Islam, A., Mateo, F., Berenguer, A., Petit, A., Catala, I., Brunet, J., Feliubadalo, L., Tornero, E., Benitez, J., Osorio, A., Cajal, T. Y., Nevanlinna, H., Aittomaki, K., Arun, B. K., Toland, A. E., Karlan, B. Y., Walsh, C., Lester, J., Greene, M. H., Mai, P. L., Nussbaum, R. L., Andrulis, I. L., Domchek, S. M., Nathanson, K. L., Rebbeck, T. R., Barkardottir, R. B., Jakubowska, A., Lubinski, J., Durda, K., Jaworska-Bieniek, K., Claes, K., Van Maerken, T., Diez, O., Hansen, T. V., Jonson, L., Gerdes, A., Ejlertsen, B., de la Hoya, M., Caldes, T., Dunning, A. M., Oliver, C., Fineberg, E., Cook, M., Peock, S., McCann, E., Murray, A., Jacobs, C., Pichert, G., Lalloo, F., Chu, C., Dorkins, H., Paterson, J., Ong, K., Teixeira, M. R., Teixeira, Hogervorst, F. L., van der Hout, A. H., Seynaeve, C., van der Luijt, R. B., Ligtenberg, M. L., Devilee, P., Wijnen, J. T., Rookus, M. A., Meijers-Heijboer, H. J., Blok, M. J., van den Ouweland, A. W., Aalfs, C. M., Rodriguez, G. C., Phillips, K. A., Piedmonte, M., Nerenstone, S. R., Bae-Jump, V. L., O'Malley, D. M., Ratner, E. S., Schmutzler, R. K., Wappenschmidt, B., Rhiem, K., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Plendl, H. J., Niederacher, D., Sutter, C., Wang-Gohrke, S., Steinemann, D., Preisler-Adams, S., Kast, K., Varon-Mateeva, R., Gehrig, A., Bojesen, A., Pedersen, I., Sunde, L., Jensen, U., Thomassen, M., Kruse, T. A., Foretova, L., Peterlongo, P., Bernard, L., Peissel, B., Scuvera, G., Manoukian, S., Radice, P., Ottini, L., Montagna, M., Agata, S., Maugard, C., Simard, J., Soucy, P., Berger, A., Fink-Retter, A., Singer, C. F., Rappaport, C., Geschwantler-Kaulich, D., Tea, M., Pfeiler, G., John, E. M., Miron, A., Neuhausen, S. L., Terry, M., Chung, W. K., Daly, M. B., Goldgar, D. E., Janavicius, R., Dorfling, C. M., van Rensburg, E. J., Fostira, F., Konstantopoulou, I., Garber, J., Godwin, A. K., Olah, E., Narod, S. A., Rennert, G., Paluch, S., Laitman, Y., Friedman, E., Liljegren, A., Rantala, J., Stenmark-Askmalm, M., Loman, N., Imyanitov, E. N., Hamann, U., Spurdle, A. B., Healey, S., Weitzel, J. N., Herzog, J., Margileth, D., Gorrini, C., Esteller, M., Gomez, A., Sayols, S., Vidal, E., Heyn, H., Stoppa-Lyonnet, D., Leone, M., Barjhoux, L., Fassy-Colcombet, M., de Pauw, A., Lasset, C., Ferrer, S., Castera, L., Berthet, P., Cornelis, F., Bignon, Y., Damiola, F., Mazoyer, S., Sinilnikova, O. M., Maxwell, C. A., Vijai, J., Robson, M., Kauff, N., Corines, M. J., Villano, D., Cunningham, J., Lee, A., Lindor, N., Lazaro, C., Easton, D. F., Offit, K., Chenevix-Trench, G., Couch, F. J., Antoniou, A. C., Angel Pujana, M., BCFR, SWE-BRCA, KConFab Investigators, GEMO 2015; 10 (4): e0120020

  Abstract

  While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

  View details for PubMedID 25830658

• Generalizability of established prostate cancer risk variants in men of African ancestry INTERNATIONAL JOURNAL OF CANCER Han, Y., Signorello, L. B., Strom, S. S., Kittles, R. A., Rybicki, B. A., Stanford, J. L., Goodman, P. J., Berndt, S. I., Carpten, J., Casey, G., Chu, L., Conti, D. V., Rand, K. A., Diver, W. R., Hennis, A. J., John, E. M., Kibel, A. S., Klein, E. A., Kolb, S., Le Marchand, L., Leske, M. C., Murphy, A. B., Neslund-Dudas, C., Park, J. Y., Pettaway, C., Rebbeck, T. R., Gapstur, S. M., Zheng, S. L., Wu, S., Witte, J. S., Xu, J., Isaacs, W., Ingles, S. A., Hsing, A., Easton, D. F., Eeles, R. A., Schumacher, F. R., Chanock, S., Nemesure, B., Blot, W. J., Stram, D. O., Henderson, B. E., Haiman, C. A. 2015; 136 (5): 1210-1217

  Abstract

  Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p < 0.05, with the most statistically significant variants being rs116041037 (p = 3.7 × 10(-26) ) and rs6983561 (p = 1.1 × 10(-16) ) at 8q24, as well as rs7210100 (p = 5.4 × 10(-8) ) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p < 0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR) = 1.12, p = 7.3 × 10(-98) ]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry.

  View details for DOI 10.1002/ijc.29066

  View details for Web of Science ID 000346350500046

  View details for PubMedCentralID PMC4268262

• MAPK Genes Interact with Diet and Lifestyle Factors to Alter Risk of Breast Cancer: The Breast Cancer Health Disparities Study NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL Slattery, M. L., Lundgreen, A., John, E. M., Torres-Mejia, G., Hines, L., Giuliano, A. R., Baumgartner, K. B., Stern, M. C., Wolff, R. K. 2015; 67 (2): 292-304

  Abstract

  Mitogen-activated protein kinases (MAPK) are integration points for multiple biochemical signals. We evaluated 13 MAPK genes with breast cancer risk and determined if diet and lifestyle factors mediated risk. Data from 3 population-based case-control studies conducted in Southwestern United States, California, and Mexico included 4183 controls and 3592 cases. Percent Indigenous American (IA) ancestry was determined from 104 ancestry informative markers. The adaptive rank truncated product (ARTP) was used to determine the significance of each gene and the pathway with breast cancer risk, by menopausal status, genetic ancestry level, and estrogen receptor (ER)/progesterone receptor (PR) strata. MAP3K9 was associated with breast cancer overall (P(ARTP) = 0.02) with strongest association among women with the highest IA ancestry (P(ARTP) = 0.04). Several SNPs in MAP3K9 were associated with ER+/PR+ tumors and interacted with dietary oxidative balance score (DOBS), dietary folate, body mass index (BMI), alcohol consumption, cigarette smoking, and a history of diabetes. DUSP4 and MAPK8 interacted with calories to alter breast cancer risk; MAPK1 interacted with DOBS, dietary fiber, folate, and BMI; MAP3K2 interacted with dietary fat; and MAPK14 interacted with dietary folate and BMI. The patterns of association across diet and lifestyle factors with similar biological properties for the same SNPs within genes provide support for associations.

  View details for DOI 10.1080/01635581.2015.990568

  View details for Web of Science ID 000350338300012

  View details for PubMedID 25629224

• Diabetes and Other Comorbidities in Breast Cancer Survival by Race/Ethnicity: The California Breast Cancer Survivorship Consortium (CBCSC). Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Wu, A. H., Kurian, A. W., Kwan, M. L., John, E. M., Lu, Y., Keegan, T. H., Gomez, S. L., Cheng, I., Shariff-Marco, S., Caan, B. J., Lee, V. S., Sullivan-Halley, J., Tseng, C., Bernstein, L., Sposto, R., Vigen, C. 2015; 24 (2): 361-368

  Abstract

  Background:The role of comorbidities in survival of breast cancer patients has not been well studied, particularly in non-white populations. Methods:We investigated the association of specific comorbidities with mortality in a multiethnic cohort of 8,952 breast cancer cases within the California Breast Cancer Survivorship Consortium (CBCSC), which pooled questionnaire and cancer registry data from five California-based studies. In total, 2,187 deaths (1,122 from breast cancer) were observed through December 31, 2010. Using multivariable Cox proportional hazards regression, we estimated hazards ratios (HR) and 95% confidence intervals (CI) for overall and breast cancer-specific mortality associated with previous cancer, diabetes, high blood pressure (HBP), and myocardial infarction (MI). Results:Risk of breast cancer-specific mortality increased among breast cancer cases with a history of diabetes (HR=1.48, 95% CI=1.18, 1.87) or MI (HR=1.94, 95% CI=1.27-2.97). Risk patterns were similar across race/ethnicity (non-Latina White, Latina, African American and Asian American), body size, menopausal status, and stage at diagnosis. In subgroup analyses, risk of breast cancer-specific mortality was significantly elevated among cases with diabetes who received neither radiation nor chemotherapy (HR=2.11, 95% CI=1.32-3.36); no increased risk was observed among those who received both treatments (HR=1.13, 95% CI= 0.70-1.84) (P interaction= 0.03). A similar pattern was found for MI by radiation and chemotherapy (P interaction=0.09). Conclusion:These results may inform future treatment guidelines for breast cancer patients with a history of diabetes or MI. Impact:Given the growing number of breast cancer survivors worldwide, we need to better understand how comorbidities may adversely affect treatment decisions and ultimately outcome.

  View details for DOI 10.1158/1055-9965.EPI-14-1140

  View details for PubMedID 25425578

• Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nature genetics Kuchenbaecker, K. B., Ramus, S. J., Tyrer, J., Lee, A., Shen, H. C., Beesley, J., Lawrenson, K., McGuffog, L., Healey, S., Lee, J. M., Spindler, T. J., Lin, Y. G., Pejovic, T., Bean, Y., Li, Q., Coetzee, S., Hazelett, D., Miron, A., Southey, M., Terry, M. B., Goldgar, D. E., Buys, S. S., Janavicius, R., Dorfling, C. M., Van Rensburg, E. J., Neuhausen, S. L., Ding, Y. C., Hansen, T. v., Jønson, L., Gerdes, A., Ejlertsen, B., Barrowdale, D., Dennis, J., Benitez, J., Osorio, A., Garcia, M. J., Komenaka, I., Weitzel, J. N., Ganschow, P., Peterlongo, P., Bernard, L., Viel, A., Bonanni, B., Peissel, B., Manoukian, S., Radice, P., Papi, L., Ottini, L., Fostira, F., Konstantopoulou, I., Garber, J., Frost, D., Perkins, J., Platte, R., Ellis, S., Godwin, A. K., Schmutzler, R. K., Meindl, A., Engel, C., Sutter, C., Sinilnikova, O. M., Damiola, F., Mazoyer, S., Stoppa-Lyonnet, D., Claes, K., De Leeneer, K., Kirk, J., Rodriguez, G. C., Piedmonte, M., O'Malley, D. M., de la Hoya, M., Caldes, T., Aittomäki, K., Nevanlinna, H., Collée, J. M., Rookus, M. A., Oosterwijk, J. C., Tihomirova, L., Tung, N., Hamann, U., Isaccs, C., Tischkowitz, M., Imyanitov, E. N., Caligo, M. A., Campbell, I. G., Hogervorst, F. B., Olah, E., Diez, O., Blanco, I., Brunet, J., Lazaro, C., Pujana, M. A., Jakubowska, A., Gronwald, J., Lubinski, J., Sukiennicki, G., Barkardottir, R. B., Plante, M., Simard, J., Soucy, P., Montagna, M., Tognazzo, S., Teixeira, M. R., Pankratz, V. S., Wang, X., Lindor, N., Szabo, C. I., Kauff, N., Vijai, J., Aghajanian, C. A., Pfeiler, G., Berger, A., Singer, C. F., Tea, M., Phelan, C. M., Greene, M. H., Mai, P. L., Rennert, G., Mulligan, A. M., Tchatchou, S., Andrulis, I. L., Glendon, G., Toland, A. E., Jensen, U. B., Kruse, T. A., Thomassen, M., Bojesen, A., Zidan, J., friedman, e., Laitman, Y., Soller, M., Liljegren, A., Arver, B., Einbeigi, Z., Stenmark-Askmalm, M., Olopade, O. I., Nussbaum, R. L., Rebbeck, T. R., Nathanson, K. L., Domchek, S. M., Lu, K. H., Karlan, B. Y., Walsh, C., Lester, J., Hein, A., Ekici, A. B., Beckmann, M. W., Fasching, P. A., Lambrechts, D., van Nieuwenhuysen, E., Vergote, I., Lambrechts, S., Dicks, E., Doherty, J. A., Wicklund, K. G., Rossing, M. A., Rudolph, A., Chang-Claude, J., Wang-Gohrke, S., Eilber, U., Moysich, K. B., Odunsi, K., Sucheston, L., Lele, S., Wilkens, L. R., Goodman, M. T., Thompson, P. J., Shvetsov, Y. B., Runnebaum, I. B., Dürst, M., Hillemanns, P., Dörk, T., Antonenkova, N., Bogdanova, N., Leminen, A., Pelttari, L. M., Butzow, R., Modugno, F., Kelley, J. L., Edwards, R. P., Ness, R. B., du Bois, A., Heitz, F., Schwaab, I., Harter, P., Matsuo, K., Hosono, S., Orsulic, S., Jensen, A., Kjaer, S. K., Hogdall, E., Hasmad, H. N., Azmi, M. A., Teo, S., Woo, Y., Fridley, B. L., Goode, E. L., Cunningham, J. M., Vierkant, R. A., Bruinsma, F., Giles, G. G., Liang, D., Hildebrandt, M. A., Wu, X., Levine, D. A., Bisogna, M., Berchuck, A., Iversen, E. S., Schildkraut, J. M., Concannon, P., Weber, R. P., Cramer, D. W., Terry, K. L., Poole, E. M., Tworoger, S. S., Bandera, E. V., Orlow, I., Olson, S. H., Krakstad, C., Salvesen, H. B., Tangen, I. L., Bjorge, L., van Altena, A. M., Aben, K. K., Kiemeney, L. A., Massuger, L. F., Kellar, M., Brooks-Wilson, A., Kelemen, L. E., Cook, L. S., Le, N. D., Cybulski, C., Yang, H., Lissowska, J., Brinton, L. A., Wentzensen, N., Hogdall, C., Lundvall, L., Nedergaard, L., Baker, H., Song, H., Eccles, D., McNeish, I., Paul, J., Carty, K., Siddiqui, N., Glasspool, R., Whittemore, A. S., Rothstein, J. H., McGuire, V., Sieh, W., Ji, B., Zheng, W., Shu, X., Gao, Y., Rosen, B., Risch, H. A., McLaughlin, J. R., Narod, S. A., Monteiro, A. N., Chen, A., Lin, H., Permuth-Wey, J., Sellers, T. A., Tsai, Y., Chen, Z., Ziogas, A., Anton-Culver, H., Gentry-Maharaj, A., Menon, U., Harrington, P., Lee, A. W., Wu, A. H., Pearce, C. L., Coetzee, G., Pike, M. C., Dansonka-Mieszkowska, A., Timorek, A., Rzepecka, I. K., Kupryjanczyk, J., Freedman, M., Noushmehr, H., Easton, D. F., Offit, K., Couch, F. J., Gayther, S., Pharoah, P. P., Antoniou, A. C., Chenevix-Trench, G. 2015; 47 (2): 164-171

  Abstract

  Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

  View details for DOI 10.1038/ng.3185

  View details for PubMedID 25581431

• Overall and abdominal adiposity and premenopausal breast cancer risk among hispanic women: the breast cancer health disparities study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology John, E. M., Sangaramoorthy, M., Hines, L. M., Stern, M. C., Baumgartner, K. B., Giuliano, A. R., Wolff, R. K., Slattery, M. L. 2015; 24 (1): 138-147

  Abstract

  Few studies in Hispanic women have examined the relation between adult body size and risk of premenopausal breast cancer defined by hormone receptor status.The Breast Cancer Health Disparities Study pooled interview and anthropometric data from two large U.S. population-based case-control studies. We examined associations of overall and abdominal adiposity with risk of estrogen receptor- and progesterone receptor-positive (ER(+)PR(+)) and -negative (ER(-)PR(-)) breast cancer in Hispanic and non-Hispanic White (NHW) women, calculating ORs and 95% confidence intervals.Among Hispanics, risk of ER(+)PR(+) breast cancer was inversely associated with measures of overall adiposity, including young-adult and current body mass index (BMI). Risk was substantially reduced among those with high (above the median) young-adult BMI and current overweight or obesity. The findings for overall adiposity were similar for Hispanics and NHWs. In the subset of Hispanics with data on genetic ancestry, inverse associations of current BMI, and weight gain with ER(+)PR(+) breast cancer were limited to those with lower Indigenous American ancestry. For ER(-)PR(-) breast cancer, height was associated with increased risk, and young-adult BMI was associated with reduced risk. For all breast cancers combined, positive associations were seen for waist circumference, waist-to-hip ratio, and waist-to-height ratio in Hispanic women only.Our findings of body size associations with specific breast cancer subtypes among premenopausal Hispanic women were similar to those reported for NHW women.Adiposity throughout the premenopausal years has a major influence on breast cancer risk in Hispanic women. Cancer Epidemiol Biomarkers Prev; 24(1); 138-47. ©2014 AACR. See related article by John et al., p. 128.

  View details for DOI 10.1158/1055-9965.EPI-13-1007-T

  View details for PubMedID 25352526

  View details for PubMedCentralID PMC4294975

• Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults. PloS one Chen, F., He, J., Zhang, J., Chen, G. K., Thomas, V., Ambrosone, C. B., Bandera, E. V., Berndt, S. I., Bernstein, L., Blot, W. J., Cai, Q., Carpten, J., Casey, G., Chanock, S. J., Cheng, I., Chu, L., Deming, S. L., Driver, W. R., Goodman, P., Hayes, R. B., Hennis, A. J., Hsing, A. W., Hu, J. J., Ingles, S. A., John, E. M., Kittles, R. A., Kolb, S., Leske, M. C., Millikan, R. C., Monroe, K. R., Murphy, A., Nemesure, B., Neslund-Dudas, C., Nyante, S., Ostrander, E. A., Press, M. F., Rodriguez-Gil, J. L., Rybicki, B. A., Schumacher, F., Stanford, J. L., Signorello, L. B., Strom, S. S., Stevens, V., Van Den Berg, D., Wang, Z., Witte, J. S., Wu, S., Yamamura, Y., Zheng, W., Ziegler, R. G., Stram, A. H., Kolonel, L. N., Le Marchand, L., Henderson, B. E., Haiman, C. A., Stram, D. O. 2015; 10 (6)

  Abstract

  Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.

  View details for DOI 10.1371/journal.pone.0131106

  View details for PubMedID 26125186

• Body size throughout adult life influences postmenopausal breast cancer risk among hispanic women: the breast cancer health disparities study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology John, E. M., Sangaramoorthy, M., Hines, L. M., Stern, M. C., Baumgartner, K. B., Giuliano, A. R., Wolff, R. K., Slattery, M. L. 2015; 24 (1): 128-137

  Abstract

  Few studies have assessed the association of body size with postmenopausal breast cancer risk in Hispanic women. Findings are inconsistent and appear to contradict those reported for non-Hispanic white (NHW) women.We pooled interview and anthropometric data for 2,023 Hispanic and 2,384 NHW women from two U.S. population-based case-control studies. Using logistic regression analysis, we examined associations of overall and abdominal adiposity with risk of postmenopausal breast cancer defined by estrogen receptor (ER) and progesterone receptor (PR) status.Weight gain was associated with increased risk of ER(+)PR(+) breast cancer in Hispanics not currently using menopausal hormone therapy (HT), but only among those with a low young-adult body mass index (BMI). In the subset of Hispanics with data on genetic ancestry, the association with weight gain was limited to women with lower Indigenous American ancestry. Young-adult BMI was inversely associated with both ER(+)PR(+) and ER(-)PR(-) breast cancers for both ethnicities combined, with similar, although nonsignificant, inverse trends in Hispanics and NHWs. Among all Hispanics, regardless of HT use, height was associated with risk of ER(-)PR(-) breast cancer and hip circumference with risk of breast cancer overall.Body size throughout adult life is associated with breast cancer risk among postmenopausal Hispanic women, as has been reported for NHW women. Associations were specific for breast cancer subtypes defined by hormone receptor status.Avoiding weight gain and maintaining a healthy weight are important strategies to reduce the risk of postmenopausal ER(+)PR(+) breast cancer, the most common breast cancer subtype. Cancer Epidemiol Biomarkers Prev; 24(1); 128-37. ©2014 AACR. See related article by John et al., p. 138.

  View details for DOI 10.1158/1055-9965.EPI-14-0560

  View details for PubMedID 25352523

  View details for PubMedCentralID PMC4295775

• Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers BREAST CANCER RESEARCH Kuchenbaecker, K. B., Neuhausen, S. L., Robson, M., Barrowdale, D., McGuffog, L., Mulligan, A., Andrulis, I. L., Spurdle, A. B., Schmidt, M. K., Schmutzler, R. K., Engel, C., Wappenschmidt, B., Nevanlinna, H., Thomassen, M., Southey, M., Radice, P., Ramus, S. J., Domchek, S. M., Nathanson, K. L., Lee, A., Healey, S., Nussbaum, R. L., Rebbeck, T. R., Arun, B. K., James, P., Karlan, B. Y., Lester, J., Cass, I., Terry, M., Daly, M. B., Goldgar, D. E., Buys, S. S., Janavicius, R., Tihomirova, L., Tung, N., Dorfling, C. M., van Rensburg, E. J., Steele, L., Hansen, T. O., Ejlertsen, B., Gerdes, A., Nielsen, F. C., Dennis, J., Cunningham, J., Hart, S., Slager, S., Osorio, A., Benitez, J., Duran, M., Weitzel, J. N., Tafur, I., Hander, M., Peterlongo, P., Manoukian, S., Peissel, B., Roversi, G., Scuvera, G., Bonanni, B., Mariani, P., Volorio, S., Dolcetti, R., Varesco, L., Papi, L., Tibiletti, M., Giannini, G., Fostira, F., Konstantopoulou, I., Garber, J., Hamann, U., Donaldson, A., Brewer, C., Foo, C., Evans, D., Frost, D., Eccles, D., Douglas, F., Brady, A., Cook, J., Tischkowitz, M., Adlard, J., Barwell, J., Ong, K., Walker, L., Izatt, L., Side, L. E., Kennedy, M., Rogers, M. T., Porteous, M. E., Morrison, P. J., Platte, R., Eeles, R., Davidson, R., Hodgson, S., Ellis, S., Godwin, A. K., Rhiem, K., Meindl, A., Ditsch, N., Arnold, N., Plendl, H., Niederacher, D., Sutter, C., Steinemann, D., Bogdanova-Markov, N., Kast, K., Varon-Mateeva, R., Wang-Gohrke, S., Gehrig, A., Markiefka, B., Buecher, B., Lefol, C., Stoppa-Lyonnet, D., Rouleau, E., Prieur, F., Damiola, F., Barjhoux, L., Faivre, L., Longy, M., Sevenet, N., Sinilnikova, O. M., Mazoyer, S., Bonadona, V., Caux-Moncoutier, V., Isaacs, C., Van Maerken, T., Claes, K., Piedmonte, M., Andrews, L., Hays, J., Rodriguez, G. C., Caldes, T., de la Hoya, M., Khan, S., Hogervorst, F. L., Aalfs, C. M., de lange, J. L., Meijers-Heijboer, H. J., van der Hout, A. H., Wijnen, J. T., van Roozendaal, K. P., Mensenkamp, A. R., van den Ouweland, A. W., van Deurzen, C. M., van der Luijt, R. B., Olah, E., Diez, O., Lazaro, C., Blanco, I., Teule, A., Menendez, M., Jakubowska, A., Lubinski, J., Cybulski, C., Gronwald, J., Jaworska-Bieniek, K., Durda, K., Arason, A., Maugard, C., Soucy, P., Montagna, M., Agata, S., Teixeira, M. R., Olswold, C., Lindor, N., Pankratz, V. S., Hallberg, E., Wang, X., Szabo, C. I., Vijai, J., Jacobs, L., Corines, M., Lincoln, A., Berger, A., Fink-Retter, A., Singer, C. F., Rappaport, C., Kaulich, D., Pfeiler, G., Tea, M., Phelan, C. M., Mai, P. L., Greene, M. H., Rennert, G., Imyanitov, E. N., Glendon, G., Toland, A., Bojesen, A., Pedersen, I., Jensen, U., Caligo, M. A., Friedman, E., Berger, R., Laitman, Y., Rantala, J., Arver, B., Loman, N., Borg, A., Ehrencrona, H., Olopade, O. I., Simard, J., Easton, D. F., Chenevix-Trench, G., Offit, K., Couch, F. J., Antoniou, A. C., Breast Canc Family Registry, EMBRACE Study, GEMO Study Collaborators, HEBON, KConFab Investigators, CIMBA 2014; 16: 3416

  Abstract

  More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers.We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement.The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement.Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.

  View details for DOI 10.1186/s13058-014-0492-9

  View details for Web of Science ID 000209772500001

  View details for PubMedID 25919761

  View details for PubMedCentralID PMC4406179

• Diet and lifestyle factors modify immune/inflammation response genes to alter breast cancer risk and prognosis: The Breast Cancer Health Disparities Study MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS Slattery, M. L., Lundgreen, A., Torres-Mejia, G., Wolff, R. K., Hines, L., Baumgartner, K., John, E. M. 2014; 770: 19-28

  Abstract

  Tumor necrosis factor-α (TNF) and toll-like receptors (TLR) are important mediators of inflammation. We examined 10 of these genes with respect to breast cancer risk and mortality in a genetically admixed population of Hispanic/Native American (NA) (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1585 controls) women. Additionally, we explored if diet and lifestyle factors modified associations with these genes. Overall, these genes (collectively) were associated with breast cancer risk among women with >70% NA ancestry (P(ARTP) = 0.0008), with TLR1 rs7696175 being the primary risk contributor (OR 1.77, 95% CI 1.25, 2.51). Overall, TLR1 rs7696175 (HR 1.40, 95% CI 1.03, 1.91; P(adj) = 0.032), TLR4 rs5030728 (HR 1.96, 95% CI 1.30, 2.95; P(adj) = 0.014), and TNFRSF1A rs4149578 (HR 2.71, 95% CI 1.28, 5.76; P(adj) = 0.029) were associated with increased breast cancer mortality. We observed several statistically significant interactions after adjustment for multiple comparisons, including interactions between our dietary oxidative balance score and CD40LG and TNFSF1A; between cigarette smoking and TLR1, TLR4, and TNF; between body mass index (BMI) among pre-menopausal women and TRAF2; and between regular use of aspirin/non-steroidal anti-inflammatory drugs and TLR3 and TRA2. In conclusion, our findings support a contributing role of certain TNF-α and TLR genes in both breast cancer risk and survival, particularly among women with higher NA ancestry. Diet and lifestyle factors appear to be important mediators of the breast cancer risk associated with these genes.

  View details for DOI 10.1016/j.mrfmmm.2014.08.009

  View details for Web of Science ID 000345647400003

  View details for PubMedCentralID PMC4201121

• Tobacco smoking, polymorphisms in carcinogen metabolism enzyme genes, and risk of localized and advanced prostate cancer: results from the California Collaborative Prostate Cancer Study CANCER MEDICINE Shahabi, A., Corral, R., Catsburg, C., Joshi, A. D., Kim, A., Lewinger, J. P., Koo, J., John, E. M., Ingles, S. A., Stern, M. C. 2014; 3 (6): 1644-1655

  Abstract

  The relationship between tobacco smoking and prostate cancer (PCa) remains inconclusive. This study examined the association between tobacco smoking and PCa risk taking into account polymorphisms in carcinogen metabolism enzyme genes as possible effect modifiers (9 polymorphisms and 1 predicted phenotype from metabolism enzyme genes). The study included cases (n = 761 localized; n = 1199 advanced) and controls (n = 1139) from the multiethnic California Collaborative Case-Control Study of Prostate Cancer. Multivariable conditional logistic regression was performed to evaluate the association between tobacco smoking variables and risk of localized and advanced PCa risk. Being a former smoker, regardless of time of quit smoking, was associated with an increased risk of localized PCa (odds ratio [OR] = 1.3; 95% confidence interval [CI] = 1.0-1.6). Among non-Hispanic Whites, ever smoking was associated with an increased risk of localized PCa (OR = 1.5; 95% CI = 1.1-2.1), whereas current smoking was associated with risk of advanced PCa (OR = 1.4; 95% CI = 1.0-1.9). However, no associations were observed between smoking intensity, duration or pack-year variables, and advanced PCa. No statistically significant trends were seen among Hispanics or African-Americans. The relationship between smoking status and PCa risk was modified by the CYP1A2 rs7662551 polymorphism (P-interaction = 0.008). In conclusion, tobacco smoking was associated with risk of PCa, primarily localized disease among non-Hispanic Whites. This association was modified by a genetic variant in CYP1A2, thus supporting a role for tobacco carcinogens in PCa risk.

  View details for DOI 10.1002/cam4.334

  View details for Web of Science ID 000348226000020

  View details for PubMedID 25355624

  View details for PubMedCentralID PMC4298391

• Associations between CYP19A1 polymorphisms, Native American ancestry, and breast cancer risk and mortality: the Breast Cancer Health Disparities Study CANCER CAUSES & CONTROL Boone, S. D., Baumgartner, K. B., Baumgartner, R. N., Connor, A. E., Pinkston, C. M., Rai, S. N., Riley, E. C., Hines, L. M., Giuliano, A. R., John, E. M., Stern, M. C., Torres-Mejia, G., Wolff, R. K., Slattery, M. L. 2014; 25 (11): 1461-1471

  Abstract

  The cytochrome p450 family 19 gene (CYP19A1) encodes for aromatase, which catalyzes the final step in estrogen biosynthesis and conversion of androgens to estrogens. Genetic variation in CYP19A1 is linked to higher circulating estrogen levels and increased aromatase expression. Using data from the Breast Cancer Health Disparities Study, a consortium of three population-based case-control studies in the United States (n = 3,030 non-Hispanic Whites; n = 2,893 Hispanic/Native Americans (H/NA) and Mexico (n = 1,810), we examined influence of 25 CYP19A1 tagging single-nucleotide polymorphisms (SNPs) on breast cancer risk and mortality, considering NA ancestry. Odds ratios (ORs) and 95 % confidence intervals (CIs) and hazard ratios estimated breast cancer risk and mortality. After multiple comparison adjustment, none of the SNPs were significantly associated with breast cancer risk or mortality. Two SNPs remained significantly associated with increased breast cancer risk in women of moderate to high NA ancestry (≥29 %): rs700518, ORGG 1.36, 95 % CI 1.11-1.67 and rs11856927, ORGG 1.35, 95 % CI 1.05-1.72. A significant interaction was observed for rs2470144 and menopausal status (p adj = 0.03); risk was increased in postmenopausal (ORAA 1.22, 95 % CI 1.05-1.14), but not premenopausal (ORAA 0.78, 95 % CI 0.64-0.95) women. The absence of an overall association with CYP19A1 and breast cancer risk is similar to previous literature. However, this analysis provides support that variation in CYP19A1 may influence breast cancer risk differently in women with moderate to high NA ancestry. Additional research is warranted to investigate the how variation in an estrogen-regulating gene contributes to racial/ethnic disparities in breast cancer.

  View details for DOI 10.1007/s10552-014-0448-5

  View details for Web of Science ID 000344532000004

  View details for PubMedCentralID PMC4435673

• Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25. Nature communications Fejerman, L., Ahmadiyeh, N., Hu, D., Huntsman, S., Beckman, K. B., Caswell, J. L., Tsung, K., John, E. M., Torres-Mejia, G., Carvajal-Carmona, L., Echeverry, M. M., Tuazon, A. M., Ramirez, C., Gignoux, C. R., Eng, C., Gonzalez-Burchard, E., Henderson, B., Le Marchand, L., Kooperberg, C., Hou, L., Agalliu, I., Kraft, P., Lindström, S., Perez-Stable, E. J., Haiman, C. A., Ziv, E. 2014; 5: 5260

  Abstract

  The genetic contributions to breast cancer development among Latinas are not well understood. Here we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5' of the Estrogen Receptor 1 gene (ESR1; 6q25 region). The minor allele for this variant is strongly protective (rs140068132: odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53-0.67, P=9 × 10(-18)), originates from Indigenous Americans and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21-0.54) than oestrogen receptor-positive disease (OR 0.63, 95% CI 0.49-0.80; P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor-binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations.

  View details for DOI 10.1038/ncomms6260

  View details for PubMedID 25327703

  View details for PubMedCentralID PMC4204111

• A comprehensive examination of breast cancer risk loci in African American women HUMAN MOLECULAR GENETICS Feng, Y., Stram, D. O., Rhie, S. K., Millikan, R. C., Ambrosone, C. B., John, E. M., Bernstein, L., Zheng, W., Olshan, A. F., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Palmer, J. R., Olopade, O. I., Huo, D., Adebamowo, C. A., Ogundiran, T., Chen, G. K., Stram, A., Park, K., Rand, K. A., Chanock, S. J., Le Marchand, L., Kolonel, L. N., Conti, D. V., Easton, D., Henderson, B. E., Haiman, C. A. 2014; 23 (20): 5518-5526

  Abstract

  Genome-wide association studies have identified 73 breast cancer risk variants mainly in European populations. Given considerable differences in linkage disequilibrium structure between populations of European and African ancestry, the known risk variants may not be informative for risk in African ancestry populations. In a previous fine-mapping investigation of 19 breast cancer loci, we were able to identify SNPs in four regions that better captured risk associations in African American women. In this study of breast cancer in African American women (3016 cases, 2745 controls), we tested an additional 54 novel breast cancer risk variants. Thirty-eight variants (70%) were found to have an association with breast cancer in the same direction as previously reported, with eight (15%) replicating at P < 0.05. Through fine-mapping, in three regions (1q32, 3p24, 10q25), we identified variants that better captured associations with overall breast cancer or estrogen receptor positive disease. We also observed suggestive associations with variants (at P < 5 × 10(-6)) in three separate regions (6q25, 14q13, 22q12) that may represent novel risk variants. Directional consistency of association observed for ∼65-70% of currently known genetic variants for breast cancer in women of African ancestry implies a shared functional common variant at most loci. To validate and enhance the spectrum of alleles that define associations at the known breast cancer risk loci, as well as genome-wide, will require even larger collaborative efforts in women of African ancestry.

  View details for DOI 10.1093/hmg/ddu252

  View details for Web of Science ID 000343202400018

  View details for PubMedCentralID PMC4168823

• A comprehensive examination of breast cancer risk loci in African American women. Human molecular genetics Feng, Y., Stram, D. O., Rhie, S. K., Millikan, R. C., Ambrosone, C. B., John, E. M., Bernstein, L., Zheng, W., Olshan, A. F., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Palmer, J. R., Olopade, O. I., Huo, D., Adebamowo, C. A., Ogundiran, T., Chen, G. K., Stram, A., Park, K., Rand, K. A., Chanock, S. J., Le Marchand, L., Kolonel, L. N., Conti, D. V., Easton, D., Henderson, B. E., Haiman, C. A. 2014; 23 (20): 5518-26

  Abstract

  Genome-wide association studies have identified 73 breast cancer risk variants mainly in European populations. Given considerable differences in linkage disequilibrium structure between populations of European and African ancestry, the known risk variants may not be informative for risk in African ancestry populations. In a previous fine-mapping investigation of 19 breast cancer loci, we were able to identify SNPs in four regions that better captured risk associations in African American women. In this study of breast cancer in African American women (3016 cases, 2745 controls), we tested an additional 54 novel breast cancer risk variants. Thirty-eight variants (70%) were found to have an association with breast cancer in the same direction as previously reported, with eight (15%) replicating at P < 0.05. Through fine-mapping, in three regions (1q32, 3p24, 10q25), we identified variants that better captured associations with overall breast cancer or estrogen receptor positive disease. We also observed suggestive associations with variants (at P < 5 × 10(-6)) in three separate regions (6q25, 14q13, 22q12) that may represent novel risk variants. Directional consistency of association observed for ∼65-70% of currently known genetic variants for breast cancer in women of African ancestry implies a shared functional common variant at most loci. To validate and enhance the spectrum of alleles that define associations at the known breast cancer risk loci, as well as genome-wide, will require even larger collaborative efforts in women of African ancestry.

  View details for DOI 10.1093/hmg/ddu252

  View details for PubMedID 24852375

  View details for PubMedCentralID PMC4168823

• Genome-wide Scan of 29,141 African Americans Finds No Evidence of Directional Selection since Admixture AMERICAN JOURNAL OF HUMAN GENETICS Bhatia, G., Tandon, A., Patterson, N., Aldrich, M. C., Ambrosone, C. B., Amos, C., Bandera, E. V., Berndt, S. I., Bernstein, L., Blot, W. J., Bock, C. H., Caporaso, N., Casey, G., Deming, S. L., Diver, W. R., Gapstur, S. M., Gillanders, E. M., Harris, C. C., Henderson, B. E., Ingles, S. A., Isaacs, W., De Jager, P. L., John, E. M., Kittles, R. A., Larkin, E., McNeill, L. H., Millikan, R. C., Murphy, A., Neslund-Dudas, C., Nyante, S., Press, M. F., Rodriguez-Gil, J. L., Rybicki, B. A., Schwartz, A. G., Signorello, L. B., Spitz, M., Strom, S. S., Tucker, M. A., Wiencke, J. K., Witte, J. S., Wu, X., Yamamura, Y., Zanetti, K. A., Zheng, W., Ziegler, R. G., Chanock, S. J., Haiman, C. A., Reich, D., Price, A. L. 2014; 95 (4): 437-444

  Abstract

  The extent of recent selection in admixed populations is currently an unresolved question. We scanned the genomes of 29,141 African Americans and failed to find any genome-wide-significant deviations in local ancestry, indicating no evidence of selection influencing ancestry after admixture. A recent analysis of data from 1,890 African Americans reported that there was evidence of selection in African Americans after their ancestors left Africa, both before and after admixture. Selection after admixture was reported on the basis of deviations in local ancestry, and selection before admixture was reported on the basis of allele-frequency differences between African Americans and African populations. The local-ancestry deviations reported by the previous study did not replicate in our very large sample, and we show that such deviations were expected purely by chance, given the number of hypotheses tested. We further show that the previous study's conclusion of selection in African Americans before admixture is also subject to doubt. This is because the FST statistics they used were inflated and because true signals of unusual allele-frequency differences between African Americans and African populations would be best explained by selection that occurred in Africa prior to migration to the Americas.

  View details for DOI 10.1016/j.ajhg.2014.08.011

  View details for Web of Science ID 000342654300008

  View details for PubMedCentralID PMC4185117

• Genome-wide scan of 29,141 African Americans finds no evidence of directional selection since admixture. American journal of human genetics Bhatia, G., Tandon, A., Patterson, N., Aldrich, M. C., Ambrosone, C. B., Amos, C., Bandera, E. V., Berndt, S. I., Bernstein, L., Blot, W. J., Bock, C. H., Caporaso, N., Casey, G., Deming, S. L., Diver, W. R., Gapstur, S. M., Gillanders, E. M., Harris, C. C., Henderson, B. E., Ingles, S. A., Isaacs, W., De Jager, P. L., John, E. M., Kittles, R. A., Larkin, E., McNeill, L. H., Millikan, R. C., Murphy, A., Neslund-Dudas, C., Nyante, S., Press, M. F., Rodriguez-Gil, J. L., Rybicki, B. A., Schwartz, A. G., Signorello, L. B., Spitz, M., Strom, S. S., Tucker, M. A., Wiencke, J. K., Witte, J. S., Wu, X., Yamamura, Y., Zanetti, K. A., Zheng, W., Ziegler, R. G., Chanock, S. J., Haiman, C. A., Reich, D., Price, A. L. 2014; 95 (4): 437-44

  Abstract

  The extent of recent selection in admixed populations is currently an unresolved question. We scanned the genomes of 29,141 African Americans and failed to find any genome-wide-significant deviations in local ancestry, indicating no evidence of selection influencing ancestry after admixture. A recent analysis of data from 1,890 African Americans reported that there was evidence of selection in African Americans after their ancestors left Africa, both before and after admixture. Selection after admixture was reported on the basis of deviations in local ancestry, and selection before admixture was reported on the basis of allele-frequency differences between African Americans and African populations. The local-ancestry deviations reported by the previous study did not replicate in our very large sample, and we show that such deviations were expected purely by chance, given the number of hypotheses tested. We further show that the previous study's conclusion of selection in African Americans before admixture is also subject to doubt. This is because the FST statistics they used were inflated and because true signals of unusual allele-frequency differences between African Americans and African populations would be best explained by selection that occurred in Africa prior to migration to the Americas.

  View details for DOI 10.1016/j.ajhg.2014.08.011

  View details for PubMedID 25242497

  View details for PubMedCentralID PMC4185117

• Neighborhood influences on recreational physical activity and survival after breast cancer CANCER CAUSES & CONTROL Keegan, T. H., Shariff-Marco, S., Sangaramoorthy, M., Koo, J., Hertz, A., Schupp, C. W., Yang, J., John, E. M., Gomez, S. L. 2014; 25 (10): 1295-1308

  Abstract

  Higher levels of physical activity have been associated with improved survival after breast cancer diagnosis. However, no previous studies have considered the influence of the social and built environment on physical activity and survival among breast cancer patients.Our study included 4,345 women diagnosed with breast cancer (1995-2008) from two population-based studies conducted in the San Francisco Bay Area. We examined questionnaire-based moderate/strenuous recreational physical activity during the 3 years before diagnosis. Neighborhood characteristics were based on data from the 2000 US Census, business listings, parks, farmers' markets, and Department of Transportation. Survival was evaluated using multivariable Cox proportional hazards models, with follow-up through 2009.Women residing in neighborhoods with no fast-food restaurants (vs. fewer fast-food restaurants) to other restaurants, high traffic density, and a high percentage of foreign-born residents were less likely to meet physical activity recommendations set by the American Cancer Society. Women who were not recreationally physically active had a 22% higher risk of death from any cause than women that were the most active. Poorer overall survival was associated with lower neighborhood socioeconomic status (SES) (p(trend) = 0.02), whereas better breast cancer-specific survival was associated with a lack of parks, especially among women in high-SES neighborhoods.Certain aspects of the neighborhood have independent associations with recreational physical activity among breast cancer patients and their survival. Considering neighborhood factors may aide in the design of more effective, tailored physical activity programs for breast cancer survivors.

  View details for DOI 10.1007/s10552-014-0431-1

  View details for Web of Science ID 000343718900006

  View details for PubMedCentralID PMC4194215

• A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nature genetics Al Olama, A. A., Kote-Jarai, Z., Berndt, S. I., Conti, D. V., Schumacher, F., Han, Y., Benlloch, S., Hazelett, D. J., Wang, Z., Saunders, E., Leongamornlert, D., Lindstrom, S., Jugurnauth-Little, S., Dadaev, T., Tymrakiewicz, M., Stram, D. O., Rand, K., Wan, P., Stram, A., Sheng, X., Pooler, L. C., Park, K., Xia, L., Tyrer, J., Kolonel, L. N., Le Marchand, L., Hoover, R. N., Machiela, M. J., Yeager, M., Burdette, L., Chung, C. C., Hutchinson, A., Yu, K., Goh, C., Ahmed, M., Govindasami, K., Guy, M., Tammela, T. L., Auvinen, A., Wahlfors, T., Schleutker, J., Visakorpi, T., Leinonen, K. A., Xu, J., Aly, M., Donovan, J., Travis, R. C., Key, T. J., Siddiq, A., Canzian, F., Khaw, K., Takahashi, A., Kubo, M., Pharoah, P., Pashayan, N., Weischer, M., Nordestgaard, B. G., Nielsen, S. F., Klarskov, P., Røder, M. A., Iversen, P., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., Stanford, J. L., Kolb, S., Holt, S., Knudsen, B., Coll, A. H., Gapstur, S. M., Diver, W. R., Stevens, V. L., Maier, C., Luedeke, M., Herkommer, K., Rinckleb, A. E., Strom, S. S., Pettaway, C., Yeboah, E. D., Tettey, Y., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Chokkalingam, A. P., Cannon-Albright, L., Cybulski, C., Wokolorczyk, D., Kluzniak, W., Park, J., Sellers, T., Lin, H., Isaacs, W. B., Partin, A. W., Brenner, H., Dieffenbach, A. K., Stegmaier, C., Chen, C., Giovannucci, E. L., Ma, J., Stampfer, M., Penney, K. L., Mucci, L., John, E. M., Ingles, S. A., Kittles, R. A., Murphy, A. B., Pandha, H., Michael, A., Kierzek, A. M., Blot, W., Signorello, L. B., Zheng, W., Albanes, D., Virtamo, J., Weinstein, S., Nemesure, B., Carpten, J., Leske, C., Wu, S., Hennis, A., Kibel, A. S., Rybicki, B. A., Neslund-Dudas, C., Hsing, A. W., Chu, L., Goodman, P. J., Klein, E. A., Zheng, S. L., Batra, J., Clements, J., Spurdle, A., Teixeira, M. R., Paulo, P., Maia, S., Slavov, C., Kaneva, R., Mitev, V., Witte, J. S., Casey, G., Gillanders, E. M., Seminara, D., Riboli, E., Hamdy, F. C., Coetzee, G. A., Li, Q., Freedman, M. L., Hunter, D. J., Muir, K., Gronberg, H., Neal, D. E., Southey, M., Giles, G. G., Severi, G., Cook, M. B., Nakagawa, H., Wiklund, F., Kraft, P., Chanock, S. J., Henderson, B. E., Easton, D. F., Eeles, R. A., Haiman, C. A. 2014; 46 (10): 1103-1109

  Abstract

  Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

  View details for DOI 10.1038/ng.3094

  View details for PubMedID 25217961

• Neighborhood influences on recreational physical activity and survival after breast cancer. Cancer causes & control Keegan, T. H., Shariff-Marco, S., Sangaramoorthy, M., Koo, J., Hertz, A., Schupp, C. W., Yang, J., John, E. M., Gomez, S. L. 2014; 25 (10): 1295-1308

  Abstract

  Higher levels of physical activity have been associated with improved survival after breast cancer diagnosis. However, no previous studies have considered the influence of the social and built environment on physical activity and survival among breast cancer patients.Our study included 4,345 women diagnosed with breast cancer (1995-2008) from two population-based studies conducted in the San Francisco Bay Area. We examined questionnaire-based moderate/strenuous recreational physical activity during the 3 years before diagnosis. Neighborhood characteristics were based on data from the 2000 US Census, business listings, parks, farmers' markets, and Department of Transportation. Survival was evaluated using multivariable Cox proportional hazards models, with follow-up through 2009.Women residing in neighborhoods with no fast-food restaurants (vs. fewer fast-food restaurants) to other restaurants, high traffic density, and a high percentage of foreign-born residents were less likely to meet physical activity recommendations set by the American Cancer Society. Women who were not recreationally physically active had a 22% higher risk of death from any cause than women that were the most active. Poorer overall survival was associated with lower neighborhood socioeconomic status (SES) (p(trend) = 0.02), whereas better breast cancer-specific survival was associated with a lack of parks, especially among women in high-SES neighborhoods.Certain aspects of the neighborhood have independent associations with recreational physical activity among breast cancer patients and their survival. Considering neighborhood factors may aide in the design of more effective, tailored physical activity programs for breast cancer survivors.

  View details for DOI 10.1007/s10552-014-0431-1

  View details for PubMedID 25088804

  View details for PubMedCentralID PMC4194215

• A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer NATURE GENETICS Al Olama, A. A., Kote-Jarai, Z., Berndt, S. I., Conti, D. V., Schumacher, F., Han, Y., Benlloch, S., Hazelett, D. J., Wang, Z., Saunders, E., Leongamornlert, D., Lindstrom, S., Jugurnauth-Little, S., Dadaev, T., Tymrakiewicz, M., Stram, D. O., Rand, K., Wan, P., Stram, A., Sheng, X., Pooler, L. C., Park, K., Xia, L., Tyrer, J., Kolonel, L. N., Le Marchand, L., Hoover, R. N., Machiela, M. J., Yeager, M., Burdette, L., Chung, C. C., Hutchinson, A., Yu, K., Goh, C., Ahmed, M., Govindasami, K., Guy, M., Tammela, T. L., Auvinen, A., Wahlfors, T., Schleutker, J., Visakorpi, T., Leinonen, K. A., Xu, J., Aly, M., Donovan, J., Travis, R. C., Key, T. J., Siddiq, A., Canzian, F., Khaw, K., Takahashi, A., Kubo, M., Pharoah, P., Pashayan, N., Weischer, M., Nordestgaard, B. G., Nielsen, S. F., Klarskov, P., Roder, M. A., Iversen, P., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., Stanford, J. L., Kolb, S., Holt, S., Knudsen, B., Coll, A. H., Gapstur, S. M., Diver, W. R., Stevens, V. L., Maier, C., Luedeke, M., Herkommer, K., Rinckleb, A. E., Strom, S. S., Pettaway, C., Yeboah, E. D., Tettey, Y., Biritwum, R. B., Adjei, A. A., Tay, E., Truelove, A., Niwa, S., Choklcalingam, A. P., Cannon-Albright, L., Cybulski, C., Wokolorczyk, D., Kluzniak, W., Park, J., Sellers, T., Lin, H., Isaacs, W. B., Partin, A. W., Brenner, H., Dieffenbach, A. K., Stegmaier, C., Chen, C., Giovannucci, E. L., Ma, J., Stampfer, M., Penney, K. L., Mucci, L., John, E. M., Ingles, S. A., Kittles, R. A., Murphy, A. B., Pandha, H., Michael, A., Kierzek, A. M., Blot, W., Signorello, L. B., Zheng, W., Albanes, D., Virtamo, J., Weinstein, S., Nemesure, B., Carpten, J., Leske, C., Wu, S., Hennis, A., Kibel, A. S., Rybicki, B. A., Neslund-Dudas, C., Hsing, A. W., Chu, L., Goodman, P. J., Klein, E. A., Zheng, S. L., Batra, J., Clements, J., Spurdle, A., Teixeira, M. R., Paulo, P., Maia, S., Slavov, C., Kaneva, R., Mitev, V., Witte, J. S., Casey, G., Gillanders, E. M., Seminara, D., Riboli, E., Hamdy, F. C., Coetzee, G. A., Li, Q., Freedman, M. L., Hunter, D. J., Muir, K., Gronberg, H., Nea, D. E., Southey, M., Giles, G. G., Severi, G., Cook, M. B., Nakagawa, H., Wiklund, F., Kraft, P., Chanock, S. J., Henderson, B. E., Easton, D. F., Eeles, R. A., Haiman, C. A. 2014; 46 (10): 1103-1109

  Abstract

  Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

  View details for DOI 10.1038/ng.3094

  View details for Web of Science ID 000342554100013

• Genome wide association study of breast cancer in Latinas identifies protective variants of Indigenous American origin on 6q25 Fejerman, L., Ahmadiyeh, N., Hu, D., Huntsman, S., Beckman, K., Caswell, J., John, E. M., Torres-Mejia, G., Carvajal-Carmona, L., Echeverry, M., Tuazon, A., Ramirez, C., Gignoux, C., Eng, C., Gonzalez-Burchard, E., Henderson, B., Marchand, L. L., Perez-Stable, E. J., Haiman, C. A., Ziv, E., COLUMBUS Consortium AMER ASSOC CANCER RESEARCH. 2014

  View details for DOI 10.1158/1538-7445.AM2014-LB-299

  View details for Web of Science ID 000349910205332

• Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25 NATURE COMMUNICATIONS Fejerman, L., Ahmadiyeh, N., Hu, D., Huntsman, S., Beckman, K. B., Caswell, J. L., Tsung, K., John, E. M., Torres-Mejia, G., Carvajal-Carmona, L., Echeverry, M. M., Tuazon, A. M., Ramirez, C., Gignoux, C. R., Eng, C., Gonzalez-Burchard, E., Henderson, B., Le Marchand, L., Kooperberg, C., Hou, L., Agalliu, I., Kraft, P., Lindstroem, S., Perez-Stable, E. J., Haiman, C. A., Ziv, E. 2014; 5

  Abstract

  The genetic contributions to breast cancer development among Latinas are not well understood. Here we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5' of the Estrogen Receptor 1 gene (ESR1; 6q25 region). The minor allele for this variant is strongly protective (rs140068132: odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53-0.67, P=9 × 10(-18)), originates from Indigenous Americans and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21-0.54) than oestrogen receptor-positive disease (OR 0.63, 95% CI 0.49-0.80; P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor-binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations.

  View details for DOI 10.1038/ncomms6260

  View details for Web of Science ID 000343985400009

  View details for PubMedCentralID PMC4204111

• Human subjects protection: an event monitoring committee for research studies of girls from breast cancer families. journal of adolescent health Harris, D., Patrick-Miller, L., Schwartz, L., Lantos, J., Daugherty, C., Daly, M., Andrulis, I. L., Buys, S. S., Chung, W. K., Frost, C. J., John, E. M., Keegan, T. H., Knight, J. A., Terry, M. B., Bradbury, A. R. 2014; 55 (3): 352-357

  Abstract

  Researchers must monitor the safety of research participants, particularly in studies involving children and adolescents. Yet, there is limited guidance for the development and implementation of oversight committees for psychosocial, behavioral intervention, and observational studies.We implemented a model for an Event Monitoring Committee (EMC) in three related studies recruiting 6- to 19-year-old girls from families with and without breast cancer.The EMC model can be valuable for investigators and local institutional review boards when additional oversight is desired. Recommendations are provided and intended to be broadly applicable to a wide range of research activities designed to improve the health of children, adolescents, and families. EMC goals, membership, and procedures for monitoring and assessing risks and benefits should be defined but should also be flexible and tailored to the study design and population. The EMC model also provides an independent comprehensive, study-wide oversight mechanism for multicenter psychosocial, behavioral intervention, and observational studies.An EMC provides an alternative oversight approach where additional independent assessment and oversight of study-related risks are desired, particularly in the setting of vulnerable populations, children and adolescents, or where risks nontraditional to the medical field (i.e., social, emotional, or cultural) are possible.

  View details for DOI 10.1016/j.jadohealth.2014.03.007

  View details for PubMedID 24845866

• Diet and lifestyle factors interact with MAPK genes to influence survival: the Breast Cancer Health Disparities Study CANCER CAUSES & CONTROL Slattery, M. L., Hines, L. H., Lundgreen, A., Baumgartner, K. B., Wolff, R. K., Stern, M. C., John, E. M. 2014; 25 (9): 1211-1225

  Abstract

  MAPK genes are activated by a variety of factors related to growth factors, hormones, and environmental stress.We evaluated associations between 13 MAPK genes and survival among 1,187 nonHispanic White and 1,155 Hispanic/Native American (NA) women diagnosed with breast cancer. We assessed the influence of diet, lifestyle, and genetic ancestry on these associations. Percent NA ancestry was determined from 104 Ancestry Informative Markers. Adaptive rank truncation product (ARTP) was used to determine gene and pathway significance.Associations were predominantly observed among women with lower NA ancestry. Specifically, the mitogen-activated protein kinases (MAPK) pathway was associated with all-cause mortality (P ARTP = 0.02), but not with breast cancer-specific mortality (P ARTP = 0.10). However, MAP2K1 and MAP3K9 were associated with both breast cancer-specific and all-cause mortality. MAPK12 (P ARTP = 0.05) was only associated with breast cancer-specific mortality, and MAP3K1 (P ARTP = 0.02) and MAPK1 (P ARTP = 0.05) were only associated with all-cause mortality. Among women with higher NA ancestry, MAP3K2 was significantly associated with all-cause mortality (P ARTP = 0.04). Several diet and lifestyle factors, including alcohol consumption, caloric intake, dietary folate, and cigarette smoking, significantly modified the associations with MAPK genes and all-cause mortality.Our study supports an association between MAPK genes and survival after diagnosis with breast cancer, especially among women with low NA ancestry. The interaction between genetic variation in the MAPK pathway with diet and lifestyle factors for all women supports the important role of these factors for breast cancer survivorship.

  View details for DOI 10.1007/s10552-014-0426-y

  View details for Web of Science ID 000341784400013

  View details for PubMedID 24993294

  View details for PubMedCentralID PMC4156917

• Genetic variation in the JAK/STAT/SOCS signaling pathway influences breast cancer-specific mortality through interaction with cigarette smoking and use of aspirin/NSAIDs: the Breast Cancer Health Disparities Study BREAST CANCER RESEARCH AND TREATMENT Slattery, M. L., Lundgreen, A., Hines, L. M., Torres-Mejia, G., Wolff, R. K., Stern, M. C., John, E. M. 2014; 147 (1): 145-158

  Abstract

  The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is involved in immune function and cell growth; genetic variation in this pathway could influence breast cancer risk. We examined 12 genes in the JAK/STAT/SOCS signaling pathway with breast cancer risk and mortality in an admixed population of Hispanic (2,111 cases, 2,597 controls) and non-Hispanic white (1,481 cases, 1,585 controls) women. Associations were assessed by Indigenous American (IA) ancestry. After adjustment for multiple comparisons, JAK1 (three of ten SNPs) and JAK2 (4 of 11 SNPs) interacted with body mass index (BMI) among pre-menopausal women, while STAT3 (four of five SNPs) interacted significantly with BMI among post-menopausal women to alter breast cancer risk. STAT6 rs3024979 and TYK2 rs280519 altered breast cancer-specific mortality among all women. Associations with breast cancer-specific mortality differed by IA ancestry; SOCS1 rs193779, STAT3 rs1026916, and STAT4 rs11685878 associations were limited to women with low IA ancestry, and associations with JAK1 rs2780890, rs2254002, and rs310245 and STAT1 rs11887698 were observed among women with high IA ancestry. JAK2 (5 of 11 SNPs), SOCS2 (one of three SNPs), and STAT4 (2 of 20 SNPs) interacted with cigarette smoking status to alter breast cancer-specific mortality. SOCS2 (one of three SNPs) and all STAT3, STAT5A, and STAT5B SNPs significantly interacted with use of aspirin/NSAIDs to alter breast cancer-specific mortality. Genetic variation in the JAK/STAT/SOCS pathway was associated with breast cancer-specific mortality. The proportion of SNPs within a gene that significantly interacted with lifestyle factors lends support for the observed associations.

  View details for DOI 10.1007/s10549-014-3071-y

  View details for Web of Science ID 000340547800014

  View details for PubMedID 25104439

  View details for PubMedCentralID PMC4167366

• Genetic variants in interleukin genes are associated with breast cancer risk and survival in a genetically admixed population: the Breast Cancer Health Disparities Study. Carcinogenesis Slattery, M. L., Herrick, J. S., Torres-Mejia, G., John, E. M., Giuliano, A. R., Hines, L. M., Stern, M. C., Baumgartner, K. B., Presson, A. P., Wolff, R. K. 2014; 35 (8): 1750-1759

  Abstract

  Interleukins (ILs) are key regulators of immune response. Genetic variation in IL genes may influence breast cancer risk and mortality given their role in cell growth, angiogenesis and regulation of inflammatory process. We examined 16 IL genes with breast cancer risk and mortality in an admixed population of Hispanic/Native American (NA) (2111 cases and 2597 controls) and non-Hispanic white (NHW) (1481 cases and 1585 controls) women. Adaptive Rank Truncated Product (ARTP) analysis was conducted to determine gene significance and lasso (least absolute shrinkage and selection operator) was used to identify potential gene by gene and gene by lifestyle interactions. The pathway was statistically significant for breast cancer risk overall (P ARTP = 0.0006), for women with low NA ancestry (P ARTP = 0.01), for premenopausal women (P ARTP = 0.02), for estrogen receptor (ER)+/progesterone receptor (PR)+ tumors (P ARTP = 0.03) and ER-/PR- tumors (P ARTP = 0.02). Eight of the 16 genes evaluated were associated with breast cancer risk (IL1A, IL1B, IL1RN, IL2, IL2RA, IL4, IL6 and IL10); four genes were associated with breast cancer risk among women with low NA ancestry (IL1B, IL6, IL6R and IL10), two were associated with breast cancer risk among women with high NA ancestry (IL2 and IL2RA) and four genes were associated with premenopausal breast cancer risk (IL1A, IL1B, IL2 and IL3). IL4, IL6R, IL8 and IL17A were associated with breast cancer-specific mortality. We confirmed associations with several functional polymorphisms previously associated with breast cancer risk and provide support that their combined effect influences the carcinogenic process.

  View details for DOI 10.1093/carcin/bgu078

  View details for PubMedID 24670917

• Rare Mutations in RINT1 Predispose Carriers to Breast and Lynch Syndrome-Spectrum Cancers CANCER DISCOVERY Park, D. J., Tao, K., Le Calvez-Kelm, F., Tu Nguyen-Dumont, N. D., Robinot, N., Hammet, F., Odefrey, F., Tsimiklis, H., Teo, Z. L., Thingholm, L. B., Young, E. L., Voegele, C., Lonie, A., Pope, B. J., Roane, T. C., Bell, R., Hu, H., Shankaracharya, Huff, C. D., Ellis, J., Li, J., Makunin, I. V., John, E. M., Andrulis, I. L., Terry, M. B., Daly, M., Buys, S. S., Snyder, C., Lynch, H. T., Devilee, P., Giles, G. G., Hopper, J. L., Feng, B., Lesueur, F., Tavtigian, S. V., Southey, M. C., Goldgar, D. E. 2014; 4 (7): 804-815

  Abstract

  Approximately half of the familial aggregation of breast cancer remains unexplained. A multiple-case breast cancer family exome-sequencing study identified three likely pathogenic mutations in RINT1 (NM_021930.4) not present in public sequencing databases: RINT1 c.343C>T (p.Q115X), c.1132_1134del (p.M378del), and c.1207G>T (p.D403Y). On the basis of this finding, a population-based case-control mutation-screening study was conducted that identified 29 carriers of rare (minor allele frequency < 0.5%), likely pathogenic variants: 23 in 1,313 early-onset breast cancer cases and six in 1,123 frequency-matched controls [OR, 3.24; 95% confidence interval (CI), 1.29-8.17; P = 0.013]. RINT1 mutation screening of probands from 798 multiple-case breast cancer families identified four additional carriers of rare genetic variants. Analysis of the incidence of first primary cancers in families of women carrying RINT1 mutations estimated that carriers were at increased risk of Lynch syndrome-spectrum cancers [standardized incidence ratio (SIR), 3.35; 95% CI, 1.7-6.0; P = 0.005], particularly for relatives diagnosed with cancer under the age of 60 years (SIR, 10.9; 95% CI, 4.7-21; P = 0.0003).The work described in this study adds RINT1 to the growing list of genes in which rare sequence variants are associated with intermediate levels of breast cancer risk. Given that RINT1 is also associated with a spectrum of cancers with mismatch repair defects, these findings have clinical applications and raise interesting biological questions.

  View details for DOI 10.1158/2159-8290.CD-14-0212

  View details for Web of Science ID 000338708900026

  View details for PubMedID 25050558

• Correlation of DNA methylation levels in blood and saliva DNA in young girls of the LEGACY Girls study. Epigenetics Wu, H., Wang, Q., Chung, W. K., Andrulis, I. L., Daly, M. B., John, E. M., Keegan, T. H., Knight, J., Bradbury, A. R., Kappil, M. A., Gurvich, I., Santella, R. M., Terry, M. B. 2014; 9 (7): 929-933

  Abstract

  Many epidemiologic studies of environmental exposures and disease susceptibility measure DNA methylation in white blood cells (WBC). Some studies are also starting to use saliva DNA as it is usually more readily available in large epidemiologic studies. However, little is known about the correlation of methylation between WBC and saliva DNA. We examined DNA methylation in three repetitive elements, Sat2, Alu, and LINE-1, and in four CpG sites, including AHRR (cg23576855, cg05575921), cg05951221 at 2q37.1, and cg11924019 at CYP1A1, in 57 girls aged 6-15 years with blood and saliva collected on the same day. We measured all DNA methylation markers by bisulfite-pyrosequencing, except for Sat2 and Alu, which were measured by the MethyLight assay. Methylation levels measured in saliva DNA were lower than those in WBC DNA, with differences ranging from 2.8% for Alu to 14.1% for cg05575921. Methylation levels for the three repetitive elements measured in saliva DNA were all positively correlated with those in WBC DNA. However, there was a wide range in the Spearman correlations, with the smallest correlation found for Alu (0.24) and the strongest correlation found for LINE-1 (0.73). Spearman correlations for cg05575921, cg05951221, and cg11924019 were 0.33, 0.42, and 0.79, respectively. If these findings are replicated in larger studies, they suggest that, for selected methylation markers (e.g., LINE-1), methylation levels may be highly correlated between blood and saliva, while for others methylation markers, the levels may be more tissue specific. Thus, in studies that differ by DNA source, each interrogated site should be separately examined in order to evaluate the correlation in DNA methylation levels across DNA sources.

  View details for DOI 10.4161/epi.28902

  View details for PubMedID 24756002

• Correlation of DNA methylation levels in blood and saliva DNA in young girls of the LEGACY Girls study EPIGENETICS Wu, H., Wang, Q., Chung, W. K., Andrulis, I. L., Daly, M. B., John, E. M., Keegan, T. H., Knight, J., Bradbury, A. R., Kappil, M. A., Gurvich, I., Santella, R. M., Terry, M. B. 2014; 9 (7): 929-933

  Abstract

  Many epidemiologic studies of environmental exposures and disease susceptibility measure DNA methylation in white blood cells (WBC). Some studies are also starting to use saliva DNA as it is usually more readily available in large epidemiologic studies. However, little is known about the correlation of methylation between WBC and saliva DNA. We examined DNA methylation in three repetitive elements, Sat2, Alu, and LINE-1, and in four CpG sites, including AHRR (cg23576855, cg05575921), cg05951221 at 2q37.1, and cg11924019 at CYP1A1, in 57 girls aged 6-15 years with blood and saliva collected on the same day. We measured all DNA methylation markers by bisulfite-pyrosequencing, except for Sat2 and Alu, which were measured by the MethyLight assay. Methylation levels measured in saliva DNA were lower than those in WBC DNA, with differences ranging from 2.8% for Alu to 14.1% for cg05575921. Methylation levels for the three repetitive elements measured in saliva DNA were all positively correlated with those in WBC DNA. However, there was a wide range in the Spearman correlations, with the smallest correlation found for Alu (0.24) and the strongest correlation found for LINE-1 (0.73). Spearman correlations for cg05575921, cg05951221, and cg11924019 were 0.33, 0.42, and 0.79, respectively. If these findings are replicated in larger studies, they suggest that, for selected methylation markers (e.g., LINE-1), methylation levels may be highly correlated between blood and saliva, while for others methylation markers, the levels may be more tissue specific. Thus, in studies that differ by DNA source, each interrogated site should be separately examined in order to evaluate the correlation in DNA methylation levels across DNA sources.

  View details for DOI 10.4161/epi.28902

  View details for Web of Science ID 000338429500001

  View details for PubMedCentralID PMC4143407

• Meta-analysis of loci associated with age at natural menopause in African-American women HUMAN MOLECULAR GENETICS Chen, C. T., Liu, C., Chen, G. K., Andrews, J. S., Arnold, A. M., Dreyfus, J., Franceschini, N., Garcia, M. E., Kerr, K. F., Li, G., Lohman, K. K., Musani, S. K., Nalls, M. A., Raffel, L. J., Smith, J., Ambrosone, C. B., Bandera, E. V., Bernstein, L., Britton, A., Brzyski, R. G., Cappola, A., Carlson, C. S., Couper, D., Deming, S. L., Goodarzi, M. O., Heiss, G., John, E. M., Lu, X., Le Marchand, L., Marciante, K., McKnight, B., Millikan, R., Nock, N. L., Olshan, A. F., Press, M. F., Vaiyda, D., Woods, N. F., Taylor, H. A., Zhao, W., Zheng, W., Evans, M. K., Harris, T. B., Henderson, B. E., Kardia, S. L., Kooperberg, C., Liu, Y., Mosley, T. H., Psaty, B., Wellons, M., Windham, B. G., Zonderman, A. B., Cupples, L. A., Demerath, E. W., Haiman, C., Murabito, J. M., Rajkovic, A. 2014; 23 (12): 3327-3342

  Abstract

  Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA.

  View details for DOI 10.1093/hmg/ddu041

  View details for PubMedID 24493794

• Alcohol Consumption and Survival after a Breast Cancer Diagnosis: A Literature-Based Meta-analysis and Collaborative Analysis of Data for 29,239 Cases CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ali, A. G., Schmidt, M. K., Bolla, M. K., Wang, Q., Gago-Dominguez, M., Esteban Castelao, J., Carracedo, A., Munoz Garzon, V., Bojesen, S. E., Nordestgaard, B. G., Flyger, H., Chang-Claude, J., Vrieling, A., Rudolph, A., Seibold, P., Nevanlinna, H., Muranen, T. A., Aaltonen, K., Blomqvist, C., Matsuo, K., Ito, H., Iwata, H., Horio, A., John, E. M., Sherman, M., Lissowska, J., Figueroa, J., Garcia-Closas, M., Anton-Culver, H., Shah, M., Hopper, J. L., Trichopoulou, A., Bueno-de-Mesquita, B., Krogh, V., Weiderpass, E., Andersson, A., Clavel-Chapelon, F., Dossus, L., Fagherazzi, G., Peeters, P. H., Olsen, A., Wishart, G. C., Easton, D. F., Borgquist, S., Overvad, K., Barricarte, A., Gonzalez, C. A., Sanchez, M., Amiano, P., Riboli, E., Key, T., Pharoah, P. D. 2014; 23 (6): 934–45

  Abstract

  Evidence for an association of alcohol consumption with prognosis after a diagnosis of breast cancer has been inconsistent. We have reviewed and summarized the published evidence and evaluated the association using individual patient data from multiple case cohorts.A MEDLINE search to identify studies published up to January 2013 was performed. We combined published estimates of survival time for "moderate drinkers" versus nondrinkers. An analysis of individual participant data using Cox regression was carried out using data from 11 case cohorts.We identified 11 published studies suitable for inclusion in the meta-analysis. Moderate postdiagnosis alcohol consumption was not associated with overall survival [HR, 0.95; 95% confidence interval (CI), 0.85-1.05], but there was some evidence of better survival associated with prediagnosis consumption (HR, 0.80; 95% CI, 0.73-0.88). Individual data on alcohol consumption for 29,239 cases with 4,839 deaths were available from the 11 case cohorts, all of which had data on estrogen receptor (ER) status. For women with ER-positive disease, there was little evidence that pre- or postdiagnosis alcohol consumption is associated with breast cancer-specific mortality, with some evidence of a negative association with all-cause mortality. On the basis of a single study, moderate postdiagnosis alcohol intake was associated with a small reduction in breast cancer-specific mortality for women with ER-negative disease. There was no association with prediagnosis intake for women with ER-negative disease.There was little evidence that pre- or post-diagnosis alcohol consumption is associated with breast cancer-specific mortality for women with ER-positive disease. There was weak evidence that moderate post-diagnosis alcohol intake is associated with a small reduction in breast cancer-specific mortality in ER-negative disease.Considering the totality of the evidence, moderate postdiagnosis alcohol consumption is unlikely to have a major adverse effect on the survival of women with breast cancer.

  View details for DOI 10.1158/1055-9965.EPI-13-0901

  View details for Web of Science ID 000345270800005

  View details for PubMedID 24636975

  View details for PubMedCentralID PMC4542077

• Impact of Neighborhood and Individual Socioeconomic Status on Survival after Breast Cancer Varies by Race/Ethnicity: The Neighborhood and Breast Cancer Study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Shariff-Marco, S., Yang, J., John, E. M., Sangaramoorthy, M., Hertz, A., Koo, J., Nelson, D. O., Schupp, C. W., Shema, S. J., Cockburn, M., Satariano, W. A., Yen, I. H., Ponce, N. A., Winkleby, M., Keegan, T. H., Gomez, S. L. 2014; 23 (5): 793-811

  Abstract

  Research is limited on the independent and joint effects of individual- and neighborhood-level socioeconomic status (SES) on breast cancer survival across different racial/ethnic groups.We studied individual-level SES, measured by self-reported education, and a composite neighborhood SES (nSES) measure in females (1,068 non-Hispanic whites, 1,670 Hispanics, 993 African-Americans, and 674 Asian-Americans), ages 18 to 79 years and diagnosed 1995 to 2008, in the San Francisco Bay Area. We evaluated all-cause and breast cancer-specific survival using stage-stratified Cox proportional hazards models with cluster adjustment for census block groups.In models adjusting for education and nSES, lower nSES was associated with worse all-cause survival among African-Americans (P trend = 0.03), Hispanics (P trend = 0.01), and Asian-Americans (P trend = 0.01). Education was not associated with all-cause survival. For breast cancer-specific survival, lower nSES was associated with poorer survival only among Asian-Americans (P trend = 0.01). When nSES and education were jointly considered, women with low education and low nSES had 1.4 to 2.7 times worse all-cause survival than women with high education and high nSES across all races/ethnicities. Among African-Americans and Asian-Americans, women with high education and low nSES had 1.6 to 1.9 times worse survival, respectively. For breast cancer-specific survival, joint associations were found only among Asian-Americans with worse survival for those with low nSES regardless of education.Both neighborhood and individual SES are associated with survival after breast cancer diagnosis, but these relationships vary by race/ethnicity.A better understanding of the relative contributions and interactions of SES with other factors will inform targeted interventions toward reducing long-standing disparities in breast cancer survival.

  View details for DOI 10.1158/1055-9965.EPI-13-0924

  View details for PubMedID 24618999

• DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers. PLoS genetics Osorio, A., Milne, R. L., Kuchenbaecker, K., Vaclová, T., Pita, G., Alonso, R., Peterlongo, P., Blanco, I., de la Hoya, M., Duran, M., Díez, O., Ramón y Cajal, T., Konstantopoulou, I., Martínez-Bouzas, C., Andrés Conejero, R., Soucy, P., McGuffog, L., Barrowdale, D., Lee, A., Swe-Brca, Arver, B., Rantala, J., Loman, N., Ehrencrona, H., Olopade, O. I., Beattie, M. S., Domchek, S. M., Nathanson, K., Rebbeck, T. R., Arun, B. K., Karlan, B. Y., Walsh, C., Lester, J., John, E. M., Whittemore, A. S., Daly, M. B., Southey, M., Hopper, J., Terry, M. B., Buys, S. S., Janavicius, R., Dorfling, C. M., Van Rensburg, E. J., Steele, L., Neuhausen, S. L., Ding, Y. C., Hansen, T. v., Jønson, L., Ejlertsen, B., Gerdes, A., Infante, M., Herráez, B., Moreno, L. T., Weitzel, J. N., Herzog, J., Weeman, K., Manoukian, S., Peissel, B., Zaffaroni, D., Scuvera, G., Bonanni, B., Mariette, F., Volorio, S., Viel, A., Varesco, L., Papi, L., Ottini, L., Tibiletti, M. G., Radice, P., Yannoukakos, D., Garber, J., Ellis, S., Frost, D., Platte, R., Fineberg, E., Evans, G., Lalloo, F., Izatt, L., Eeles, R., Adlard, J., Davidson, R., Cole, T., Eccles, D., Cook, J., Hodgson, S., Brewer, C., Tischkowitz, M., Douglas, F., Porteous, M., Side, L., Walker, L., Morrison, P., Donaldson, A., Kennedy, J., Foo, C., Godwin, A. K., Schmutzler, R. K., Wappenschmidt, B., Rhiem, K., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Plendl, H. J., Niederacher, D., Sutter, C., Wang-Gohrke, S., Steinemann, D., Preisler-Adams, S., Kast, K., Varon-Mateeva, R., Gehrig, A., Stoppa-Lyonnet, D., Sinilnikova, O. M., Mazoyer, S., Damiola, F., Poppe, B., Claes, K., Piedmonte, M., Tucker, K., Backes, F., Rodríguez, G., Brewster, W., Wakeley, K., Rutherford, T., Caldés, T., Nevanlinna, H., Aittomäki, K., Rookus, M. A., van Os, T. A., van der Kolk, L., de Lange, J. L., Meijers-Heijboer, H. E., van der Hout, A. H., van Asperen, C. J., Gómez Garcia, E. B., Hoogerbrugge, N., Collée, J. M., van Deurzen, C. H., van der Luijt, R. B., Devilee, P., Hebon, Olah, E., Lázaro, C., Teulé, A., Menéndez, M., Jakubowska, A., Cybulski, C., Gronwald, J., Lubinski, J., Durda, K., Jaworska-Bieniek, K., Johannsson, O. T., Maugard, C., Montagna, M., Tognazzo, S., Teixeira, M. R., Healey, S., Investigators, K., Olswold, C., Guidugli, L., Lindor, N., Slager, S., Szabo, C. I., Vijai, J., Robson, M., Kauff, N., Zhang, L., Rau-Murthy, R., Fink-Retter, A., Singer, C. F., Rappaport, C., Geschwantler Kaulich, D., Pfeiler, G., Tea, M., Berger, A., Phelan, C. M., Greene, M. H., Mai, P. L., Lejbkowicz, F., Andrulis, I., Mulligan, A. M., Glendon, G., Toland, A. E., Bojesen, A., Pedersen, I. S., Sunde, L., Thomassen, M., Kruse, T. A., Jensen, U. B., friedman, e., Laitman, Y., Shimon, S. P., Simard, J., Easton, D. F., Offit, K., Couch, F. J., Chenevix-Trench, G., Antoniou, A. C., Benitez, J. 2014; 10 (4)

  Abstract

  Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.

  View details for DOI 10.1371/journal.pgen.1004256

  View details for PubMedID 24698998

• A Genome-wide Association Study of Early-Onset Breast Cancer Identifies PFKM as a Novel Breast Cancer Gene and Supports a Common Genetic Spectrum for Breast Cancer at Any Age. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Ahsan, H., Halpern, J., Kibriya, M. G., Pierce, B. L., Tong, L., Gamazon, E., McGuire, V., Felberg, A., Shi, J., Jasmine, F., Roy, S., Brutus, R., Argos, M., Melkonian, S., Chang-Claude, J., Andrulis, I., Hopper, J. L., John, E. M., Malone, K., Ursin, G., Gammon, M. D., Thomas, D. C., Seminara, D., Casey, G., Knight, J. A., Southey, M. C., Giles, G. G., Santella, R. M., Lee, E., Conti, D., Duggan, D., Gallinger, S., Haile, R., Jenkins, M., Lindor, N. M., Newcomb, P., Michailidou, K., Apicella, C., Park, D. J., Peto, J., Fletcher, O., dos Santos Silva, I., Lathrop, M., Hunter, D. J., Chanock, S. J., Meindl, A., Schmutzler, R. K., Müller-Myhsok, B., Lochmann, M., Beckmann, L., Hein, R., Makalic, E., Schmidt, D. F., Bui, Q. M., Stone, J., Flesch-Janys, D., Dahmen, N., Nevanlinna, H., Aittomäki, K., Blomqvist, C., Hall, P., Czene, K., Irwanto, A., Liu, J., Rahman, N., Turnbull, C., Dunning, A. M., Pharoah, P., Waisfisz, Q., Meijers-Heijboer, H., Uitterlinden, A. G., Rivadeneira, F., Nicolae, D., Easton, D. F., Cox, N. J., Whittemore, A. S. 2014; 23 (4): 658-669

  Abstract

  Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ≤ 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10(-8)) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10(-4)) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10(-6). In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer. Cancer Epidemiol Biomarkers Prev; 23(4); 658-69. ©2014 AACR.

  View details for DOI 10.1158/1055-9965.EPI-13-0340

  View details for PubMedID 24493630

• Heterogeneity of breast cancer subtypes and survival among Hispanic women with invasive breast cancer in California BREAST CANCER RESEARCH AND TREATMENT Banegas, M. P., Tao, L., Altekruse, S., Anderson, W. F., John, E. M., Clarke, C. A., Gomez, S. L. 2014; 144 (3): 625-634

  Abstract

  There are limited data regarding breast cancer subtypes among Hispanic women. The current study assessed the distribution and prognosis of molecular subtypes defined by joint expression of the hormone receptors (HR; estrogen and progesterone) and human epidermal growth factor receptor 2 (HER2). Using California Cancer Registry data, we identified Hispanic women diagnosed with invasive breast cancer from 2005 to 2010. Breast cancer subtypes were defined as HR+/HER2-, HR+/HER2+, HR-/HER2+, and HR-/HER2- (triple negative). We estimated breast cancer subtype frequencies and used polytomous logistic regression, Kaplan-Meier survival plots and Cox regression to examine differences in relation to demographic and clinical characteristics. Among 16,380 Hispanic women with breast cancer, HR+/HER- subtype was the most common (63 %), followed by triple negative (16 %), HR+/HER2+ (14 %), and HR-/HER2+ (8 %). Women in lower SES neighborhoods had greater risk of triple negative and HR-/HER2+ subtypes relative to HR+/HER2- (p < 0.05). Hispanic women with triple negative and HR-/HER2+ tumors experienced poorer survival than those with HR+/HER- tumors. Breast cancer-specific mortality increased with decreasing SES, relative to the highest SES quintile, from HR = 1.38 for quintile 4 to HR = 1.76 for quintile 1 (lowest SES level). Our findings indicate that Hispanic women residing in low SES neighborhoods had significantly increased risk of developing and dying from HR- than HR+ breast cancers. Similar patterns of subtype frequency and prognosis among California Hispanic women and studies of other racial/ethnic groups underscore the need to better understand the impact of SES on risk factor exposures that increase the risk of breast cancer subtypes with poor prognosis.

  View details for DOI 10.1007/s10549-014-2882-1

  View details for Web of Science ID 000333360700018

  View details for PubMedID 24658879

• Reproductive risk factors and oestrogen/progesterone receptor-negative breast cancer in the Breast Cancer Family Registry BRITISH JOURNAL OF CANCER Work, M. E., John, E. M., Andrulis, I. L., Knight, J. A., Liao, Y., Mulligan, A. M., Southey, M. C., Giles, G. G., Dite, G. S., Apicella, C., Hibshoosh, H., Hopper, J. L., Terry, M. B. 2014; 110 (5): 1367–77

  Abstract

  Oestrogen receptor (ER)- and progesterone receptor (PR)-negative (ER-PR-) breast cancer is associated with poorer prognosis compared with other breast cancer subtypes. High parity has been associated with an increased risk of ER-PR- cancer, but emerging evidence suggests that breastfeeding may reduce this risk. Whether this potential breastfeeding benefit extends to women at high risk of breast cancer remains critical to understand for prevention.Using population-based ascertained cases (n=4011) and controls (2997) from the Breast Cancer Family Registry, we examined reproductive risk factors in relation to ER and PR status.High parity (≥3 live births) without breastfeeding was positively associated only with ER-PR- tumours (odds ratio (OR)=1.57, 95% confidence interval (CI), 1.10-2.24); there was no association with parity in women who breastfed (OR=0.93, 95% CI 0.71-1.22). Across all race/ethnicities, associations for ER-PR- cancer were higher among women who did not breastfeed than among women who did. Oral contraceptive (OC) use before 1975 was associated with an increased risk of ER-PR- cancer only (OR=1.32, 95% CI 1.04-1.67). For women who began OC use in 1975 or later there was no increased risk.Our findings support that there are modifiable factors for ER-PR- breast cancer and that breastfeeding in particular may mitigate the increased risk of ER-PR- cancers seen from multiparity.

  View details for PubMedID 24548865

  View details for PubMedCentralID PMC3950851

• The influence of genetic ancestry and ethnicity on breast cancer survival associated with genetic variation in the TGF-ß-signaling pathway: The Breast Cancer Health Disparities Study. Cancer causes & control Slattery, M. L., Lundgreen, A., Stern, M. C., Hines, L., Wolff, R. K., Giuliano, A. R., Baumgartner, K. B., John, E. M. 2014; 25 (3): 293-307

  Abstract

  The TGF-β signaling pathway regulates cellular proliferation and differentiation. We evaluated genetic variation in this pathway, its association with breast cancer survival, and survival differences by genetic ancestry and self-reported ethnicity. The Breast Cancer Health Disparities Study includes participants from the 4-Corners Breast Cancer Study (n = 1,391 cases) and the San Francisco Bay Area Breast Cancer Study (n = 946 cases) who have been followed for survival. We evaluated 28 genes in the TGF-β signaling pathway using a tagSNP approach. Adaptive rank truncated product (ARTP) was used to test the gene and pathway significance by Native American (NA) ancestry and by self-reported ethnicity (non-Hispanic white (NHW) and Hispanic/NA). Genetic variation in the TGF-β signaling pathway was associated with overall breast cancer survival (P ARTP = 0.05), especially for women with low NA ancestry (P ARTP = 0.007) and NHW women (P ARTP = 0.006). BMP2, BMP4, RUNX1, and TGFBR3 were significantly associated with breast cancer survival overall (P ARTP = 0.04, 0.02, 0.002, and 0.04, respectively). Among women with low NA, ancestry associations were as follows: BMP4 (P ARTP = 0.007), BMP6 (P ARTP = 0.001), GDF10 (P ARTP = 0.05), RUNX1 (P ARTP = 0.002), SMAD1 (P ARTP = 0.05), and TGFBR2 (P ARTP = 0.02). A polygenic risk model showed that women with low NA ancestry and high numbers of at-risk alleles had twice the risk of dying from breast cancer as did women with high NA ancestry. Our data suggest that genetic variation in the TGF-β signaling pathway influences breast cancer survival. Associations were similar when the analyses were stratified by genetic ancestry or by self-reported ethnicity.

  View details for DOI 10.1007/s10552-013-0331-9

  View details for PubMedID 24337772

• Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer. PLoS genetics Saunders, E. J., Dadaev, T., Leongamornlert, D. A., Jugurnauth-Little, S., Tymrakiewicz, M., Wiklund, F., Al Olama, A. A., Benlloch, S., Neal, D. E., Hamdy, F. C., Donovan, J. L., Giles, G. G., Severi, G., Gronberg, H., Aly, M., Haiman, C. A., Schumacher, F., Henderson, B. E., Lindstrom, S., Kraft, P., Hunter, D. J., Gapstur, S., Chanock, S., Berndt, S. I., Albanes, D., Andriole, G., Schleutker, J., Weischer, M., Nordestgaard, B. G., Canzian, F., Campa, D., Riboli, E., Key, T. J., Travis, R. C., Ingles, S. A., John, E. M., Hayes, R. B., Pharoah, P., Khaw, K., Stanford, J. L., Ostrander, E. A., Signorello, L. B., Thibodeau, S. N., Schaid, D., Maier, C., Kibel, A. S., Cybulski, C., Cannon-Albright, L., Brenner, H., Park, J. Y., Kaneva, R., Batra, J., Clements, J. A., Teixeira, M. R., Xu, J., Mikropoulos, C., Goh, C., Govindasami, K., Guy, M., Wilkinson, R. A., Sawyer, E. J., Morgan, A., Easton, D. F., Muir, K., Eeles, R. A., Kote-Jarai, Z. 2014; 10 (2)

  Abstract

  The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

  View details for DOI 10.1371/journal.pgen.1004129

  View details for PubMedID 24550738

• Angiogenesis genes, dietary oxidative balance and breast cancer risk and progression: The Breast Cancer Health Disparities Study INTERNATIONAL JOURNAL OF CANCER Slattery, M. L., John, E. M., Torres-Mejia, G., Lundgreen, A., Lewinger, J. P., Stern, M. C., Hines, L., Baumgartner, K. B., Giuliano, A. R., Wolff, R. K. 2014; 134 (3): 629-644

  Abstract

  Angiogenesis is essential for tumor development and progression. Genetic variation in angiogenesis-related genes may influence breast carcinogenesis. We evaluated dietary factors associated with oxidative balance, DDIT4 (1 SNP), FLT1 (35 SNPs), HIF1A (4 SNPs), KDR (19 SNPs), MPO (1 SNP), NOS2A (15 SNPs), TEK (40 SNPs), and VEGFA (8 SNPs) and breast cancer risk among Hispanic (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1586 controls) women in the Breast Cancer Health Disparities Study. Adaptive Rank Truncated Product (ARTP) analysis was used to determine gene and pathway significance with breast cancer. TEK was associated with breast cancer overall (PARTP = 0.03) and with breast cancer survival (PARTP = 0.01). KDR was of borderline significance overall (PARTP = 0.07), although significantly associated with breast cancer in both low and intermediate Native American (NA) ancestry groups (PARTP = 0.02) and ER+/PR- tumor phenotype (PARTP = 0.008). Both VEGFA and NOS2A were associated with ER-/PR- tumor phenotype (PARTP = 0.01 and PARTP = 0.04 respectively). FLT1 was associated with breast cancer survival among those with low NA ancestry (PARTP = 0.009). With respect to diet, having a higher dietary oxidative balance score (DOBS) was significantly associated with lower breast cancer risk (OR 0.74 95% CI 0.64-0.84), with the strongest associations observed for women with the highest NA ancestry (OR 0.44 95 %CI 0.30-0.65). We observed few interactions between DOBS and angiogenesis-related genes. Our data suggest that dietary factors and genetic variation in angiogenesis-related genes contribute to breast cancer carcinogenesis. © 2013 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ijc.28377

  View details for Web of Science ID 000326880600014

• Obesity and Mortality After Breast Cancer by Race/Ethnicity: The California Breast Cancer Survivorship Consortium AMERICAN JOURNAL OF EPIDEMIOLOGY Kwan, M. L., John, E. M., Caan, B. J., Lee, V. S., Bernstein, L., Cheng, I., Gomez, S. L., Henderson, B. E., Keegan, T. H., Kurian, A. W., Lu, Y., Monroe, K. R., Roh, J. M., Shariff-Marco, S., Sposto, R., Vigen, C., Wu, A. H. 2014; 179 (1): 95-111

  Abstract

  We investigated body size and survival by race/ethnicity in 11,351 breast cancer patients diagnosed from 1993 to 2007 with follow-up through 2009 by using data from questionnaires and the California Cancer Registry. We calculated hazard ratios and 95% confidence intervals from multivariable Cox proportional hazard model-estimated associations of body size (body mass index (BMI) (weight (kg)/height (m)(2)) and waist-hip ratio (WHR)) with breast cancer-specific and all-cause mortality. Among 2,744 ascertained deaths, 1,445 were related to breast cancer. Being underweight (BMI <18.5) was associated with increased risk of breast cancer mortality compared with being normal weight in non-Latina whites (hazard ratio (HR) = 1.91, 95% confidence interval (CI): 1.14, 3.20), whereas morbid obesity (BMI ≥ 40) was suggestive of increased risk (HR = 1.43, 95% CI: 0.84, 2.43). In Latinas, only the morbidly obese were at high risk of death (HR = 2.26, 95% CI: 1.23, 4.15). No BMI-mortality associations were apparent in African Americans and Asian Americans. High WHR (quartile 4 vs. quartile 1) was associated with breast cancer mortality in Asian Americans (HR = 2.21, 95% CI: 1.21, 4.03; P for trend = 0.01), whereas no associations were found in African Americans, Latinas, or non-Latina whites. For all-cause mortality, even stronger BMI and WHR associations were observed. The impact of obesity and body fat distribution on breast cancer patients' risk of death may vary across racial/ethnic groups.

  View details for DOI 10.1093/aje/kwt233

  View details for Web of Science ID 000329061100013

  View details for PubMedID 24107615

  View details for PubMedCentralID PMC3864715

• Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia. Breast cancer research Spurdle, A. B., Couch, F. J., Parsons, M. T., McGuffog, L., Barrowdale, D., Bolla, M. K., Wang, Q., Healey, S., Schmutzler, R., Wappenschmidt, B., Rhiem, K., Hahnen, E., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Plendl, H., Niederacher, D., Sutter, C., Wang-Gohrke, S., Steinemann, D., Preisler-Adams, S., Kast, K., Varon-Mateeva, R., Ellis, S., Frost, D., Platte, R., Perkins, J., Evans, D. G., Izatt, L., Eeles, R., Adlard, J., Davidson, R., Cole, T., Scuvera, G., Manoukian, S., Bonanni, B., Mariette, F., Fortuzzi, S., Viel, A., Pasini, B., Papi, L., Varesco, L., Balleine, R., Nathanson, K. L., Domchek, S. M., Offitt, K., Jakubowska, A., Lindor, N., Thomassen, M., Jensen, U. B., Rantala, J., Borg, Å., Andrulis, I. L., Miron, A., Hansen, T. v., Caldes, T., Neuhausen, S. L., Toland, A. E., Nevanlinna, H., Montagna, M., Garber, J., Godwin, A. K., Osorio, A., Factor, R. E., Terry, M. B., Rebbeck, T. R., Karlan, B. Y., Southey, M., Rashid, M. U., Tung, N., Pharoah, P. D., Blows, F. M., Dunning, A. M., Provenzano, E., Hall, P., Czene, K., Schmidt, M. K., Broeks, A., Cornelissen, S., Verhoef, S., Fasching, P. A., Beckmann, M. W., Ekici, A. B., Slamon, D. J., Bojesen, S. E., Nordestgaard, B. G., Nielsen, S. F., Flyger, H., Chang-Claude, J., Flesch-Janys, D., Rudolph, A., Seibold, P., Aittomäki, K., Muranen, T. A., Heikkilä, P., Blomqvist, C., Figueroa, J., Chanock, S. J., Brinton, L., Lissowska, J., Olson, J. E., Pankratz, V. S., John, E. M., Whittemore, A. S., West, D. W., Hamann, U., Torres, D., Ulmer, H. U., Rüdiger, T., Devilee, P., Tollenaar, R. A., Seynaeve, C., van Asperen, C. J., Eccles, D. M., Tapper, W. J., Durcan, L., Jones, L., Peto, J., Dos-Santos-Silva, I., Fletcher, O., Johnson, N., Dwek, M., Swann, R., Bane, A. L., Glendon, G., Mulligan, A. M., Giles, G. G., Milne, R. L., Baglietto, L., McLean, C., Carpenter, J., Clarke, C., Scott, R., Brauch, H., Brüning, T., Ko, Y., Cox, A., Cross, S. S., Reed, M. W., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Gronwald, J., Dörk, T., Bogdanova, N., Park-Simon, T., Hillemanns, P., Haiman, C. A., Henderson, B. E., Schumacher, F., Le Marchand, L., Burwinkel, B., Marme, F., Surovy, H., Yang, R., Anton-Culver, H., Ziogas, A., Hooning, M. J., Collée, J. M., Martens, J. W., Tilanus-Linthorst, M. M., Brenner, H., Dieffenbach, A. K., Arndt, V., Stegmaier, C., Winqvist, R., Pylkäs, K., Jukkola-Vuorinen, A., Grip, M., Lindblom, A., Margolin, S., Joseph, V., Robson, M., Rau-Murthy, R., González-Neira, A., Arias, J. I., Zamora, P., Benítez, J., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Peterlongo, P., Zaffaroni, D., Barile, M., Capra, F., Radice, P., Teo, S. H., Easton, D. F., Antoniou, A. C., Chenevix-Trench, G., Goldgar, D. E. 2014; 16 (6): 3419-?

  Abstract

  The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling.Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach.ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)).These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.

  View details for DOI 10.1186/s13058-014-0474-y

  View details for PubMedID 25857409

• Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study BREAST CANCER RESEARCH Damiola, F., Pertesi, M., Oliver, J., Le Calvez-Kelm, F., Voegele, C., Young, E. L., Robinot, N., Forey, N., Durand, G., Vallee, M. P., Tao, K., Roane, T. C., Williams, G. J., Hopper, J. L., Southey, M. C., Andrulis, I. L., John, E. M., Goldgar, D. E., Lesueur, F., Tavtigian, S. V. 2014; 16 (3): R58

  Abstract

  The MRE11A-RAD50-Nibrin (MRN) complex plays several critical roles related to repair of DNA double-strand breaks. Inherited mutations in the three components predispose to genetic instability disorders and the MRN genes have been implicated in breast cancer susceptibility, but the underlying data are not entirely convincing. Here, we address two related questions: (1) are some rare MRN variants intermediate-risk breast cancer susceptibility alleles, and if so (2) do the MRN genes follow a BRCA1/BRCA2 pattern wherein most susceptibility alleles are protein-truncating variants, or do they follow an ATM/CHEK2 pattern wherein half or more of the susceptibility alleles are missense substitutions?Using high-resolution melt curve analysis followed by Sanger sequencing, we mutation screened the coding exons and proximal splice junction regions of the MRN genes in 1,313 early-onset breast cancer cases and 1,123 population controls. Rare variants in the three genes were pooled using bioinformatics methods similar to those previously applied to ATM, BRCA1, BRCA2, and CHEK2, and then assessed by logistic regression.Re-analysis of our ATM, BRCA1, and BRCA2 mutation screening data revealed that these genes do not harbor pathogenic alleles (other than modest-risk SNPs) with minor allele frequencies>0.1% in Caucasian Americans, African Americans, or East Asians. Limiting our MRN analyses to variants with allele frequencies of <0.1% and combining protein-truncating variants, likely spliceogenic variants, and key functional domain rare missense substitutions, we found significant evidence that the MRN genes are indeed intermediate-risk breast cancer susceptibility genes (odds ratio (OR)=2.88, P=0.0090). Key domain missense substitutions were more frequent than the truncating variants (24 versus 12 observations) and conferred a slightly higher OR (3.07 versus 2.61) with a lower P value (0.029 versus 0.14).These data establish that MRE11A, RAD50, and NBN are intermediate-risk breast cancer susceptibility genes. Like ATM and CHEK2, their spectrum of pathogenic variants includes a relatively high proportion of missense substitutions. However, the data neither establish whether variants in each of the three genes are best evaluated under the same analysis model nor achieve clinically actionable classification of individual variants observed in this study.

  View details for DOI 10.1186/bcr3669

  View details for Web of Science ID 000349083900014

  View details for PubMedID 24894818

  View details for PubMedCentralID PMC4229874

• Genetic variants and non-genetic factors predict circulating vitamin D levels in Hispanic and non-Hispanic White women: the Breast Cancer Health Disparities Study. International journal of molecular epidemiology and genetics Wang, W., Ingles, S. A., Torres-Mejía, G., Stern, M. C., Stanczyk, F. Z., Schwartz, G. G., Nelson, D. O., Fejerman, L., Wolff, R. K., Slattery, M. L., John, E. M. 2014; 5 (1): 31-46

  Abstract

  Genome-wide association studies (GWAS) have identified common polymorphisms in or near GC, CYP2R1, CYP24A1, and NADSYN1/DHCR7 genes to be associated with circulating levels of 25-hydroxyvitamin D [25(OH)D] in European populations. To replicate these GWAS findings, we examined six selected polymorphisms from these regions and their relation with circulating 25(OH)D levels in 1,605 Hispanic women (629 U.S. Hispanics and 976 Mexicans) and 354 non-Hispanic White (NHW) women. We also assessed the potential interactions between these variants and known non-genetic predictors of 25(OH)D levels, including body mass index (BMI), sunlight exposure and vitamin D intake from diet and supplements. The minor alleles of the two GC polymorphisms (rs7041 and rs2282679) were significantly associated with lower 25(OH)D levels in both Hispanic and NHW women. The CYP2R1 polymorphism, rs2060793, also was significantly associated with 25(OH)D levels in both groups. We found no significant associations for the polymorphisms in the CYP24A1. In Hispanic controls, 25(OH)D levels were significantly associated with the rs12785878T and rs1790349G haplotype in the NADSYN1/DHCR7 region. Significant interactions between GC rs2282679 and BMI and between rs12785878 and time spent in outdoor activities were observed. These results provide further support for the contribution of common genetic variants to individual variability in circulating 25(OH)D levels. The observed interactions between SNPs and non-genetic factors warrant confirmation.

  View details for PubMedID 24596595

• Genetic Ancestry and Risk of Mortality among US Latinas with Breast Cancer CANCER RESEARCH Fejerman, L., Hu, D., Huntsman, S., John, E. M., Stern, M. C., Haiman, C. A., Perez-Stable, E. J., Ziv, E. 2013; 73 (24): 7243-7253

  Abstract

  Multiple studies have reported that Latina women in the United States are diagnosed with breast cancer at more advanced stages and have poorer survival than non-Latina White women. However, Latinas are a heterogeneous group with individuals having different proportions of European, Indigenous American, and African genetic ancestry. In this study, we evaluated the association between genetic ancestry and survival after breast cancer diagnosis among 899 Latina women from the San Francisco Bay area. Genetic ancestry was estimated from single-nucleotide polymorphisms from an Affymetrix 6.0 array and we used Cox proportional hazards models to evaluate the association between genetic ancestry and breast cancer-specific mortality (tests were two-sided). Women were followed for an average of 9 years during which 75 died from breast cancer. Our results showed that Individuals with higher Indigenous American ancestry had increased risk of breast cancer-specific mortality [HR: 1.57 per 25% increase in Indigenous American ancestry; 95% confidence interval (CI): 1.08-2.29]. Adjustment for demographic factors, tumor characteristics, and some treatment information did not explain the observed association (HR: 1.75; 95%CI, 1.12-2.74). In an analysis in which ancestry was dichotomized, the hazard of mortality showed a two-fold increase when comparing women with less than 50% Indigenous American ancestry to women with 50% or more [HR, 1.89, 95%CI, 1.10-3.24]. This was also reflected by Kaplan-Meier survival estimates (P for log-rank test of 0.003). Overall, results suggest that genetic factors and/or unmeasured differences in treatment or access to care should be further explored to understand and reduce ethnic disparities in breast cancer outcomes.

  View details for DOI 10.1158/0008-5472.CAN-13-2014

  View details for PubMedID 24177181

• Body size, modifying factors, and postmenopausal breast cancer risk in a multiethnic population: the San Francisco Bay Area Breast Cancer Study. SpringerPlus John, E. M., Phipps, A. I., Sangaramoorthy, M. 2013; 2 (1): 239-?

  Abstract

  Data on body size and postmenopausal breast cancer in Hispanic and African American women are inconsistent, possibly due to the influence of modifying factors. We examined associations between adiposity and risk of breast cancer defined by hormone receptor status in a population-based case-control study conducted from 1995-2004 in the San Francisco Bay Area. Multivariate adjusted odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. Associations with body size were limited to women not currently using menopausal hormone therapy (801 cases, 1336 controls). High young-adult body mass index (BMI) was inversely associated with postmenopausal breast cancer risk, regardless of hormone receptor status, whereas high current BMI and high adult weight gain were associated with two-fold increased risk of estrogen receptor and progesterone receptor positive breast cancer, but only in women with a low young-adult BMI (≤22.4 kg/m(2)) or those with ≥15 years since menopause. Odds ratios were stronger among non-Hispanic Whites than Hispanics and African Americans. Waist circumference and waist-to-height ratio increased breast cancer risk in Hispanics and African Americans only, independent of BMI. These findings emphasize the importance of considering tumor hormone receptor status and other modifying factors in studies of racially/ethnically diverse populations.

  View details for DOI 10.1186/2193-1801-2-239

  View details for PubMedID 23762816

• The California Breast Cancer Survivorship Consortium (CBCSC): prognostic factors associated with racial/ethnic differences in breast cancer survival CANCER CAUSES & CONTROL Wu, A. H., Gomez, S. L., Vigen, C., Kwan, M. L., Keegan, T. H., Lu, Y., Shariff-Marco, S., Monroe, K. R., Kurian, A. W., Cheng, I., Caan, B. J., Lee, V. S., Roh, J. M., Sullivan-Halley, J., Henderson, B. E., Bernstein, L., John, E. M., Sposto, R. 2013; 24 (10): 1821-1836

  Abstract

  Racial/ethnic disparities in mortality among US breast cancer patients are well documented. Our knowledge of the contribution of lifestyle factors to disease prognosis is based primarily on non-Latina Whites and is limited for Latina, African American, and Asian American women. To address this knowledge gap, the California Breast Cancer Survivorship Consortium (CBCSC) harmonized and pooled interview information (e.g., demographics, family history of breast cancer, parity, smoking, alcohol consumption) from six California-based breast cancer studies and assembled corresponding cancer registry data (clinical characteristics, mortality), resulting in 12,210 patients (6,501 non-Latina Whites, 2,060 African Americans, 2,032 Latinas, 1,505 Asian Americans, 112 other race/ethnicity) diagnosed with primary invasive breast cancer between 1993 and 2007. In total, 3,047 deaths (1,570 breast cancer specific) were observed with a mean (SD) follow-up of 8.3 (3.5) years. Cox proportional hazards regression models were fit to data to estimate hazards ratios (HRs) and 95 % confidence intervals (CIs) for overall and breast cancer-specific mortality. Compared with non-Latina Whites, the HR of breast cancer-specific mortality was 1.13 (95 % CI 0.97-1.33) for African Americans, 0.84 (95 % CI 0.70-1.00) for Latinas, and 0.60 (95 % CI 0.37-0.97) for Asian Americans after adjustment for age, tumor characteristics, and select lifestyle factors. The CBCSC represents a large and racially/ethnically diverse cohort of breast cancer patients from California. This cohort will enable analyses to jointly consider a variety of clinical, lifestyle, and contextual factors in attempting to explain the long-standing disparities in breast cancer outcomes.

  View details for DOI 10.1007/s10552-013-0260-7

  View details for Web of Science ID 000324252500007

  View details for PubMedID 23864487

• Diagnostic Chest X-Rays and Breast Cancer Risk before Age 50 Years for BRCA1 and BRCA2 Mutation Carriers CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION John, E. M., McGuire, V., Thomas, D., Haile, R., Ozcelik, H., Milne, R. L., Felberg, A., West, D. W., Miron, A., Knight, J. A., Terry, M. B., Daly, M., Buys, S. S., Andrulis, I. L., Hopper, J. L., Southey, M. C., Giles, G. G., Apicella, C., Thorne, H., Whittemore, A. S. 2013; 22 (9): 1547-1556

  Abstract

  Background: The effects of low-dose medical radiation on breast cancer risk are uncertain, and few studies have included genetically susceptible women, such as those who carry germline BRCA1 and BRCA2 mutations. Methods: We studied 454 BRCA1 and 273 BRCA2 mutation carriers aged <50 years from three breast cancer family registries in the USA, Canada, and Australia/New Zealand. We estimated breast cancer risk associated with diagnostic chest x-rays by comparing mutation carriers with breast cancer (cases) with those without breast cancer (controls). Exposure to chest x-rays was self-reported. Mammograms were not considered in the analysis. Results: After adjusting for known risk factors for breast cancer, the odds ratio (OR) for a history of diagnostic chest x-rays, excluding those for tuberculosis or pneumonia, was 1.16 (95% confidence interval (CI) = 0.64-2.11) for BRCA1 mutations carriers and 1.22 (95% CI=0.62-2.42) for BRCA2 mutations carriers. The OR was statistically elevated for BRCA2 mutation carriers with 3-5 diagnostic chest x-rays (p = 0.01), but not for those with 6 or more chest x-rays. Few women reported chest fluoroscopy for tuberculosis or chest x-rays for pneumonia; the OR estimates were elevated, but not statistically significant, for BRCA1 mutation carriers. Conclusions: Our findings do not support a positive association between diagnostic chest x-rays and breast cancer risk before age 50 years for BRCA1 or BRCA2 mutation carriers. Impact: Given the increasing use of diagnostic imaging involving higher ionizing radiation doses, further studies of genetically predisposed women are warranted.

  View details for DOI 10.1158/1055-9965.EPI-13-0189

  View details for Web of Science ID 000324674500008

  View details for PubMedID 23853209

• Associations between genetic variants in the TGF-ß signaling pathway and breast cancer risk among Hispanic and non-Hispanic white women. Breast cancer research and treatment Boone, S. D., Baumgartner, K. B., Baumgartner, R. N., Connor, A. E., Pinkston, C. M., John, E. M., Hines, L. M., Stern, M. C., Giuliano, A. R., Torres-Mejia, G., Brock, G. N., Groves, F. D., Kerber, R. A., Wolff, R. K., Slattery, M. L. 2013; 141 (2): 287-297

  Abstract

  The TGF-β signaling pathway has a significant role in breast cancer initiation and promotion by regulating various cellular processes. We evaluated whether genetic variation in eight genes (TGF-β1, TGF-β2, TGF-βR1, TGF-βR2, TGF-βR3, RUNX1, RUNX2, and RUNX3) is associated with breast cancer risk in women from the Breast Cancer Health Disparities Study. A total of 3,524 cases (1,431 non-Hispanic whites (NHW); 2,093 Hispanics/Native Americans(NA)) and 4,209 population-based controls (1,599 NHWs; 2,610 Hispanics/NAs) were included in analyses. Genotypes for 47 single nucleotide polymorphisms (SNPs) were determined. Additionally, 104 ancestral informative markers estimated proportion of NA ancestry. Associations with breast cancer risk overall, by menopausal status, NA ancestry, and estrogen receptor (ER)/progesterone receptor tumor phenotype were evaluated. After adjustment for multiple comparisons, two SNPs were significantly associated with breast cancer risk: RUNX3 (rs906296 ORCG/GG = 1.15 95 % CI 1.04-1.26) and TGF-β1 (rs4803455 ORCA/AA = 0.89 95 % CI 0.81-0.98). RUNX3 (rs906296) and TGF-βR2 (rs3773644) were associated with risk in pre-menopausal women (p adj = 0.002 and 0.02, respectively) and in those with intermediate to high NA ancestry (p adj = 0.04 and 0.01, respectively). Self-reported race was strongly correlated with NA ancestry (r = 0.86). There was a significant interaction between NA ancestry and RUNX1 (rs7279383, p adj = 0.04). Four RUNX SNPs were associated with increased risk of ER- tumors. Results provide evidence that genetic variation in TGF-β and RUNX genes are associated with breast cancer risk. This is the first report of significant associations between genetic variants in TGF-β and RUNX genes and breast cancer risk among women of NA ancestry.

  View details for DOI 10.1007/s10549-013-2690-z

  View details for PubMedID 24036662

• Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. Journal of clinical oncology Phillips, K., Milne, R. L., Rookus, M. A., Daly, M. B., Antoniou, A. C., Peock, S., Frost, D., Easton, D. F., Ellis, S., Friedlander, M. L., Buys, S. S., Andrieu, N., Noguès, C., Stoppa-Lyonnet, D., Bonadona, V., Pujol, P., McLachlan, S. A., John, E. M., Hooning, M. J., Seynaeve, C., Tollenaar, R. A., Goldgar, D. E., Terry, M. B., Caldes, T., Weideman, P. C., Andrulis, I. L., Singer, C. F., Birch, K., Simard, J., Southey, M. C., Olsson, H. L., Jakubowska, A., Olah, E., Gerdes, A., Foretova, L., Hopper, J. L. 2013; 31 (25): 3091-3099

  Abstract

  To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers.Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and Breast Cancer Family Registry. Eligible women were BRCA1 and BRCA2 mutation carriers diagnosed with unilateral BC since 1970 and no other invasive cancer or tamoxifen use before first BC. Hazard ratios (HRs) for CBC associated with tamoxifen use were estimated using Cox regression, adjusting for year and age of diagnosis, country, and bilateral oophorectomy and censoring at contralateral mastectomy, death, or loss to follow-up.Of 1,583 BRCA1 and 881 BRCA2 mutation carriers, 383 (24%) and 454 (52%), respectively, took tamoxifen after first BC diagnosis. There were 520 CBCs over 20,104 person-years of observation. The adjusted HR estimates were 0.38 (95% CI, 0.27 to 0.55) and 0.33 (95% CI, 0.22 to 0.50) for BRCA1 and BRCA2 mutation carriers, respectively. After left truncating at recruitment to the cohort, adjusted HR estimates were 0.58 (95% CI, 0.29 to 1.13) and 0.48 (95% CI, 0.22 to 1.05) based on 657 BRCA1 and 426 BRCA2 mutation carriers with 100 CBCs over 4,392 person-years of prospective follow-up. HRs did not differ by estrogen receptor status of the first BC (missing for 56% of cases).This study provides evidence that tamoxifen use is associated with a reduction in CBC risk for BRCA1 and BRCA2 mutation carriers. Further follow-up of these cohorts will provide increased statistical power for future prospective analyses.

  View details for DOI 10.1200/JCO.2012.47.8313

  View details for PubMedID 23918944

  View details for PubMedCentralID PMC3753701

• Genome-wide association study of age at menarche in African-American women HUMAN MOLECULAR GENETICS Demerath, E. W., Liu, C., Franceschini, N., Chen, G., Palmer, J. R., Smith, E. N., Chen, C. T., Ambrosone, C. B., Arnold, A. M., Bandera, E. V., Berenson, G. S., Bernstein, L., Britton, A., Cappola, A. R., Carlson, C. S., Chanock, S. J., Chen, W., Chen, Z., Deming, S. L., Elks, C. E., Evans, M. K., Gajdos, Z., Henderson, B. E., Hu, J. J., Ingles, S., John, E. M., Kerr, K. F., Kolonel, L. N., Le Marchand, L., Lu, X., Millikan, R. C., Musani, S. K., Nock, N. L., North, K., Nyante, S., Press, M. F., Rodriquez-Gil, J. L., Ruiz-Narvaez, E. A., Schork, N. J., Srinivasan, S. R., Woods, N. F., Zheng, W., Ziegler, R. G., Zonderman, A., Heiss, G., Windham, B. G., Wellons, M., Murray, S. S., Nalls, M., Pastinen, T., Rajkovic, A., Hirschhorn, J., Cupples, L. A., Kooperberg, C., Murabito, J. M., Haiman, C. A. 2013; 22 (16): 3329-3346

  Abstract

  African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single-nucleotide polymorphisms (SNPs) in a total of 18 089 AA women in 15 studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2850 women (Stage 2). First, while no SNP passed the pre-specified P < 5 × 10(-8) threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified in EA women. Secondly, an investigation of SNPs in 42 previously identified menarche loci in EA women demonstrated that 25 (60%) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women.

  View details for DOI 10.1093/hmg/ddt181

  View details for Web of Science ID 000322341300014

• Genetic ancestry modifies the association between genetic risk variants and breast cancer risk among Hispanic and non-Hispanic white women CARCINOGENESIS Fejerman, L., Stern, M. C., Ziv, E., John, E. M., Torres-Mejia, G., Hines, L. M., Wolff, R., Wang, W., Baumgartner, K. B., Giuliano, A. R., Slattery, M. L. 2013; 34 (8): 1787-1793

  Abstract

  Hispanic women in the USA have lower breast cancer incidence than non-Hispanic white (NHW) women. Genetic factors may contribute to this difference. Breast cancer genome-wide association studies (GWAS) conducted in women of European or Asian descent have identified multiple risk variants. We tested the association between 10 previously reported single nucleotide polymorphisms (SNPs) and risk of breast cancer in a sample of 4697 Hispanic and 3077 NHW women recruited as part of three population-based case-control studies of breast cancer. We used stratified logistic regression analyses to compare the associations with different genetic variants in NHWs and Hispanics classified by their proportion of Indigenous American (IA) ancestry. Five of 10 SNPs were statistically significantly associated with breast cancer risk. Three of the five significant variants (rs17157903-RELN, rs7696175-TLR1 and rs13387042-2q35) were associated with risk among Hispanics but not in NHWs. The odds ratio (OR) for the heterozygous at 2q35 was 0.75 [95% confidence interval (CI) = 0.50-1.15] for low IA ancestry and 1.38 (95% CI = 1.04-1.82) for high IA ancestry (P interaction 0.02). The ORs for association at RELN were 0.87 (95% CI = 0.59-1.29) and 1.69 (95% CI = 1.04-2.73), respectively (P interaction 0.03). At the TLR1 locus, the ORs for women homozygous for the rare allele were 0.74 (95% CI = 0.42-1.31) and 1.73 (95% CI = 1.19-2.52) (P interaction 0.03). Our results suggest that the proportion of IA ancestry modifies the magnitude and direction of the association of 3 of the 10 previously reported variants. Genetic ancestry should be considered when assessing risk in women of mixed descent and in studies designed to discover causal mutations.

  View details for DOI 10.1093/carcin/bgt110

  View details for Web of Science ID 000322666800011

  View details for PubMedID 23563089

• Associations with growth factor genes (FGF1, FGF2, PDGFB, FGFR2, NRG2, EGF, ERBB2) with breast cancer risk and survival: the Breast Cancer Health Disparities Study. Breast cancer research and treatment Slattery, M. L., John, E. M., Stern, M. C., Herrick, J., Lundgreen, A., Giuliano, A. R., Hines, L., Baumgartner, K. B., Torres-Mejia, G., Wolff, R. K. 2013; 140 (3): 587-601

  Abstract

  Growth factors (GF) stimulate cell proliferation through binding to cell membrane receptors and are thought to be involved in cancer risk and survival. We examined how genetic variation in epidermal growth factor (EGF), neuregulin 2 (NRG2), ERBB2 (HER2/neu), fibroblast growth factors 1 and 2 (FGF1 and FGF2) and its receptor 2 (FGFR2), and platelet-derived growth factor B (PDGFB) independently and collectively influence breast cancer risk and survival. We analyzed data from the Breast Cancer Health Disparities Study which includes Hispanic (2,111 cases, 2,597 controls) and non-Hispanic white (1,481 cases, 1,586 controls) women. Adaptive rank-truncated product (ARTP) analysis was conducted to determine gene significance. Odds ratios (OR) and 95 % confidence intervals were obtained from conditional logistic regression models to estimate breast cancer risk and Cox proportional hazard models were used to estimate hazard ratios (HR) of dying from breast cancer. We assessed Native American (NA) ancestry using 104 ancestry informative markers. We observed few significant associations with breast cancer risk overall or by menopausal status other than for FGFR2 rs2981582. This SNP was significantly associated with ER+/PR+ (OR 1.66, 95 % CI 1.37-2.00) and ER+/PR- (OR 1.54, 95 % CI 1.03-2.31) tumors. Multiple SNPs in FGF1, FGF2, and NRG2 significantly interacted with multiple SNPs in EGFR, ERBB2, FGFR2, and PDGFB, suggesting that breast cancer risk is dependent on the collective effects of genetic variants in other GFs. Both FGF1 and ERBB2 significantly influenced overall survival, especially among women with low levels of NA ancestry (P ARTP = 0.007 and 0.003, respectively). Our findings suggest that genetic variants in growth factors signaling appear to influence breast cancer risk through their combined effects. Genetic variation in ERBB2 and FGF1 appear to be associated with survival after diagnosis with breast cancer.

  View details for DOI 10.1007/s10549-013-2644-5

  View details for PubMedID 23912956

• Tumour morphology predicts PALB2 germline mutation status BRITISH JOURNAL OF CANCER Teo, Z. L., Provenzano, E., Dite, G. S., Park, D. J., Apicella, C., Sawyer, S. D., James, P. A., Mitchell, G., Trainer, A. H., Lindeman, G. J., SHACKLETON, K., Cicciarelli, L., Buys, S. S., Andrulis, I. L., Mulligan, A. M., Glendon, G., John, E. M., Terry, M. B., Daly, M., Odefrey, F. A., Nguyen-Dumont, T., Giles, G. G., Dowty, J. G., Winship, I., Goldgar, D. E., Hopper, J. L., Southey, M. C. 2013; 109 (1): 154-163

  Abstract

  Background:Population-based studies of breast cancer have estimated that at least some PALB2 mutations are associated with high breast cancer risk. For women carrying PALB2 mutations, knowing their carrier status could be useful in directing them towards effective cancer risk management and therapeutic strategies. We sought to determine whether morphological features of breast tumours can predict PALB2 germline mutation status.Methods:Systematic pathology review was conducted on breast tumours from 28 female carriers of PALB2 mutations (non-carriers of other known high-risk mutations, recruited through various resources with varying ascertainment) and on breast tumours from a population-based sample of 828 Australian women diagnosed before the age of 60 years (which included 40 BRCA1 and 18 BRCA2 mutation carriers). Tumour morphological features of the 28 PALB2 mutation carriers were compared with those of 770 women without high-risk mutations.Results:Tumours arising in PALB2 mutation carriers were associated with minimal sclerosis (odds ratio (OR)=19.7; 95% confidence interval (CI)=6.0-64.6; P=5 × 10(-7)). Minimal sclerosis was also a feature that distinguished PALB2 mutation carriers from BRCA1 (P=0.05) and BRCA2 (P=0.04) mutation carriers.Conclusion:This study identified minimal sclerosis to be a predictor of germline PALB2 mutation status. Morphological review can therefore facilitate the identification of women most likely to carry mutations in PALB2.

  View details for DOI 10.1038/bjc.2013.295

  View details for Web of Science ID 000321702400021

  View details for PubMedID 23787919

  View details for PubMedCentralID PMC3708559

• Fine mapping of breast cancer genome-wide association studies loci in women of African ancestry identifies novel susceptibility markers CARCINOGENESIS Zheng, Y., Ogundiran, T. O., Falusi, A. G., Nathanson, K. L., John, E. M., Hennis, A. J., Ambs, S., Domchek, S. M., Rebbeck, T. R., Simon, M. S., Nemesure, B., Wu, S., Leske, M. C., Odetunde, A., Niu, Q., Zhang, J., Afolabi, C., Gamazon, E. R., Cox, N. J., Olopade, C. O., Olopade, O. I., Huo, D. 2013; 34 (7): 1520-1528

  Abstract

  Numerous single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified by genome-wide association studies (GWAS). However, these SNPs were primarily discovered and validated in women of European and Asian ancestry. Because linkage disequilibrium is ancestry-dependent and heterogeneous among racial/ethnic populations, we evaluated common genetic variants at 22 GWAS-identified breast cancer susceptibility loci in a pooled sample of 1502 breast cancer cases and 1378 controls of African ancestry. None of the 22 GWAS index SNPs could be validated, challenging the direct generalizability of breast cancer risk variants identified in Caucasians or Asians to other populations. Novel breast cancer risk variants for women of African ancestry were identified in regions including 5p12 (odds ratio [OR] = 1.40, 95% confidence interval [CI] = 1.11-1.76; P = 0.004), 5q11.2 (OR = 1.22, 95% CI = 1.09-1.36; P = 0.00053) and 10p15.1 (OR = 1.22, 95% CI = 1.08-1.38; P = 0.0015). We also found positive association signals in three regions (6q25.1, 10q26.13 and 16q12.1-q12.2) previously confirmed by fine mapping in women of African ancestry. In addition, polygenic model indicated that eight best markers in this study, compared with 22 GWAS-identified SNPs, could better predict breast cancer risk in women of African ancestry (per-allele OR = 1.21, 95% CI = 1.16-1.27; P = 9.7 × 10(-16)). Our results demonstrate that fine mapping is a powerful approach to better characterize the breast cancer risk alleles in diverse populations. Future studies and new GWAS in women of African ancestry hold promise to discover additional variants for breast cancer susceptibility with clinical implications throughout the African diaspora.

  View details for DOI 10.1093/carcin/bgt090

  View details for Web of Science ID 000321753000013

  View details for PubMedID 23475944

• Telomere length, telomere-related genes, and breast cancer risk: The breast cancer health disparities study. Genes, chromosomes & cancer Pellatt, A. J., Wolff, R. K., Torres-Mejia, G., John, E. M., Herrick, J. S., Lundgreen, A., Baumgartner, K. B., Giuliano, A. R., Hines, L. M., Fejerman, L., Cawthon, R., Slattery, M. L. 2013; 52 (7): 595-609

  Abstract

  Telomeres are involved in maintaining genomic stability. Previous studies have linked both telomere length (TL) and telomere-related genes with cancer. We evaluated associations between telomere-related genes, TL, and breast cancer risk in an admixed population of US non-Hispanic white (1,481 cases, 1,586 controls) and U.S. Hispanic and Mexican women (2,111 cases, 2,597 controls) from the Breast Cancer Health Disparities Study. TL was assessed in 1,500 women based on their genetic ancestry. TL-related genes assessed were MEN1, MRE11A, RECQL5, TEP1, TERC, TERF2, TERT, TNKS, and TNKS2. Longer TL was associated with increased breast cancer risk [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.38, 2.55], with the highest risk (OR 3.11, 95% CI 1.74, 5.67 p interaction 0.02) among women with high Indigenous American ancestry. Several TL-related single nucleotide polymorphisms had modest association with breast cancer risk overall, including TEP1 rs93886 (OR 0.82, 95% CI 0.70,0.95); TERF2 rs3785074 (OR 1.13, 95% CI 1.03,1.24); TERT rs4246742 (OR 0.85, 95% CI 0.77,0.93); TERT rs10069690 (OR 1.13, 95% CI 1.03,1.24); TERT rs2242652 (OR 1.51, 95% CI 1.11,2.04); and TNKS rs6990300 (OR 0.89, 95% CI 0.81,0.97). Several differences in association were detected by hormone receptor status of tumors. Most notable were associations with TERT rs2736118 (ORadj 6.18, 95% CI 2.90, 13.19) with estrogen receptor negative/progesterone receptor positive (ER-/PR+) tumors and TERT rs2735940 (ORadj 0.73, 95% CI 0.59, 0.91) with ER-/PR- tumors. These data provide support for an association between TL and TL-related genes and risk of breast cancer. The association may be modified by hormone receptor status and genetic ancestry. © 2013 Wiley Periodicals, Inc.

  View details for DOI 10.1002/gcc.22056

  View details for PubMedID 23629941

• Genetic variation in bone morphogenetic proteins and breast cancer risk in hispanic and non-hispanic white women: The breast cancer health disparities study INTERNATIONAL JOURNAL OF CANCER Slattery, M. L., John, E. M., Torres-Mejia, G., Herrick, J. S., Giuliano, A. R., Baumgartner, K. B., Hines, L. M., Wolff, R. K. 2013; 132 (12): 2928-2939

  Abstract

  Bone morphogenetic proteins (BMP) are thought to be important in breast cancer promotion and progression. We evaluated genetic variation in BMP-related genes and breast cancer risk among Hispanic (2,111 cases, 2,597 controls) and non-Hispanic White (NHW) (1,481 cases, 1,586 controls) women who participated in the 4-Corner's Breast Cancer Study, the Mexico Breast Cancer Study and the San Francisco Bay Area Breast Cancer Study. BMP genes and their receptors evaluated include ACVR1, AVCR2A, ACVR2B, ACVRL1, BMP1, BMP2, BMP4, BMP6, BMP7, BMPR1A, BMPR1B, BMPR2, MSTN and GDF10. Additionally, 104 ancestral informative markers were assessed to discriminate between European and native American ancestry. The importance of estrogen on BMP-related associations was suggested through unique associations by menopausal status and estrogen (ER) and progesterone (PR) receptor status of tumors. After adjustment for multiple comparisons ACVR1 (8 SNPs) was modestly associated with ER+PR+ tumors [odds ratios (ORs) between 1.18 and 1.39 padj < 0.05]. ACVR1 (3 SNPs) and BMP4 (3 SNPs) were associated with ER+PR- tumors (ORs 0.59-2.07; padj < 0.05). BMPR2 was associated with ER-PR+ tumors (OR 4.20; 95% CI 1.62, 10.91; padj < 0.05) as was GDF10 (2 SNPs; ORs 3.62 and 3.85; padj < 0.05). After adjustment for multiple comparisons several SNPs remained associated with ER-PR- tumors (padj < 0.05) including ACVR1 BMP4 and GDF10 (ORs between 0.53 and 2.12). Differences in association also were observed by percentage of native ancestry and menopausal status. Results support the hypothesis that genetic variation in BMPs is associated with breast cancer in this admixed population.

  View details for DOI 10.1002/ijc.27960

  View details for Web of Science ID 000317593100023

  View details for PubMedID 23180569

  View details for PubMedCentralID PMC3653321

• Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression. Human molecular genetics Kote-Jarai, Z., Saunders, E. J., Leongamornlert, D. A., Tymrakiewicz, M., Dadaev, T., Jugurnauth-Little, S., Ross-Adams, H., Al Olama, A. A., Benlloch, S., Halim, S., Russel, R., Dunning, A. M., Luccarini, C., Dennis, J., Neal, D. E., Hamdy, F. C., Donovan, J. L., Muir, K., Giles, G. G., Severi, G., Wiklund, F., Gronberg, H., Haiman, C. A., Schumacher, F., Henderson, B. E., Le Marchand, L., Lindstrom, S., Kraft, P., Hunter, D. J., Gapstur, S., Chanock, S., Berndt, S. I., Albanes, D., Andriole, G., Schleutker, J., Weischer, M., Canzian, F., Riboli, E., Key, T. J., Travis, R. C., Campa, D., Ingles, S. A., John, E. M., Hayes, R. B., Pharoah, P., Khaw, K., Stanford, J. L., Ostrander, E. A., Signorello, L. B., Thibodeau, S. N., Schaid, D., Maier, C., Vogel, W., Kibel, A. S., Cybulski, C., Lubinski, J., Cannon-Albright, L., Brenner, H., Park, J. Y., Kaneva, R., Batra, J., Spurdle, A., Clements, J. A., Teixeira, M. R., Govindasami, K., Guy, M., Wilkinson, R. A., Sawyer, E. J., Morgan, A., Dicks, E., Baynes, C., Conroy, D., Bojesen, S. E., Kaaks, R., Vincent, D., Bacot, F., Tessier, D. C., Easton, D. F., Eeles, R. A. 2013; 22 (12): 2520-2528

  Abstract

  Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease.

  View details for DOI 10.1093/hmg/ddt086

  View details for PubMedID 23535824

  View details for PubMedCentralID PMC3658165

• Matrix Metalloproteinase Genes Are Associated with Breast Cancer Risk and Survival: The Breast Cancer Health Disparities Study PLOS ONE Slattery, M. L., John, E., Torres-Mejia, G., Stern, M., Lundgreen, A., Hines, L., Giuliano, A., Baumgartner, K., Herrick, J., Wolff, R. K. 2013; 8 (5)

  Abstract

  Matrix metalloproteinases (MMPs) contribute to cancer through their involvement in cancer invasion and metastasis. We evaluated genetic variation in MMP1 (9 SNPs), MMP2 (8 SNPs), MMP3 (4 SNPs), and MMP9 (3 SNPs) and breast cancer risk among Hispanic (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1586 controls) women in the Breast Cancer Health Disparities Study. Ancestral informative markers (n = 104) were assessed to determine Native American (NA) ancestry. MMP1 [4 single nucleotide polymorphisms (SNPs)] and MMP2 (2 SNPs) were associated with breast cancer overall. MMP1 rs996999 had strongest associations among women with the most NA ancestry (OR 1.61,95% CI 1.09,2.40) as did MMP3 rs650108 (OR 1.36, 95% CI 1.05,1.75) and MMP9 rs3787268 (OR 1.52, 95% CI 1.09,2.13). The adaptive rank truncated product (ARTP) showed a significant pathway p(artp)  value of 0.04, with a stronger association among women with the most NA ancestry (p(artp) = 0.02). Significant pathway genes using the ARTP were MMP1 for all women (p(artp) = 0.02) and MMP9 for women with the most NA ancestry (p(artp) = 0.024); MMP2 was borderline significant overall (p(artp) =0.06) and MMP1 and MMP3 were borderline significant for women with the most NA ancestry (p(artp) = 0.07 and 0.06 respectively). MMP1 and MMP2 were associated with ER+/PR+ and ER+/PR-tumors; MMP3 and MMP9 were associated with ER-/PR- tumors. The pathway was highly significant with survival (p(artp) = 0.0041) with MMP2 having the strongest gene association (p(artp) = 0.0007). Our findings suggest that genetic variation in MMP genes influence breast cancer development and survival in this genetically admixed population.

  View details for DOI 10.1371/journal.pone.0063165

  View details for Web of Science ID 000319081900013

  View details for PubMedID 23696797

  View details for PubMedCentralID PMC3655963

• Genetic variants associated with breast cancer risk for Ashkenazi Jewish women with strong family histories but no identifiable BRCA1/2 mutation HUMAN GENETICS Rinella, E. S., Shao, Y., Yackowski, L., Pramanik, S., Oratz, R., Schnabel, F., Guha, S., Leduc, C., Campbell, C. L., Klugman, S. D., Terry, M. B., Senie, R. T., Andrulis, I. L., Daly, M., John, E. M., Roses, D., Chung, W. K., Ostrer, H. 2013; 132 (5): 523-536

  Abstract

  The ability to establish genetic risk models is critical for early identification and optimal treatment of breast cancer. For such a model to gain clinical utility, more variants must be identified beyond those discovered in previous genome-wide association studies (GWAS). This is especially true for women at high risk because of family history, but without BRCA1/2 mutations. This study incorporates three datasets in a GWAS analysis of women with Ashkenazi Jewish (AJ) homogeneous ancestry. Two independent discovery cohorts comprised 239 and 238 AJ women with invasive breast cancer or preinvasive ductal carcinoma in situ and strong family histories of breast cancer, but lacking the three BRCA1/2 founder mutations, along with 294 and 230 AJ controls, respectively. An independent, third cohort of 203 AJ cases with familial breast cancer history and 263 healthy controls of AJ women was used for validation. A total of 19 SNPs were identified as associated with familial breast cancer risk in AJ women. Among these SNPs, 13 were identified from a panel of 109 discovery SNPs, including an FGFR2 haplotype. In addition, six previously identified breast cancer GWAS SNPs were confirmed in this population. Seven of the 19 markers were significant in a multivariate predictive model of familial breast cancer in AJ women, three novel SNPs [rs17663555(5q13.2), rs566164(6q21), and rs11075884(16q22.2)], the FGFR2 haplotype, and three previously published SNPs [rs13387042(2q35), rs2046210(ESR1), and rs3112612(TOX3)], yielding moderate predictive power with an area under the curve (AUC) of the ROC (receiver-operator characteristic curve) of 0.74. Population-specific genetic variants in addition to variants shared with populations of European ancestry may improve breast cancer risk prediction among AJ women from high-risk families without founder BRCA1/2 mutations.

  View details for DOI 10.1007/s00439-013-1269-4

  View details for Web of Science ID 000317691100004

  View details for PubMedID 23354978

• Risk of pancreatic cancer in breast cancer families from the breast cancer family registry. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Mocci, E., Milne, R. L., Méndez-Villamil, E. Y., Hopper, J. L., John, E. M., Andrulis, I. L., Chung, W. K., Daly, M., Buys, S. S., Malats, N., Goldgar, D. E. 2013; 22 (5): 803-811

  Abstract

  Increased risk of pancreatic cancer has been reported in breast cancer families carrying BRCA1and BRCA2 mutations; however, pancreatic cancer risk in mutation-negative (BRCAX) families has not been explored to date. The aim of this study was to estimate pancreatic cancer risk in high-risk breast cancer families according to the BRCA mutation status.A retrospective cohort analysis was applied to estimate standardized incidence ratios (SIR) for pancreatic cancer. A total of 5,799 families with ≥1 breast cancer case tested for mutations in BRCA1 and/or BRCA2 were eligible. Families were divided into four classes: BRCA1, BRCA2, BRCAX with ≥2 breast cancer diagnosed before age 50 (class 3), and the remaining BRCAX families (class 4).BRCA1 mutation carriers were at increased risk of pancreatic cancer [SIR = 4.11; 95% confidence interval (CI), 2.94-5.76] as were BRCA2 mutation carriers (SIR = 5.79; 95% CI, 4.28-7.84). BRCAX family members were also at increased pancreatic cancer risk, which did not appear to vary by number of members with early-onset breast cancer (SIR = 1.31; 95% CI, 1.06-1.63 for class 3 and SIR = 1.30; 95% CI, 1.13-1.49 for class 4).Germline mutations in BRCA1 and BRCA2 are associated with an increased risk of pancreatic cancer. Members of BRCAX families are also at increased risk of pancreatic cancer, pointing to the existence of other genetic factors that increase the risk of both pancreatic cancer and breast cancer. Impact: This study clarifies the relationship between familial breast cancer and pancreatic cancer. Given its high mortality, pancreatic cancer should be included in risk assessment in familial breast cancer counseling. Cancer Epidemiol Biomarkers Prev; 22(5); 803-11. ©2013 AACR.

  View details for DOI 10.1158/1055-9965.EPI-12-0195

  View details for PubMedID 23456555

• A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry. Nature genetics Monda, K. L., Chen, G. K., Taylor, K. C., Palmer, C., Edwards, T. L., Lange, L. A., Ng, M. C., Adeyemo, A. A., Allison, M. A., Bielak, L. F., Chen, G., Graff, M., Irvin, M. R., Rhie, S. K., Li, G., Liu, Y., Liu, Y., Lu, Y., Nalls, M. A., Sun, Y. V., Wojczynski, M. K., Yanek, L. R., Aldrich, M. C., Ademola, A., Amos, C. I., Bandera, E. V., Bock, C. H., Britton, A., Broeckel, U., Cai, Q., Caporaso, N. E., Carlson, C. S., Carpten, J., Casey, G., Chen, W., Chen, F., Chen, Y. I., Chiang, C. W., Coetzee, G. A., Demerath, E., Deming-Halverson, S. L., Driver, R. W., Dubbert, P., Feitosa, M. F., Feng, Y., Freedman, B. I., Gillanders, E. M., Gottesman, O., Guo, X., Haritunians, T., Harris, T., Harris, C. C., Hennis, A. J., Hernandez, D. G., McNeill, L. H., Howard, T. D., Howard, B. V., Howard, V. J., Johnson, K. C., Kang, S. J., Keating, B. J., Kolb, S., Kuller, L. H., Kutlar, A., Langefeld, C. D., Lettre, G., Lohman, K., Lotay, V., Lyon, H., Manson, J. E., Maixner, W., Meng, Y. A., Monroe, K. R., Morhason-Bello, I., Murphy, A. B., Mychaleckyj, J. C., Nadukuru, R., Nathanson, K. L., Nayak, U., N'Diaye, A., Nemesure, B., Wu, S., Leske, M. C., Neslund-Dudas, C., Neuhouser, M., Nyante, S., Ochs-Balcom, H., Ogunniyi, A., Ogundiran, T. O., Ojengbede, O., Olopade, O. I., Palmer, J. R., Ruiz-Narvaez, E. A., Palmer, N. D., Press, M. F., Rampersaud, E., Rasmussen-Torvik, L. J., Rodriguez-Gil, J. L., Salako, B., Schadt, E. E., Schwartz, A. G., Shriner, D. A., Siscovick, D., Smith, S. B., Wassertheil-Smoller, S., Speliotes, E. K., Spitz, M. R., Sucheston, L., Taylor, H., Tayo, B. O., Tucker, M. A., Van den Berg, D. J., Edwards, D. R., Wang, Z., Wiencke, J. K., Winkler, T. W., Witte, J. S., Wrensch, M., Wu, X., Yang, J. J., Levin, A. M., Young, T. R., Zakai, N. A., Cushman, M., Zanetti, K. A., Zhao, J. H., Zhao, W., Zheng, Y., Zhou, J., Ziegler, R. G., Zmuda, J. M., Fernandes, J. K., Gilkeson, G. S., Kamen, D. L., Hunt, K. J., Spruill, I. J., Ambrosone, C. B., Ambs, S., Arnett, D. K., Atwood, L., Becker, D. M., Berndt, S. I., Bernstein, L., Blot, W. J., Borecki, I. B., Bottinger, E. P., Bowden, D. W., Burke, G., Chanock, S. J., Cooper, R. S., Ding, J., Duggan, D., Evans, M. K., Fox, C., Garvey, W. T., Bradfield, J. P., Hakonarson, H., Grant, S. F., Hsing, A., Chu, L., Hu, J. J., Huo, D., Ingles, S. A., John, E. M., Jordan, J. M., Kabagambe, E. K., Kardia, S. L., Kittles, R. A., Goodman, P. J., Klein, E. A., Kolonel, L. N., Le Marchand, L., Liu, S., McKnight, B., Millikan, R. C., Mosley, T. H., Padhukasahasram, B., Williams, L. K., Patel, S. R., Peters, U., Pettaway, C. A., Peyser, P. A., Psaty, B. M., Redline, S., Rotimi, C. N., Rybicki, B. A., Sale, M. M., Schreiner, P. J., Signorello, L. B., Singleton, A. B., Stanford, J. L., Strom, S. S., Thun, M. J., Vitolins, M., Zheng, W., Moore, J. H., Williams, S. M., Ketkar, S., Zhu, X., Zonderman, A. B., Kooperberg, C., Papanicolaou, G. J., Henderson, B. E., Reiner, A. P., Hirschhorn, J. N., Loos, R. J., North, K. E., Haiman, C. A. 2013; 45 (6): 690-696

  Abstract

  Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

  View details for DOI 10.1038/ng.2608

  View details for PubMedID 23583978

• Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array NATURE GENETICS Eeles, R. A., Al Olama, A. A., Benlloch, S., Saunders, E. J., Leongamornlert, D. A., Tymrakiewicz, M., Ghoussaini, M., Luccarini, C., Dennis, J., Jugurnauth-Little, S., Dadaev, T., Neal, D. E., Hamdy, F. C., Donovan, J. L., Muir, K., Giles, G. G., Severi, G., Wiklund, F., Gronberg, H., Haiman, C. A., Schumacher, F., Henderson, B. E., Le Marchand, L., Lindstrom, S., Kraft, P., Hunter, D. J., Gapstur, S., Chanock, S. J., Berndt, S. I., Albanes, D., Andriole, G., Schleutker, J., Weischer, M., Canzian, F., Riboli, E., Key, T. J., Travis, R. C., Campa, D., Ingles, S. A., John, E. M., Hayes, R. B., Pharoah, P. D., Pashayan, N., Khaw, K., Stanford, J. L., Ostrander, E. A., Signorello, L. B., Thibodeau, S. N., Schaid, D., Maier, C., Vogel, W., Kibel, A. S., Cybulski, C., Lubhiski, J., Cannon-Albright, L., Brenner, H., Park, J. Y., Kaneva, R., Batra, J., Spurdle, A. B., Clements, J. A., Teixeira, M. R., Dicks, E., Lee, A., Dunning, A. M., Baynes, C., Conroy, D., Maranian, M. J., Ahmed, S., Govindasami, K., Guy, M., Wilkinson, R. A., Sawyer, E. J., Morgan, A., Dearnaley, D. P., Horwich, A., Huddart, R. A., Khoo, V. S., Parker, C. C., van As, N. J., Woodhouse, C. J., Thompson, A., Dudderidge, T., Ogden, C., Cooper, C. S., Lophatananon, A., Cox, A., Southey, M. C., Hopper, J. L., English, D. R., Aly, M., Adolfsson, J., Xu, J., Zheng, S. L., Yeager, M., Kaaks, R., Diver, W. R., Gaudet, M. M., Stern, M. C., Corral, R., Joshi, A. D., Shahabi, A., Wahlfors, T., Tammela, T. L., Auvinen, A., Virtamo, J., Klarskov, P., Nordestgaard, B. G., Roder, M. A., Nielsen, S. F., Bojesen, S. E., Siddiq, A., FitzGerald, L. M., Kolb, S., Kwon, E. M., Karyadi, D. M., Blot, W. J., Zheng, W., Cai, Q., McDonnell, S. K., Rinckleb, A. E., Drake, B., Colditz, G., Wokolorczyk, D., Stephenson, R. A., Teerlink, C., Muller, H., Rothenbacher, D., Sellers, T. A., Lin, H., Slavov, C., Mitev, V., Lose, F., Srinivasan, S., Maia, S., Paulo, P., Lange, E., Cooney, K. A., Antoniou, A. C., Vincent, D., Bacot, F., Tessier, D. C., Kote-Jarai, Z., Easton, D. F. 2013; 45 (4): 385-391

  Abstract

  Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.

  View details for DOI 10.1038/ng.2560

  View details for Web of Science ID 000316840600008

  View details for PubMedID 23535732

• Genome-wide association studies identify four ER negative-specific breast cancer risk loci NATURE GENETICS Garcia-Closas, M., Couch, F. J., Lindstrom, S., Michailidouo, K., Schmidt, M. K., Brook, M. N., Orr, N., Rhie, S. K., Riboli, E., Feigelson, H. S., Le Marchand, L., Buring, J. E., Eccles, D., Miron, P., Fasching, P. A., Brauch, H., Chang-Claude, J., Carpenter, J., Godwin, A. K., Nevanlinna, H., Giles, G. G., Cox, A., Hopper, J. L., Bolla, M. K., Wang, Q., Dennis, J., Dicks, E., Howat, W. J., Schoof, N., Bojesen, S. E., Lambrechts, D., Broeks, A., Andrulis, I. L., Guenel, P., Burwinkel, B., Sawyer, E. J., Hollestelle, A., Fletcher, O., Winqvist, R., Brenner, H., Mannermaa, A., Hamann, U., Meindl, A., Lindblom, A., Zheng, W., Devillee, P., Goldberg, M. S., Lubinski, J., Kristensen, V., Swerdlow, A., Anton-Culver, H., Doerk, T., Muir, K., Matsuo, K., Wu, A. H., Radice, P., Teo, S. H., Shu, X., Blot, W., Kang, D., Hartman, M., Sangrajrang, S., Shen, C., Southey, M. C., Park, D. J., Hammet, F., Stone, J., van't Veer, L. J., Rutgers, E. J., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Peto, J., Schrauder, M. G., Ekici, A. B., Beckmann, M. W., Silva, I. d., Johnson, N., Warren, H., Tomlins, I., Kerin, M. J., Miller, N., Marme, F., Schneeweiss, A., Sohn, C., Therese Truong, T., Laurent-Puig, P., Kerbrat, P., Nordestgaard, B. G., Nielsen, S. F., Flyger, H., Milne, R. L., Arias Perez, J. I., Menendez, P., Mueller, H., Arndt, V., Stegmaier, C., Lichtner, P., Lochmann, M., Justenhoven, C., Ko, Y., Muranen, T. A., Aittomaki, K., Blomqvist, C., Greco, D., Heikkinen, T., Ito, H., Iwata, H., Yatabe, Y., Antonenkova, N. N., Margolin, S., Kataja, V., Kosma, V., Hartikainen, J. M., Balleine, R., Tseng, C., Van Den Berg, D., Stram, D. O., Neven, P., Dieudonne, A., Leunen, K., Rudolph, A., Nickels, S., Flesch-Janys, D., Peterlongo, P., Peissel, B., Bernard, L., Olson, J. E., Wang, X., Stevens, K., Severi, G., Baglietto, L., McLean, C., Coetzee, G. A., Feng, Y., Henderson, B. E., Schumacher, F., Bogdanova, N. V., Labreche, F., Dumont, M., Yip, C. H., Taib, N. A., Cheng, C., Shrubsole, M., Long, J., Pylkas, K., Jukkola-Vuorinen, A., Kauppila, S., Knight, J. A., Glendon, G., Mulligan, A. M., Tollenaar, R. A., Seynaeve, C. M., Kriege, M., Hooning, M. J., van den Ouweland, A. M., van Deurzen, C. H., Lu, W., Gao, Y., Cai, H., Balasubramanian, S. P., Cross, S. S., Reed, M. W., Signorello, L., Cai, Q., Shah, M., Miao, H., Chan, C. W., Chia, K. S., Jakubowska, A., Jaworska, K., Durda, K., Hsiung, C., Wu, P., Yu, J., Ashworth, A., Jones, M., Tessier, D. C., Gonzalez-Neira, A., Pita, G., Alonso, M. R., Vincent, D., Bacot, F., Ambrosone, C. B., Bandera, E. V., John, E. M., Chen, G. K., Hu, J. J., Rodriguez-Gil, J. L., Bernstein, L., Press, M. F., Ziegler, R. G., Millikan, R. M., Deming-Halverson, S. L., Nyante, S., Ingles, S. A., Waisfisz, Q., Tsimiklis, H., Makalic, E., Schmidt, D., Bui, M., Gibson, L., Mueller-Myhsok, B., Schmutzler, R. K., Hein, R., Dahmen, N., Beckmann, L., Aaltonen, K., Czene, K., Irwanto, A., Liu, J., Turnbull, C., Rahman, N., Meijers-Heijboer, H., Uitterlinden, A. G., Rivadeneira, F., Olswold, C., Slager, S., Pilarski, R., Ademuyiwa, F., Konstantopoulou, I., Martin, N. G., Montgomery, G. W., Slamon, D. J., Rauh, C., Lux, M. P., Jud, S. M., Bruning, T., Weaver, J., Harma, P., Pathak, H., Tapper, W., Gerty, S., Durcan, L., Trichopoulos, D., Tumino, R., Peeters, P. H., Kaaks, R., Campa, D., Canzian, F., Weiderpass, E., Johansson, M., Khaw, K., Travis, R., Clavel-Chapelon, F., Kolonel, L. N., Chen, C., Beck, A., Hankinson, S. E., Berg, C. D., Hoover, R. N., Lissowska, J., Figueroa, J. D., Chasman, D. I., Gaudet, M. M., Diver, W. R., Willett, W. C., Hunter, D. J., Simard, J., Benitez, J., Dunning, A. M., Sherman, M. E., Chenevix-Trench, G., Chanock, S. J., Hall, P., Pharoah, P. D., Vachon, C., Easton, D. F., Haiman, C. A., Kraft, P. 2013; 45 (4): 392-398

  Abstract

  Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.

  View details for DOI 10.1038/ng.2561

  View details for Web of Science ID 000316840600009

  View details for PubMedID 23535733

  View details for PubMedCentralID PMC3771695

• Evidence of Gene-Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors PLOS GENETICS Nickels, S., Truong, T., Hein, R., Stevens, K., Buck, K., Behrens, S., Eilber, U., Schmidt, M., Haeberle, L., Vrieling, A., Gaudet, M., Figueroa, J., Schoof, N., Spurdle, A. B., Rudolph, A., Fasching, P. A., Hopper, J. L., Makalic, E., Schmidt, D. F., Southey, M. C., Beckmann, M. W., Ekici, A. B., Fletcher, O., Gibson, L., Silva, I. d., Peto, J., Humphreys, M. K., Wang, J., Cordina-Duverger, E., Menegaux, F., Nordestgaard, B. G., Bojesen, S. E., Lanng, C., Anton-Culver, H., Ziogas, A., Bernstein, L., Clarke, C. A., Brenner, H., Mueller, H., Arndt, V., Stegmaier, C., Brauch, H., Bruening, T., Harth, V., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Lambrechts, D., Smeets, D., Neven, P., Paridaens, R., Flesch-Janys, D., Obi, N., Wang-Gohrke, S., Couch, F. J., Olson, J. E., Vachon, C. M., Giles, G. G., Severi, G., Baglietto, L., Offit, K., John, E. M., Miron, A., Andrulis, I. L., Knight, J. A., Glendon, G., Mulligan, A. M., Chanock, S. J., Lissowska, J., Liu, J., Cox, A., Cramp, H., Connley, D., Balasubramanian, S., Dunning, A. M., Shah, M., Trentham-Dietz, A., Newcomb, P., Titus, L., Egan, K., Cahoon, E. K., Rajaraman, P., Sigurdson, A. J., Doody, M. M., Guenel, P., Pharoah, P. D., Schmidt, M. K., Hall, P., Easton, D. F., Garcia-Closas, M., Milne, R. L., Chang-Claude, J. 2013; 9 (3)

  Abstract

  Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4 × 10(-6)) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1 × 10(-4)). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14-1.85) in those who drank ≥ 20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3 × 10(-5)), with a per-allele OR of 1.14 (1.11-1.17) in parous women and 0.98 (0.92-1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.

  View details for DOI 10.1371/journal.pgen.1003284

  View details for Web of Science ID 000316866700004

  View details for PubMedID 23544014

  View details for PubMedCentralID PMC3609648

• Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk PLOS GENETICS Couch, F. J., Wang, X., McGuffog, L., Lee, A., Olswold, C., Kuchenbaecker, K. B., Soucy, P., Fredericksen, Z., Barrowdale, D., Dennis, J., Gaudet, M. M., Dicks, E., Kosel, M., Healey, S., Sinilnikova, O. M., Lee, A., Bacot, F., Vincent, D., Hogervorst, F. B., Peock, S., Stoppa-Lyonnet, D., Jakubowska, A., Radice, P., Schmutzler, R. K., Domchek, S. M., Piedmonte, M., Singer, C. F., friedman, e., Thomassen, M., Hansen, T. v., Neuhausen, S. L., Szabo, C. I., Blanco, I., Greene, M. H., Karlan, B. Y., Garber, J., Phelan, C. M., Weitzel, J. N., Montagna, M., Olah, E., Andrulis, I. L., Godwin, A. K., Yannoukakos, D., Goldgar, D. E., Caldes, T., Nevanlinna, H., Osorio, A., Terry, M. B., Daly, M. B., Van Rensburg, E. J., Hamann, U., Ramus, S. J., Toland, A. E., Caligo, M. A., Olopade, O. I., Tung, N., Claes, K., Beattie, M. S., Southey, M. C., Imyanitov, E. N., Tischkowitz, M., Janavicius, R., John, E. M., Kwong, A., Diez, O., Balmana, J., Barkardottir, R. B., Arun, B. K., Rennert, G., Teo, S., Ganz, P. A., Campbell, I., van der Hout, A. H., van Deurzen, C. H., Seynaeve, C., Garcia, E. B., van Leeuwen, F. E., Meijers-Heijboer, H. E., Gille, J. J., Ausems, M. G., Blok, M. J., Ligtenberg, M. J., Rookus, M. A., Devilee, P., Verhoef, S., van Os, T. A., Wijnen, J. T., Frost, D., Ellis, S., Fineberg, E., Platte, R., Evans, D. G., Izatt, L., Eeles, R. A., Adlard, J., Eccles, D. M., Cook, J., Brewer, C., Douglas, F., Hodgson, S., Morrison, P. J., Side, L. E., Donaldson, A., Houghton, C., Rogers, M. T., Dorkins, H., Eason, J., Gregory, H., McCann, E., Murray, A., Calender, A., Hardouin, A., Berthet, P., Delnatte, C., Nogues, C., Lasset, C., Houdayer, C., Leroux, D., Rouleau, E., Prieur, F., Damiola, F., Sobol, H., Coupier, I., Venat-Bouvet, L., Castera, L., Gauthier-Villars, M., Leone, M., Pujol, P., Mazoyer, S., Bignon, Y., Zlowocka-Perlowska, E., Gronwald, J., Lubinski, J., Durda, K., Jaworska, K., Huzarski, T., Spurdle, A. B., Viel, A., Peissel, B., Bonanni, B., Melloni, G., Ottini, L., Papi, L., Varesco, L., Tibiletti, M. G., Peterlongo, P., Volorio, S., Manoukian, S., Pensotti, V., Arnold, N., Engel, C., Deissler, H., Gadzicki, D., Gehrig, A., Kast, K., Rhiem, K., Meindl, A., Niederacher, D., Ditsch, N., Plendl, H., Preisler-Adams, S., Engert, S., Sutter, C., Varon-Mateeva, R., Wappenschmidt, B., Weber, B. H., Arver, B., Stenmark-Askmalm, M., Loman, N., Rosenquist, R., Einbeigi, Z., Nathanson, K. L., Rebbeck, T. R., Blank, S. V., Cohn, D. E., Rodriguez, G. C., Small, L., Friedlander, M., Bae-Jump, V. L., Fink-Retter, A., Rappaport, C., Gschwantler-Kaulich, D., Pfeiler, G., Tea, M., Lindor, N. M., Kaufman, B., Paluch, S. S., Laitman, Y., Skytte, A., Gerdes, A., Pedersen, I. S., Moeller, S. T., Kruse, T. A., Jensen, U. B., Vijai, J., Sarrel, K., Robson, M., Kauff, N., Mulligan, A. M., Glendon, G., Ozcelik, H., Ejlertsen, B., Nielsen, F. C., Jonson, L., Andersen, M. K., Ding, Y. C., Steele, L., Foretova, L., Teule, A., Lazaro, C., Brunet, J., Angel Pujana, M., Mai, P. L., Loud, J. T., Walsh, C., Lester, J., Orsulic, S., Narod, S. A., Herzog, J., Sand, S. R., Tognazzo, S., Agata, S., Vaszko, T., Weaver, J., Stavropoulou, A. V., Buys, S. S., Romero, A., de la Hoya, M., Aittomaki, K., Muranen, T. A., Duran, M., Chung, W. K., Lasa, A., Dorfling, C. M., Miron, A., Benitez, J., Senter, L., Huo, D., Chan, S. B., Sokolenko, A. P., Chiquette, J., Tihomirova, L., Friebel, T. M., Agnarsson, B. A., Lu, K. H., Lejbkowicz, F., James, P. A., Hall, P., Dunning, A. M., Tessier, D., Cunningham, J., Slager, S. L., Wang, C., Hart, S., Stevens, K., Simard, J., Pastinen, T., Pankratz, V. S., Offit, K., Easton, D. F., Chenevix-Trench, G., Antoniou, A. C. 2013; 9 (3)

  Abstract

  BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

  View details for DOI 10.1371/journal.pgen.1003212

  View details for Web of Science ID 000316866700002

  View details for PubMedID 23544013

• A Genome-Wide Scan for Breast Cancer Risk Haplotypes among African American Women PLOS ONE Song, C., Chen, G. K., Millikan, R. C., Ambrosone, C. B., John, E. M., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Deming, S. L., Rodriguez-Gil, J. L., Chanock, S. J., Wan, P., Sheng, X., Pooler, L. C., Van den Berg, D. J., Le Marchand, L., Kolonel, L. N., Henderson, B. E., Haiman, C. A., Stram, D. O. 2013; 8 (2)

  Abstract

  Genome-wide association studies (GWAS) simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP) have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls) using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645), thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density.

  View details for DOI 10.1371/journal.pone.0057298

  View details for Web of Science ID 000315524900070

  View details for PubMedID 23468962

  View details for PubMedCentralID PMC3585353

• Risk of Asynchronous Contralateral Breast Cancer in Noncarriers of BRCA1 and BRCA2 Mutations With a Family History of Breast Cancer: A Report From the Women's Environmental Cancer and Radiation Epidemiology Study JOURNAL OF CLINICAL ONCOLOGY Reiner, A. S., John, E. M., Brooks, J. D., Lynch, C. F., Bernstein, L., Mellemkjaer, L., Malone, K. E., Knight, J. A., Capanu, M., Teraoka, S. N., Concannon, P., Liang, X., Figueiredo, J. C., Smith, S. A., Stovall, M., Pike, M. C., Haile, R. W., Thomas, D. C., Begg, C. B., Bernstein, J. L. 2013; 31 (4): 433-439

  Abstract

  To fully characterize the risk of contralateral breast cancer (CBC) in patients with breast cancer with a family history who test negative for BRCA1 and BRCA2 mutations.From our population-based case-control study comparing women with CBC to women with unilateral breast cancer (UBC), we selected women who tested negative for BRCA1 and BRCA2 mutations (594 patients with CBC/1,119 control patients with UBC). Rate ratios (RRs) and 95% CIs were estimated to examine the association between family history of breast cancer and risk of asynchronous CBC. Age- and family history-specific 10-year cumulative absolute risks of CBC were estimated.Family history of breast cancer was associated with increased CBC risk; risk was highest among young women (< 45 years) with first-degree relatives affected at young ages (< 45 years; RR, 2.5; 95% CI, 1.1 to 5.3) or women with first-degree relatives with bilateral disease (RR, 3.6; 95% CI, 2.0 to 6.4). Women diagnosed with UBC before age 55 years with a first-degree family history of CBC had a 10-year risk of CBC of 15.6%.Young women with breast cancer who have a family history of breast cancer and who test negative for deleterious mutations in BRCA1 and BRCA2 are at significantly greater risk of CBC than other breast cancer survivors. This risk varies with diagnosis age, family history of CBC, and degree of relationship to an affected relative. Women with a first-degree family history of bilateral disease have risks of CBC similar to mutation carriers. This has important implications for the clinical management of patients with breast cancer with family history of the disease.

  View details for DOI 10.1200/JCO.2012.43.2013

  View details for Web of Science ID 000314099800010

  View details for PubMedID 23269995

• A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease HUMAN MOLECULAR GENETICS Al Olama, A. A., Kote-Jarai, Z., Schumacher, F. R., Wiklund, F., Berndt, S. I., Benlloch, S., Giles, G. G., Severi, G., Neal, D. E., Hamdy, F. C., Donovan, J. L., Hunter, D. J., Henderson, B. E., Thun, M. J., Gaziano, M., Giovannucci, E. L., Siddiq, A., Travis, R. C., Cox, D. G., Canzian, F., Riboli, E., Key, T. J., Andriole, G., Albanes, D., Hayes, R. B., Schleutker, J., Auvinen, A., Tammela, T. L., Weischer, M., Stanford, J. L., Ostrander, E. A., Cybulski, C., Lubinski, J., Thibodeau, S. N., Schaid, D. J., Sorensen, K. D., Batra, J., Clements, J. A., Chambers, S., Aitken, J., Gardiner, R. A., Maier, C., Vogel, W., Doerk, T., Brenner, H., Habuchi, T., Ingles, S., John, E. M., Dickinson, J. L., Cannon-Albright, L., Teixeira, M. R., Kaneva, R., Zhang, H., Lu, Y., Park, J. Y., Cooney, K. A., Muir, K. R., Leongamornlert, D. A., Saunders, E., Tymrakiewicz, M., Mahmud, N., Guy, M., Govindasami, K., O'Brien, L. T., Wilkinson, R. A., Hall, A. L., Sawyer, E. J., Dadaev, T., Morrison, J., Dearnaley, D. P., Horwich, A., Huddart, R. A., Khoo, V. S., Parker, C. C., Van As, N., Woodhouse, C. J., Thompson, A., Dudderidge, T., Ogden, C., Cooper, C. S., Lophatonanon, A., Southey, M. C., Hopper, J. L., English, D., Virtamo, J., Le Marchand, L., Campa, D., Kaaks, R., Lindstrom, S., Diver, W. R., Gapstur, S., Yeager, M., Cox, A., Stern, M. C., Corral, R., Aly, M., Isaacs, W., Adolfsson, J., Xu, J., Zheng, S. L., Wahlfors, T., Taari, K., Kujala, P., Klarskov, P., Nordestgaard, B. G., Roder, M. A., Frikke-Schmidt, R., Bojesen, S. E., FitzGerald, L. M., Kolb, S., Kwon, E. M., Karyadi, D. M., Orntoft, T. F., Borre, M., Rinckleb, A., Luedeke, M., Herkommer, K., Meyer, A., Serth, J., Marthick, J. R., Patterson, B., Wokolorczyk, D., Spurdle, A., Lose, F., McDonnell, S. K., Joshi, A. D., Shahabi, A., Pinto, P., Santos, J., Ray, A., Sellers, T. A., Lin, H., Stephenson, R. A., Teerlink, C., Muller, H., Rothenbacher, D., Tsuchiya, N., Narita, S., Cao, G., Slavov, C., Mitev, V., Chanock, S., Gronberg, H., Haiman, C. A., Kraft, P., Easton, D. F., Eeles, R. A. 2013; 22 (2): 408-415

  Abstract

  Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.

  View details for DOI 10.1093/hmg/dds425

  View details for Web of Science ID 000312651800018

  View details for PubMedCentralID PMC3526158

• Prevalence and Type of BRCA Mutations in Hispanics Undergoing Genetic Cancer Risk Assessment in the Southwestern United States: A Report From the Clinical Cancer Genetics Community Research Network JOURNAL OF CLINICAL ONCOLOGY Weitzel, J. N., Clague, J., Martir-Negron, A., Ogaz, R., Herzog, J., Ricker, C., Jungbluth, C., Cina, C., Duncan, P., Unzeitig, G., Saldivar, J. S., Beattie, M., Feldman, N., Sand, S., Port, D., Barragan, D. I., John, E. M., Neuhausen, S. L., Larson, G. P. 2013; 31 (2): 210-216

  Abstract

  To determine the prevalence and type of BRCA1 and BRCA2 (BRCA) mutations among Hispanics in the Southwestern United States and their potential impact on genetic cancer risk assessment (GCRA).Hispanics (n = 746) with a personal or family history of breast and/or ovarian cancer were enrolled in an institutional review board-approved registry and received GCRA and BRCA testing within a consortium of 14 clinics. Population-based Hispanic breast cancer cases (n = 492) enrolled in the Northern California Breast Cancer Family Registry, negative by sequencing for BRCA mutations, were analyzed for the presence of the BRCA1 ex9-12del large rearrangement.Deleterious BRCA mutations were detected in 189 (25%) of 746 familial clinic patients (124 BRCA1, 65 BRCA2); 21 (11%) of 189 were large rearrangement mutations, of which 62% (13 of 21) were BRCA1 ex9-12del. Nine recurrent mutations accounted for 53% of the total. Among these, BRCA1 ex9-12del seems to be a Mexican founder mutation and represents 10% to 12% of all BRCA1 mutations in clinic- and population-based cohorts in the United States.BRCA mutations were prevalent in the largest study of Hispanic breast and/or ovarian cancer families in the United States to date, and a significant proportion were large rearrangement mutations. The high frequency of large rearrangement mutations warrants screening in every case. We document the first Mexican founder mutation (BRCA1 ex9-12del), which, along with other recurrent mutations, suggests the potential for a cost-effective panel approach to ancestry-informed GCRA.

  View details for DOI 10.1200/JCO.2011.41.0027

  View details for Web of Science ID 000313345100014

  View details for PubMedID 23233716

  View details for PubMedCentralID PMC3532393

• A genome-wide association study of breast cancer in women of African ancestry HUMAN GENETICS Chen, F., Chen, G. K., Stram, D. O., Millikan, R. C., Ambrosone, C. B., John, E. M., Bernstein, L., Zheng, W., Palmer, J. R., Hu, J. J., Rebbeck, T. R., Ziegler, R. G., Nyante, S., Bandera, E. V., Ingles, S. A., Press, M. F., Ruiz-Narvaez, E. A., Deming, S. L., Rodriguez-Gil, J. L., DeMichele, A., Chanock, S. J., Blot, W., Signorello, L., Cai, Q., Li, G., Long, J., Huo, D., Zheng, Y., Cox, N. J., Olopade, O. I., Ogundiran, T. O., Adebamowo, C., Nathanson, K. L., Domchek, S. M., Simon, M. S., Hennis, A., Nemesure, B., Wu, S., Leske, M. C., Ambs, S., Hutter, C. M., Young, A., Kooperberg, C., Peters, U., Rhie, S. K., Wan, P., Sheng, X., Pooler, L. C., Van den Berg, D. J., Le Marchand, L., Kolonel, L. N., Henderson, B. E., Haiman, C. A. 2013; 132 (1): 39-48

  Abstract

  Genome-wide association studies (GWAS) in diverse populations are needed to reveal variants that are more common and/or limited to defined populations. We conducted a GWAS of breast cancer in women of African ancestry, with genotyping of >1,000,000 SNPs in 3,153 African American cases and 2,831 controls, and replication testing of the top 66 associations in an additional 3,607 breast cancer cases and 11,330 controls of African ancestry. Two of the 66 SNPs replicated (p < 0.05) in stage 2, which reached statistical significance levels of 10(-6) and 10(-5) in the stage 1 and 2 combined analysis (rs4322600 at chromosome 14q31: OR = 1.18, p = 4.3 × 10(-6); rs10510333 at chromosome 3p26: OR = 1.15, p = 1.5 × 10(-5)). These suggestive risk loci have not been identified in previous GWAS in other populations and will need to be examined in additional samples. Identification of novel risk variants for breast cancer in women of African ancestry will demand testing of a substantially larger set of markers from stage 1 in a larger replication sample.

  View details for DOI 10.1007/s00439-012-1214-y

  View details for Web of Science ID 000313005800005

  View details for PubMedID 22923054

• Obesity and Mortality After Breast Cancer by Race/Ethnicity: The California Breast Cancer Survivorship Consortium AMERICAN JOURNAL OF EPIDEMIOLOGY Kwan, M. L., John, E. M., Caan, B. J., Lee, V. S., Bernstein, L., Cheng, I., Gomez, S. L., Henderson, B. E., Keegan, T. H., Kurian, A. W., Lu, Y., Monroe, K. R., Roh, J. M., Shariff-Marco, S., Sposto, R., Vigen, C., Wu, A. H. 2013; electronic publication ahead of print
• Protective Effects of Low Calcium Intake and Low Calcium Absorption Vitamin D Receptor Genotype in the California Collaborative Prostate Cancer Study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Rowland, G. W., Schwartz, G. G., John, E. M., Ingles, S. A. 2013; 22 (1): 16-24

  Abstract

  High calcium intake is consistently associated with increased prostate cancer risk in epidemiologic studies. We previously reported that the positive association between calcium intake and risk of aggressive prostate cancer was modified by the single-nucleotide polymorphism (SNP) in the CDX-2 binding site of the vitamin D receptor (VDR) gene, among African American men.We expanded our previous study to include White men, a population with a higher calcium intake and a higher prevalence of the low absorption allele. We also examined VDR polymorphisms at other loci unrelated to calcium absorption. The study included 1,857 prostate cancer cases (1,140 with advanced stage at diagnosis, 717 with localized stage) and 1,096 controls. OR were estimated using conditional logistic regression.Among both Blacks and Whites, we observed a threshold for calcium intake (604 mg/d) below which prostate cancer risk declined sharply. Low calcium intake was most strongly associated with decreased risk among men with the VDR Cdx2 low calcium absorption genotype (P for interaction = 0.001 and P = 0.06 for Whites and African Americans, respectively). Among all men with this genotype, those in the lowest quartile of calcium intake (≤604 mg/d) had a 50% reduction in risk as compared with those in the upper three quartiles [OR = 0.49; 95% confidence interval (CI), 0.36-0.67]. The association between calcium intake and prostate cancer risk was not modified by genotype at other VDR loci.Our findings support the hypothesis that genetic determinants of calcium absorption influence prostate cancer risk.The differences between African Americans and Whites in calcium absorption and dietary calcium intake may contribute to racial disparities in prostate cancer incidence and mortality rates.

  View details for DOI 10.1158/1055-9965.EPI-12-0922-T

  View details for Web of Science ID 000313531900003

  View details for PubMedID 23129590

• Mammographic density and breast cancer: a comparison of related and unrelated controls in the Breast Cancer Family Registry BREAST CANCER RESEARCH Linton, L., Martin, L. J., Li, Q., Huszti, E., Minkin, S., John, E. M., Rommens, J., Paterson, A. D., Boyd, N. F. 2013; 15 (3)

  Abstract

  INTRODUCTION: Percent mammographic density (PMD) is a strong and highly heritable risk factor for breast cancer. Studies of the role of PMD in familial breast cancer may require controls, such as the sisters of cases, selected from the same "risk set" as the cases. The use of sister controls would allow control for factors that have been shown to influence risk of breast cancer such as race/ethnicity, socio-economic status and a family history of breast cancer, but may introduce "overmatching" and attenuate case-control differences in PMD. METHODS: To examine the potential effects of using sister controls rather than unrelated controls in a case-control study we examined PMD in triplets, each comprised of a case with invasive breast cancer, an unaffected full sister control, and an unaffected unrelated control. Both controls were matched to cases on age at mammogram. Total breast area and dense area in the mammogram were measured in the unaffected breast of cases and a randomly selected breast in controls, and the non-dense area and PMD calculated from these measurements. RESULTS: The mean difference in PMD between cases and controls, and the standard deviation (SD) of the difference, were slightly less for sister controls (4.2% (SD=20.0)) than for unrelated controls (4.9% (SD=25.7)). We found statistically significant correlations in PMD between cases (n=228) and sister controls (n=228) (r= 0.39 (95% CI: 0.28, 0.50; p<0.0001)), but not between cases and unrelated controls (n=228) (r= 0.04 (95% CI: -0.09, 0.17; p=0.51)). After adjusting for other risk factors, square root transformed PMD was associated with an increased risk of breast cancer when comparing cases to sister controls (adjusted odds ratio (inter-quintile odds ratio (IQOR) = 2.19, 95% CI= 1.20, 4.00) or to unrelated controls (adjusted IQOR= 2.62, 95% CI= 1.62, 4.25). CONCLUSIONS: The use of sister controls in case-control studies of PMD resulted in a modest attenuation of case-control differences and risk estimates, but showed a statistically significant association with risk and allowed control for race/ethnicity, socio-economic status and family history.

  View details for DOI 10.1186/bcr3430

  View details for Web of Science ID 000328937600007

• SEPP1 Influences Breast Cancer Risk among Women with Greater Native American Ancestry: The Breast Cancer Health Disparities Study. PloS one Pellatt, A. J., Wolff, R. K., John, E. M., Torres-Mejia, G., Hines, L. M., Baumgartner, K. B., Giuliano, A. R., Lundgreen, A., Slattery, M. L. 2013; 8 (11)

  Abstract

  Selenoproteins are a class of proteins containing a selenocysteine residue, many of which have been shown to have redox functions, acting as antioxidants to decrease oxidative stress. Selenoproteins have previously been associated with risk of various cancers and redox-related diseases. In this study we evaluated possible associations between breast cancer risk and survival and single nucleotide polymorphisms (SNPs) in the selenoprotein genes GPX1, GPX2, GPX3, GPX4, SELS, SEP15, SEPN1, SEPP1, SEPW1, TXNRD1, and TXNRD2 among Hispanic/Native American (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1586 controls) women in the Breast Cancer Health Disparities Study. Adaptive Rank Truncated Product (ARTP) analysis was used to determine both gene and pathway significance with these genes. The overall selenoprotein pathway PARTP was not significantly associated with breast cancer risk (PARTP = 0.69), and only one gene, GPX3, was of borderline significance for the overall population (PARTP =0.09) and marginally significant among women with 0-28% Native American (NA) ancestry (PARTP=0.06). The SEPP1 gene was statistically significantly associated with breast cancer risk among women with higher NA ancestry (PARTP=0.002) and contributed to a significant pathway among those women (PARTP=0.04). GPX1, GPX3, and SELS were associated with Estrogen Receptor-/Progesterone Receptor+ status (PARTP = 0.002, 0.05, and 0.01, respectively). Four SNPs (GPX3 rs2070593, rsGPX4 rs2074451, SELS rs9874, and TXNRD1 rs17202060) significantly interacted with dietary oxidative balance score after adjustment for multiple comparisons to alter breast cancer risk. GPX4 was significantly associated with breast cancer survival among those with the highest NA ancestry (PARTP = 0.05) only. Our data suggest that SEPP1 alters breast cancer risk among women with higher levels of NA ancestry.

  View details for DOI 10.1371/journal.pone.0080554

  View details for PubMedID 24278290

  View details for PubMedCentralID PMC3835321

• Epidermal growth factor receptor (EGFR) polymorphisms and breast cancer among Hispanic and non-Hispanic white women: the Breast Cancer Health Disparities Study. International journal of molecular epidemiology and genetics Connor, A. E., Baumgartner, R. N., Baumgartner, K. B., Pinkston, C. M., John, E. M., Torres-Mejía, G., Hines, L. M., Giuliano, A. R., Wolff, R. K., Slattery, M. L. 2013; 4 (4): 235-249

  Abstract

  The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, functions in cellular processes essential to the development of cancer. Overexpression of EGFR in primary breast tumors has been linked with poor prognosis. We investigated the associations between 34 EGFR tagging SNPs and breast cancer risk and breast cancer-specific mortality in 4,703 Hispanic and 3,030 non-Hispanic white women from the Breast Cancer Health Disparities Study. We evaluated associations with risk of breast cancer defined by estrogen/progesterone receptor (ER/PR) tumor phenotype. Only one association remained statistically significant after adjusting for multiple comparisons. Rs2075112GA/AA was associated with reduced risk for ER-/PR+ tumor phenotype (odds ratio (OR), 0.34; 95% confidence interval (CI) 0.18-0.63, p adj=0.01). All additional results were significant prior to adjustment for multiple comparisons. Two of the EGFR polymorphisms were associated with breast cancer risk in the overall study population (rs11770531TT: OR, 0.56, 95% CI 0.37-0.84; and rs2293348AA: OR, 1.20, 95% CI 1.04-1.38) and two polymorphisms were associated with risk among Hispanics: rs6954351AA: OR, 2.50, 95% CI 1.32-4.76; and rs845558GA/AA: OR, 1.15, 95% CI 1.01-1.30. With regard to breast cancer-specific mortality, we found positive associations with rs6978771TT hazard ratio (HR), 1.68; 95% CI 1.11-2.56; rs9642391CC HR, 1.64; 95% CI 1.04-2.58; rs4947979AG/GG HR, 1.36; 95% CI 1.03-1.79; and rs845552GG HR, 1.62; 95% CI 1.05-2.49. Our findings provide additional insight for the role of EGFR in breast cancer development and prognosis. Further research is needed to elucidate EGFR's contribution to ethnic disparities in breast cancer.

  View details for PubMedID 24319539

  View details for PubMedCentralID PMC3852643

• Body size, modifying factors, and postmenopausal breast cancer risk in a multiethnic population: the San Francisco Bay Area Breast Cancer Study SPRINGERPLUS John, E. M., Phipps, A. I., Sangaramoorthy, M. 2013; 2

  Abstract

  Data on body size and postmenopausal breast cancer in Hispanic and African American women are inconsistent, possibly due to the influence of modifying factors. We examined associations between adiposity and risk of breast cancer defined by hormone receptor status in a population-based case-control study conducted from 1995-2004 in the San Francisco Bay Area. Multivariate adjusted odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. Associations with body size were limited to women not currently using menopausal hormone therapy (801 cases, 1336 controls). High young-adult body mass index (BMI) was inversely associated with postmenopausal breast cancer risk, regardless of hormone receptor status, whereas high current BMI and high adult weight gain were associated with two-fold increased risk of estrogen receptor and progesterone receptor positive breast cancer, but only in women with a low young-adult BMI (≤22.4 kg/m(2)) or those with ≥15 years since menopause. Odds ratios were stronger among non-Hispanic Whites than Hispanics and African Americans. Waist circumference and waist-to-height ratio increased breast cancer risk in Hispanics and African Americans only, independent of BMI. These findings emphasize the importance of considering tumor hormone receptor status and other modifying factors in studies of racially/ethnically diverse populations.

  View details for DOI 10.1186/2193-1801-2-239

  View details for Web of Science ID 000209465000038

  View details for PubMedCentralID PMC3676738

• Global patterns of prostate cancer incidence, aggressiveness, and mortality in men of african descent. Prostate cancer Rebbeck, T. R., Devesa, S. S., Chang, B., Bunker, C. H., Cheng, I., Cooney, K., Eeles, R., Fernandez, P., Giri, V. N., Gueye, S. M., Haiman, C. A., Henderson, B. E., Heyns, C. F., Hu, J. J., Ingles, S. A., Isaacs, W., Jalloh, M., John, E. M., Kibel, A. S., Kidd, L. R., Layne, P., Leach, R. J., Neslund-Dudas, C., Okobia, M. N., Ostrander, E. A., Park, J. Y., Patrick, A. L., Phelan, C. M., Ragin, C., Roberts, R. A., Rybicki, B. A., Stanford, J. L., Strom, S., Thompson, I. M., Witte, J., Xu, J., Yeboah, E., Hsing, A. W., Zeigler-Johnson, C. M. 2013; 2013: 560857-?

  Abstract

  Prostate cancer (CaP) is the leading cancer among men of African descent in the USA, Caribbean, and Sub-Saharan Africa (SSA). The estimated number of CaP deaths in SSA during 2008 was more than five times that among African Americans and is expected to double in Africa by 2030. We summarize publicly available CaP data and collected data from the men of African descent and Carcinoma of the Prostate (MADCaP) Consortium and the African Caribbean Cancer Consortium (AC3) to evaluate CaP incidence and mortality in men of African descent worldwide. CaP incidence and mortality are highest in men of African descent in the USA and the Caribbean. Tumor stage and grade were highest in SSA. We report a higher proportion of T1 stage prostate tumors in countries with greater percent gross domestic product spent on health care and physicians per 100,000 persons. We also observed that regions with a higher proportion of advanced tumors reported lower mortality rates. This finding suggests that CaP is underdiagnosed and/or underreported in SSA men. Nonetheless, CaP incidence and mortality represent a significant public health problem in men of African descent around the world.

  View details for DOI 10.1155/2013/560857

  View details for PubMedID 23476788

  View details for PubMedCentralID PMC3583061

• Total energy intake and breast cancer risk in sisters: the Breast Cancer Family Registry BREAST CANCER RESEARCH AND TREATMENT Zhang, F. F., John, E. M., Knight, J. A., Kaur, M., Daly, M., Buys, S., Andrulis, I. L., Stearman, B., West, D., Terry, M. B. 2013; 137 (2): 541-551

  Abstract

  Energy restriction inhibits mammary tumor development in animal models. Epidemiologic studies in humans generally do not support an association between dietary energy intake and breast cancer risk, although some studies suggest a more complex interplay between measures of energy intake, physical activity, and body size. We examined the association between total energy intake jointly with physical activity and body mass index (BMI) and the risk of breast cancer among 1,775 women diagnosed with breast cancer between 1995 and 2006 and 2,529 of their unaffected sisters, enrolled in the Breast Cancer Family Registry. We collected dietary data using the Hawaii-Los Angeles Multiethnic Cohort food frequency questionnaire. Using conditional logistic regression to estimate the odds ratios (OR) and 95 % confidence intervals (CI) associated with total energy intake, we observed an overall 60-70 % increased risk of breast cancer among women in the highest quartile of total energy intake compared to those in the lowest quartile (Q4 vs. Q1: OR = 1.6, 95 % CI: 1.3-2.0; P (trend) < 0.0001); these associations were limited to pre-menopausal women or women with hormone receptor-positive cancers. Although the associations were slightly stronger among women with a higher BMI or lower level of average lifetime physical activity, we observed a positive association between total energy intake and breast cancer risk across different strata of physical activity and BMI. Our results suggest that within sisters, high energy intake may increase the risk of breast cancer independent of physical activity and body size. If replicated in prospective studies, then these findings suggest that reductions in total energy intake may help in modifying breast cancer risk.

  View details for DOI 10.1007/s10549-012-2342-8

  View details for Web of Science ID 000313201100021

  View details for PubMedID 23225141

• RAD51 and Breast Cancer Susceptibility: No Evidence for Rare Variant Association in the Breast Cancer Family Registry Study PLOS ONE Le Calvez-Kelm, F., Oliver, J., Damiola, F., Forey, N., Robinot, N., Durand, G., Voegele, C., Vallee, M. P., Byrnes, G., Hopper, J. L., Southey, M. C., Andrulis, I. L., John, E. M., Tavtigian, S. V., Lesueur, F. 2012; 7 (12)

  Abstract

  Although inherited breast cancer has been associated with germline mutations in genes that are functionally involved in the DNA homologous recombination repair (HRR) pathway, including BRCA1, BRCA2, TP53, ATM, BRIP1, CHEK2 and PALB2, about 70% of breast cancer heritability remains unexplained. Because of their critical functions in maintaining genome integrity and already well-established associations with breast cancer susceptibility, it is likely that additional genes involved in the HRR pathway harbor sequence variants associated with increased risk of breast cancer. RAD51 plays a central biological function in DNA repair and despite the fact that rare, likely dysfunctional variants in three of its five paralogs, RAD51C, RAD51D, and XRCC2, have been associated with breast and/or ovarian cancer risk, no population-based case-control mutation screening data are available for the RAD51 gene. We thus postulated that RAD51 could harbor rare germline mutations that confer increased risk of breast cancer.We screened the coding exons and proximal splice junction regions of the gene for germline sequence variation in 1,330 early-onset breast cancer cases and 1,123 controls from the Breast Cancer Family Registry, using the same population-based sampling and analytical strategy that we developed for assessment of rare sequence variants in ATM and CHEK2. In total, 12 distinct very rare or private variants were characterized in RAD51, with 10 cases (0.75%) and 9 controls (0.80%) carrying such a variant. Variants were either likely neutral missense substitutions (3), silent substitutions (4) or non-coding substitutions (5) that were predicted to have little effect on efficiency of the splicing machinery.Altogether, our data suggest that RAD51 tolerates so little dysfunctional sequence variation that rare variants in the gene contribute little, if anything, to breast cancer susceptibility.

  View details for DOI 10.1371/journal.pone.0052374

  View details for Web of Science ID 000312829100045

  View details for PubMedID 23300655

  View details for PubMedCentralID PMC3531476

• A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11 HUMAN MOLECULAR GENETICS Siddiq, A., Couch, F. J., Chen, G. K., Lindstrom, S., Eccles, D., Millikan, R. C., Michailidou, K., Stram, D. O., Beckmann, L., Rhie, S. K., Ambrosone, C. B., Aittomaki, K., Amiano, P., Apicella, C., Baglietto, L., Bandera, E. V., Beckmann, M. W., Berg, C. D., Bernstein, L., Blomqvist, C., Brauch, H., Brinton, L., Bui, Q. M., Buring, J. E., Buys, S. S., Campa, D., Carpenter, J. E., Chasman, D. I., Chang-Claude, J., Chen, C., Clavel-Chapelon, F., Cox, A., Cross, S. S., Czene, K., Deming, S. L., Diasio, R. B., Diver, W. R., Dunning, A. M., Durcan, L., Ekici, A. B., Fasching, P. A., Feigelson, H. S., Fejerman, L., Figueroa, J. D., Fletcher, O., Flesch-Janys, D., Gaudet, M. M., Gerty, S. M., Rodriguez-Gil, J. L., Giles, G. G., van Gils, C. H., Godwin, A. K., Graham, N., Greco, D., Hall, P., Hankinson, S. E., Hartmann, A., Hein, R., Heinz, J., Hoover, R. N., Hopper, J. L., Hu, J. J., Huntsman, S., Ingles, S. A., Irwanto, A., Isaacs, C., Jacobs, K. B., John, E. M., Justenhoven, C., Kaaks, R., Kolonel, L. N., Coetzee, G. A., Lathrop, M., Le Marchand, L., Lee, A. M., Lee, I., Lesnick, T., Lichtner, P., Liu, J., Lund, E., Makalic, E., Martin, N. G., McLean, C. A., Meijers-Heijboer, H., Meindl, A., Miron, P., Monroe, K. R., Montgomery, G. W., Mueller-Myhsok, B., Nickels, S., Nyante, S. J., Olswold, C., Overvad, K., Palli, D., Park, D. J., Palmer, J. R., Pathak, H., Peto, J., Pharoah, P., Rahman, N., Rivadeneira, F., Schmidt, D. F., Schmutzler, R. K., Slager, S., Southey, M. C., Stevens, K. N., Sinn, H., Press, M. F., Ross, E., Riboli, E., Ridker, P. M., Schumacher, F. R., Severi, G., Silva, I. d., Stone, J., Sund, M., Tapper, W. J., Thun, M. J., Travis, R. C., Turnbull, C., Uitterlinden, A. G., Waisfisz, Q., Wang, X., Wang, Z., Weaver, J., Schulz-Wendtland, R., Wilkens, L. R., Van Den Berg, D., Zheng, W., Ziegler, R. G., Ziv, E., Nevanlinna, H., Easton, D. F., Hunter, D. J., Henderson, B. E., Chanock, S. J., Garcia-Closas, M., Kraft, P., Haiman, C. A., Vachon, C. M. 2012; 21 (24): 5373-5384

  Abstract

  Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.

  View details for DOI 10.1093/hmg/dds381

  View details for Web of Science ID 000311965600012

  View details for PubMedID 22976474

  View details for PubMedCentralID PMC3510753

• CHEK2*1100delC Heterozygosity in Women With Breast Cancer Associated With Early Death, Breast Cancer-Specific Death, and Increased Risk of a Second Breast Cancer JOURNAL OF CLINICAL ONCOLOGY Weischer, M., Nordestgaard, B. G., Pharoah, P., Bolla, M. K., Nevanlinna, H., van't Veer, L. J., Garcia-Closas, M., Hopper, J. L., Hall, P., Andrulis, I. L., Devilee, P., Fasching, P. A., Anton-Culver, H., Lambrechts, D., Hooning, M., Cox, A., Giles, G. G., Burwinkel, B., Lindblom, A., Couch, F. J., Mannermaa, A., Alnaes, G. G., John, E. M., Doerk, T., Flyger, H., Dunning, A. M., Wang, Q., Muranen, T. A., van Hien, R., Figueroa, J., Southey, M. C., Czene, K., Knight, J. A., Tollenaar, R. A., Beckmann, M. W., Ziogas, A., Christiaens, M., Collee, J. M., Reed, M. W., Severi, G., Marme, F., Margolin, S., Olson, J. E., Kosma, V., Kristensen, V. N., Miron, A., Bogdanova, N., Shah, M., Blomqvist, C., Broeks, A., Sherman, M., Phillips, K., Li, J., Liu, J., Glendon, G., Seynaeve, C., Ekici, A. B., Leunen, K., Kriege, M., Cross, S. S., Baglietto, L., Sohn, C., Wang, X., Kataja, V., Borresen-Dale, A., Meyer, A., Easton, D. F., Schmidt, M. K., Bojesen, S. E. 2012; 30 (35): 4308-4316

  Abstract

  We tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer-specific death, and risk of a second breast cancer in women with a first breast cancer.From 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer-specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies.CHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor-positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P = .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P < .001) for breast cancer-specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P < .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P < .001) in women with estrogen receptor-positive first breast cancer only.Among women with estrogen receptor-positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer-specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer.

  View details for DOI 10.1200/JCO.2012.42.7336

  View details for Web of Science ID 000312195900011

  View details for PubMedID 23109706

  View details for PubMedCentralID PMC3515767

• Identification of fifteen novel germline variants in the BRCA1 3 ' UTR reveals a variant in a breast cancer case that introduces a functional miR-103 target site HUMAN MUTATION Brewster, B. L., Rossiello, F., French, J. D., Edwards, S. L., Wong, M., Wronski, A., Whiley, P., Waddell, N., Chen, X., Bove, B., Hopper, J. L., John, E. M., Andrulis, I., Daly, M., Volorio, S., Bernard, L., Peissel, B., Manoukian, S., Barile, M., Pizzamiglio, S., Verderio, P., Spurdle, A. B., Radice, P., Godwin, A. K., Southey, M. C., Brown, M. A., Peterlongo, P. 2012; 33 (12): 1665-1675

  Abstract

  Mutations in the BRCA1 gene confer a substantial increase in breast cancer risk, yet routine clinical genetic screening is limited to the coding regions and intron-exon boundaries, precluding the identification of mutations in noncoding and untranslated regions (UTR). As 3'UTR mutations can influence cancer susceptibility by altering protein and microRNA (miRNA) binding regions, we screened the BRCA1 3'UTR for mutations in a large series of BRCA-mutation negative, population and clinic-based breast cancer cases, and controls. Fifteen novel BRCA1 3'UTR variants were identified, the majority of which were unique to either cases or controls. Using luciferase reporter assays, three variants found in cases, c.* 528G>C, c.* 718A>G, and c.* 1271T>C and four found in controls, c.* 309T>C, c.* 379G>A, c.* 823C>T, and c.* 264C>T, reduced 3'UTR activity (P < 0.02), whereas two variants found in cases, c.* 291C>T and c.* 1139G>T, increased 3'UTR activity (P < 0.01). Three case variants, c.* 718A>G, c.* 800T>C, and c.* 1340_1342delTGT, were predicted to create new miRNA binding sites and c.* 1340_1342delTGT caused a reduction (25%, P = 0.0007) in 3'UTR reporter activity when coexpressed with the predicted targeting miRNA, miR-103. This is the most comprehensive identification and analysis of BRCA1 3'UTR variants published to date.

  View details for DOI 10.1002/humu.22159

  View details for Web of Science ID 000310975900008

  View details for PubMedID 22753153

• Variation in Genes Related to Obesity, Weight, and Weight Change and Risk of Contralateral Breast Cancer in the WECARE Study Population CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Brooks, J. D., Bernstein, L., Teraoka, S. N., Knight, J. A., Mellemkjaer, L., John, E. M., Malone, K. E., Reiner, A. S., Lynch, C. F., Concannon, P., Haile, R. W., Bernstein, J. L. 2012; 21 (12): 2261-2267

  Abstract

  Body mass index (BMI), a known breast cancer risk factor, could influence breast risk through mechanistic pathways related to sex hormones, insulin resistance, chronic inflammation, and altered levels of adipose-derived hormones. Results from studies of the relationship between BMI and second primary breast cancer have been mixed. To explore the relationship between BMI and asynchronous contralateral breast cancer (CBC), we examined whether variants in genes related to obesity, weight, and weight change are associated with CBC risk.Variants in 20 genes [182 single-nucleotide polymorphisms (SNP)] involved in adipose tissue metabolism, energy balance, insulin resistance, and inflammation, as well as those identified through genome-wide association studies (GWAS) of BMI and type II-diabetes were evaluated. We examined the association between variants in these genes and the risk of CBC among Caucasian participants [643 cases with CBC and 1,271 controls with unilateral breast cancer (UBC)] in the population-based Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study using conditional logistic regression.After adjustment for multiple comparisons, no statistically significant associations between any variant and CBC risk were seen. Stratification by menopausal or estrogen receptor (ER) status did not alter these findings.Among women with early-onset disease who survive a first breast cancer diagnosis, there was no association between variation in obesity-related genes and risk of CBC.Genetic variants in genes related to obesity are not likely to strongly influence subsequent risk of developing a second primary breast cancer.

  View details for DOI 10.1158/1055-9965.EPI-12-1036

  View details for Web of Science ID 000312280800015

  View details for PubMedID 23033454

  View details for PubMedCentralID PMC3518741

• Reproductive Status at First Diagnosis Influences Risk of Radiation-Induced Second Primary Contralateral Breast Cancer in the WECARE Study INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Brooks, J. D., Boice, J. D., Stovall, M., Reiner, A. S., Bernstein, L., John, E. M., Lynch, C. F., Mellemkjaer, L., Knight, J. A., Thomas, D. C., Haile, R. W., Smith, S. A., Capanu, M., Bernstein, J. L., Shore, R. E. 2012; 84 (4): 917-924

  Abstract

  Our study examined whether reproductive and hormonal factors before, at the time of, or after radiation treatment for a first primary breast cancer modify the risk of radiation-induced second primary breast cancer.The Women's Environmental, Cancer and Radiation Epidemiology (WECARE) Study is a multicenter, population-based study of 708 women (cases) with asynchronous contralateral breast cancer (CBC) and 1399 women (controls) with unilateral breast cancer. Radiotherapy (RT) records, coupled with anthropomorphic phantom simulations, were used to estimate quadrant-specific radiation dose to the contralateral breast for each patient. Rate ratios (RR) and 95% confidence intervals (CI) were computed to assess the relationship between reproductive factors and risk of CBC.Women who were nulliparous at diagnosis and exposed to ≥1 Gy to the contralateral breast had a greater risk for CBC than did matched unexposed nulliparous women (RR=2.2; 95% CI, 1.2-4.0). No increased risk was seen in RT-exposed parous women (RR=1.1; 95% CI, 0.8-1.4). Women treated with RT who later became pregnant (8 cases and 9 controls) had a greater risk for CBC (RR=6.0; 95% CI, 1.3-28.4) than unexposed women (4 cases and 7 controls) who also became pregnant. The association of radiation with risk of CBC did not vary by number of pregnancies, history of breastfeeding, or menopausal status at the time of first breast cancer diagnosis.Nulliparous women treated with RT were at an increased risk for CBC. Although based on small numbers, women who become pregnant after first diagnosis also seem to be at an increased risk for radiation-induced CBC.

  View details for DOI 10.1016/j.ijrobp.2012.01.047

  View details for Web of Science ID 000310565300027

  View details for PubMedID 22483700

  View details for PubMedCentralID PMC3394928

• Red meat and poultry, cooking practices, genetic susceptibility and risk of prostate cancer: results from a multiethnic case-control study CARCINOGENESIS Joshi, A. D., Corral, R., Catsburg, C., Lewinger, J. P., Koo, J., John, E. M., Ingles, S. A., Stern, M. C. 2012; 33 (11): 2108-2118

  Abstract

  Red meat, processed and unprocessed, has been considered a potential prostate cancer (PCA) risk factor; epidemiological evidence, however, is inconclusive. An association between meat intake and PCA may be due to potent chemical carcinogens that are generated when meats are cooked at high temperatures. We investigated the association between red meat and poultry intake and localized and advanced PCA taking into account cooking practices and polymorphisms in enzymes that metabolize carcinogens that accumulate in cooked meats. We analyzed data for 1096 controls, 717 localized and 1140 advanced cases from the California Collaborative Prostate Cancer Study, a multiethnic, population-based case-control study. We examined nutrient density-adjusted intake of red meat and poultry and tested for effect modification by 12 SNPs and 2 copy number variants in 10 carcinogen metabolism genes: GSTP1, PTGS2, CYP1A2, CYP2E1, EPHX1, CYP1B1, UGT1A6, NAT2, GSTM1 and GSTT1. We observed a positive association between risk of advanced PCA and high intake of red meat cooked at high temperatures (trend P = 0.026), cooked by pan-frying (trend P = 0.035), and cooked until well-done (trend P = 0.013). An inverse association was observed for baked poultry and advanced PCA risk (trend P = 0.023). A gene-by-diet interaction was observed between an SNP in the PTGS2 gene and the estimated levels of meat mutagens (interaction P = 0.008). Our results support a role for carcinogens that accumulate in meats cooked at high temperatures as potential PCA risk factors, and may support a role for heterocyclic amines (HCAs) in PCA etiology.

  View details for DOI 10.1093/carcin/bgs242

  View details for Web of Science ID 000310624400012

  View details for PubMedID 22822096

  View details for PubMedCentralID PMC3584966

• Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies LANCET ONCOLOGY Beral, V., Bull, D., Pirie, K., Reeves, G., Peto, R., Skegg, D., LAVECCHIA, C., Magnusson, C., Pike, M. C., Thomas, D., Hamajima, N., Hirose, K., Tajima, K., Rohan, T., Friedenreich, C. M., Calle, E. E., Gapstur, S. M., Patel, A. V., Coates, R. J., Liff, J. M., Talamini, R., CHANTARAKUL, N., KOETSAWANG, S., RACHAWAT, D., Marcou, Y., Kakouri, E., Duffy, S. W., Morabia, A., Schuman, L., Stewart, W., Szklo, M., Coogan, P. F., Palmer, J. R., Rosenberg, L., Band, P., Coldman, A. J., Gallagher, R. P., Hislop, T. G., Yang, P., Cummings, S. R., Canfell, K., Sitas, F., Chao, P., Lissowska, J., Horn-Ross, P. L., John, E. M., Kolonel, L. M., Nomura, A. M., Ghiasvand, R., Hu, J., Johnson, K. C., Mao, Y., Callaghan, K., Crossley, B., Goodill, A., Green, J., Hermon, C., Key, T., Lindgard, I., Liu, B., Pirie, K., Reeves, G., Collins, R., DOLL, R., Peto, R., Bishop, T., Fentiman, I. S., De Sanjose, S., Gonzaler, C. A., Lee, N., Marchbanks, P., Ory, H. W., Peterson, H. B., Wingo, P., Ebeling, K., Kunde, D., Nishan, P., Hopper, J. L., ELIASSEN, H., Gajalakshmi, V., Martin, N., PARDTHAISONG, T., SILPISORNKOSOL, S., Theetranont, C., BOOSIRI, B., CHUTIVONGSE, S., Jimakorn, P., Virutamasen, P., Wongsrichanalai, C., Neugut, A., Santella, R., Baines, C. J., Kreiger, N., Miller, A. B., WALL, C., Tjonneland, A., Jorgensen, T., Stahlberg, C., Pedersen, A. T., Flesch-Janys, D., Hakansson, N., Cauley, J., Heuch, I., Adami, H. O., Persson, I., Weiderpass, E., Magnusson, C., Chang-Claude, J., Kaaks, R., McCredie, M., Paul, C., Skegg, D. C., Spears, G. F., Iwasaki, M., Tsugane, S., Anderson, G., Daling, J. R., Hampton, J., Hutchinson, W. B., Li, C. I., Malone, K., Mandelson, M., Newcomb, P., NOONAN, E. A., Ray, R. M., Stanford, J. L., Tang, M. T., Thomas, D. B., Weiss, N. S., White, E., Izquierdo, A., Viladiu, P., Fourkala, E. O., Jacobs, I., Menon, U., Ryan, A., Cuevas, H. R., Ontiveros, P., PALET, A., Salazar, S. B., ARISTIZABAL, N., Cuadros, A., Tryggvadottir, L., Tulinius, H., Riboli, E., Andrieu, N., Bachelot, A., Le, M. G., Bremond, A., Gairard, B., Lansac, J., Piana, L., Renaud, R., Clavel-Chapelon, F., Fournier, A., Touillaud, M., Mesrine, S., Chabbert-Buffet, N., Boutron-Ruault, M. C., Wolk, A., Torres-Mejia, G., Franceschi, S., Romieu, I., Boyle, P., Lubin, F., Modan, B., Ron, E., Wax, Y., Friedman, G. D., Hiatt, R. A., Levi, F., Kosmelj, K., Primic-Zakelj, M., Ravnihar, B., Stare, J., Ekbom, A., Erlandsson, G., Persson, I., Beeson, W. L., Fraser, G., Peto, J., Hanson, R. L., Leske, M. C., Mahoney, M. C., Nasca, P. C., Varma, A. O., Weinstein, A. L., Hartman, M. L., Olsson, H., Goldbohm, R. A., van den Brandt, P. A., Palli, D., Teitelbaum, S., APELO, R. A., BAENS, J., de la Cruz, J. R., JAVIER, B., Lacaya, L. B., Ngelangel, C. A., La Vecchia, C., Negri, E., Marubini, E., Ferraroni, M., Pike, M. C., Gerber, M., Richardson, S., Segala, C., Gatei, D., Kenya, P., Kungu, A., Mati, J. G., Brinton, L. A., Freedman, M., Hoover, R., Schairer, C., Ziegler, R., Banks, E., Spirtas, R., Lee, H. P., Rookus, M. A., van Leeuwen, F. E., Schoenberg, J. A., Graff-Iversen, S., Selmer, R., Jones, L., McPherson, K., Neil, A., Vessey, M., Yeates, D., Mabuchi, K., Preston, D., Hannaford, P., Kay, C., McCann, S. E., Rosero-Bixby, L., Gao, Y. T., Jin, F., Yuan, J., Wei, H. Y., Yun, T., Zhiheng, C., Berry, G., Booth, J. C., JELIHOVSKY, T., MACLENNAN, R., SHEARMAN, R., Hadjisavvas, A., Kyriacou, K., Loisidou, M., Zhou, X., Wang, Q., Kawai, M., Minami, Y., Tsuji, I., Lund, E., Kumle, M., Stalsberg, H., Shu, X. O., Zheng, W., Monninkhof, E. M., Onland-Moret, N. C., Peeters, P. H., Katsouyanni, K., Trichopoulou, A., Trichopoulos, D., Tzonou, A., Baltzell, K. A., DABANCENS, A., Martinez, L., Molina, R., SALAS, O., Alexander, F. E., Anderson, K., Folsom, A. R., Gammon, M. D., Hulka, B. S., Millikan, R., Chilvers, C. E., Lumachi, F., Bain, C., Schofield, F., Siskind, V., Rebbeck, T. R., Bernstein, L. R., Enger, S., Haile, R. W., Paganini-Hill, A., Ross, R. K., Ursin, G., Wu, A. H., Yu, M. C., Ewertz, D. M., Clarke, E. A., Bergkvist, L., Anderson, G. L., Gass, M., O'Sullivan, M. J., Kalache, A., Farley, T. M., Holck, S., MEIRIK, O., Fukao, A. 2012; 13 (11): 1141-1151

  Abstract

  Menarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women.Individual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression.Breast cancer risk increased by a factor of 1·050 (95% CI 1·044-1·057; p<0·0001) for every year younger at menarche, and independently by a smaller amount (1·029, 1·025-1·032; p<0·0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45-54 years 1·43, 1·33-1·52, p<0·001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women's year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p<0·006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p<0·01 for both comparisons).The effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women's total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours.Cancer Research UK.

  View details for DOI 10.1016/S1470-2045(12)70425-4

  View details for Web of Science ID 000310570900045

  View details for PubMedCentralID PMC3488186

• Associations between TCF7L2 polymorphisms and risk of breast cancer among Hispanic and non-Hispanic White women: the Breast Cancer Health Disparities Study BREAST CANCER RESEARCH AND TREATMENT Connor, A. E., Baumgartner, R. N., Baumgartner, K. B., Kerber, R. A., Pinkston, C., John, E. M., Torres-Mejia, G., Hines, L., Giuliano, A., Wolff, R. K., Slattery, M. L. 2012; 136 (2): 593-602

  Abstract

  The transcription factor 7-like 2 (TCF7L2) gene is part of the Wnt/β-catenin signaling pathway and plays a critical role in cell development and growth regulation. TCF7L2 variants rs12255372 and rs7903146 have been associated with risk of Type 2 diabetes. Few epidemiological studies have examined the association between TCF7L2 and breast cancer risk. We investigated the associations between 25 TCF7L2 single nucleotide polymorphisms (SNPs) and breast cancer in Hispanic and non-Hispanic white (NHW) women from the 4-Corner's Breast Cancer Study, the San Francisco Bay Area Breast Cancer Study, and the Mexico Breast Cancer Study. A total of 4,703 Hispanic (2,093 cases, 2,610 controls) and 3,031 NHW (1,431 cases, 1,600 controls) women were included. Odds ratios (OR) and 95 % confidence intervals (CI) were calculated using logistic regression to estimate the association between the TCF7L2 SNPs and breast cancer risk. We also examined effect modification by self-reported ethnicity, genetic admixture, and diabetes history. After adjusting for multiple comparisons, four TCF7L2 SNPs were significantly associated with breast cancer overall: rs7903146 (OR(TT) 1.24; 95 % CI 1.03-1.49), rs3750805 (OR(AT/TT) 1.15; 95 % CI 1.03-1.28), rs7900150 (OR(AA) 1.23; 95 % 1.07-1.42), and rs1225404 (OR(CC) 0.82; 95 % 0.70-0.94). Among women with a history of diabetes, the TT genotype of rs3750804 increased breast cancer risk (OR, 2.46; 95 % CI 1.28-4.73). However, there was no association among women without a diabetes history (OR, 1.06; 95 % CI 0.85-1.32). We did not find significant interactions by ethnicity or by genetic admixture. Findings support an association between TCF7L2 and breast cancer and history of diabetes modifies this association for specific variants.

  View details for DOI 10.1007/s10549-012-2299-7

  View details for Web of Science ID 000310378700027

  View details for PubMedID 23085767

  View details for PubMedCentralID PMC3662467

• 9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Warren, H., Dudbridge, F., Fletcher, O., Orr, N., Johnson, N., Hopper, J. L., Apicella, C., Southey, M. C., Mahmoodi, M., Schmidt, M. K., Broeks, A., Cornelissen, S., Braaf, L. M., Muir, K. R., Lophatananon, A., Chaiwerawattana, A., Wiangnon, S., Fasching, P. A., Beckmann, M. W., Ekici, A. B., Schulz-Wendtland, R., Sawyer, E. J., Tomlinson, I., Kerin, M., Burwinkel, B., Marme, F., Schneeweiss, A., Sohn, C., Guenel, P., Therese Truong, T., Laurent-Puig, P., Mulot, C., Bojesen, S. E., Nielsen, S. F., Flyger, H., Nordestgaard, B. G., Milne, R. L., Benitez, J., Arias-Perez, J., Pilar Zamora, M., Anton-Culver, H., Ziogas, A., Bernstein, L., Dur, C. C., Brenner, H., Mueller, H., Arndt, V., Langheinz, A., Meindl, A., Golatta, M., Bartram, C. R., Schmutzler, R. K., Brauch, H., Justenhoven, C., Bruening, T., Chang-Claude, J., Wang-Gohrke, S., Eilber, U., Doerk, T., Schuermann, P., Bremer, M., Hillemanns, P., Nevanlinna, H., Muranen, T. A., Aittomaki, K., Blomqvist, C., Bogdanova, N., Antonenkova, N., Rogov, Y., Bermisheva, M., Prokofyeva, D., Zinnatullina, G., Khusnutdinova, E., Lindblom, A., Margolin, S., Mannermaa, A., Kosma, V., Hartikainen, J. M., Kataja, V., Chenevix-Trench, G., Beesley, J., Chen, X., Lambrechts, D., Smeets, A., Paridaens, R., Weltens, C., Flesch-Janys, D., Buck, K., Behrens, S., Peterlongo, P., Bernard, L., Manoukian, S., Radice, P., Couch, F. J., Vachon, C., Wang, X., Olson, J., Giles, G., Baglietto, L., McLean, C. A., Severi, G., John, E. M., Miron, A., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Andrulis, I. L., Knight, J. A., Mulligan, A. M., Weerasooriya, N., Devilee, P., Tollenaar, R. A., Martens, J. W., Seynaeve, C. M., Hooning, M. J., Hollestelle, A., Jager, A., Tilanus-Linthorst, M. M., Hall, P., Czene, K., Liu, J., Li, J., Cox, A., Cross, S. S., Brock, I. W., Reed, M. W., Pharoah, P., Blows, F. M., Dunning, A. M., Ghous-saini, M., Ashworth, A., Swerdlow, A., Jones, M., Schoemaker, M., Easton, D. F., Humphreys, M., Wang, Q., Peto, J., dos-Santos-Silva, I. 2012; 21 (10): 1783-1791

  Abstract

  Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls).This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10(-29)] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (P(het)) = 1.3 × 10(-143)], but no evidence of ethnic differences in per allele OR (P(het) = 0.43). rs865686 was associated with estrogen receptor-positive (ER(+)) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10(-22)) but less strongly, if at all, with ER-negative (ER(-)) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; P(het) = 1.16 × 10(-6)), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER(+) tumors.This study is the first to show that rs865686 is a susceptibility marker for ER(+) breast cancer.The findings further support the view that genetic susceptibility varies according to tumor subtype.

  View details for DOI 10.1158/1055-9965.EPI-12-0526

  View details for Web of Science ID 000309576100022

  View details for PubMedID 22859399

• The role of genetic breast cancer susceptibility variants as prognostic factors HUMAN MOLECULAR GENETICS Fasching, P. A., Pharoah, P. D., Cox, A., Nevanlinna, H., Bojesen, S. E., Karn, T., Broeks, A., van Leeuwen, F. E., van 't Veer, L. J., Udo, R., Dunning, A. M., Greco, D., Aittomaki, K., Blomqvist, C., Shah, M., Nordestgaard, B. G., Flyger, H., Hopper, J. L., Southey, M. C., Apicella, C., Garcia-Closas, M., Sherman, M., Lissowska, J., Seynaeve, C., Huijts, P. E., Tollenaar, R. A., Ziogas, A., Ekici, A. B., Rauh, C., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Andrulis, I. L., Ozcelik, H., Mulligan, A., Glendon, G., Hall, P., Czene, K., Liu, J., Chang-Claude, J., Wang-Gohrke, S., Eilber, U., Nickels, S., Doerk, T., Schiekel, M., Bremer, M., Park-Simon, T., Giles, G. G., Severi, G., Baglietto, L., Hooning, M. J., Martens, J. W., Jager, A., Kriege, M., Lindblom, A., Margolin, S., Couch, F. J., Stevens, K. N., Olson, J. E., Kosei, M., Cross, S. S., Balasubramanian, S. P., Reed, M. W., Miron, A., John, E. M., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Kauppila, S., Burwinkel, B., Marme, F., Schneeweiss, A., Sohn, C., Chenevix-Trench, G., Lambrechts, D., Dieudonne, A., Hatse, S., Van Limbergen, E., Benitez, J., Milne, R. L., Pilar Zamora, M., Arias Perez, J. I., Bonanni, B., Peissel, B., Loris, B., Peterlongo, P., Rajaraman, P., Schonfeld, S. J., Anton-Culver, H., Devilee, P., Beckmann, M. W., Slamon, D. J., Phillips, K., Figueroa, J. D., Humphreys, M. K., Easton, D. F., Schmidt, M. K. 2012; 21 (17): 3926-3939

  Abstract

  Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.

  View details for DOI 10.1093/hmg/dds159

  View details for Web of Science ID 000307504100018

  View details for PubMedCentralID PMC3412377

• Racial and Ethnic Differences in Adjuvant Hormonal Therapy Use JOURNAL OF WOMENS HEALTH Livaudais, J. C., Li, C., John, E. M., Terry, M. B., Daly, M., Buys, S. S., Habel, L., Thompson, B., Yanez, N. D., Coronado, G. D. 2012; 21 (9): 950-958

  Abstract

  In the United States, 5-year breast cancer survival is highest among Asian American women, followed by non-Hispanic white, Hispanic, and African American women. Breast cancer treatment disparities may play a role. We examined racial/ethnic differences in adjuvant hormonal therapy use among women aged 18-64 years, diagnosed with hormone receptor-positive breast cancer, using data collected by the Northern California Breast Cancer Family Registry (NC-BCFR), and explored changes in use over time.Odds ratios (OR) comparing self-reported ever-use by race/ethnicity (African American, Hispanic, non-Hispanic white vs. Asian American) were estimated using multivariable adjusted logistic regression. Analyses were stratified by recruitment phase (phase I, diagnosed January 1995-September 1998, phase II, diagnosed October 1998-April 2003) and genetic susceptibility, as cases with increased genetic susceptibility were oversampled.Among 1385 women (731 phase I, 654 phase II), no significant racial/ethnic differences in use were observed among phase I or phase II cases. However, among phase I cases with no susceptibility indicators, African American and non-Hispanic white women were less likely than Asian American women to use hormonal therapy (OR 0.20, 95% confidence interval [CI]0.06-0.60; OR 0.40, CI 0.17-0.94, respectively). No racial/ethnic differences in use were observed among women with 1+ susceptibility indicators from either recruitment phase.Racial/ethnic differences in adjuvant hormonal therapy use were limited to earlier diagnosis years (phase I) and were attenuated over time. Findings should be confirmed in other populations but indicate that in this population, treatment disparities between African American and Asian American women narrowed over time as adjuvant hormonal treatments became more commonly prescribed.

  View details for DOI 10.1089/jwh.2011.3254

  View details for Web of Science ID 000308409200011

  View details for PubMedID 22731764

  View details for PubMedCentralID PMC3430474

• Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC) PLOS ONE Hein, R., Maranian, M., Hopper, J. L., Kapuscinski, M. K., Southey, M. C., Park, D. J., Schmidt, M. K., Broeks, A., Hogervorst, F. B., Bueno-de-Mesquit, H. B., Muir, K. R., Lophatananon, A., Rattanamongkongul, S., Puttawibul, P., Fasching, P. A., Hein, A., Ekici, A. B., Beckmann, M. W., Fletcher, O., Johnson, N., Silva, I. d., Peto, J., Sawyer, E., Tomlinson, I., Kerin, M., Miller, N., Marmee, F., Schneeweiss, A., Sohn, C., Burwinkel, B., Guenel, P., Cordina-Duverger, E., Menegaux, F., Truong, T., Bojesen, S. E., Nordestgaard, B. G., Flyger, H., Milne, R. L., Arias Perez, J. I., Pilar Zamora, M., Benitez, J., Anton-Culver, H., Ziogas, A., Bernstein, L., Clarke, C. A., Brenner, H., Mueller, H., Arndt, V., Stegmaier, C., Rahman, N., Seal, S., Turnbull, C., Renwick, A., Meindl, A., Schott, S., Bartram, C. R., Schmutzler, R. K., Brauch, H., Hamann, U., Ko, Y., Wang-Gohrke, S., Doerk, T., Schuermann, P., Karstens, J. H., Hillemanns, P., Nevanlinna, H., Heikkinen, T., Aittomaki, K., Blomqvist, C., Bogdanova, N. V., Zalutsky, I. V., Antonenkova, N. N., Bermisheva, M., Prokovieva, D., Farahtdinova, A., Khusnutdinova, E., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J., Chen, X., Beesley, J., Lambrechts, D., Zhao, H., Neven, P., Wildiers, H., Nickels, S., Flesch-Janys, D., Radice, P., Peterlongo, P., Manoukian, S., Barile, M., Couch, F. J., Olson, J. E., Wang, X., Fredericksen, Z., Giles, G. G., Baglietto, L., McLean, C. A., Severi, G., Offit, K., Robson, M., Gaudet, M. M., Vijai, J., Alnaes, G. G., Kristensen, V., Borresen-Dale, A., John, E. M., Miron, A., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Andrulis, I. L., Knight, J. A., Glendon, G., Mulligan, A. M., Figueroa, J. D., Garcia-Closas, M., Lissowska, J., Sherman, M. E., Hooning, M., Martens, J. W., Seynaeve, C., Collee, M., Hall, P., Humpreys, K., Czene, K., Liu, J., Cox, A., Brock, I. W., Cross, S. S., Reed, M. W., Ahmed, S., Ghoussaini, M., Pharoah, P. D., Kang, D., Yoo, K., Noh, D., Jakubowska, A., Jaworska, K., Durda, K., Zlowocka, E., Sangrajrang, S., Gaborieau, V., Brennan, P., McKay, J., Shen, C., Yu, J., Hsu, H., Hou, M., Orr, N., Schoemaker, M., Ashworth, A., Swerdlow, A., Trentham-Dietz, A., Newcomb, P. A., Titus, L., Egan, K. M., Chenevix-Trench, G., Antoniou, A. C., Humphreys, M. K., Morrison, J., Chang-Claude, J., Easton, D. F., Dunning, A. M. 2012; 7 (8)

  Abstract

  The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.

  View details for DOI 10.1371/journal.pone.0042380

  View details for Web of Science ID 000307437900035

• A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ding, Y. C., McGuffog, L., Healey, S., friedman, e., Laitman, Y., Shani-Paluch-Shimon, Kaufman, B., Liljegren, A., Lindblom, A., Olsson, H., Kristoffersson, U., Stenmark-Askmalm, M., Melin, B., Domchek, S. M., Nathanson, K. L., Rebbeck, T. R., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Gronwald, J., Huzarski, T., Cybulski, C., Byrski, T., Osorio, A., Ramony Cajal, T., Stavropoulou, A. V., Benitez, J., Hamann, U., Rookus, M., Aalfs, C. M., de Lange, J. L., Meijers-Heijboer, H. E., Oosterwijk, J. C., van Asperen, C. J., Garcia, E. B., Hoogerbrugge, N., Jager, A., van der Luijt, R. B., Easton, D. F., Peock, S., Frost, D., Ellis, S. D., Platte, R., Fineberg, E., Evans, D. G., Lalloo, F., Izatt, L., Eeles, R., Adlard, J., Davidson, R., Eccles, D., Cole, T., Cook, J., Brewer, C., Tischkowitz, M., Godwin, A. K., Pathak, H., Stoppa-Lyonnet, D., Sinilnikova, O. M., Mazoyer, S., Barjhoux, L., Leone, M., Gauthier-Villars, M., Caux-Moncoutier, V., De Pauw, A., Hardouin, A., Berthet, P., Dreyfus, H., Ferrer, S. F., Collonge-Rame, M., Sokolowska, J., Buys, S., Daly, M., Miron, A., Terry, M. B., Chung, W., John, E. M., Southey, M., Goldgar, D., Singer, C. F., Tea, M. M., Gschwantler-Kaulich, D., Fink-Retter, A., Hansen, T. v., Ejlertsen, B., Johannsson, O. T., Offit, K., Sarrel, K., Gaudet, M. M., Vijai, J., Robson, M., Piedmonte, M. R., Andrews, L., Cohn, D., DeMars, L. R., DiSilvestro, P., Rodriguez, G., Toland, A. E., Montagna, M., Agata, S., Imyanitov, E., Isaacs, C., Janavicius, R., Lazaro, C., Blanco, I., Ramus, S. J., Sucheston, L., Karlan, B. Y., Gross, J., Ganz, P. A., Beattie, M. S., Schmutzler, R. K., Wappenschmidt, B., Meindl, A., Arnold, N., Niederacher, D., Preisler-Adams, S., Gadzicki, D., Varon-Mateeva, R., Deissler, H., Gehrig, A., Sutter, C., Kast, K., Nevanlinna, H., Aittomaki, K., Simard, J., Spurdle, A. B., Beesley, J., Chen, X., Tomlinson, G. E., Weitzel, J., Garber, J. E., Olopade, O. I., Rubinstein, W. S., Tung, N., Blum, J. L., Narod, S. A., Brummel, S., Gillen, D. L., Lindor, N., Fredericksen, Z., Pankratz, V. S., Couch, F. J., Radice, P., Peterlongo, P., Greene, M. H., Loud, J. T., Mai, P. L., Andrulis, I. L., Glendon, G., Ozcelik, H., Gerdes, A., Thomassen, M., Jensen, U. B., Skytte, A., Caligo, M. A., Lee, A., Chenevix-Trench, G., Antoniou, A. C., Neuhausen, S. L. 2012; 21 (8): 1362-1370

  Abstract

  We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers.IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers.Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03).The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers.These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.

  View details for DOI 10.1158/1055-9965.EPI-12-0229

  View details for Web of Science ID 000307433800016

  View details for PubMedID 22729394

  View details for PubMedCentralID PMC3415567

• Risk factors for uncommon histologic subtypes of breast cancer using centralized pathology review in the Breast Cancer Family Registry BREAST CANCER RESEARCH AND TREATMENT Work, M. E., Andrulis, I. L., John, E. M., Hopper, J. L., Liao, Y., Zhang, F. F., Knight, J. A., West, D. W., Milne, R. L., Giles, G. G., Longacre, T. A., O'Malley, F., Mulligan, A. M., Southey, M. C., Hibshoosh, H., Terry, M. B. 2012; 134 (3): 1209-1220

  Abstract

  Epidemiologic studies of histologic types of breast cancer including mucinous, medullary, and tubular carcinomas have primarily relied on International Classification of Diseases-Oncology (ICD-O) codes assigned by local pathologists to define histology. Using data from the Breast Cancer Family Registry (BCFR), we compared histologic agreement between centralized BCFR pathology review and ICD-O codes available from local tumor registries among 3,260 breast cancer cases. Agreement was low to moderate for less common histologies; for example, only 55 and 26 % of cases classified as mucinous and medullary, respectively, by centralized review were similarly classified using ICD-O coding. We then evaluated risk factors for each histologic subtype by comparing each histologic case group defined by centralized review with a common set of 2,997 population-based controls using polytomous logistic regression. Parity [odds ratio (OR) = 0.4, 95 % confidence interval (95 % CI): 0.2-0.9, for parous vs. nulliparous], age at menarche (OR = 0.5, 95 % CI: 0.3-0.9, for age ≥13 vs. ≤11), and use of oral contraceptives (OCs) (OR = 0.5, 95 % CI: 0.2-0.8, OC use >5 years vs. never) were associated with mucinous carcinoma (N = 92 cases). Body mass index (BMI) (OR = 1.05, 95 % CI: 1.0-1.1, per unit of BMI) and high parity (OR = 2.6, 95 % CI: 1.1-6.0 for ≥3 live births vs. nulliparous) were associated with medullary carcinoma (N = 90 cases). We did not find any associations between breast cancer risk factors and tubular carcinoma (N = 86 cases). Relative risk estimates from analyses using ICD-O classifications of histology, rather than centralized review, resulted in attenuated, and/or more imprecise, associations. These findings suggest risk factor heterogeneity across breast cancer tumor histologies, and demonstrate the value of centralized pathology review for classifying rarer tumor types.

  View details for DOI 10.1007/s10549-012-2056-y

  View details for Web of Science ID 000307273300029

  View details for PubMedID 22527103

  View details for PubMedCentralID PMC4470278

• Genetic variation in genes involved in hormones, inflammation and energetic factors and breast cancer risk in an admixed population CARCINOGENESIS Slattery, M. L., John, E. M., Torres-Mejia, G., Lundgreen, A., Herrick, J. S., Baumgartner, K. B., Hines, L. M., Stern, M. C., Wolff, R. K. 2012; 33 (8): 1512-1521

  Abstract

  Breast cancer incidence rates are characterized by unique racial and ethnic differences. Native American ancestry has been associated with reduced breast cancer risk. We explore the biological basis of disparities in breast cancer risk in Hispanic and non-Hispanic white women by evaluating genetic variation in genes involved in inflammation, insulin and energy homeostasis in conjunction with genetic ancestry. Hispanic (2111 cases, 2597 controls) and non-Hispanic white (1481 cases, 1586 controls) women enrolled in the 4-Corner's Breast Cancer Study, the Mexico Breast Cancer Study and the San Francisco Bay Area Breast Cancer Study were included. Genetic admixture was determined from 104 ancestral informative markers that discriminate between European and Native American ancestry. Twenty-one genes in the CHIEF candidate pathway were evaluated. Higher Native American ancestry was associated with reduced risk of breast cancer (odds ratio = 0.79, 95% confidence interval 0.65, 0.95) but was limited to postmenopausal women (odds ratio = 0.66, 95% confidence interval 0.52, 0.85). After adjusting for genetic ancestry and multiple comparisons, four genes were significantly associated with breast cancer risk, NFκB1, NFκB1A, PTEN and STK11. Within admixture strata, breast cancer risk among women with low Native American ancestry was associated with IkBKB, NFκB1, PTEN and RPS6KA2, whereas among women with high Native American ancestry, breast cancer risk was associated with IkBKB, mTOR, PDK2, PRKAA1, RPS6KA2 and TSC1. Higher Native American ancestry was associated with reduced breast cancer risk. Breast cancer risk differed by genetic ancestry along with genetic variation in genes involved in inflammation, insulin, and energy homeostasis.

  View details for DOI 10.1093/carcin/bgs163

  View details for Web of Science ID 000307781000010

  View details for PubMedID 22562547

  View details for PubMedCentralID PMC3499059

• 11q13 is a susceptibility locus for hormone receptor positive breast cancer HUMAN MUTATION Lambrechts, D., Truong, T., Justenhoven, C., Humphreys, M. K., Wang, J., Hopper, J. L., Dite, G. S., Apicella, C., Southey, M. C., Schmidt, M. K., Broeks, A., Cornelissen, S., van Hien, R., Sawyer, E., Tomlinson, I., Kerin, M., Miller, N., Milne, R. L., Pilar Zamora, M., Arias Perez, J. I., Benitez, J., Hamann, U., Ko, Y., Bruening, T., Chang-Claude, J., Eilber, U., Hein, R., Nickels, S., Flesch-Janys, D., Wang-Gohrke, S., John, E. M., Miron, A., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Chenevix-Trench, G., Beesley, J., Chen, X., Menegaux, F., Cordina-Duverger, E., Shen, C., Yu, J., Wu, P., Hou, M., Andrulis, I. L., Selander, T., Glendon, G., Mulligan, A. M., Anton-Culver, H., Ziogas, A., Muir, K. R., Lophatananon, A., Rattanamongkongul, S., Puttawibul, P., Jones, M., Orr, N., Ashworth, A., Swerdlow, A., Severi, G., Baglietto, L., Giles, G., Southey, M., Marme, F., Schneeweiss, A., Sohn, C., Burwinkel, B., Yesilyurt, B. T., Neven, P., Paridaens, R., Wildiers, H., Brenner, H., Mueller, H., Arndt, V., Stegmaier, C., Meindl, A., Schott, S., Bartram, C. R., Schmutzler, R. K., Cox, A., Brock, I. W., Elliott, G., Cross, S. S., Fasching, P. A., Schulz-Wendtland, R., Ekici, A. B., Beckmann, M. W., Fletcher, O., Johnson, N., Silva, I. d., Peto, J., Nevanlinna, H., Muranen, T. A., Aittomaki, K., Blomqvist, C., Doerk, T., Schuermann, P., Bremer, M., Hillemanns, P., Bogdanova, N. V., Antonenkova, N. N., Rogov, Y. I., Karstens, J. H., Khusnutdinova, E., Bermisheva, M., Prokofieva, D., Gancev, S., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Nordestgaard, B. G., Bojesen, S. E., Lanng, C., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Radice, P., Peterlongo, P., Manoukian, S., Bernard, L., Couch, F. J., Olson, J. E., Wang, X., Fredericksen, Z., Alnaes, G. G., Kristensen, V., Borresen-Dale, A., Devilee, P., Tollenaar, R. A., Seynaeve, C. M., Hooning, M. J., Garcia-Closas, M., Chanock, S. J., Lissowska, J., Sherman, M. E., Hall, P., Liu, J., Czene, K., Kang, D., Yoo, K., Noh, D., Lindblom, A., Margolin, S., Dunning, A. M., Pharoah, P. D., Easton, D. F., Guenel, P., Brauch, H. 2012; 33 (7): 1123-1132

  Abstract

  A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P ≤ 3 × 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 × 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype.

  View details for DOI 10.1002/humu.22089

  View details for Web of Science ID 000304815100017

  View details for PubMedID 22461340

  View details for PubMedCentralID PMC3370081

• Polymorphisms in carcinogen metabolism enzymes, fish intake, and risk of prostatecancer CARCINOGENESIS Catsburg, C., Joshi, A. D., Corral, R., Lewinger, J. P., Koo, J., John, E. M., Ingles, S. A., Stern, M. C. 2012; 33 (7): 1352-1359

  Abstract

  Cooking fish at high temperature can produce potent carcinogens such as heterocyclic amines and polycyclic aromatic hydrocarbons. The effects of these carcinogens may undergo modification by the enzymes responsible for their detoxification and/or activation. In this study, we investigated genetic polymorphisms in nine carcinogen metabolism enzymes and their modifying effects on the association between white or dark fish consumption and prostate cancer (PCA) risk. We genotyped 497 localized and 936 advanced PCA cases and 760 controls from the California Collaborative Case-Control Study of Prostate Cancer. Three polymorphisms, EPHX1 Tyr113His, CYP1B1 Leu432Val and GSTT1 null/present, were associated with localized PCA risk. The PTGS2 765 G/C polymorphism modified the association between white fish consumption and advanced PCA risk (interaction P 5 0.002), with high white fish consumption being positively associated with risk only among carriers of the C allele. This effect modification by PTGS2 genotype was stronger when restricted to consumption of well-done white fish (interaction P 5 0.021). These findings support the hypotheses that changes in white fish brought upon by high-temperature cooking methods, such as carcinogen accumulation and/or fatty acid composition changes, may contribute to prostate carcinogenesis. However, the gene-diet interactions should be interpreted with caution given the limited sample size. Thus, our findings require further validation with additional studies.

  View details for DOI 10.1093/carcin/bgs175

  View details for Web of Science ID 000306925600014

  View details for PubMedID 22610071

  View details for PubMedCentralID PMC3499053

• Genome-wide meta-analyses of smoking behaviors in African Americans TRANSLATIONAL PSYCHIATRY David, S. P., Hamidovic, A., Chen, G. K., Bergen, A. W., Wessel, J., Kasberger, J. L., BROWN, W. M., Petruzella, S., Thacker, E. L., Kim, Y., Nalls, M. A., Tranah, G. J., Sung, Y. J., Ambrosone, C. B., Arnett, D., Bandera, E. V., Becker, D. M., BECKER, L., Berndt, S. I., Bernstein, L., Blot, W. J., Broeckel, U., Buxbaum, S. G., Caporaso, N., Casey, G., Chanock, S. J., Deming, S. L., Diver, W. R., Eaton, C. B., Evans, D. S., Evans, M. K., Fornage, M., Franceschini, N., Harris, T. B., Henderson, B. E., Hernandez, D. G., Hitsman, B., Hu, J. J., Hunt, S. C., Ingles, S. A., John, E. M., Kittles, R., Kolb, S., Kolonel, L. N., Le Marchand, L., Liu, Y., Lohman, K. K., McKnight, B., Millikan, R. C., Murphy, A., Neslund-Dudas, C., Nyante, S., Press, M., Psaty, B. M., Rao, D. C., Redline, S., Rodriguez-Gil, J. L., Rybicki, B. A., Signorello, L. B., Singleton, A. B., Smoller, J., Snively, B., Spring, B., Stanford, J. L., Strom, S. S., Swan, G. E., Taylor, K. D., Thun, M. J., Wilson, A. F., Witte, J. S., Yamamura, Y., Yanek, L. R., Yu, K., Zheng, W., Ziegler, R. G., Zonderman, A. B., Jorgenson, E., Haiman, C. A., Furberg, H. 2012; 2

  Abstract

  The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

  View details for DOI 10.1038/tp.2012.41

  View details for Web of Science ID 000312895700012

  View details for PubMedID 22832964

  View details for PubMedCentralID PMC3365260

• Admixture mapping identifies a locus on 6q25 associated with breast cancer risk in US Latinas HUMAN MOLECULAR GENETICS Fejerman, L., Chen, G. K., Eng, C., Huntsman, S., Hu, D., Williams, A., Pasaniuc, B., John, E. M., Via, M., Gignoux, C., Ingles, S., Monroe, K. R., Kolonel, L. N., Torres-Mejia, G., Perez-Stable, E. J., Burchard, E. G., Henderson, B. E., Haiman, C. A., Ziv, E. 2012; 21 (8): 1907-1917

  Abstract

  Among US Latinas and Mexican women, those with higher European ancestry have increased risk of breast cancer. We combined an admixture mapping and genome-wide association mapping approach to search for genomic regions that may explain this observation. Latina women with breast cancer (n= 1497) and Latina controls (n= 1272) were genotyped using Affymetrix and Illumina arrays. We inferred locus-specific genetic ancestry and compared the ancestry between cases and controls. We also performed single nucleotide polymorphism (SNP) association analyses in regions of interest. Correction for multiple-hypothesis testing was conducted using permutations (P(corrected)). We identified one region where genetic ancestry was significantly associated with breast cancer risk: 6q25 [odds ratio (OR) per Indigenous American chromosome 0.75, 95% confidence interval (CI): 0.65-0.85, P= 1.1 × 10(-5), P(corrected)= 0.02]. A second region on 11p15 showed a trend towards association (OR per Indigenous American chromosome 0.77, 95% CI: 0.68-0.87, P= 4.3 × 10(-5), P(corrected)= 0.08). In both regions, breast cancer risk decreased with higher Indigenous American ancestry in concordance with observations made on global ancestry. The peak of the 6q25 signal includes the estrogen receptor 1 (ESR1) gene and 5' region, a locus previously implicated in breast cancer. Genome-wide association analysis found that a multi-SNP model explained the admixture signal in both regions. Our results confirm that the association between genetic ancestry and breast cancer risk in US Latinas is partly due to genetic differences between populations of European and Indigenous Americans origin. Fine-mapping within the 6q25 and possibly the 11p15 loci will lead to the discovery of the biologically functional variant/s behind this association.

  View details for DOI 10.1093/hmg/ddr617

  View details for Web of Science ID 000302302400019

  View details for PubMedID 22228098

  View details for PubMedCentralID PMC3313799

• Rare Mutations in XRCC2 Increase the Risk of Breast Cancer AMERICAN JOURNAL OF HUMAN GENETICS Park, D. J., Lesueur, F., Nguyen-Dumont, T., Pertesi, M., Odefrey, F., Hammet, F., Neuhausen, S. L., John, E. M., Andrulis, I. L., Terry, M. B., Daly, M., Buys, S., Le Calvez-Kelm, F., LONIE, A., Pope, B. J., Tsimiklis, H., VOEGELE, C., Hilbers, F. M., Hoogerbrugge, N., Barroso, A., Osorio, A., Giles, G. G., Devilee, P., Benitez, J., Hopper, J. L., Tavtigian, S. V., Goldgar, D. E., Southey, M. C. 2012; 90 (4): 734-739

  Abstract

  An exome-sequencing study of families with multiple breast-cancer-affected individuals identified two families with XRCC2 mutations, one with a protein-truncating mutation and one with a probably deleterious missense mutation. We performed a population-based case-control mutation-screening study that identified six probably pathogenic coding variants in 1,308 cases with early-onset breast cancer and no variants in 1,120 controls (the severity grading was p < 0.02). We also performed additional mutation screening in 689 multiple-case families. We identified ten breast-cancer-affected families with protein-truncating or probably deleterious rare missense variants in XRCC2. Our identification of XRCC2 as a breast cancer susceptibility gene thus increases the proportion of breast cancers that are associated with homologous recombination-DNA-repair dysfunction and Fanconi anemia and could therefore benefit from specific targeted treatments such as PARP (poly ADP ribose polymerase) inhibitors. This study demonstrates the power of massively parallel sequencing for discovering susceptibility genes for common, complex diseases.

  View details for DOI 10.1016/j.ajhg.2012.02.027

  View details for Web of Science ID 000302833400018

  View details for PubMedID 22464251

  View details for PubMedCentralID PMC3322233

• Evaluation of 19 susceptibility loci of breast cancer in women of African ancestry CARCINOGENESIS Huo, D., Zheng, Y., Ogundiran, T. O., Adebamowo, C., Nathanson, K. L., Domchek, S. M., Rebbeck, T. R., Simon, M. S., John, E. M., Hennis, A., Nemesure, B., Wu, S., Leske, M. C., Ambs, S., Niu, Q., Zhang, J., Cox, N. J., Olopade, O. I. 2012; 33 (4): 835-840

  Abstract

  Multiple breast cancer susceptibility loci have been identified in genome-wide association studies (GWAS) in populations of European and Asian ancestry using array chips optimized for populations of European ancestry. It is important to examine whether these loci are associated with breast cancer risk in women of African ancestry. We evaluated 25 single nucleotide polymorphisms (SNPs) at 19 loci in a pooled case-control study of breast cancer, which included 1509 cases and 1383 controls. Cases and controls were enrolled in Nigeria, Barbados and the USA; all women were of African ancestry. We found significant associations for three SNPs, which were in the same direction and of similar magnitude as those reported in previous fine-mapping studies in women of African ancestry. The allelic odds ratios were 1.24 [95% confidence interval (CI): 1.04-1.47; P = 0.018] for the rs2981578-G allele (10q26/FGFR2), 1.34 (95% CI: 1.10-1.63; P = 0.0035) for the rs9397435-G allele (6q25) and 1.12 (95% CI: 1.00-1.25; P = 0.04) for the rs3104793-C allele (16q12). Although a significant association was observed for an additional index SNP (rs3817198), it was in the opposite direction to prior GWAS studies. In conclusion, this study highlights the complexity of applying current GWAS findings across racial/ethnic groups, as none of GWAS-identified index SNPs could be replicated in women of African ancestry. Further fine-mapping studies in women of African ancestry will be needed to reveal additional and causal variants for breast cancer.

  View details for DOI 10.1093/carcin/bgs093

  View details for Web of Science ID 000302493800014

  View details for PubMedID 22357627

  View details for PubMedCentralID PMC3324445

• Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Couch, F. J., Gaudet, M. M., Antoniou, A. C., Ramus, S. J., Kuchenbaecker, K. B., Soucy, P., Beesley, J., Chen, X., Wang, X., Kirchhoff, T., McGuffog, L., Barrowdale, D., Lee, A., Healey, S., Sinilnikova, O. M., Andrulis, I. L., Ozcelik, H., Mulligan, A. M., Thomassen, M., Gerdes, A., Jensen, U. B., Skytte, A., Kruse, T. A., Caligo, M. A., von Wachenfeldt, A., Barbany-Bustinza, G., Loman, N., Soller, M., Ehrencrona, H., Karlsson, P., Nathanson, K. L., Rebbeck, T. R., Domchek, S. M., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Zlowocka, E., Huzarski, T., Byrski, T., Gronwald, J., Cybulski, C., Gorski, B., Osorio, A., Duran, M., Isabel Tejada, M., Benitez, J., Hamann, U., Hogervorst, F. B., van Os, T. A., van Leeuwen, F. E., Meijers-Heijboer, H. E., Wijnen, J., Blok, M. J., Kets, M., Hooning, M. J., Oldenburg, R. A., Ausems, M. G., Peock, S., Frost, D., Ellis, S. D., Platte, R., Fineberg, E., Evans, D. G., Jacobs, C., Eeles, R. A., Adlard, J., Davidson, R., Eccles, D. M., Cole, T., Cook, J., Paterson, J., Brewer, C., Douglas, F., Hodgson, S. V., Morrison, P. J., Walker, L., Porteous, M. E., Kennedy, M. J., Side, L. E., Bove, B., Godwin, A. K., Stoppa-Lyonnet, D., Fassy-Colcombet, M., Castera, L., Cornelis, F., Mazoyer, S., Leone, M., Boutry-Kryza, N., Bressac-de Paillerets, B., Caron, O., Pujol, P., Coupier, I., Delnatte, C., Akloul, L., Lynch, H. T., Snyder, C. L., Buys, S. S., Daly, M. B., Terry, M., Chung, W. K., John, E. M., Miron, A., Southey, M. C., Hopper, J. L., Goldgar, D. E., Singer, C. F., Rappaport, C., Tea, M. M., Fink-Retter, A., Hansen, T. v., Nielsen, F. C., Arason, A., Vijai, J., Shah, S., Sarrel, K., Robson, M. E., Piedmonte, M., Phillips, K., Basil, J., Rubinstein, W. S., Boggess, J., Wakeley, K., Ewart-Toland, A., Montagna, M., Agata, S., Imyanitov, E. N., Isaacs, C., Janavicius, R., Lazaro, C., Blanco, I., Feliubadalo, L., Brunet, J., Gayther, S. A., Pharoah, P. P., Odunsi, K. O., Karlan, B. Y., Walsh, C. S., Olah, E., Teo, S. H., Ganz, P. A., Beattie, M. S., Van Rensburg, E. J., Dorfling, C. M., Diez, O., Kwong, A., Schmutzler, R. K., Wappenschmidt, B., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Heidemann, S., Niederacher, D., Preisler-Adams, S., Gadzicki, D., Varon-Mateeva, R., Deissler, H., Gehrig, A., Sutter, C., Kast, K., Fiebig, B., Heinritz, W., Caldes, T., de la Hoya, M., Muranen, T. A., Nevanlinna, H., Tischkowitz, M., Spurdle, A. B., Neuhausen, S. L., Ding, Y. C., Lindor, N. M., Fredericksen, Z., Pankratz, V. S., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Barile, M., Bernard, L., Viel, A., Giannini, G., Varesco, L., Radice, P., Greene, M. H., Mai, P. L., Easton, D. F., Chenevix-Trench, G., Offit, K., Simard, J. 2012; 21 (4): 645-657

  Abstract

  Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined.We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07-1.27; P = 7.42 × 10(-4)] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73-0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94-1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05-1.29; P = 3.8 × 10(-4)) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10-1.52; P = 1.8 × 10(-3)).19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers.These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers.

  View details for DOI 10.1158/1055-9965.EPI-11-0888

  View details for Web of Science ID 000302220600010

  View details for PubMedID 22351618

  View details for PubMedCentralID PMC3319317

• 19p13.1 Is a Triple-Negative-Specific Breast Cancer Susceptibility Locus CANCER RESEARCH Stevens, K. N., Fredericksen, Z., Vachon, C. M., Wang, X., Margolin, S., Lindblom, A., Nevanlinna, H., Greco, D., Aittomaki, K., Blomqvist, C., Chang-Claude, J., Vrieling, A., Flesch-Janys, D., Sinn, H., Wang-Gohrke, S., Nickels, S., Brauch, H., Ko, Y., Fischer, H., Schmutzler, R. K., Meindl, A., Bartram, C. R., Schott, S., Engel, C., Godwin, A. K., Weaver, J., Pathak, H. B., Sharma, P., Brenner, H., Mueller, H., Arndt, V., Stegmaier, C., Miron, P., Yannoukakos, D., Stavropoulou, A., Fountzilas, G., Gogas, H. J., Swann, R., Dwek, M., Perkins, A., Milne, R. L., Benitez, J., Pilar Zamora, M., Arias Perez, J. I., Bojesen, S. E., Nielsen, S. F., Nordestgaard, B. G., Flyger, H., Guenel, P., Therese Truong, T., Menegaux, F., Cordina-Duverger, E., Burwinkel, B., Marme, F., Schneeweiss, A., Sohn, C., Sawyer, E., Tomlinson, I., Kerin, M. J., Peto, J., Johnson, N., Fletcher, O., dos Santos Silva, I., Fasching, P. A., Beckmann, M. W., Hartmann, A., Ekici, A. B., Lophatananon, A., Muir, K., Puttawibul, P., Wiangnon, S., Schmidt, M. K., Broeks, A., Braaf, L. M., Rosenberg, E. H., Hopper, J. L., Apicella, C., Park, D. J., Southey, M. C., Swerdlow, A. J., Ashworth, A., Orr, N., Schoemaker, M. J., Anton-Culver, H., Ziogas, A., Bernstein, L., Dur, C. C., Shen, C., Yu, J., Hsu, H., Hsiung, C., Hamann, U., Duennebier, T., Ruediger, T., Ulmer, H. U., Pharoah, P. P., Dunning, A. M., Humphreys, M. K., Wang, Q., Cox, A., Cross, S. S., Reed, M. W., Hall, P., Czene, K., Ambrosone, C. B., Ademuyiwa, F., Hwang, H., Eccles, D. M., Garcia-Closas, M., Figueroa, J. D., Sherman, M. E., Lissowska, J., Devilee, P., Seynaeve, C., Tollenaar, R. A., Hooning, M. J., Andrulis, I. L., Knight, J. A., Glendon, G., Mulligan, A. M., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., John, E. M., Miron, A., Alnaes, G. G., Kristensen, V., Borresen-Dale, A., Giles, G. G., Baglietto, L., McLean, C. A., Severi, G., Kosel, M. L., Pankratz, V. S., Slager, S., Olson, J. E., Radice, P., Peterlongo, P., Manoukian, S., Barile, M., Lambrechts, D., Hatse, S., Dieudonne, A., Christiaens, M., Chenevix-Trench, G., Beesley, J., Chen, X., Mannermaa, A., Kosma, V., Hartikainen, J. M., Soini, Y., Easton, D. F., Couch, F. J. 2012; 72 (7): 1795-1803

  Abstract

  The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10(-7)). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P = 3.31 × 10(-13)]. Thus, 19p13.1 is the first triple-negative-specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways.

  View details for DOI 10.1158/0008-5472.CAN-11-3364

  View details for Web of Science ID 000302551800022

  View details for PubMedID 22331459

  View details for PubMedCentralID PMC3319792

• Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers HUMAN MUTATION Ramus, S. J., Antoniou, A. C., Kuchenbaecker, K. B., Soucy, P., Beesley, J., Chen, X., McGuffog, L., Sinilnikova, O. M., Healey, S., Barrowdale, D., Lee, A., Thomassen, M. 2012; 33 (4): 690-702

  Abstract

  Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.

  View details for DOI 10.1002/humu.22025

  View details for Web of Science ID 000301338900017

  View details for PubMedID 22253144

• Genetic Susceptibility to Type 2 Diabetes and Breast Cancer Risk in Women of European and African Ancestry CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Hou, N., Zheng, Y., Gamazon, E. R., Ogundiran, T. O., Adebamowo, C., Nathanson, K. L., Domchek, S. M., Rebbeck, T. R., Simon, M. S., John, E. M., Hennis, A., Nemesure, B., Wu, S., Leske, M. C., Ambs, S., Niu, Q., Zhang, J., Pierce, B., Cox, N. J., Olopade, O. I., Huo, D. 2012; 21 (3): 552-556

  Abstract

  Epidemiologic studies have reported a positive association between type 2 diabetes (T2D) and breast cancer risk, independent of body weight.We investigated 40 genetic variants known to be associated with T2D in relation to breast cancer risk among 2,651 breast cancer cases and 2,520 controls of African or European ancestry that were pooled from seven studies.We found that two T2D risk alleles in Caucasian women (rs5945326-G, rs12518099-C) and one in women of African ancestry (rs7578597-T) were positively associated with breast cancer risk at a nominal significance level of 0.05, whereas two T2D risk alleles were inversely associated with breast cancer risk in Caucasian women (rs1111875-C, rs10923931-T). The composite T2D susceptibility score (the number of risk allele) was not significantly associated with breast cancer risk.The association between established T2D genetic susceptibility variants and breast cancer risk in women of African or European ancestry is likely weak, if it does exist.The pleiotropic effects of known T2D risk alleles cannot explain the association between T2D and breast cancer risk.

  View details for DOI 10.1158/1055-9965.EPI-11-0979

  View details for Web of Science ID 000301284100021

  View details for PubMedID 22237986

  View details for PubMedCentralID PMC3297695

• Fish intake, cooking practices, and risk of prostate cancer: results from a multi-ethnic case-control study CANCER CAUSES & CONTROL Joshi, A. D., John, E. M., Koo, J., Ingles, S. A., Stern, M. C. 2012; 23 (3): 405-420

  Abstract

  Studies conducted to assess the association between fish consumption and prostate cancer (PCA) risk are inconclusive. However, few studies have distinguished between fatty and lean fish, and no studies have considered the role of different cooking practices, which may lead to differential accumulation of chemical carcinogens. In this study, we investigated the association between fish intake and localized and advanced PCA taking into account fish types (lean vs. fatty) and cooking practices.We analyzed data for 1,096 controls, 717 localized and 1,140 advanced cases from the California Collaborative Prostate Cancer Study, a multiethnic, population-based case-control study. We used multivariate conditional logistic regression to estimate odds ratios using nutrient density converted variables of fried fish, tuna, dark fish and white fish consumption. We tested for effect modification by cooking methods (high- vs. low-temperature methods) and levels of doneness.We observed that high white fish intake was associated with increased risk of advanced PCA among men who cooked with high-temperature methods (pan-frying, oven-broiling and grilling) until fish was well done (p (trend) = 0.001). No associations were found among men who cooked fish at low temperature and/or just until done (white fish x cooking method p (interaction) = 0.040).Our results indicate that consideration of fish type (oily vs. lean), specific fish cooking practices and levels of doneness of cooked fish helps elucidate the association between fish intake and PCA risk and suggest that avoiding high-temperature cooking methods for white fish may lower PCA risk.

  View details for DOI 10.1007/s10552-011-9889-2

  View details for Web of Science ID 000300891100002

  View details for PubMedID 22207320

• Genome-wide association analysis identifies three new breast cancer susceptibility loci NATURE GENETICS Ghoussaini, M., Fletcher, O., Michailidou, K., Turnbull, C., Schmidt, M. K., Dicks, E., Dennis, J., Wang, Q., Humphreys, M. K., Luccarini, C., Baynes, C., Conroy, D., Maranian, M., Ahmed, S., Driver, K., Johnson, N., Orr, N., Silva, I. d., Waisfisz, Q., Meijers-Heijboer, H., Uitterlinden, A. G., Rivadeneira, F., Hall, P., Czene, K., Irwanto, A., Liu, J., Nevanlinna, H., Aittomaki, K., Blomqvist, C., Meindl, A., Schmutzler, R. K., Mueller-Myhsok, B., Lichtner, P., Chang-Claude, J., Hein, R., Nickels, S., Flesch-Janys, D., Tsimiklis, H., Makalic, E., Schmidt, D., Bui, M., Hopper, J. L., Apicella, C., Park, D. J., Southey, M., Hunter, D. J., Chanock, S. J., Broeks, A., Verhoef, S., Hogervorst, F. B., Fasching, P. A., Lux, M. P., Beckmann, M. W., Ekici, A. B., Sawyer, E., Tomlinson, I., Kerin, M., Marme, F., Schneeweiss, A., Sohn, C., Burwinkel, B., Guenel, P., Truong, T., Cordina-Duverger, E., Menegaux, F., Bojesen, S. E., Nordestgaard, B. G., Nielsen, S. F., Flyger, H., Milne, R. L., Rosario Alonso, M., Gonzalez-Neira, A., Benitez, J., Anton-Culver, H., Ziogas, A., Bernstein, L., Dur, C. C., Brenner, H., Mueller, H., Arndt, V., Stegmaier, C., Justenhoven, C., Brauch, H., Bruening, T., Wang-Gohrke, S., Eilber, U., Doerk, T., Schuermann, P., Bremer, M., Hillemanns, P., Bogdanova, N. V., Antonenkova, N. N., Rogov, Y. I., Karstens, J. H., Bermisheva, M., Prokofieva, D., Khusnutdinova, E., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Lambrechts, D., Yesilyurt, B. T., Floris, G., Leunen, K., Manoukian, S., Bonanni, B., Fortuzzi, S., Peterlongo, P., Couch, F. J., Wang, X., Stevens, K., Lee, A., Giles, G. G., Baglietto, L., Severi, G., McLean, C., Alnaes, G. G., Kristensen, V., Borrensen-Dale, A., John, E. M., Miron, A., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Kauppila, S., Andrulis, I. L., Glendon, G., Mulligan, A. M., Devilee, P., Van Asperen, C. J., Tollenaar, R. A., Seynaeve, C., Figueroa, J. D., Garcia-Closas, M., Brinton, L., Lissowska, J., Hooning, M. J., Hollestelle, A., Oldenburg, R. A., van den Ouweland, A. M., Cox, A., Reed, M. W., Shah, M., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Jones, M., Schoemaker, M., Ashworth, A., Swerdlow, A., Beesley, J., Chen, X., Muir, K. R., Lophatananon, A., Rattanamongkongul, S., Chaiwerawattana, A., Kang, D., Yoo, K., Noh, D., Shen, C., Yu, J., Wu, P., Hsiung, C., Perkins, A., Swann, R., Velentzis, L., Eccles, D. M., Tapper, W. J., Gerty, S. M., Graham, N. J., Ponder, B. A., Chenevix-Trench, G., Pharoah, P. D., Lathrop, M., Dunning, A. M., Rahman, N., Peto, J., Easton, D. F. 2012; 44 (3): 312-U120

  Abstract

  Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.

  View details for DOI 10.1038/ng.1049

  View details for Web of Science ID 000300843600018

  View details for PubMedID 22267197

  View details for PubMedCentralID PMC3653403

• Lack of association between common single nucleotide polymorphisms in the TERT-CLPTM1L locus and breast cancer in women of African ancestry BREAST CANCER RESEARCH AND TREATMENT Zheng, Y., Ogundiran, T. O., Adebamowo, C., Nathanson, K. L., Domchek, S. M., Rebbeck, T. R., Simon, M. S., John, E. M., Hennis, A., Nemesure, B., Wu, S., Leske, M. C., Ambs, S., Niu, Q., Zhang, J., Cox, N. J., Olopade, O. I., Huo, D. 2012; 132 (1): 341-345

  Abstract

  As one of the most common cancers worldwide, breast cancer places an extraordinary burden on the populations of African ancestry. Common SNPs in the TERT-CLPTM1L locus have been reported to be associated with several types of cancer, including breast cancer. We sought to investigate whether the previously reported common single nucleotide polymorphisms (SNPs) in the TERT-CLPTM1L locus could also contribute to the breast cancer risk in women of African ancestry. We genotyped eleven SNPs in 2,892 women of African descent but were unable to detect any significant association between TERT-CLPTM1L SNPs and their predispositions for breast cancer risk. Given the differences in linkage disequilibrium patterns across populations, our findings suggest that larger independent studies from diverse populations are expected to evaluate the importance of the TERT-CLPTM1L locus in breast cancer.

  View details for DOI 10.1007/s10549-011-1890-7

  View details for Web of Science ID 000300278400035

  View details for PubMedID 22134622

  View details for PubMedCentralID PMC3670987

• A Review of Cancer in US Hispanic Populations CANCER PREVENTION RESEARCH Haile, R. W., John, E. M., Levine, A. J., Cortessis, V. K., Unger, J. B., Gonzales, M., Ziv, E., Thompson, P., Spruijt-Metz, D., Tucker, K. L., Bernstein, J. L., Rohan, T. E., Ho, G. Y., Bondy, M. L., Martinez, M. E., Cook, L., Stern, M. C., Correa, M. C., Wright, J., Schwartz, S. J., Baezconde-Garbanati, L., Blinder, V., Miranda, P., Hayes, R., Friedman-Jimenez, G., Monroe, K. R., Haiman, C. A., Henderson, B. E., Thomas, D. C., Boffetta, P. 2012; 5 (2): 150-163

  Abstract

  There are compelling reasons to conduct studies of cancer in Hispanics, the fastest growing major demographic group in the United States (from 15% to 30% of the U.S. population by 2050). The genetically admixed Hispanic population coupled with secular trends in environmental exposures and lifestyle/behavioral practices that are associated with immigration and acculturation offer opportunities for elucidating the effects of genetics, environment, and lifestyle on cancer risk and identifying novel risk factors. For example, traditional breast cancer risk factors explain less of the breast cancer risk in Hispanics than in non-Hispanic whites (NHW), and there is a substantially greater proportion of never-smokers with lung cancer in Hispanics than in NHW. Hispanics have higher incidence rates for cancers of the cervix, stomach, liver, and gall bladder than NHW. With respect to these cancers, there are intriguing patterns that warrant study (e.g., depending on country of origin, the five-fold difference in gastric cancer rates for Hispanic men but not Hispanic women). Also, despite a substantially higher incidence rate and increasing secular trend for liver cancer in Hispanics, there have been no studies of Hispanics reported to date. We review the literature and discuss study design options and features that should be considered in future studies.

  View details for DOI 10.1158/1940-6207.CAPR-11-0447

  View details for Web of Science ID 000300043500002

  View details for PubMedID 22307564

• Evaluating breast cancer risk projections for Hispanic women BREAST CANCER RESEARCH AND TREATMENT Banegas, M. P., Gail, M. H., LaCroix, A., Thompson, B., Martinez, M. E., Wactawski-Wende, J., John, E. M., Hubbell, F. A., Yasmeen, S., Katki, H. A. 2012; 132 (1): 347-353

  Abstract

  For Hispanic women, the Breast Cancer Risk Assessment Tool (BCRAT; "Gail Model") combines 1990-1996 breast cancer incidence for Hispanic women with relative risks for breast cancer risk factors from non-Hispanic white (NHW) women. BCRAT risk projections have never been comprehensively evaluated for Hispanic women. We compared the relative risks and calibration of BCRAT risk projections for 6,353 Hispanic to 128,976 NHW postmenopausal participants aged 50 and older in the Women's Health Initiative (WHI). Calibration was assessed by the ratio of the number of breast cancers observed with that expected by the BCRAT (O/E). We re-evaluated calibration for an updated BCRAT that combined BCRAT relative risks with 1993-2007 breast cancer incidence that is contemporaneous with the WHI. Cox regression was used to estimate relative risks. Discriminatory accuracy was assessed using the concordance statistic (AUC). In the WHI Main Study, the BCRAT underestimated the number of breast cancers by 18% in both Hispanics (O/E = 1.18, P = 0.06) and NHWs (O/E = 1.18, P < 0.001). Updating the BCRAT improved calibration for Hispanic women (O/E = 1.08, P = 0.4) and NHW women (O/E = 0.98, P = 0.2). For Hispanic women, relative risks for number of breast biopsies (1.71 vs. 1.27, P = 0.03) and age at first birth (0.97 vs. 1.24, P = 0.02) differed between the WHI and BCRAT. The AUC was higher for Hispanic women than NHW women (0.63 vs. 0.58, P = 0.03). Updating the BCRAT with contemporaneous breast cancer incidence rates improved calibration in the WHI. The modest discriminatory accuracy of the BCRAT for Hispanic women might improve by using risk factor relative risks specific to Hispanic women.

  View details for DOI 10.1007/s10549-011-1900-9

  View details for Web of Science ID 000300278400036

  View details for PubMedID 22147080

• Calcium intake and prostate cancer among African Americans: Effect modification by vitamin D receptor calcium absorption genotype JOURNAL OF BONE AND MINERAL RESEARCH Rowland, G. W., Schwartz, G. G., John, E. M., Ingles, S. A. 2012; 27 (1): 187-194

  Abstract

  High dietary intake of calcium has been classified as a probable cause of prostate cancer, although the mechanism underlying the association between dietary calcium and prostate cancer risk is unclear. The vitamin D receptor (VDR) is a key regulator of calcium absorption. In the small intestine, VDR expression is regulated by the CDX-2 transcription factor, which binds a polymorphic site in the VDR gene promoter. We examined VDR Cdx2 genotype and calcium intake, assessed by a food frequency questionnaire, in 533 African-American prostate cancer cases (256 with advanced stage at diagnosis, 277 with localized stage) and 250 African-American controls who participated in the California Collaborative Prostate Cancer Study. We examined the effects of genotype, calcium intake, and diet-gene interactions by conditional logistic regression. Compared with men in the lowest quartile of calcium intake, men in the highest quartile had an approximately twofold increased risk of localized and advanced prostate cancer (odds ratio [OR] = 2.20, 95% confidence interval [CI] = 1.40, 3.46), with a significant dose-response. Poor absorbers of calcium (VDR Cdx2 GG genotype) had a significantly lower risk of advanced prostate cancer (OR = 0.41, 95% CI = 0.19, 0.90). The gene-calcium interaction was statistically significant (p = 0.03). Among men with calcium intake below the median (680 mg/day), carriers of the G allele had an approximately 50% decreased risk compared with men with the AA genotype. These findings suggest a link between prostate cancer risk and high intestinal absorption of calcium.

  View details for DOI 10.1002/jbmr.505

  View details for Web of Science ID 000298479000021

  View details for PubMedID 21887707

  View details for PubMedCentralID PMC3234334

• Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers BREAST CANCER RESEARCH Antoniou, A. C., Kuchenbaecker, K. B., Soucy, P., Beesley, J., Chen, X., McGuffog, L., Lee, A., Barrowdale, D., Healey, S., Sinilnikova, O. M., Caligo, M. A., Loman, N., Harbst, K., Lindblom, A., Arver, B., Rosenquist, R., Karlsson, P., Nathanson, K., Domchek, S., Rebbeck, T., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Zlowowcka-Perlowska, E., Osorio, A., Duran, M., Andres, R., Benitez, J., Hamann, U., Hogervorst, F. B., van Os, T. A., Verhoef, S., Meijers-Heijboer, H. E., Wijnen, J., Garcia, E. B., Ligtenberg, M. J., Kriege, M., Collee, M., Ausems, M. G., Oosterwijk, J. C., Peock, S., Frost, D., Ellis, S. D., Platte, R., Fineberg, E., Evans, D. G., Lalloo, F., Jacobs, C., Eeles, R., Adlard, J., Davidson, R., Cole, T., Cook, J., Paterson, J., Douglas, F., Brewer, C., Hodgson, S., Morrison, P. J., Walker, L., Rogers, M. T., Donaldson, A., Dorkins, H., Godwin, A. K., Bove, B., Stoppa-Lyonnet, D., Houdayer, C., Buecher, B., De Pauw, A., Mazoyer, S., Calender, A., Leone, M., Bressac-de Paillerets, B., Caron, O., Sobol, H., Frenay, M., Prieur, F., Ferrer, S. F., Mortemousque, I., Buys, S., Daly, M., Miron, A., Terry, M. B., Hopper, J. L., John, E. M., Southey, M., Goldgar, D., Singer, C. F., Fink-Retter, A., Tea, M., Kaulich, D. G., Hansen, T. v., Nielsen, F. C., Barkardottir, R. B., Gaudet, M., Kirchhoff, T., Joseph, V., Dutra-Clarke, A., Offit, K., Piedmonte, M., Kirk, J., Cohn, D., Hurteau, J., Byron, J., Fiorica, J., Toland, A. E., Montagna, M., Oliani, C., Imyanitov, E., Isaacs, C., Tihomirova, L., Blanco, I., Lazaro, C., Teule, A., Del Valle, J., Gayther, S. A., Odunsi, K., Gross, J., Karlan, B. Y., Olah, E., Teo, S., Ganz, P. A., Beattie, M. S., Dorfling, C. M., van Rensburg, E. J., Diez, O., Kwong, A., Schmutzler, R. K., Wappenschmidt, B., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Heidemann, S., Niederacher, D., Preisler-Adams, S., Gadzicki, D., Varon-Mateeva, R., Deissler, H., Gehrig, A., Sutter, C., Kast, K., Fiebig, B., Schaefer, D., Caldes, T., de la Hoya, M., Nevanlinna, H., Muranen, T. A., Lesperance, B., Spurdle, A. B., Neuhausen, S. L., Ding, Y. C., Wang, X., Fredericksen, Z., Pankratz, V. S., Lindor, N. M., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Bonanni, B., Bernard, L., Dolcetti, R., Papi, L., Ottini, L., Radice, P., Greene, M. H., Loud, J. T., Andrulis, I. L., Ozcelik, H., Mulligan, A. M., Glendon, G., Thomassen, M., Gerdes, A., Jensen, U. B., Skytte, A., Kruse, T. A., Chenevix-Trench, G., Couch, F. J., Simard, J., Easton, D. F. 2012; 14 (1)

  Abstract

  Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.

  View details for DOI 10.1186/bcr3121

  View details for Web of Science ID 000307444100042

  View details for PubMedID 22348646

  View details for PubMedCentralID PMC3496151

• Pathology of Breast and Ovarian Cancers among BRCA1 and BRCA2 Mutation Carriers: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Mavaddat, N., Barrowdale, D., Andrulis, I. L., Domchek, S. M., Eccles, D., Nevanlinna, H., Ramus, S. J., Spurdle, A., Robson, M., Sherman, M., Mulligan, A. M., Couch, F. J., Engel, C., McGuffog, L., Healey, S., Sinilnikova, O. M., Southey, M. C., Terry, M. B., Goldgar, D., O'Malley, F., John, E. M., Janavicius, R., Tihomirova, L., Hansen, T. v., Nielsen, F. C., Osorio, A., Stavropoulou, A., Benitez, J., Manoukian, S., Peissel, B., Barile, M., Volorio, S., Pasini, B., Dolcetti, R., Putignano, A. L., Ottini, L., Radice, P., Hamann, U., Rashid, M. U., Hogervorst, F. B., Kriege, M., van der Luijt, R. B., Peock, S., Frost, D., Evans, D. G., Brewer, C., Walker, L., Rogers, M. T., Side, L. E., Houghton, C., Weaver, J., Godwin, A. K., Schmutzler, R. K., Wappenschmidt, B., Meindl, A., Kast, K., Arnold, N., Niederacher, D., Sutter, C., Deissler, H., Gadzicki, D., Preisler-Adams, S., Varon-Mateeva, R., Schoenbuchner, I., Gevensleben, H., Stoppa-Lyonnet, D., Belotti, M., Barjhoux, L., Isaacs, C., Peshkin, B. N., Caldes, T., de la Hoya, M., Canadas, C., Heikkinen, T., Heikkila, P., Aittomaki, K., Blanco, I., Lazaro, C., Brunet, J., Agnarsson, B. A., Arason, A., Barkardottir, R. B., Dumont, M., Simard, J., Montagna, M., Agata, S., D'Andrea, E., Yan, M., Fox, S., Rebbeck, T. R., Rubinstein, W., Tung, N., Garber, J. E., Wang, X., Fredericksen, Z., Pankratz, V. S., Lindor, N. M., Szabo, C., Offit, K., Sakr, R., Gaudet, M. M., Singer, C. F., Tea, M., Rappaport, C., Mai, P. L., Greene, M. H., Sokolenko, A., Imyanitov, E., Toland, A. E., Senter, L., Sweet, K., Thomassen, M., Gerdes, A., Kruse, T., Caligo, M., Aretini, P., Rantala, J., von Wachenfeld, A., Henriksson, K., Steele, L., Neuhausen, S. L., Nussbaum, R., Beattie, M., Odunsi, K., Sucheston, L., Gayther, S. A., Nathanson, K., Gross, J., Walsh, C., Karlan, B., Chenevix-Trench, G., Easton, D. F., Antoniou, A. C. 2012; 21 (1): 134-147

  Abstract

  Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization.We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers.There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10(-5)), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10(-6)). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10(-13) for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0-12.6 and PR-positive OR = 1.7, 95% CI: 1.3-2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4-4.4; P = 4.4 × 10(-14)), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18-0.35; P = 2.3 × 10(-15)). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%). CONCLUSIONS/IMPACT: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis.

  View details for DOI 10.1158/1055-9965.EPI-11-0775

  View details for Web of Science ID 000299051500014

  View details for PubMedID 22144499

• Breast Cancer Prognosis in BRCA1 and BRCA2 Mutation Carriers: An International Prospective Breast Cancer Family Registry Population-Based Cohort Study JOURNAL OF CLINICAL ONCOLOGY Goodwin, P. J., Phillips, K., West, D. W., Ennis, M., Hopper, J. L., John, E. M., O'Malley, F. P., Milne, R. L., Andrulis, I. L., Friedlander, M. L., Southey, M. C., Apicella, C., Giles, G. G., Longacre, T. A. 2012; 30 (1): 19-26

  Abstract

  To compare breast cancer prognosis in BRCA1 and BRCA2 mutation carriers with that in patients with sporadic disease.An international population-based cohort study was conducted in Canada, the United States, and Australia of 3,220 women with incident breast cancer diagnosed between 1995 and 2000 and observed prospectively. Ninety-three had BRCA1 mutations; 71, BRCA2 mutations; one, both mutations; 1,550, sporadic breast cancer; and 1,505, familial breast cancer (without known BRCA1 or BRCA2 mutation). Distant recurrence and death were analyzed.Mean age at diagnosis was 45.3 years; mean follow-up was 7.9 years. Risks of distant recurrence and death did not differ significantly between BRCA1 mutation carriers and those with sporadic disease in univariable and multivariable analyses. Risk of distant recurrence was higher for BRCA2 mutation carriers compared with those with sporadic disease in univariable analysis (hazard ratio [HR], 1.63; 95% CI, 1.02 to 2.60; P = .04). Risk of death was also higher in BRCA2 carriers in univariable analysis (HR, 1.81; 95% CI, 1.15 to 2.86; P = .01). After adjustment for age, tumor stage and grade, nodal status, hormone receptors, and year of diagnosis, no differences were observed for distant recurrence (HR, 1.00; 95% CI, 0.62 to 1.61; P = 1.00) or death (HR, 1.12; 95% CI, 0.70 to 1.79; P = .64).Outcomes of BRCA1 mutation carriers were similar to those of patients with sporadic breast cancer. Worse outcomes in BRCA2 mutation carriers in univariable analysis seem to reflect the presence of more adverse tumor characteristics in these carriers. Similar outcomes were identified in BRCA2 carriers and those with sporadic disease in multivariable analyses.

  View details for DOI 10.1200/JCO.2010.33.0068

  View details for Web of Science ID 000302617900009

  View details for PubMedID 22147742

• Body mass index and risk of second primary breast cancer: The WECARE Study BREAST CANCER RESEARCH AND TREATMENT Brooks, J. D., John, E. M., Mellemkjaer, L., Reiner, A. S., Malone, K. E., Lynch, C. F., Figueiredo, J. C., Haile, R. W., Shore, R. E., Bernstein, J. L., Bernstein, L. 2012; 131 (2): 571-580

  Abstract

  The identification of potentially modifiable risk factors, such as body size, could allow for interventions that could help reduce the burden of contralateral breast cancer (CBC) among breast cancer survivors. Studies examining the relationship between body mass index (BMI) and CBC have yielded mixed results. From the population-based, case-control, Women's Environmental, Cancer and Radiation Epidemiology (WECARE) Study, we included 511 women with CBC (cases) and 999 women with unilateral breast cancer (controls) who had never used postmenopausal hormone therapy. Rate ratios (RR) and 95% confidence intervals (CI) were used to assess the relationship between BMI and CBC risk. No associations between BMI at first diagnosis or weight-change between first diagnosis and date of CBC diagnosis (or corresponding date in matched controls) and CBC risk were seen. However, obese (BMI ≥ 30 kg/m(2)) postmenopausal women with estrogen receptor (ER)-negative first primary tumors (n = 12 cases and 9 controls) were at an increased risk of CBC compared with normal weight women (BMI < 25 kg/m(2)) (n = 43 cases and 98 controls) (RR = 5.64 (95% CI 1.76, 18.1)). No association between BMI and CBC risk was seen in premenopausal or postmenopausal women with ER-positive first primaries. Overall, BMI is not associated with CBC risk in this population of young breast cancer survivors. Our finding of an over five-fold higher risk of CBC in a small subgroup of obese postmenopausal women with an ER-negative first primary breast cancer is based on limited numbers and requires confirmation in a larger study.

  View details for DOI 10.1007/s10549-011-1743-4

  View details for Web of Science ID 000298752200021

  View details for PubMedID 21892703

  View details for PubMedCentralID PMC3251700

• Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk BRITISH JOURNAL OF CANCER Stevens, K. N., Garcia-Closas, M., Fredericksen, Z., Kosel, M., Pankratz, V. S., Hopper, J. L., Dite, G. S., Apicella, C., Southey, M. C., Schmidt, M. K., Broeks, A., van 't Veer, L. J., Tollenaar, R. A., Fasching, P. A., Beckmann, M. W., Hein, A., Ekici, A. B., Johnson, N., Peto, J., Silva, I. d., Gibson, L., Sawyer, E., Tomlinson, I., Kerin, M. J., Chanock, S., Lissowska, J., Hunter, D. J., HOOVER, R. N., Thomas, G. D., Milne, R. L., Perez, J. I., Gonzalez-Neira, A., Benitez, J., Burwinkel, B., Meindl, A., Schmutzler, R. K., Bartrar, C. R., Hamann, U., Ko, Y. D., Bruening, T., Chang-Claude, J., HEIN, R., Wang-Gohrke, S., Doerk, T., Schuermann, P., Bremer, M., Hillemanns, P., Bogdanova, N., Zalutsky, J. V., Rogov, Y. I., Antonenkova, N., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J., Chenevix-Trench, G., Chen, X., Peterlongo, P., Bonanni, B., Bernard, L., Manoukian, S., Wang, X., Cerhan, J., Vachon, C. M., Olson, J., Giles, G. G., Baglietto, L., McLean, C. A., Severi, G., John, E. M., Miron, A., Winqvist, R., Pylkaes, K., Jukkola-Vuorinen, A., Grip, M., Andrulis, I., Knight, J. A., Glendon, G., Mulligan, A. M., Cox, A., Brock, I. W., Elliott, G., Cross, S. S., Pharoah, P. P., Dunning, A. M., Pooley, K. A., Humphreys, M. K., Wang, J., Kang, D., Yoo, K., Noh, D., Sangrajrang, S., Gabrieau, V., Brennan, P., McKay, J., Anton-Culver, H., Ziogas, A., Couch, F. J., Easton, D. F. 2011; 105 (12): 1934-1939

  Abstract

  Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer.A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC).Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139).Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.

  View details for DOI 10.1038/bjc.2011.448

  View details for Web of Science ID 000298140800018

  View details for PubMedID 22033276

  View details for PubMedCentralID PMC3251877

• Breast Cancer Risk for Noncarriers of Family-Specific BRCA1 and BRCA2 Mutations: Findings From the Breast Cancer Family Registry JOURNAL OF CLINICAL ONCOLOGY Kurian, A. W., Gong, G. D., John, E. M., Johnston, D. A., Felberg, A., West, D. W., Miron, A., Andrulis, I. L., Hopper, J. L., Knight, J. A., Ozcelik, H., Dite, G. S., Apicella, C., Southey, M. C., Whittemore, A. S. 2011; 29 (34): 4505-4509

  Abstract

  Women with germline BRCA1 and BRCA2 mutations have five- to 20-fold increased risks of developing breast and ovarian cancer. A recent study claimed that women testing negative for their family-specific BRCA1 or BRCA2 mutation (noncarriers) have a five-fold increased risk of breast cancer. We estimated breast cancer risks for noncarriers by using a population-based sample of patients with breast cancer and their female first-degree relatives (FDRs).Patients were women with breast cancer and their FDRs enrolled in the population-based component of the Breast Cancer Family Registry; patients with breast cancer were tested for BRCA1 and BRCA2 mutations, as were FDRs of identified mutation carriers. We used segregation analysis to fit a model that accommodates familial correlation in breast cancer risk due to unobserved shared risk factors.We studied 3,047 families; 160 had BRCA1 and 132 had BRCA2 mutations. There was no evidence of increased breast cancer risk for noncarriers of identified mutations compared with FDRs from families without BRCA1 or BRCA2 mutations: relative risk was 0.39 (95% CI, 0.04 to 3.81). Residual breast cancer correlation within families was strong, suggesting substantial risk heterogeneity in women without BRCA1 or BRCA2 mutations, with some 3.4% of them accounting for roughly one third of breast cancer cases.These results support the practice of advising noncarriers that they do not have any increase in breast cancer risk attributable to the family-specific BRCA1 or BRCA2 mutation.

  View details for DOI 10.1200/JCO.2010.34.4440

  View details for PubMedID 22042950

  View details for PubMedCentralID PMC3236651

• Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers HUMAN MOLECULAR GENETICS Cox, D. G., Simard, J., Sinnett, D., Hamdi, Y., Soucy, P., Ouimet, M., Barjhoux, L., Verny-Pierre, C., McGuffog, L., Healey, S., Szabo, C., Greene, M. H., Mai, P. L., Andrulis, I. L., Thomassen, M., Gerdes, A., Caligo, M. A., Friedman, E., Laitman, Y., Kaufman, B., Paluch, S. S., Borg, A., Karlsson, P., Askmalm, M., Bustinza, G., Nathanson, K. L., Domchek, S. M., Rebbeck, T. R., Benitez, J., Hamann, U., Rookus, M. A., van den Ouweland, A. W., Ausems, M. M., Aalfs, C. M., van Asperen, C. J., Devilee, P., Gille, H. P., Peock, S., Frost, D., Evans, D., Eeles, R., Izatt, L., Adlard, J., Paterson, J., Eason, J., Godwin, A. K., Remon, M., Moncoutier, V., Gauthier-Villars, M., Lasset, C., Giraud, S., Hardouin, A., Berthet, P., Sobol, H., Eisinger, F., de Paillerets, B., Caron, O., Delnatte, C., Goldgar, D., Miron, A., Ozcelik, H., Buys, S., Southey, M. C., Terry, M., Singer, C. F., Dressler, A., Tea, M., Hansen, T. O., Johannsson, O., Piedmonte, M., Rodriguez, G. C., Basil, J. B., Blank, S., Toland, A. E., Montagna, M., Isaacs, C., Blanco, I., Gayther, S. A., Moysich, K. B., Schmutzler, R. K., Wappenschmidt, B., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Niederacher, D., Sutter, C., Gadzicki, D., Fiebig, B., Caldes, T., Laframboise, R., Nevanlinna, H., Chen, X., Beesley, J., Spurdle, A. B., Neuhausen, S. L., Ding, Y. C., Couch, F. J., Wang, X., Peterlongo, P., Manoukian, S., Bernard, L., Radice, P., Easton, D. F., Chenevix-Trench, G., Antoniou, A. C., Stoppa-Lyonnet, D., Mazoyer, S., Sinilnikova, O. M., Ontario Canc Genetics Network, SWE-BRCA Collaborators, HEBON, EMBRACE, GEMO Study Collaborators, Breast Canc Family Registry, Consortium Investigators Modifiers 2011; 20 (23): 4732–47

  Abstract

  Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

  View details for DOI 10.1093/hmg/ddr388

  View details for Web of Science ID 000297049600019

  View details for PubMedID 21890493

  View details for PubMedCentralID PMC3733139

• Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium HUMAN MOLECULAR GENETICS Figueroa, J. D., Garcia-Closas, M., Humphreys, M., Platte, R., Hopper, J. L., Southey, M. C., Apicella, C., Hammet, F., Schmidt, M. K., Broeks, A., Tollenaar, R. A., van't Veer, L. J., Fasching, P. A., Beckmann, M. W., Ekici, A. B., Strick, R., Peto, J., Silva, I. d., Fletcher, O., Johnson, N., Sawyer, E., Tomlinson, I., Kerin, M., Burwinkel, B., Marme, F., Schneeweiss, A., Sohn, C., Bojesen, S., Flyger, H., Nordestgaard, B. G., Benitez, J., Milne, R. L., Ignacio Arias, J., Pilar Zamora, M., Brenner, H., Mueller, H., Arndt, V., Rahman, N., Turnbull, C., Seal, S., Renwick, A., Brauch, H., Justenhoven, C., Bruening, T., Chang-Claude, J., Hein, R., Wang-Gohrke, S., Doerk, T., Schuermann, P., Bremer, M., Hillemanns, P., Nevanlinna, H., Heikkinen, T., Aittomaki, K., Blomqvist, C., Bogdanova, N., Antonenkova, N., Rogov, Y. I., Karstens, J. H., Bermisheva, M., Prokofieva, D., Gantcev, S. H., Khusnutdinova, E., Lindblom, A., Margolin, S., Chenevix-Trench, G., Beesley, J., Chen, X., Mannermaa, A., Kosma, V., Soini, Y., Kataja, V., Lambrechts, D., Yesilyurt, B. T., Chrisiaens, M., Peeters, S., Radice, P., Peterlongo, P., Manoukian, S., Barile, M., Couch, F., Lee, A. M., Diasio, R., Wang, X., Giles, G. G., Severi, G., Baglietto, L., Maclean, C., Offit, K., Robson, M., Joseph, V., Gaudet, M., John, E. M., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Andrulis, I., Knight, J. A., Mulligan, A. M., O'Malley, F. P., Brinton, L. A., Sherman, M. E., Lissowska, J., Chanock, S. J., Hooning, M., Martens, J. W., van den Ouweland, A. M., Collee, J. M., Hall, P., Czene, K., Cox, A., Brock, I. W., Reed, M. W., Cross, S. S., Pharoah, P., Dunning, A. M., Kang, D., Yoo, K., Noh, D., Ahn, S., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Sangrajrang, S., Gaborieau, V., Brennan, P., McKay, J., Shen, C., Ding, S., Hsu, H., Yu, J., Anton-Culver, H., Ziogas, A., Ashworth, A., Swerdlow, A., Jones, M., Orr, N., Trentham-Dietz, A., Egan, K., Newcomb, P., Titus-Ernstoff, L., Easton, D., Spurdle, A. B. 2011; 20 (23): 4693-4706

  Abstract

  A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2)= 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10-1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98-1.07, case-only P-heterogeneity = 7.6 × 10(-5)]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P= 6.7 × 10(-3)) and lobular histology (case-only P= 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer.

  View details for DOI 10.1093/hmg/ddr368

  View details for Web of Science ID 000297049600015

  View details for PubMedID 21852249

  View details for PubMedCentralID PMC3209823

• Early-Life Factors and Breast Cancer Risk in Hispanic Women: the Role of Adolescent Body Size CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Sangaramoorthy, M., Phipps, A. I., Horn-Ross, P. L., Koo, J., John, E. M. 2011; 20 (12): 2572-2582

  Abstract

  Adult body size has long been known to influence breast cancer risk, and there is now increasing evidence that childhood and adolescent body size may also play a role.We assessed the association with body size at ages 10, 15, and 20 years in 475 premenopausal and 775 postmenopausal Hispanic women who participated in a population-based case-control study of breast cancer conducted from 1995 to 2004 in the San Francisco Bay Area. We used unconditional logistic regression to estimate ORs and 95% CIs for the associations with self-reported relative weight compared with peers and body build at ages 10, 15, and 20 years.In premenopausal women, we found inverse associations with relative weight compared with peers, with ORs of 0.63 (P(trend) = 0.05), 0.31 (P(trend) < 0.01), and 0.44 (P(trend) = 0.02) for heavier versus lighter weight at ages 10, 15, and 20 years, respectively. These inverse associations were stronger in currently overweight women and U.S.-born women and did not differ significantly for case groups defined by estrogen receptor status. In postmenopausal women, not currently using hormone therapy, inverse associations with relative weight were limited to U.S.-born Hispanics.Large body size at a young age may have a long-lasting influence on breast cancer risk in premenopausal, and possibly postmenopausal, Hispanic women that is independent of current body mass index.These findings need to be weighed against adverse health effects associated with early-life obesity.

  View details for DOI 10.1158/1055-9965.EPI-11-0848

  View details for Web of Science ID 000298234900013

  View details for PubMedID 22056503

  View details for PubMedCentralID PMC3461314

• A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer NATURE GENETICS Haiman, C. A., Chen, G. K., Vachon, C. M., Canzian, F., Dunning, A., Millikan, R. C., Wang, X., Ademuyiwa, F., Ahmed, S., Ambrosone, C. B., Baglietto, L., Balleine, R., Bandera, E. V., Beckmann, M. W., Berg, C. D., Bernstein, L., Blomqvist, C., Blot, W. J., Brauch, H., Buring, J. E., Carey, L. A., Carpenter, J. E., Chang-Claude, J., Chanock, S. J., Chasman, D. I., Clarke, C. L., Cox, A., Cross, S. S., Deming, S. L., Diasio, R. B., Dimopoulos, A. M., Driver, W. R., Duennebier, T., Durcan, L., Eccles, D., Edlund, C. K., Ekici, A. B., Fasching, P. A., Feigelson, H. S., Flesch-Janys, D., Fostira, F., Foersti, A., Fountzilas, G., Gerty, S. M., Giles, G. G., Godwin, A. K., Goodfellow, P., Graham, N., Greco, D., Hamann, U., Hankinson, S. E., Hartmann, A., Hein, R., Heinz, J., Holbrook, A., Hoover, R. N., Hu, J. J., Hunter, D. J., Ingles, S. A., Irwanto, A., Ivanovich, J., John, E. M., Johnson, N., Jukkola-Vuorinen, A., Kaaks, R., Ko, Y., Kolonel, L. N., Konstantopoulou, I., Kosma, V., Kulkarni, S., Lambrechts, D., Lee, A. M., Le Marchand, L., Lesnick, T., Liu, J., Lindstrom, S., Mannermaa, A., Margolin, S., Martin, N. G., Miron, P., Montgomery, G. W., Nevanlinna, H., Nickels, S., Nyante, S., Olswold, C., Palmer, J., Pathak, H., Pectasides, D., Perou, C. M., Peto, J., Pharoah, P. D., Pooler, L. C., Press, M. F., Pylkas, K., Rebbeck, T. R., Rodriguez-Gil, J. L., Rosenberg, L., Ross, E., Ruediger, T., Silva, I. d., Sawyer, E., Schmidt, M. K., Schulz-Wendtland, R., Schumacher, F., Severi, G., Sheng, X., Signorello, L. B., Sinn, H., Stevens, K. N., Southey, M. C., Tapper, W. J., Tomlinson, I., Hogervorst, F. B., Wauters, E., Weaver, J., Wildiers, H., Winqvist, R., Van Den Berg, D., Wan, P., Xia, L. Y., Yannoukakos, D., Zheng, W., Ziegler, R. G., Siddiq, A., Slager, S. L., Stram, D. O., Easton, D., Kraft, P., Henderson, B. E., Couch, F. J. 2011; 43 (12): 1210-U61

  Abstract

  Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.

  View details for DOI 10.1038/ng.985

  View details for Web of Science ID 000297931400013

  View details for PubMedID 22037553

  View details for PubMedCentralID PMC3279120

• Fine-mapping of breast cancer susceptibility loci characterizes genetic risk in African Americans HUMAN MOLECULAR GENETICS Chen, F., Chen, G. K., Millikan, R. C., John, E. M., Ambrosone, C. B., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Deming, S. L., Bandera, E. V., Nyante, S., Palmer, J. R., Rebbeck, T. R., Ingles, S. A., Press, M. F., Rodriguez-Gil, J. L., Chanock, S. J., Le Marchand, L., Kolonel, L. N., Henderson, B. E., Stram, D. O., Haiman, C. A. 2011; 20 (22): 4491-4503

  Abstract

  Genome-wide association studies (GWAS) have revealed 19 common genetic variants that are associated with breast cancer risk. Testing of the index signals found through GWAS and fine-mapping of each locus in diverse populations will be necessary for characterizing the role of these risk regions in contributing to inherited susceptibility. In this large study of breast cancer in African-American women (3016 cases and 2745 controls), we tested the 19 known risk variants identified by GWAS and replicated associations (P < 0.05) with only 4 variants. Through fine-mapping, we identified markers in four regions that better capture the association with breast cancer risk in African Americans as defined by the index signal (2q35, 5q11, 10q26 and 19p13). We also identified statistically significant associations with markers in four separate regions (8q24, 10q22, 11q13 and 16q12) that are independent of the index signals and may represent putative novel risk variants. In aggregate, the more informative markers found in the study enhance the association of these risk regions with breast cancer in African Americans [per allele odds ratio (OR) = 1.18, P = 2.8 × 10(-24) versus OR = 1.04, P = 6.1 × 10(-5)]. In this detailed analysis of the known breast cancer risk loci, we have validated and improved upon markers of risk that better characterize their association with breast cancer in women of African ancestry.

  View details for DOI 10.1093/hmg/ddr367

  View details for Web of Science ID 000296103800017

  View details for PubMedID 21852243

  View details for PubMedCentralID PMC3196889

• Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers HUMAN GENETICS Im, K. M., Kirchhoff, T., Wang, X., Green, T., Chow, C. Y., Vijai, J., Korn, J., Gaudet, M. M., Fredericksen, Z., Pankratz, V. S., Guiducci, C., Crenshaw, A., McGuffog, L., Kartsonaki, C., Morrison, J., Healey, S., Sinilnikova, O. M., Mai, P. L., Greene, M. H., Piedmonte, M., Rubinstein, W. S., Hogervorst, F. B., Rookus, M. A., Collee, J. M., Hoogerbrugge, N., van Asperen, C. J., Meijers-Heijboer, H. E., van Roozendaal, C. E., Caldes, T., Perez-Segura, P., Jakubowska, A., Lubinski, J., Huzarski, T., Blecharz, P., Nevanlinna, H., Aittomaki, K., Lazaro, C., Blanco, I., Barkardottir, R. B., Montagna, M., D'Andrea, E., Devilee, P., Olopade, O. I., Neuhausen, S. L., Peissel, B., Bonanni, B., Peterlongo, P., Singer, C. F., Rennert, G., Lejbkowicz, F., Andrulis, I. L., Glendon, G., Ozcelik, H., Toland, A. E., Caligo, M. A., Beattie, M. S., Chan, S., Domchek, S. M., Nathanson, K. L., Rebbeck, T. R., Phelan, C., Narod, S., John, E. M., Hopper, J. L., Buys, S. S., Daly, M. B., Southey, M. C., Terry, M., Tung, N., Hansen, T. v., Osorio, A., Benitez, J., Duran, M., Weitzel, J. N., Garber, J., Hamann, U., Peock, S., Cook, M., Oliver, C. T., Frost, D., Platte, R., Evans, D. G., Eeles, R., Izatt, L., Paterson, J., Brewer, C., Hodgson, S., Morrison, P. J., Porteous, M., Walker, L., Rogers, M. T., Side, L. E., Godwin, A. K., Schmutzler, R. K., Wappenschmidt, B., Laitman, Y., Meindl, A., Deissler, H., Varon-Mateeva, R., Preisler-Adams, S., Kast, K., Venat-Bouvet, L., Stoppa-Lyonnet, D., Chenevix-Trench, G., Easton, D. F., Klein, R. J., Daly, M. J., friedman, e., Dean, M., Clark, A. G., Altshuler, D. M., Antoniou, A. C., Couch, F. J., Offit, K., Gold, B. 2011; 130 (5): 685-699

  Abstract

  Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.

  View details for DOI 10.1007/s00439-011-1003-z

  View details for Web of Science ID 000295939900009

  View details for PubMedID 21597964

• Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer PLOS BIOLOGY Maxwell, C. A., Benitez, J., Gomez-Baldo, L., Osorio, A., Bonifaci, N., Fernandez-Ramires, R., Costes, S. V., Guino, E., Chen, H., Evans, G. J., Mohan, P., Catala, I., Petit, A., Aguilar, H., Villanueva, A., Aytes, A., Serra-Musach, J., Rennert, G., Lejbkowicz, F., Peterlongo, P., Manoukian, S., Peissel, B., Ripamonti, C. B., Bonanni, B., Viel, A., Allavena, A., Bernard, L., Radice, P., friedman, e., Kaufman, B., Laitman, Y., Dubrovsky, M., Milgrom, R., Jakubowska, A., Cybulski, C., Gorski, B., Jaworska, K., Durda, K., Sukiennicki, G., Lubinski, J., Shugart, Y. Y., Domchek, S. M., Letrero, R., Weber, B. L., Hogervorst, F. B., Rookus, M. A., Collee, J. M., Devilee, P., Ligtenberg, M. J., van der Luijt, R. B., Aalfs, C. M., Waisfisz, Q., Wijnen, J., van Roozendaal, C. E., Easton, D. F., Peock, S., Cook, M., Oliver, C., Frost, D., Harrington, P., Evans, D. G., Lalloo, F., Eeles, R., Izatt, L., Chu, C., Eccles, D., Douglas, F., Brewer, C., Nevanlinna, H., Heikkinen, T., Couch, F. J., Lindor, N. M., Wang, X., Godwin, A. K., Caligo, M. A., Lombardi, G., Loman, N., Karlsson, P., Ehrencrona, H., von Wachenfeldt, A., Barkardottir, R. B., Hamann, U., Rashid, M. U., Lasa, A., Caldes, T., Andres, R., Schmitt, M., Assmann, V., Stevens, K., Offit, K., Curado, J., Tilgner, H., Guigo, R., Aiza, G., Brunet, J., Castellsague, J., Martrat, G., Urruticoechea, A., Blanco, I., Tihomirova, L., Goldgar, D. E., Buys, S., John, E. M., Miron, A., Southey, M., Daly, M. B., Schmutzler, R. K., Wappenschmidt, B., Meindl, A., Arnold, N., Deissler, H., Varon-Mateeva, R., Sutter, C., Niederacher, D., Imyamitov, E., Sinilnikova, O. M., Stoppa-Lyonne, D., Mazoyer, S., Verny-Pierre, C., Castera, L., De Pauw, A., Bignon, Y., Uhrhammer, N., Peyrat, J., Vennin, P., Ferrer, S. F., Collonge-Rame, M., Mortemousque, I., Spurdle, A. B., Beesley, J., Chen, X., Healey, S., Barcellos-Hoff, M. H., Vidal, M., Gruber, S. B., Lazaro, C., Capella, G., McGuffog, L., Nathanson, K. L., Antoniou, A. C., Chenevix-Trench, G., Fleisch, M. C., Moreno, V., Angel Pujana, M. 2011; 9 (11)

  Abstract

  Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.

  View details for DOI 10.1371/journal.pbio.1001199

  View details for Web of Science ID 000298152600012

  View details for PubMedID 22110403

  View details for PubMedCentralID PMC3217025

• The potential value of sibling controls compared with population controls for association studies of lifestyle-related risk factors: an example from the Breast Cancer Family Registry INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Milne, R. L., John, E. M., Knight, J. A., Dite, G. S., Southey, M. C., Giles, G. G., Apicella, C., West, D. W., Andrulis, I. L., Whittemore, A. S., Hopper, J. L. 2011; 40 (5): 1342-1354

  Abstract

  A previous Australian population-based breast cancer case-control study found indirect evidence that control participation, although high, was not random. We hypothesized that unaffected sisters may provide a more appropriate comparison group than unrelated population controls.Three population-based case-control-family studies of breast cancer in women of white European origin were carried out by the Australian, Ontario and Northern California sites of the Breast Cancer Family Registry. We compared risk factors between 3643 cases, 2444 of their unaffected sisters and 2877 population controls and conducted separate case-control analyses based on population and sister controls using unconditional multivariable logistic regression.Compared with sister controls, population controls were more highly educated, had an earlier age at menarche, fewer births, their first birth at a later age and their last birth more recently. The established breast cancer associations detected using sister controls, but not detected using population controls, were decreasing risk with each of later age at menarche, more births, younger age at first birth and greater time since last birth.Since participation of population controls might be unintentionally related to some risk factors, we hypothesize that sister controls could provide more valid relative risk estimates and be recruited at lower cost. Given declining study participation by population controls, this contention is highly relevant to epidemiologic research.

  View details for DOI 10.1093/ije/dyr110

  View details for Web of Science ID 000296634900025

  View details for PubMedID 21771852

  View details for PubMedCentralID PMC3204209

• Confirmation of 5p12 As a Susceptibility Locus for Progesterone-Receptor-Positive, Lower Grade Breast Cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Milne, R. L., Goode, E. L., Garca-Closas, M., Couch, F. J., Severi, G., Hein, R., Fredericksen, Z., Malats, N., Pilar Zamora, M., Arias Perez, J. I., Benitez, J., Doerk, T., Schuermann, P., Karstens, J. H., Hillemanns, P., Cox, A., Brock, I. W., Elliot, G., Cross, S. S., Seal, S., Turnbull, C., Renwick, A., Rahman, N., Shen, C., Yu, J., Huang, C., Hou, M., Nordestgaard, B. G., Bojesen, S. E., Lanng, C., Alnaes, G. G., Kristensen, V., Borrensen-Dale, A., Hopper, J. L., Dite, G. S., Apicella, C., Southey, M. C., Lambrechts, D., Yesilyurt, B. T., Floris, G., Leunen, K., Sangrajrang, S., Gaborieau, V., Brennan, P., McKay, J., Chang-Claude, J., Wang-Gohrke, S., Radice, P., Peterlongo, P., Manoukian, S., Barile, M., Giles, G. G., Baglietto, L., John, E. M., Miron, A., Chanock, S. J., Lissowska, J., Sherman, M. E., Figueroa, J. D., Bogdanova, N. V., Antonenkova, N. N., Zalutsky, I. V., Rogov, Y. I., Fasching, P. A., Bayer, C. M., Ekici, A. B., Beckmann, M. W., Brenner, H., Mueller, H., Arndt, V., Stegmaier, C., Andrulis, I. L., Knight, J. A., Glendon, G., Mulligan, A. M., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Meindl, A., Heil, J., Bartram, C. R., Schmutzler, R. K., Thomas, G. D., Hoover, R. N., Fletcher, O., Gibson, L. J., Silva, I. d., Peto, J., Nickels, S., Flesch-Janys, D., Anton-Culver, H., Ziogas, A., Sawyer, E., Tomlinson, I., Kerin, M., Miller, N., Schmidt, M. K., Broeks, A., van't Veer, L. J., Tollenaar, R. A., Pharoah, P. D., Dunning, A. M., Pooley, K. A., Marme, F., Schneeweiss, A., Sohn, C., Burwinkel, B., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Kang, D., Yoo, K., Noh, D., Ahn, S., Hunter, D. J., Hankinson, S. E., Kraft, P., Lindstrom, S., Chen, X., Beesley, J., Hamann, U., Harth, V., Justenhoven, C., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Hooning, M., Hollestelle, A., Oldenburg, R. A., Tilanus-Linthorst, M., Khusnutdinova, E., Bermisheva, M., Prokofieva, D., Farahtdinova, A., Olson, J. E., Wang, X., Humphreys, M. K., Wang, Q., Chenevix-Trench, G., Easton, D. F. 2011; 20 (10): 2222-2231

  Abstract

  The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium.Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS), and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression.For white Europeans, the per-allele OR associated with 5p12-rs10941679 was 1.11 (95% CI = 1.08-1.14, P = 7 × 10(-18)) for invasive breast cancer and 1.10 (95% CI = 1.01-1.21, P = 0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR = 1.07, 95%CI = 0.99-1.15, P = 0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per-allele OR = 1.16, 95% CI = 1.12-1.20, P = 1 × 10(-18) vs. OR = 1.03, 95% CI = 0.99-1.07, P = 0.2 for PR-negative disease; P(heterogeneity) = 2 × 10(-7)); heterogeneity by ER status was not observed (P = 0.2) once PR status was accounted for. The association was also stronger for lower grade tumors [per-allele OR (95% CI) = 1.20 (1.14-1.25), 1.13 (1.09-1.16), and 1.04 (0.99-1.08) for grade 1, 2, and 3/4, respectively; P(trend) = 5 × 10(-7)].5p12 is a breast cancer susceptibility locus for PR-positive, lower grade breast cancer.Multicenter fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants.

  View details for DOI 10.1158/1055-9965.EPI-11-0569

  View details for Web of Science ID 000295717900028

  View details for PubMedID 21795498

• Identification, Replication, and Fine-Mapping of Loci Associated with Adult Height in Individuals of African Ancestry PLOS GENETICS N'Diaye, A., Chen, G. K., Palmer, C. D., Ge, B., Tayo, B., Mathias, R. A., Ding, J., Nalls, M. A., Adeyemo, A., Adoue, V., Ambrosone, C. B., Atwood, L., Bandera, E. V., Becker, L. C., Berndt, S. I., Bernstein, L., Blot, W. J., Boerwinkle, E., Britton, A., Casey, G., Chanock, S. J., Demerath, E., Deming, S. L., Diver, W. R., Fox, C., Harris, T. B., Hernandez, D. G., Hu, J. J., Ingles, S. A., John, E. M., Johnson, C., Keating, B., Kittles, R. A., Kolonel, L. N., Kritchevsky, S. B., Le Marchand, L., Lohman, K., Liu, J., Millikan, R. C., Murphy, A., Musani, S., Neslund-Dudas, C., North, K. E., Nyante, S., Ogunniyi, A., Ostrander, E. A., Papanicolaou, G., Patel, S., Pettaway, C. A., Press, M. F., Redline, S., Rodriguez-Gil, J. L., Rotimi, C., Rybicki, B. A., Salako, B., Schreiner, P. J., Signorello, L. B., Singleton, A. B., Stanford, J. L., Stram, A. H., Stram, D. O., Strom, S. S., Suktitipat, B., Thun, M. J., Witte, J. S., Yanek, L. R., Ziegler, R. G., Zheng, W., Zhu, X., Zmuda, J. M., Zonderman, A. B., Evans, M. K., Liu, Y., Becker, D. M., Cooper, R. S., Pastinen, T., Henderson, B. E., Hirschhorn, J. N., Lettre, G., Haiman, C. A. 2011; 7 (10)

  Abstract

  Adult height is a classic polygenic trait of high heritability (h(2) approximately 0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain approximately10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis of genome-wide association (GWA) results for adult height in 20,427 individuals of African ancestry with replication in up to 16,436 African Americans. We found two novel height loci (Xp22-rs12393627, P = 3.4×10(-12) and 2p14-rs4315565, P = 1.2×10(-8)). As a group, height associations discovered in European-ancestry samples replicate in individuals of African ancestry (P = 1.7×10(-4) for overall replication). Fine-mapping of the European height loci in African-ancestry individuals showed an enrichment of SNPs that are associated with expression of nearby genes when compared to the index European height SNPs (P<0.01). Our results highlight the utility of genetic studies in non-European populations to understand the etiology of complex human diseases and traits.

  View details for DOI 10.1371/journal.pgen.1002298

  View details for Web of Science ID 000296665400007

  View details for PubMedID 21998595

  View details for PubMedCentralID PMC3188544

• Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers HUMAN MOLECULAR GENETICS Antoniou, A. C., Kartsonaki, C., Sinilnikova, O. M., Soucy, P., McGuffog, L., Healey, S., Lee, A., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Cattaneo, E., Barile, M., Pensotti, V., Pasini, B., Dolcetti, R., Giannini, G., Putignano, A. L., Varesco, L., Radice, P., Mai, P. L., Greene, M. H., Andrulis, I. L., Glendon, G., Ozcelik, H., Thomassen, M., Gerdes, A., Kruse, T. A., Jensen, U. B., Crueger, D. G., Caligo, M. A., Laitman, Y., Milgrom, R., Kaufman, B., Paluch-Shimon, S., friedman, e., Loman, N., Harbst, K., Lindblom, A., Arver, B., Ehrencrona, H., Melin, B., Nathanson, K. L., Domchek, S. M., Rebbeck, T., Jakubowska, A., Lubinski, J., Gronwald, J., Huzarski, T., Byrski, T., Cybulski, C., Gorski, B., Osorio, A., Ramon y Cajal, T., Fostira, F., Andres, R., Benitez, J., Hamann, U., Hogervorst, F. B., Rookus, M. A., Hooning, M. J., Nelen, M. R., van der Luijt, R. B., van Os, T. A., van Asperen, C. J., Devilee, P., Meijers-Heijboer, H. E., Garcia, E. B., Peock, S., Cook, M., Frost, D., Platte, R., Leyland, J., Evans, D. G., Lalloo, F., Eeles, R., Izatt, L., Adlard, J., Davidson, R., Eccles, D., Ong, K., Cook, J., Douglas, F., Paterson, J., Kennedy, M. J., Miedzybrodzka, Z., Godwin, A., Stoppa-Lyonnet, D., Buecher, B., Belotti, M., Tirapo, C., Mazoyer, S., Barjhoux, L., Lasset, C., Leroux, D., Faivre, L., Bronner, M., Prieur, F., Nogues, C., Rouleau, E., Pujol, P., Coupier, I., Frenay, M., Hopper, J. L., Daly, M. B., Terry, M. B., John, E. M., Buys, S. S., Yassin, Y., Miron, A., Goldgar, D., Singer, C. F., Tea, M., Pfeiler, G., Dressler, A. C., Hansen, T. v., Jonson, L., Ejlertsen, B., Barkardottir, R. B., Kirchhoff, T., Offit, K., Piedmonte, M., Rodriguez, G., Small, L., Boggess, J., Blank, S., Basil, J., Azodi, M., Toland, A. E., Montagna, M., Tognazzo, S., Agata, S., Imyanitov, E., Janavicius, R., Lazaro, C., Blanco, I., Pharoah, P. D., Sucheston, L., Karlan, B. Y., Walsh, C. S., Olah, E., Bozsik, A., Teo, S., Seldon, J. L., Beattie, M. S., Van Rensburg, E. J., Sluiter, M. D., Diez, O., Schmutzler, R. K., Wappenschmidt, B., Engel, C., Meindl, A., Ruehl, I., Varon-Mateeva, R., Kast, K., Deissler, H., Niederacher, D., Arnold, N., Gadzicki, D., Schoenbuchner, I., Caldes, T., de la Hoya, M., Nevanlinna, H., Aittomaki, K., Dumont, M., Chiquette, J., Tischkowitz, M., Chen, X., Beesley, J., Spurdle, A. B., Neuhausen, S. L., Ding, Y. C., Fredericksen, Z., Wang, X., Pankratz, V. S., Couch, F., Simard, J., Easton, D. F., Chenevix-Trench, G. 2011; 20 (16): 3304-3321

  Abstract

  Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

  View details for DOI 10.1093/hmg/ddr226

  View details for Web of Science ID 000293027100017

  View details for PubMedID 21593217

• The landscape of recombination in African Americans NATURE Hinch, A. G., Tandon, A., Patterson, N., Song, Y., Rohland, N., Palmer, C. D., Chen, G. K., Wang, K., Buxbaum, S. G., Akylbekova, E. L., Aldrich, M. C., Ambrosone, C. B., Amos, C., Bandera, E. V., Berndt, S. I., Bernstein, L., Blot, W. J., Bock, C. H., Boerwinkle, E., Cai, Q., Caporaso, N., Casey, G., Cupples, L. A., Deming, S. L., Diver, W. R., Divers, J., Fornage, M., Gillanders, E. M., Glessner, J., Harris, C. C., Hu, J. J., Ingles, S. A., Isaacs, W., John, E. M., Kao, W. H., Keating, B., Kittles, R. A., Kolonel, L. N., Larkin, E., Le Marchand, L., McNeill, L. H., Millikan, R. C., Murphy, A., Musani, S., Neslund-Dudas, C., Nyante, S., Papanicolaou, G. J., Press, M. F., Psaty, B. M., Reiner, A. P., Rich, S. S., Rodriguez-Gil, J. L., Rotter, J. I., Rybicki, B. A., Schwartz, A. G., Signorello, L. B., Spitz, M., Strom, S. S., Thun, M. J., Tucker, M. A., Wang, Z., Wiencke, J. K., Witte, J. S., Wrensch, M., Wu, X., Yamamura, Y., Zanetti, K. A., Zheng, W., Ziegler, R. G., Zhu, X., Redline, S., Hirschhorn, J. N., Henderson, B. E., Taylor, H. A., Price, A. L., Hakonarson, H., Chanock, S. J., Haiman, C. A., Wilson, J. G., Reich, D., Myers, S. R. 2011; 476 (7359): 170-U67

  Abstract

  Recombination, together with mutation, gives rise to genetic variation in populations. Here we leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P value < 10(-245)). We identify a 17-base-pair DNA sequence motif that is enriched in these hotspots, and is an excellent match to the predicted binding target of PRDM9 alleles common in West Africans and rare in Europeans. Sites of this motif are predicted to be risk loci for disease-causing genomic rearrangements in individuals carrying these alleles. More generally, this map provides a resource for research in human genetic variation and evolution.

  View details for DOI 10.1038/nature10336

  View details for Web of Science ID 000293731900028

  View details for PubMedID 21775986

  View details for PubMedCentralID PMC3154982

• Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study NATURE GENETICS Kote-Jarai, Z., Al Olama, A. A., Giles, G. G., Severi, G., Schleutker, J., Weischer, M., Campa, D., Riboli, E., Key, T., Gronberg, H., Hunter, D. J., Kraft, P., Thun, M. J., Ingles, S., Chanock, S., Albanes, D., Hayes, R. B., Neal, D. E., Hamdy, F. C., Donovan, J. L., Pharoah, P., Schumacher, F., Henderson, B. E., Stanford, J. L., Ostrander, E. A., Sorensen, K. D., Dork, T., Andriole, G., Dickinson, J. L., Cybulski, C., Lubinski, J., Spurdle, A., Clements, J. A., Chambers, S., Aitken, J., Gardiner, R. A., Thibodeau, S. N., Schaid, D., John, E. M., Maier, C., Vogel, W., Cooney, K. A., Park, J. Y., Cannon-Albright, L., Brenner, H., Habuchi, T., Zhang, H., Lu, Y., Kaneva, R., Muir, K., Benlloch, S., Leongamornlert, D. A., Saunders, E. J., Tymrakiewicz, M., Mahmud, N., Guy, M., O'Brien, L. T., Wilkinson, R. A., Hall, A. L., Sawyer, E. J., Dadaev, T., Morrison, J., Dearnaley, D. P., Horwich, A., Huddart, R. A., Khoo, V. S., Parker, C. C., Van As, N., Woodhouse, C. J., Thompson, A., Christmas, T., Ogden, C., Cooper, C. S., Lophatonanon, A., Southey, M. C., Hopper, J. L., English, D. R., Wahlfors, T., Tammela, T. L., Klarskov, P., Nordestgaard, B. G., Roder, M. A., Tybjaerg-Hansen, A., Bojesen, S. E., Travis, R., Canzian, F., Kaaks, R., Wiklund, F., Aly, M., Lindstrom, S., Diver, W. R., Gapstur, S., Stern, M. C., Corral, R., Virtamo, J., Cox, A., Haiman, C. A., Le Marchand, L., FitzGerald, L., Kolb, S., Kwon, E. M., Karyadi, D. M., Orntoft, T. F., Borre, M., Meyer, A., Serth, J., Yeager, M., Berndt, S. I., Marthick, J. R., Patterson, B., Wokolorczyk, D., Batra, J., Lose, F., McDonnell, S. K., Joshi, A. D., Shahabi, A., Rinckleb, A. E., Ray, A., Sellers, T. A., Lin, H., Stephenson, R. A., Farnham, J., Muller, H., Rothenbacher, D., Tsuchiya, N., Narita, S., Cao, G., Slavov, C., Mitev, V., Easton, D. F., Eeles, R. A. 2011; 43 (8): 785-U96

  Abstract

  Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 × 10(-8) to P = 2.7 × 10(-24)). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ∼25% of the familial risk in this disease, have now been identified.

  View details for DOI 10.1038/ng.882

  View details for Web of Science ID 000293178300015

  View details for PubMedID 21743467

  View details for PubMedCentralID PMC3396006

• Genome-wide association study of prostate cancer in men of African ancestry identifies a susceptibility locus at 17q21 NATURE GENETICS Haiman, C. A., Chen, G. K., Blot, W. J., Strom, S. S., Berndt, S. I., Kittles, R. A., Rybicki, B. A., Isaacs, W. B., Ingles, S. A., Stanford, J. L., Diver, W. R., Witte, J. S., Hsing, A. W., Nemesure, B., Rebbeck, T. R., Cooney, K. A., Xu, J., Kibel, A. S., Hu, J. J., John, E. M., Gueye, S. M., Watya, S., Signorello, L. B., Hayes, R. B., Wang, Z., Yeboah, E., Tettey, Y., Cai, Q., Kolb, S., Ostrander, E. A., Zeigler-Johnson, C., Yamamura, Y., Neslund-Dudas, C., Haslag-Minoff, J., Wu, W., Thomas, V., Allen, G. O., Murphy, A., Chang, B., Zheng, S. L., Leske, M. C., Wu, S., Ray, A. M., Hennis, A. J., Thun, M. J., Carpten, J., Casey, G., Carter, E. N., Duarte, E. R., Xia, L. Y., Sheng, X., Wan, P., Pooler, L. C., Cheng, I., Monroe, K. R., Schumacher, F., Le Marchand, L., Kolonel, L. N., Chanock, S. J., Van Den Berg, D., Stram, D. O., Henderson, B. E. 2011; 43 (6): 570-U103

  Abstract

  In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study, with 1,047,986 SNP markers examined in 3,425 African-Americans with prostate cancer (cases) and 3,290 African-American male controls. We followed up the most significant 17 new associations from stage 1 in 1,844 cases and 3,269 controls of African ancestry. We identified a new risk variant on chromosome 17q21 (rs7210100, odds ratio per allele = 1.51, P = 3.4 × 10(-13)). The frequency of the risk allele is ∼5% in men of African descent, whereas it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting genome-wide association studies in diverse populations.

  View details for DOI 10.1038/ng.839

  View details for Web of Science ID 000291017000015

  View details for PubMedID 21602798

  View details for PubMedCentralID PMC3102788

• Enhanced Statistical Tests for GWAS in Admixed Populations: Assessment using African Americans from CARe and a Breast Cancer Consortium PLOS GENETICS Pasaniuc, B., Zaitlen, N., Lettre, G., Chen, G. K., Tandon, A., Kao, W. H., Ruczinski, I., Fornage, M., Siscovick, D. S., Zhu, X., Larkin, E., Lange, L. A., Cupples, L. A., Yang, Q., Akylbekova, E. L., Musani, S. K., Divers, J., Mychaleckyj, J., Li, M., Papanicolaou, G. J., Millikan, R. C., Ambrosone, C. B., John, E. M., Bernstein, L., Zheng, W., Hu, J. J., Ziegler, R. G., Nyante, S. J., Bandera, E. V., Ingles, S. A., Press, M. F., Chanock, S. J., Deming, S. L., Rodriguez-Gil, J. L., Palmer, C. D., Buxbaum, S., Ekunwe, L., Hirschhorn, J. N., Henderson, B. E., Myers, S., Haiman, C. A., Reich, D., Patterson, N., Wilson, J. G., Price, A. L. 2011; 7 (4)

  Abstract

  While genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations.

  View details for DOI 10.1371/journal.pgen.1001371

  View details for Web of Science ID 000289977000015

  View details for PubMedID 21541012

  View details for PubMedCentralID PMC3080860

• Associations of Breast Cancer Risk Factors With Tumor Subtypes: A Pooled Analysis From the Breast Cancer Association Consortium Studies JOURNAL OF THE NATIONAL CANCER INSTITUTE Yang, X. R., Chang-Claude, J., Goode, E. L., Couch, F. J., Nevanlinna, H., Milne, R. L., Gaudet, M., Schmidt, M. K., Broeks, A., Cox, A., Fasching, P. A., Hein, R., Spurdle, A. B., Blows, F., Driver, K., Flesch-Janys, D., Heinz, J., Sinn, P., Vrieling, A., Heikkinen, T., Aittomaeki, K., Heikkilae, P., Blomqvist, C., Lissowska, J., Peplonska, B., Chanock, S., Figueroa, J., Brinton, L., Hall, P., Czene, K., Humphreys, K., Darabi, H., Liu, J., van 't Veer, L. J., van Leeuwen, F. E., Andrulis, I. L., Glendon, G., Knight, J. A., Mulligan, A. M., O'Malley, F. P., Weerasooriya, N., John, E. M., Beckmann, M. W., Hartmann, A., Weihbrecht, S. B., Wachter, D. L., Jud, S. M., Loehberg, C. R., Baglietto, L., English, D. R., Giles, G. G., McLean, C. A., Severi, G., Lambrechts, D., Vandorpe, T., Weltens, C., Paridaens, R., Smeets, A., Neven, P., Wildiers, H., Wang, X., Olson, J. E., Cafourek, V., Fredericksen, Z., Kosel, M., Vachon, C., Cramp, H. E., Connley, D., Cross, S. S., Balasubramanian, S. P., Reed, M. W., Doerk, T., Bremer, M., Meyer, A., Karstens, J. H., Ay, A., Park-Simon, T., Hillemanns, P., Arias Perez, J. I., Menendez Rodriguez, P., Zamora, P., Bentez, J., Ko, Y., Fischer, H., Hamann, U., Pesch, B., Bruening, T., Justenhoven, C., Brauch, H., Eccles, D. M., Tapper, W. J., Gerty, S. M., Sawyer, E. J., Tomlinson, I. P., Jones, A., Kerin, M., Miller, N., Mcinerney, N., Anton-Culver, H., Ziogas, A., Shen, C., Hsiung, C., Wu, P., Yang, S., Yu, J., Chen, S., Hsu, G., Haiman, C. A., Henderson, B. E., Le Marchand, L., Kolonel, L. N., Lindblom, A., Margolin, S., Jakubowska, A., Lubinski, J., Huzarski, T., Byrski, T., Gorski, B., Gronwald, J., Hooning, M. J., Hollestelle, A., van den Ouweland, A. M., Jager, A., Kriege, M., Tilanus-Linthorst, M. M., Collee, M., Wang-Gohrke, S., Pylkaes, K., Jukkola-Vuorinen, A., Mononen, K., Grip, M., Hirvikoski, P., Winqvist, R., Mannermaa, A., Kosma, V., Kauppinen, J., Kataja, V., Auvinen, P., Soini, Y., Sironen, R., Bojesen, S. E., Orsted, D. D., Kaur-Knudsen, D., Flyger, H., Nordestgaard, B. G., Holland, H., Chenevix-Trench, G., Manoukian, S., Barile, M., Radice, P., Hankinson, S. E., Hunter, D. J., Tamimi, R., Sangrajrang, S., Brennan, P., McKay, J., Odefrey, F., Gaborieau, V., Devilee, P., Huijts, P. E., Tollenaar, R. A., Seynaeve, C., Dite, G. S., Apicella, C., Hopper, J. L., Hammet, F., Tsimiklis, H., Smith, L. D., Southey, M. C., Humphreys, M. K., Easton, D., Pharoah, P., Sherman, M. E., Garcia-Closas, M. 2011; 103 (3): 250-263

  Abstract

  Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.We pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided.In case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ≥ 30 kg/m(2)) in younger women (≤50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors.This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.

  View details for DOI 10.1093/jnci/djq526

  View details for Web of Science ID 000287027000010

  View details for PubMedID 21191117

• Germline mutations in PALB2 in African-American breast cancer cases BREAST CANCER RESEARCH AND TREATMENT Ding, Y. C., Steele, L., Chu, L., Kelley, K., Davis, H., John, E. M., Tomlinson, G. E., Neuhausen, S. L. 2011; 126 (1): 227-230

  Abstract

  Breast cancer incidence is lower in African Americans than in Caucasian Americans. However, African-American women have higher breast cancer mortality rates and tend to be diagnosed with earlier-onset disease. Identifying factors correlated to the racial/ethnic variation in the epidemiology of breast cancer may provide better understanding of the more aggressive disease at diagnosis. Truncating germline mutations in PALB2 have been identified in approximately 1% of early-onset and/or familial breast cancer cases. To date, PALB2 mutation testing has not been performed in African-American breast cancer cases. We screened for germline mutations in PALB2 in 139 African-American breast cases by denaturing high-performance liquid chromatography and direct sequencing. Twelve variants were identified in these cases and none caused truncation of the protein. Three missense variants, including two rare variants (P8L and T300I) and one common variant (P210L), were predicted to be pathogenic, and were located in a coiled-coil domain of PALB2 required for RAD51- and BRCA1-binding. We investigated and found no significant association between the P210L variant and breast cancer risk in a small case-control study of African-American women. This study adds to the literature that PALB2 mutations, although rare, appear to play a role in breast cancer in all populations investigated to date.

  View details for DOI 10.1007/s10549-010-1271-7

  View details for Web of Science ID 000286470200026

  View details for PubMedID 21113654

  View details for PubMedCentralID PMC3457798

• Adult Body Size, Hormone Receptor Status, and Premenopausal Breast Cancer Risk in a Multiethnic Population The San Francisco Bay Area Breast Cancer Study AMERICAN JOURNAL OF EPIDEMIOLOGY John, E. M., Sangaramoorthy, M., Phipps, A. I., Koo, J., Horn-Ross, P. L. 2011; 173 (2): 201-216

  Abstract

  Large body size has been associated with a reduced risk of premenopausal breast cancer in non-Hispanic white women. Data on other racial/ethnic populations are limited. The authors examined the association between premenopausal breast cancer risk and adult body size in 672 cases and 808 controls aged ≥35 years from a population-based case-control study conducted in 1995-2004 in the San Francisco Bay Area (Hispanics: 375 cases, 483 controls; African Americans: 154 cases, 160 controls; non-Hispanic whites: 143 cases, 165 controls). Multivariate adjusted odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. Height was associated with increased breast cancer risk (highest vs. lowest quartile: odds ratio = 1.77, 95% confidence interval: 1.23, 2.53; P(trend) < 0.01); the association did not vary by hormone receptor status or race/ethnicity. Body mass index (measured as weight (kg) divided by height (m) squared) was inversely associated with risk in all 3 racial/ethnic groups, but only for estrogen receptor- and progesterone receptor-positive tumors (body mass index ≥30 vs. <25: odds ratio = 0.42; 95% confidence interval: 0.29, 0.61). Other body size measures (current weight, body build, adult weight gain, young adult weight and body mass index, waist circumference, and waist-to-height ratio) were similarly inversely associated with risk of estrogen receptor- and progesterone receptor-positive breast cancer but not estrogen receptor- and progesterone receptor-negative disease. Despite racial/ethnic differences in body size, inverse associations were similar across the 3 racial/ethnic groups when stratified by hormone receptor status.

  View details for DOI 10.1093/aje/kwq345

  View details for Web of Science ID 000285627500010

  View details for PubMedID 21084558

  View details for PubMedCentralID PMC3011952

• Meat Consumption, Cooking Practices, Meat Mutagens, and Risk of Prostate Cancer NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL John, E. M., Stern, M. C., Sinha, R., Koo, J. 2011; 63 (4): 525-537

  Abstract

  Consumption of red meat, particularly well-done meat, has been associated with increased prostate cancer risk. High-temperature cooking methods such as grilling and barbecuing may produce heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs), which are known carcinogens. We assessed the association with meat consumption and estimated HCA and PAH exposure in a population-based case-control study of prostate cancer. Newly diagnosed cases aged 40-79 years (531 advanced cases, 195 localized cases) and 527 controls were asked about dietary intake, including usual meat cooking methods and doneness levels. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariate logistic regression. For advanced prostate cancer, but not localized disease, increased risks were associated with higher consumption of hamburgers (OR = 1.79, CI = 1.10-2.92), processed meat (OR = 1.57, CI = 1.04-2.36), grilled red meat (OR = 1.63, CI = 0.99-2.68), and well-done red meat (OR = 1.52, CI = 0.93-2.46), and intermediate intake of 2-amino-1-methyl1-6-phenylimidazo[4,5-b]pyridine (PhIP) (Quartile 2 vs. 1: OR = 1.41, CI = 0.98-2.01; Quartile 3 vs. 1: OR = 1.42, CI = 0.98-2.04), but not for higher intake. White meat consumption was not associated with prostate cancer. These findings provide further evidence that consumption of processed meat and red meat cooked at high temperature is associated with increased risk of advanced, but not localized, prostate cancer.

  View details for DOI 10.1080/01635581.2011.539311

  View details for Web of Science ID 000290970100005

  View details for PubMedID 21526454

  View details for PubMedCentralID PMC3516139

• Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 BREAST CANCER RESEARCH Mulligan, A. M., Couch, F. J., Barrowdale, D., Domchek, S. M., Eccles, D., Nevanlinna, H., Ramus, S. J., Robson, M., Sherman, M., Spurdle, A. B., Wappenschmidt, B., Lee, A., McGuffog, L., Healey, S., Sinilnikova, O. M., Janavicius, R., Hansen, T. v., Nielsen, F. C., Ejlertsen, B., Osorio, A., Munoz-Repeto, I., Duran, M., Godino, J., Pertesi, M., Benitez, J., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Cattaneo, E., Bonanni, B., Viel, A., Pasini, B., Papi, L., Ottini, L., Savarese, A., Bernard, L., Radice, P., Hamann, U., Verheus, M., Meijers-Heijboer, H. E., Wijnen, J., Garcia, E. B., Nelen, M. R., Kets, C. M., Seynaeve, C., Tilanus-Linthorst, M. M., van der Luijt, R. B., van Os, T., Rookus, M., Frost, D., Jones, J. L., Evans, D. G., Lalloo, F., Eeles, R., Izatt, L., Adlard, J., Davidson, R., Cook, J., Donaldson, A., Dorkins, H., Gregory, H., Eason, J., Houghton, C., Barwell, J., Side, L. E., McCann, E., Murray, A., Peock, S., Godwin, A. K., Schmutzler, R. K., Rhiem, K., Engel, C., Meindl, A., Ruehl, I., Arnold, N., Niederacher, D., Sutter, C., Deissler, H., Gadzicki, D., Kast, K., Preisler-Adams, S., Varon-Mateeva, R., Schoenbuchner, I., Fiebig, B., Heinritz, W., Schaefer, D., Gevensleben, H., Caux-Moncoutier, V., Fassy-Colcombet, M., Cornelis, F., Mazoyer, S., Leone, M., Boutry-Kryza, N., Hardouin, A., Berthet, P., Muller, D., Fricker, J., Mortemousque, I., Pujol, P., Coupier, I., Lebrun, M., Kientz, C., Longy, M., Sevenet, N., Stoppa-Lyonnet, D., Isaacs, C., Caldes, T., de la Hoya, M., Heikkinen, T., Aittomaki, K., Blanco, I., Lazaro, C., Barkardottir, R. B., Soucy, P., Dumont, M., Simard, J., Montagna, M., Tognazzo, S., D'Andrea, E., Fox, S., Yan, M., Rebbeck, T., Olopade, O. I., Weitzel, J. N., Lynch, H. T., Ganz, P. A., Tomlinson, G. E., Wang, X., Fredericksen, Z., Pankratz, V. S., Lindor, N. M., Szabo, C., Offit, K., Sakr, R., Gaudet, M., Bhatia, J., Kauff, N., Singer, C. F., Tea, M., Gschwantler-Kaulich, D., Fink-Retter, A., Mai, P. L., Greene, M. H., Imyanitov, E., O'Malley, F. P., Ozcelik, H., Glendon, G., Toland, A. E., Gerdes, A., Thomassen, M., Kruse, T. A., Jensen, U. B., Skytte, A., Caligo, M. A., Soller, M., Henriksson, K., Wachenfeldt, v. A., Arver, B., Stenmark-Askmalm, M., Karlsson, P., Ding, Y. C., Neuhausen, S. L., Beattie, M., Pharoah, P. D., Moysich, K. B., Nathanson, K. L., Karlan, B. Y., Gross, J., John, E. M., Daly, M. B., Buys, S. M., Southey, M. C., Hopper, J. L., Terry, M. B., Chung, W., Miron, A. F., Goldgar, D., Chenevix-Trench, G., Easton, D. F., Andrulis, I. L., Antoniou, A. C. 2011; 13 (6)

  Abstract

  Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour.We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach.The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status.The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

  View details for DOI 10.1186/bcr3052

  View details for Web of Science ID 000301173700002

  View details for PubMedID 22053997

• Exploring the link between MORF4L1 and risk of breast cancer BREAST CANCER RESEARCH Martrat, G., Maxwell, C. A., Tominaga, E., Porta-de-la-Riva, M., Bonifaci, N., Gomez-Baldo, L., Bogliolo, M., Lazaro, C., Blanco, I., Brunet, J., Aguilar, H., Fernandez-Rodriguez, J., Seal, S., Renwick, A., Rahman, N., Kuehl, J., Neveling, K., Schindler, D., Ramirez, M. J., Castella, M., Hernandez, G., Easton, D. F., Peock, S., Cook, M., Oliver, C. T., Frost, D., Platte, R., Evans, D. G., Lalloo, F., Eeles, R., Izatt, L., Chu, C., Davidson, R., Ong, K., Cook, J., Douglas, F., Hodgson, S., Brewer, C., Morrison, P. J., Porteous, M., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Roversi, G., Barile, M., Viel, A., Pasini, B., Ottini, L., Putignano, A. L., Savarese, A., Bernard, L., Radice, P., Healey, S., Spurdle, A., Chen, X., Beesley, J., Rookus, M. A., Verhoef, S., Tilanus-Linthorst, M. A., Vreeswijk, M. P., Asperen, C. J., Bodmer, D., Ausems, M. G., van Os, T. A., Blok, M. J., Meijers-Heijboer, H. E., Hogervorst, F. B., Goldgar, D. E., Buys, S., John, E. M., Miron, A., Southey, M., Daly, M. B., Harbst, K., Borg, A., Rantala, J., Barbany-Bustinza, G., Ehrencrona, H., Stenmark-Askmalm, M., Kaufman, B., Laitman, Y., Milgrom, R., friedman, e., Domchek, S. M., Nathanson, K. L., Rebbeck, T. R., Johannsson, O. T., Couch, F. J., Wang, X., Fredericksen, Z., Cuadras, D., Moreno, V., Pientka, F. K., Depping, R., Caldes, T., Osorio, A., Benitez, J., Bueren, J., Heikkinen, T., Nevanlinna, H., Hamann, U., Torres, D., Caligo, M. A., Godwin, A. K., Imyanitov, E. N., Janavicius, R., Sinilnikova, O. M., Stoppa-Lyonnet, D., Mazoyer, S., Verny-Pierre, C., Castera, L., De Pauw, A., Bignon, Y., Uhrhammer, N., Peyrat, J., Vennin, P., Ferrer, S. F., Collonge-Rame, M., Mortemousque, I., McGuffog, L., Chenevix-Trench, G., Pereira-Smith, O. M., Antoniou, A. C., Ceron, J., Tominaga, K., Surralles, J., Angel Pujana, M. 2011; 13 (2)

  Abstract

  Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens.Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk.A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to γ-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively.While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.

  View details for DOI 10.1186/bcr2862

  View details for Web of Science ID 000292694600029

  View details for PubMedID 21466675

  View details for PubMedCentralID PMC3219203

• Rare variants in the ATM gene and risk of breast cancer BREAST CANCER RESEARCH Goldgar, D. E., Healey, S., Dowty, J. G., Da Silva, L., Chen, X., Spurdle, A. B., Terry, M. B., Daly, M. J., Buys, S. M., Southey, M. C., Andrulis, I., John, E. M., Khanna, K. K., Hopper, J. L., Oefner, P. J., Lakhani, S., Chenevix-Trench, G. 2011; 13 (4)

  Abstract

  The ataxia-telangiectasia mutated (ATM) gene (MIM ID 208900) encodes a protein kinase that plays a significant role in the activation of cellular responses to DNA double-strand breaks through subsequent phosphorylation of central players in the DNA damage-response pathway. Recent studies have confirmed that some specific variants in the ATM gene are associated with increased breast cancer (BC) risk. However, the magnitude of risk and the subset of variants that are pathogenic for breast cancer remain unresolved.To investigate the role of ATM in BC susceptibility, we studied 76 rare sequence variants in the ATM gene in a case-control family study of 2,570 cases of breast cancer and 1,448 controls. The variants were grouped into three categories based on their likely pathogenicity, as determined by in silico analysis and analyzed by conditional logistic regression. Likely pathogenic sequence variants were genotyped in 129 family members of 27 carrier probands (15 of which carried c.7271T > G), and modified segregation analysis was used to estimate the BC penetrance associated with these rare ATM variants.In the case-control analysis, we observed an odds ratio of 2.55 and 95% confidence interval (CI, 0.54 to 12.0) for the most likely deleterious variants. In the family-based analyses, the maximum-likelihood estimate of the increased risk associated with these variants was hazard ratio (HR) = 6.88 (95% CI, 2.33 to 20.3; P = 0.00008), corresponding to a 60% cumulative risk of BC by age 80 years. Analysis of loss of heterozygosity (LOH) in 18 breast tumors from women carrying likely pathogenic rare sequence variants revealed no consistent pattern of loss of the ATM variant.The risk estimates from this study suggest that women carrying the pathogenic variant, ATM c.7271T > G, or truncating mutations demonstrate a significantly increased risk of breast cancer with a penetrance that appears similar to that conferred by germline mutations in BRCA2.

  View details for DOI 10.1186/bcr2919

  View details for Web of Science ID 000297169700003

  View details for PubMedID 21787400

  View details for PubMedCentralID PMC3236337

• Contribution of large genomic BRCA1 alterations to early-onset breast cancer selected for family history and tumour morphology: a report from The Breast Cancer Family Registry BREAST CANCER RESEARCH Smith, L. D., Tesoriero, A. A., Wong, E. M., Ramus, S. J., O'Malley, F. P., Mulligan, A. M., Terry, M. B., Senie, R. T., Santella, R. M., John, E. M., Andrulis, I. L., Ozcelik, H., Daly, M. B., Godwin, A. K., Buys, S. S., Fox, S., Goldgar, D. E., Giles, G. G., Hopper, J. L., Southey, M. C. 2011; 13 (1)

  Abstract

  Selecting women affected with breast cancer who are most likely to carry a germline mutation in BRCA1 and applying the most appropriate test methodology remains challenging for cancer genetics services. We sought to test the value of selecting women for BRCA1 mutation testing on the basis of family history and/or breast tumour morphology criteria as well as the value of testing for large genomic alterations in BRCA1.We studied women participating in the Breast Cancer Family Registry (BCFR), recruited via population-based sampling, who had been diagnosed with breast cancer before the age of 40 years who had a strong family history of breast or ovarian cancer (n = 187) and/or a first primary breast tumour with morphological features consistent with carrying a BRCA1 germline mutation (n = 133; 37 met both criteria). An additional 184 women diagnosed before the age of 40 years who had a strong family history of breast or ovarian cancer and who were not known to carry a germline BRCA1 mutation were selected from among women who had been recruited into the BCFR from clinical genetics services. These 467 women had been screened for BRCA1 germline mutations, and we expanded this testing to include a screen for large genomic BRCA1 alterations using Multiplex Ligation-dependent Probe Amplification.Twelve large genomic BRCA1 alterations were identified, including 10 (4%) of the 283 women selected from among the population-based sample. In total, 18 (12%), 18 (19%) and 16 (43%) BRCA1 mutations were identified in the population-based groups selected on the basis of family history only (n = 150), the group selected on the basis of tumour morphology only (n = 96) and meeting both criteria (n = 37), respectively.Large genomic alterations accounted for 19% of all BRCA1 mutations identified. This study emphasises the value of combining information about family history, age at diagnosis and tumour morphology when selecting women for germline BRCA1 mutation testing as well as including a screen for large genomic alterations.

  View details for DOI 10.1186/bcr2822

  View details for Web of Science ID 000290278400014

  View details for PubMedID 21281505

  View details for PubMedCentralID PMC3109582

• Validation of Genome-Wide Prostate Cancer Associations in Men of African Descent CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Chang, B., Spangler, E., Gallagher, S., Haiman, C. A., Henderson, B., Isaacs, W., Benford, M. L., Kidd, L. R., Cooney, K., Strom, S., Ingles, S. A., Stern, M. C., Corral, R., Joshi, A. D., Xu, J., Giri, V. N., Rybicki, B., Neslund-Dudas, C., Kibel, A. S., Thompson, I. M., Leach, R. J., Ostrander, E. A., Stanford, J. L., Witte, J., Casey, G., Eeles, R., Hsing, A. W., Chanock, S., Hu, J. J., John, E. M., Park, J., Stefflova, K., Zeigler-Johnson, C., Rebbeck, T. R. 2011; 20 (1): 23-32

  Abstract

  Genome-wide association studies (GWAS) have identified numerous prostate cancer susceptibility alleles, but these loci have been identified primarily in men of European descent. There is limited information about the role of these loci in men of African descent.We identified 7,788 prostate cancer cases and controls with genotype data for 47 GWAS-identified loci.We identified significant associations for SNP rs10486567 at JAZF1, rs10993994 at MSMB, rs12418451 and rs7931342 at 11q13, and rs5945572 and rs5945619 at NUDT10/11. These associations were in the same direction and of similar magnitude as those reported in men of European descent. Significance was attained at all reported prostate cancer susceptibility regions at chromosome 8q24, including associations reaching genome-wide significance in region 2.We have validated in men of African descent the associations at some, but not all, prostate cancer susceptibility loci originally identified in European descent populations. This may be due to the heterogeneity in genetic etiology or in the pattern of genetic variation across populations.The genetic etiology of prostate cancer in men of African descent differs from that of men of European descent.

  View details for DOI 10.1158/1055-9965.EPI-10-0698

  View details for Web of Science ID 000285972800003

  View details for PubMedID 21071540

  View details for PubMedCentralID PMC3110616

• Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers JOURNAL OF MEDICAL GENETICS Schrader, K. A., Masciari, S., Boyd, N., Salamanca, C., Senz, J., Saunders, D. N., Yorida, E., Maines-Bandiera, S., Kaurah, P., Tung, N., Robson, M. E., Ryan, P. D., Olopade, O. I., Domchek, S. M., Ford, J., Isaacs, C., BROWN, P., Balmana, J., Razzak, A. R., Miron, P., Coffey, K., Terry, M. B., John, E. M., Andrulis, I. L., Knight, J. A., O'Malley, F. P., Daly, M., Bender, P., Moore, R., Southey, M. C., Hopper, J. L., Garber, J. E., Huntsman, D. G. 2011; 48 (1): 64-68

  Abstract

  Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer; lobular breast cancer also occurs excessively in families with such condition.To determine if CDH1 is a susceptibility gene for lobular breast cancer in women without a family history of diffuse gastric cancer, germline DNA was analysed for the presence of CDH1 mutations in 318 women with lobular breast cancer who were diagnosed before the age of 45 years or had a family history of breast cancer and were not known, or known not, to be carriers of germline mutations in BRCA1 or BRCA2. Cases were ascertained through breast cancer registries and high-risk cancer genetic clinics (Breast Cancer Family Registry, the kConFab and a consortium of breast cancer genetics clinics in the United States and Spain). Additionally, Multiplex Ligation-dependent Probe Amplification was performed for 134 cases to detect large deletions.No truncating mutations and no large deletions were detected. Six non-synonymous variants were found in seven families. Four (4/318 or 1.3%) are considered to be potentially pathogenic through in vitro and in silico analysis.Potentially pathogenic germline CDH1 mutations in women with early-onset or familial lobular breast cancer are at most infrequent.

  View details for DOI 10.1136/jmg.2010.079814

  View details for Web of Science ID 000285383600009

  View details for PubMedID 20921021

  View details for PubMedCentralID PMC3003879

• Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study BREAST CANCER RESEARCH Le Calvez-Kelm, F., Lesueur, F., Damiola, F., Vallee, M., Voegele, C., Babikyan, D., Durand, G., Forey, N., McKay-Chopin, S., Robinot, N., Nguyen-Dumont, T., Thomas, A., Byrnes, G. B., Hopper, J. L., Southey, M. C., Andrulis, I. L., John, E. M., Tavtigian, S. V. 2011; 13 (1)

  Abstract

  Both protein-truncating variants and some missense substitutions in CHEK2 confer increased risk of breast cancer. However, no large-scale study has used full open reading frame mutation screening to assess the contribution of rare missense substitutions in CHEK2 to breast cancer risk. This absence has been due in part to a lack of validated statistical methods for summarizing risk attributable to large numbers of individually rare missense substitutions.Previously, we adapted an in silico assessment of missense substitutions used for analysis of unclassified missense substitutions in BRCA1 and BRCA2 to the problem of assessing candidate genes using rare missense substitution data observed in case-control mutation-screening studies. The method involves stratifying rare missense substitutions observed in cases and/or controls into a series of grades ordered a priori from least to most likely to be evolutionarily deleterious, followed by a logistic regression test for trends to compare the frequency distributions of the graded missense substitutions in cases versus controls. Here we used this approach to analyze CHEK2 mutation-screening data from a population-based series of 1,303 female breast cancer patients and 1,109 unaffected female controls.We found evidence of risk associated with rare, evolutionarily unlikely CHEK2 missense substitutions. Additional findings were that (1) the risk estimate for the most severe grade of CHEK2 missense substitutions (denoted C65) is approximately equivalent to that of CHEK2 protein-truncating variants; (2) the population attributable fraction and the familial relative risk explained by the pool of rare missense substitutions were similar to those explained by the pool of protein-truncating variants; and (3) post hoc power calculations implied that scaling up case-control mutation screening to examine entire biochemical pathways would require roughly 2,000 cases and controls to achieve acceptable statistical power.This study shows that CHEK2 harbors many rare sequence variants that confer increased risk of breast cancer and that a substantial proportion of these are missense substitutions. The study validates our analytic approach to rare missense substitutions and provides a method to combine data from protein-truncating variants and rare missense substitutions into a one degree of freedom per gene test.

  View details for DOI 10.1186/bcr2810

  View details for Web of Science ID 000290278400006

  View details for PubMedID 21244692

  View details for PubMedCentralID PMC3109572

• A genome-wide linkage study of mammographic density, a risk factor for breast cancer BREAST CANCER RESEARCH Greenwood, C. M., Paterson, A. D., Linton, L., Andrulis, I. L., Apicella, C., Dimitromanolakis, A., Kriukov, V., Martin, L. J., Salleh, A., Samiltchuk, E., Parekh, R. V., Southey, M. C., John, E. M., Hopper, J. L., Boyd, N. F., Rommens, J. M. 2011; 13 (6)

  Abstract

  Mammographic breast density is a highly heritable (h2 > 0.6) and strong risk factor for breast cancer. We conducted a genome-wide linkage study to identify loci influencing mammographic breast density (MD).Epidemiological data were assembled on 1,415 families from the Australia, Northern California and Ontario sites of the Breast Cancer Family Registry, and additional families recruited in Australia and Ontario. Families consisted of sister pairs with age-matched mammograms and data on factors known to influence MD. Single nucleotide polymorphism (SNP) genotyping was performed on 3,952 individuals using the Illumina Infinium 6K linkage panel.Using a variance components method, genome-wide linkage analysis was performed using quantitative traits obtained by adjusting MD measurements for known covariates. Our primary trait was formed by fitting a linear model to the square root of the percentage of the breast area that was dense (PMD), adjusting for age at mammogram, number of live births, menopausal status, weight, height, weight squared, and menopausal hormone therapy. The maximum logarithm of odds (LOD) score from the genome-wide scan was on chromosome 7p14.1-p13 (LOD = 2.69; 63.5 cM) for covariate-adjusted PMD, with a 1-LOD interval spanning 8.6 cM. A similar signal was seen for the covariate adjusted area of the breast that was dense (DA) phenotype. Simulations showed that the complete sample had adequate power to detect LOD scores of 3 or 3.5 for a locus accounting for 20% of phenotypic variance. A modest peak initially seen on chromosome 7q32.3-q34 increased in strength when only the 513 families with at least two sisters below 50 years of age were included in the analysis (LOD 3.2; 140.7 cM, 1-LOD interval spanning 9.6 cM). In a subgroup analysis, we also found a LOD score of 3.3 for DA phenotype on chromosome 12.11.22-q13.11 (60.8 cM, 1-LOD interval spanning 9.3 cM), overlapping a region identified in a previous study.The suggestive peaks and the larger linkage signal seen in the subset of pedigrees with younger participants highlight regions of interest for further study to identify genes that determine MD, with the goal of understanding mammographic density and its involvement in susceptibility to breast cancer.

  View details for DOI 10.1186/bcr3078

  View details for Web of Science ID 000301173700024

  View details for PubMedID 22188651

  View details for PubMedCentralID PMC3326574

• Global DNA methylation levels in girls with and without a family history of breast cancer EPIGENETICS Wu, H., John, E. M., Ferris, J. S., Keegan, T. H., Chung, W. K., Andrulis, I., Delgado-Cruzata, L., Kappil, M., Gonzalez, K., Santella, R. M., Terry, M. B. 2011; 6 (1): 29-33

  Abstract

  Lower levels of global DNA methylation in white blood cell (WBC) DNA have been associated with adult cancers. It is unknown whether individuals with a family history of cancer also have lower levels of global DNA methylation early in life. We examined global DNA methylation in WBC (measured in three repetitive elements, LINE1, Sat2 and Alu, by MethyLight and in LINE1 by pyrosequencing) in 51 girls ages 6-17. Compared to girls without a family history of breast cancer, methylation levels were lower for all assays in girls with a family history of breast cancer, and statistically significantly lower for Alu and LINE1 pyrosequencing. After adjusting for age, body mass index (BMI), and Tanner stage, only methylation in Alu was associated with family history of breast cancer. If these findings are replicated in larger studies, they suggest that lower levels of global WBC DNA methylation observed later in life in adults with cancer may also be present early in life in children with a family history of cancer.

  View details for DOI 10.4161/epi.6.1.13393

  View details for Web of Science ID 000285828700005

  View details for PubMedID 20930546

  View details for PubMedCentralID PMC3052913

• Genetic Variation at 9p22.2 and Ovarian Cancer Risk for BRCA1 and BRCA2 Mutation Carriers JOURNAL OF THE NATIONAL CANCER INSTITUTE Ramus, S. J., Kartsonaki, C., Gayther, S. A., Pharoah, P. D., Sinilnikova, O. M., Beesley, J., Chen, X., McGuffog, L., Healey, S., Couch, F. J., Wang, X., Fredericksen, Z., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Roversi, G., Barile, M., Viel, A., Allavena, A., Ottini, L., Papi, L., Gismondi, V., Capra, F., Radice, P., Greene, M. H., Mai, P. L., Andrulis, I. L., Glendon, G., Ozcelik, H., Thomassen, M., Gerdes, A., Kruse, T. A., Cruger, D., Jensen, U. B., Caligo, M. A., Olsson, H., Kristoffersson, U., Lindblom, A., Arver, B., Karlsson, P., Askmalm, M. S., Borg, A., Neuhausen, S. L., Ding, Y. C., Nathanson, K. L., Domchek, S. M., Jakubowska, A., Lubinski, J., Huzarski, T., Byrski, T., Gronwald, J., Gorski, B., Cybulski, C., Debniak, T., Osorio, A., Duran, M., Tejada, M., Benitez, J., Hamann, U., Rookus, M. A., Verhoef, S., Tilanus-Linthorst, M. A., Vreeswijk, M. P., Bodmer, D., Ausems, M. G., van Os, T. A., Asperen, C. J., Blok, M. J., Meijers-Heijboer, H. E., Peock, S., Cook, M., Oliver, C., Frost, D., Dunning, A. M., Evans, D. G., Eeles, R., Pichert, G., Cole, T., Hodgson, S., Brewer, C., Morrison, P. J., Porteous, M., Kennedy, M. J., Rogers, M. T., Side, L. E., Donaldson, A., Gregory, H., Godwin, A., Stoppa-Lyonnet, D., Moncoutier, V., Castera, L., Mazoyer, S., Barjhoux, L., Bonadona, V., Leroux, D., Faivre, L., Lidereau, R., Nogues, C., Bignon, Y., Prieur, F., Collonge-Rame, M., Venat-Bouvet, L., Fert-Ferrer, S., Miron, A., Buys, S. S., Hopper, J. L., Daly, M. B., John, E. M., Terry, M. B., Goldgar, D., Hansen, T. v., Jonson, L., Ejlertsen, B., Agnarsson, B. A., Offit, K., Kirchhoff, T., Vijai, J., Dutra-Clarke, A. V., Przybylo, J. A., Montagna, M., Casella, C., Imyanitov, E. N., Janavicius, R., Blanco, I., Lazaro, C., Moysich, K. B., Karlan, B. Y., Gross, J., Beattie, M. S., Schmutzler, R., Wappenschmidt, B., Meindl, A., Ruehl, I., Fiebig, B., Sutter, C., Arnold, N., Deissler, H., Varon-Mateeva, R., Kast, K., Niederacher, D., Gadzicki, D., Caldes, T., de la Hoya, M., Nevanlinna, H., Aittomaeki, K., Simard, J., Soucy, P., Spurdle, A. B., Holland, H., Chenevix-Trench, G., Easton, D. F., Antoniou, A. C. 2011; 103 (2)

  Abstract

  Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2.We genotyped rs3814113 in 10,029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided.The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10(-9)) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10(-4)). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%.Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation.

  View details for DOI 10.1093/jnci/djq494

  View details for Web of Science ID 000286472800008

• Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction CANCER RESEARCH Antoniou, A. C., Beesley, J., McGuffog, L., Sinilnikova, O. M., Healey, S., Neuhausen, S. L., Ding, Y. C., Rebbeck, T. R., Weitzel, J. N., Lynch, H. T., Isaacs, C., Ganz, P. A., Tomlinson, G., Olopade, O. I., Couch, F. J., Wang, X., Lindor, N. M., Pankratz, V. S., Radice, P., Manoukian, S., Peissel, B., Zaffaroni, D., Barile, M., Viel, A., Allavena, A., Dall'Olio, V., Peterlongo, P., Szabo, C. I., Zikan, M., Claes, K., Poppe, B., Foretova, L., Mai, P. L., Greene, M. H., Rennert, G., Lejbkowicz, F., Glendon, G., Ozcelik, H., Andrulis, I. L., Thomassen, M., Gerdes, A., Sunde, L., Cruger, D., Jensen, U. B., Caligo, M., friedman, e., Kaufman, B., Laitman, Y., Milgrom, R., Dubrovsky, M., Cohen, S., Borg, A., Jernstroem, H., Lindblom, A., Rantala, J., Stenmark-Askmalm, M., Melin, B., Nathanson, K., Domchek, S., Jakubowska, A., Lubinski, J., Huzarski, T., Osorio, A., Lasa, A., Duran, M., Tejada, M., Godino, J., Benitez, J., Hamann, U., Kriege, M., Hoogerbrugge, N., van der Luijt, R. B., van Asperen, C. J., Devilee, P., Meijers-Heijboer, E. J., Blok, M. J., Aalfs, C. M., Hogervorst, F., Rookus, M., Cook, M., Oliver, C., Frost, D., Conroy, D., Evans, D. G., Lalloo, F., Pichert, G., Davidson, R., Cole, T., Cook, J., Paterson, J., Hodgson, S., Morrison, P. J., Porteous, M. E., Walker, L., Kennedy, M. J., Dorkins, H., Peock, S., Godwin, A. K., Stoppa-Lyonnet, D., De Pauw, A., Mazoyer, S., Bonadona, V., Lasset, C., Dreyfus, H., Leroux, D., Hardouin, A., Berthet, P., Faivre, L., Loustalot, C., Noguchi, T., Sobol, H., Rouleau, E., Nogues, C., Frenay, M., Venat-Bouvet, L., Hopper, J. L., Daly, M. B., Terry, M. B., John, E. M., Buys, S. S., Yassin, Y., Miron, A., Goldgar, D., Singer, C. F., Dressler, A. C., Gschwantler-Kaulich, D., Pfeiler, G., Hansen, T. v., Jnson, L., Agnarsson, B. A., Kirchhoff, T., Offit, K., Devlin, V., Dutra-Clarke, A., Piedmonte, M., Rodriguez, G. C., Wakeley, K., Boggess, J. F., Basil, J., Schwartz, P. E., Blank, S. V., Toland, A. E., Montagna, M., Casella, C., Imyanitov, E., Tihomirova, L., Blanco, I., Lazaro, C., Ramus, S. J., Sucheston, L., Karlan, B. Y., Gross, J., Schmutzler, R., Wappenschmidt, B., Engel, C., Meindl, A., Lochmann, M., Arnold, N., Heidemann, S., Varon-Mateeva, R., Niederacher, D., Sutter, C., Deissler, H., Gadzicki, D., Preisler-Adams, S., Kast, K., Schoenbuchner, I., Caldes, T., de la Hoya, M., Aittomaeki, K., Nevanlinna, H., Simard, J., Spurdle, A. B., Holland, H., Chen, X., Platte, R., Chenevix-Trench, G., Easton, D. F. 2010; 70 (23): 9742-9754

  Abstract

  The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

  View details for DOI 10.1158/0008-5472.CAN-10-1907

  View details for Web of Science ID 000285045900024

  View details for PubMedID 21118973

• A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population NATURE GENETICS Antoniou, A. C., Wang, X., Fredericksen, Z. S., McGuffog, L., Tarrell, R., Sinilnikova, O. M., Healey, S., Morrison, J., Kartsonaki, C., Lesnick, T., Ghoussaini, M., Barrowdale, D., Peock, S., Cook, M., Oliver, C., Frost, D., Eccles, D., Evans, D. G., Eeles, R., Izatt, L., Chu, C., Douglas, F., Paterson, J., Stoppa-Lyonnet, D., Houdayer, C., Mazoyer, S., Giraud, S., Lasset, C., Remenieras, A., Caron, O., Hardouin, A., Berthet, P., Hogervorst, F. B., Rookus, M. A., Jager, A., van den Ouweland, A., Hoogerbrugge, N., van der Luijt, R. B., Meijers-Heijboer, H., Garcia, E. B., Devilee, P., Vreeswijk, M. P., Lubinski, J., Jakubowska, A., Gronwald, J., Huzarski, T., Byrski, T., Gorski, B., Cybulski, C., Spurdle, A. B., Holland, H., Goldgar, D. E., John, E. M., Hopper, J. L., Southey, M., Buys, S. S., Daly, M. B., Terry, M., Schmutzler, R. K., Wappenschmidt, B., Engel, C., Meindl, A., Preisler-Adams, S., Arnold, N., Niederacher, D., Sutter, C., Domchek, S. M., Nathanson, K. L., Rebbeck, T., Blum, J. L., Piedmonte, M., Rodriguez, G. C., Wakeley, K., Boggess, J. F., Basil, J., Blank, S. V., friedman, e., Kaufman, B., Laitman, Y., Milgrom, R., Andrulis, I. L., Glendon, G., Ozcelik, H., Kirchhoff, T., Vijai, J., Gaudet, M. M., Altshuler, D., Guiducci, C., Loman, N., Harbst, K., Rantala, J., Ehrencrona, H., Gerdes, A., Thomassen, M., Sunde, L., Peterlongo, P., Manoukian, S., Bonanni, B., Viel, A., Radice, P., Caldes, T., de la Hoya, M., Singer, C. F., Fink-Retter, A., Greene, M. H., Mai, P. L., Loud, J. T., Guidugli, L., Lindor, N. M., Hansen, T. v., Nielsen, F. C., Blanco, I., Lazaro, C., Garber, J., Ramus, S. J., Gayther, S. A., Phelan, C., Narod, S., Szabo, C. I., Benitez, J., Osorio, A., Nevanlinna, H., Heikkinen, T., Caligo, M. A., Beattie, M. S., Hamann, U., Godwin, A. K., Montagna, M., Casella, C., Neuhausen, S. L., Karlan, B. Y., Tung, N., Toland, A. E., Weitzel, J., Olopade, O., Simard, J., Soucy, P., Rubinstein, W. S., Arason, A., Rennert, G., Martin, N. G., Montgomery, G. W., Chang-Claude, J., Flesch-Janys, D., Brauch, H., Severi, G., Baglietto, L., Cox, A., Cross, S. S., Miron, P., Gerty, S. M., Tapper, W., Yannoukakos, D., Fountzilas, G., Fasching, P. A., Beckmann, M. W., Silva, I. d., Peto, J., Lambrechts, D., Paridaens, R., Ruediger, T., Foersti, A., Winqvist, R., Pylkaes, K., Diasio, R. B., Lee, A. M., Eckel-Passow, J., Vachon, C., Blows, F., Driver, K., Dunning, A., Pharoah, P. P., Offit, K., Pankratz, V. S., Hakonarson, H., Chenevix-Trench, G., Easton, D. F., Couch, F. J. 2010; 42 (10): 885-?

  Abstract

  Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P(trend) = 2.3 × 10⁻⁹ to P(trend) = 3.9 × 10⁻⁷), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P(trend) = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P(trend) = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (P(trend) = 1 × 10⁻⁷) to P(trend) = 8 × 10⁻⁵; rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P(trend) = 1.1 × 10⁻⁷

  View details for DOI 10.1038/ng.669

  View details for Web of Science ID 000282276600020

  View details for PubMedID 20852631

  View details for PubMedCentralID PMC3130795

• Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer PLOS GENETICS Gaudet, M. M., Kirchhoff, T., Green, T., Vijai, J., Korn, J. M., Guiducci, C., Segre, A. V., McGee, K., McGuffog, L., Kartsonaki, C., Morrison, J., Healey, S., Sinilnikova, O. M., Stoppa-Lyonnet, D., Mazoyer, S., Gauthier-Villars, M., Sobol, H., Longy, M., Frenay, M., Hogervorst, F. B., Rookus, M. A., Collee, J. M., Hoogerbrugge, N., van Roozendaal, K. E., Piedmonte, M., Rubinstein, W., Nerenstone, S., Van Le, L., Blank, S. V., Caldes, T., de la Hoya, M., Nevanlinna, H., Aittomaki, K., Lazaro, C., Blanco, I., Arason, A., Johannsson, O. T., Barkardottir, R. B., Devilee, P., Olopade, O. I., Neuhausen, S. L., Wang, X., Fredericksen, Z. S., Peterlongo, P., Manoukian, S., Barile, M., Viel, A., Radice, P., Phelan, C. M., Narod, S., Rennert, G., Lejbkowicz, F., Flugelman, A., Andrulis, I. L., Glendon, G., Ozcelik, H., Toland, A. E., Montagna, M., D'Andrea, E., friedman, e., Laitman, Y., Borg, A., Beattie, M., Ramus, S. J., Domchek, S. M., Nathanson, K. L., Rebbeck, T., Spurdle, A. B., Chen, X., Holland, H., John, E. M., Hopper, J. L., Buys, S. S., Daly, M. B., Southey, M. C., Terry, M. B., Tung, N., Hansen, T. V., Nielsen, F. C., Greene, M. I., Mai, P. L., Osorio, A., Duran, M., Andres, R., Benitez, J., Weitzel, J. N., Garber, J., Hamann, U., Peock, S., Cook, M., Oliver, C., Frost, D., Platte, R., Evans, D. G., Lalloo, F., Eeles, R., Izatt, L., Walker, L., Eason, J., Barwell, J., Godwin, A. K., Schmutzler, R. K., Wappenschmidt, B., Engert, S., Arnold, N., Gadzicki, D., Dean, M., Gold, B., Klein, R. J., Couch, F. J., Chenevix-Trench, G., Easton, D. F., Daly, M. J., Antoniou, A. C., Altshuler, D. M., Offit, K. 2010; 6 (10)

  Abstract

  The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10(-5) and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, ) and for rs311499 was 0.72 (95% CI 0.61-0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.

  View details for DOI 10.1371/journal.pgen.1001183

  View details for Web of Science ID 000283647800014

  View details for PubMedID 21060860

• Increased cancer risks for relatives of very early-onset breast cancer cases with and without BRCA1 and BRCA2 mutations BRITISH JOURNAL OF CANCER Dite, G. S., Whittemore, A. S., Knight, J. A., John, E. M., Milne, R. L., Andrulis, I. L., Southey, M. C., McCredie, M. R., Giles, G. G., Miron, A., Phipps, A. I., West, D. W., Hopper, J. L. 2010; 103 (7): 1103-1108

  Abstract

  Little is known regarding cancer risks for relatives of women with very early-onset breast cancer.We studied 2208 parents and siblings of 504 unselected population-based Caucasian women with breast cancer diagnosed before age 35 years (103 from USA, 124 from Canada and 277 from Australia), 41 known to carry a mutation (24 in BRCA1, 16 in BRCA2 and one in both genes). Cancer-specific standardised incidence ratios (SIRs) were estimated by comparing the number of affected relatives (50% verified overall) with that expected based on incidences specific for country, sex, age and year of birth.For relatives of carriers, the female breast cancer SIRs were 13.13 (95% CI 6.57-26.26) and 12.52 (5.21-30.07) for BRCA1 and BRCA2, respectively. The ovarian cancer SIR was 12.38 (3.1-49.51) for BRCA1 and the prostate cancer SIR was 18.55 (4.64-74.17) for BRCA2. For relatives of non-carriers, the SIRs for female breast, prostate, lung, brain and urinary cancers were 4.03 (2.91-5.93), 5.25 (2.50-11.01), 7.73 (4.74-12.62), 5.19 (2.33-11.54) and 4.35 (1.81-10.46), respectively. For non-carriers, the SIRs remained elevated and were statistically significant for breast and prostate cancer when based on verified cancers.First-degree relatives of women with very early-onset breast cancer are at increased risk of cancers not explained by BRCA1 and BRCA2 mutations.

  View details for DOI 10.1038/sj.bjc.6605876

  View details for Web of Science ID 000282222000025

  View details for PubMedID 20877337

  View details for PubMedCentralID PMC2965877

• Past recreational physical activity, body size, and all-cause mortality following breast cancer diagnosis: results from the breast cancer family registry BREAST CANCER RESEARCH AND TREATMENT Keegan, T. H., Milne, R. L., Andrulis, I. L., Chang, E. T., Sangaramoorthy, M., Phillips, K., Giles, G. G., Goodwin, P. J., Apicella, C., Hopper, J. L., Whittemore, A. S., John, E. M. 2010; 123 (2): 531-542

  Abstract

  Few studies have considered the joint association of body mass index (BMI) and physical activity, two modifiable factors, with all-cause mortality after breast cancer diagnosis. Women diagnosed with invasive breast cancer (n = 4,153) between 1991 and 2000 were enrolled in the Breast Cancer Family Registry through population-based sampling in Northern California, USA; Ontario, Canada; and Melbourne and Sydney, Australia. During a median follow-up of 7.8 years, 725 deaths occurred. Baseline questionnaires assessed moderate and vigorous recreational physical activity and BMI prior to diagnosis. Associations with all-cause mortality were assessed using Cox proportional hazards regression, adjusting for established prognostic factors. Compared with no physical activity, any recreational activity during the 3 years prior to diagnosis was associated with a 34% lower risk of death [hazard ratio (HR) = 0.66, 95% confidence interval (CI): 0.51-0.85] for women with estrogen receptor (ER)-positive tumors, but not those with ER-negative tumors; this association did not appear to differ by race/ethnicity or BMI. Lifetime physical activity was not associated with all-cause mortality. BMI was positively associated with all-cause mortality for women diagnosed at age > or =50 years with ER-positive tumors (compared with normal-weight women, HR for overweight = 1.39, 95% CI: 0.90-2.15; HR for obese = 1.77, 95% CI: 1.11-2.82). BMI associations did not appear to differ by race/ethnicity. Our findings suggest that physical activity and BMI exert independent effects on overall mortality after breast cancer.

  View details for DOI 10.1007/s10549-010-0774-6

  View details for Web of Science ID 000280807900023

  View details for PubMedID 20140702

  View details for PubMedCentralID PMC2920352

• The Potential for Enhancing the Power of Genetic Association Studies in African Americans through the Reuse of Existing Genotype Data PLOS GENETICS Chen, G. K., Millikan, R. C., John, E. M., Ambrosone, C. B., Bernstein, L., Zheng, W., Hu, J. J., Chanock, S. J., Ziegler, R. G., Bandera, E. V., Henderson, B. E., Haiman, C. A., Stram, D. O. 2010; 6 (9)

  Abstract

  We consider the feasibility of reusing existing control data obtained in genetic association studies in order to reduce costs for new studies. We discuss controlling for the population differences between cases and controls that are implicit in studies utilizing external control data. We give theoretical calculations of the statistical power of a test due to Bourgain et al (Am J Human Genet 2003), applied to the problem of dealing with case-control differences in genetic ancestry related to population isolation or population admixture. Theoretical results show that there may exist bounds for the non-centrality parameter for a test of association that places limits on study power even if sample sizes can grow arbitrarily large. We apply this method to data from a multi-center, geographically-diverse, genome-wide association study of breast cancer in African-American women. Our analysis of these data shows that admixture proportions differ by center with the average fraction of European admixture ranging from approximately 20% for participants from study sites in the Eastern United States to 25% for participants from West Coast sites. However, these differences in average admixture fraction between sites are largely counterbalanced by considerable diversity in individual admixture proportion within each study site. Our results suggest that statistical correction for admixture differences is feasible for future studies of African-Americans, utilizing the existing controls from the African-American Breast Cancer study, even if case ascertainment for the future studies is not balanced over the same centers or regions that supplied the controls for the current study.

  View details for DOI 10.1371/journal.pgen.1001096

  View details for Web of Science ID 000282369200064

  View details for PubMedID 20824062

  View details for PubMedCentralID PMC2932740

• Availability and Accuracy of Medical Record Information on Language Usage of Cancer Patients from a Multi-Ethnic Population JOURNAL OF IMMIGRANT AND MINORITY HEALTH McClure, L. A., Glaser, S. L., Shema, S. J., Allen, L., Quesenberry, C., John, E. M., Gomez, S. L. 2010; 12 (4): 480-488

  Abstract

  Documentation of language usage in medical settings could be effective in identifying and addressing language barriers and would improve understanding of health disparities. This study evaluated the availability and accuracy of medical records information on language for 1,664 cancer patients likely to have poor English proficiency. Accuracy was assessed by comparison to language obtained from interview-based research studies. For patients diagnosed at facilities where information on language was not abstracted electronically, 81.6% had language information in their medical records, most often in admissions documents. For all 37 hospitals, agreement between medical records and interview language was 79.3% overall and was greater for those speaking English than another language. Language information is widely available in hospital medical records of cancer patients. However, for the data to be useful for research and reducing language barriers in medical care, the information must be collected in a consistent and accurate manner.

  View details for DOI 10.1007/s10903-009-9282-3

  View details for Web of Science ID 000281505900007

  View details for PubMedID 19685187

  View details for PubMedCentralID PMC2889213

• Prostate cancer in African-American men and polymorphism in the calcium-sensing receptor CANCER BIOLOGY & THERAPY Schwartz, G. G., John, E. M., Rowland, G., Ingles, S. A. 2010; 9 (12): 994-999

  Abstract

  Prospective epidemiologic studies indicate that the risk for advanced prostate cancer is increased among men with high levels of serum calcium. Because serum calcium levels are influenced by the calcium-sensing receptor (CaSR), we examined prostate cancer in African-American men in relation to three single nucleotide polymorphisms (SNPs) in the CaSR gene, A986S, R990G and Q1011E. This is the first study of CaSR polymorphisms and risk of prostate cancer.The CaSR genotypes were not associated with prostate cancer overall. However, we observed significant heterogeneity by disease stage for the Q1011E polymorphism (p = 0.02). Advanced cases were significantly less likely than controls or localized cases to be homozygous for the minor allele of the Q1011E polymorphism (1 vs. 5%). Cases with advanced disease were six times less likely to carry two copies of the minor allele than were controls (OR = 0.16, p = 0.02) or localized cases (OR = 0.15, p = 0.01) and were significantly older at diagnosis (68.8 ± 5.7 vs. 64.0 ± 9.0 y for the QQ and EE genotypes, p = 0.004).We genotyped three CaSR SNPs for 458 African-American prostate cancer cases and 248 controls from a population-based case-control study, the California Collaborative Prostate Cancer Study.The CaSR Q1011E minor allele, which is common in populations with African ancestry, may be associated with a less aggressive form of prostate cancer among African-American men.

  View details for DOI 10.4161/cbt.9.12.11689

  View details for Web of Science ID 000282836700009

  View details for PubMedID 20364112

• The Leu33Pro polymorphism in the ITGB3 gene does not modify BRCA1/2-associated breast or ovarian cancer risks: results from a multicenter study among 15,542 BRCA1 and BRCA2 mutation carriers BREAST CANCER RESEARCH AND TREATMENT Jakubowska, A., Rozkrut, D., Antoniou, A., Hamann, U., Lubinski, J. 2010; 121 (3): 639–49

  Abstract

  Integrins containing the beta(3) subunit are key players in tumor growth and metastasis. A functional Leu33Pro polymorphism (rs5918) in the beta(3) subunit of the integrin gene (ITGB3) has previously been suggested to act as a modifier of ovarian cancer risk in Polish BRCA1 mutation carriers. To investigate the association further, we genotyped 9,998 BRCA1 and 5,544 BRCA2 mutation carriers from 34 studies from the Consortium of Investigators of Modifiers of BRCA1/2 for the ITGB3 Leu33Pro polymorphism. Data were analysed within a Cox-proportional hazards framework using a retrospective likelihood approach. There was marginal evidence that the ITGB3 polymorphism was associated with an increased risk of ovarian cancer for BRCA1 mutation carriers (per-allele Hazard Ratio (HR) 1.11, 95% CI 1.00-1.23, p-trend 0.05). However, when the original Polish study was excluded from the analysis, the polymorphism was no longer significantly associated with ovarian cancer risk (HR 1.07, 95% CI 0.96-1.19, p-trend 0.25). There was no evidence of an association with ovarian cancer risk for BRCA2 mutation carriers (HR 1.09, 95% CI 0.89-1.32). The polymorphism was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers. The ITGB3 Leu33Pro polymorphism does not modify breast or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.

  View details for DOI 10.1007/s10549-009-0595-7

  View details for Web of Science ID 000277636000011

  View details for PubMedID 19876733

  View details for PubMedCentralID PMC3077711

• Lifetime Physical Activity and Risk of Endometrial Cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION John, E. M., Koo, J., Horn-Ross, P. L. 2010; 19 (5): 1276-1283

  Abstract

  The role of moderate physical activity and life patterns of activity in reducing endometrial cancer risk remains uncertain.We assessed lifetime histories of activity from recreation, transportation, chores, and occupation and other risk factors in a population-based case-control study of endometrial cancer conducted in the San Francisco Bay area. The analysis was based on 472 newly diagnosed cases ascertained by the regional cancer registry and 443 controls identified by random-digit dialing who completed an in-person interview.Reduced risks associated with greater lifetime physical activity (highest versus lowest tertile) were found for both total activity [odds ratio (OR), 0.61; 95% confidence interval (95% CI), 0.43-0.87; Ptrend=0.01] and activity of moderate intensity (OR, 0.44; 95% CI, 0.30-0.64; Ptrend<0.0001). Compared with women with low lifetime physical activity (below median), those with greater activity throughout life had a higher reduction in risk (OR, 0.62; 95% CI, 0.44-0.88). Inverse associations were stronger in obese and overweight women, but differences were not statistically significantly different from those in normal-weight women.These findings suggest that physical activity in adulthood, even of moderate intensity, may be effective in lowering the risk of endometrial cancer, particularly among those at highest risk for this disease.The results emphasize the importance of evaluating lifetime histories of physical activity from multiple sources, including both recreational and nonrecreational activities of various intensities, to fully understand the relation between physical activity and disease risk.

  View details for DOI 10.1158/1055-9965.EPI-09-1316

  View details for Web of Science ID 000278489800015

  View details for PubMedID 20406960

  View details for PubMedCentralID PMC3225397

• Breast Cancer Incidence Patterns among California Hispanic Women: Differences by Nativity and Residence in an Enclave CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Keegan, T. H., John, E. M., Fish, K. M., Alfaro-Velcamp, T., Clarke, C. A., Gomez, S. L. 2010; 19 (5): 1208-1218

  Abstract

  Breast cancer incidence is higher in U.S.-born Hispanic women than foreign-born Hispanics, but no studies have examined how these rates have changed over time. To better inform cancer control efforts, we examined incidence trends by nativity and incidence patterns by neighborhood socioeconomic status (SES) and Hispanic enclave (neighborhoods with high proportions of Hispanics or Hispanic immigrants).Information about all Hispanic women diagnosed with invasive breast cancer between 1988 and 2004 was obtained from the California Cancer Registry. Nativity was imputed from Social Security number for the 27% of cases with missing birthplace information. Neighborhood variables were developed from Census data.From 1988 to 2004, incidence rates for U.S.-born Hispanics were parallel but lower than those of non-Hispanic whites, showing an annual 6% decline from 2002 to 2004. Foreign-born Hispanics had an annual 4% increase in incidence rates from 1995 to 1998 and a 1.4% decline thereafter. Rates were 38% higher for U.S.- than foreign-born Hispanics, with elevations more pronounced for localized than regional/distant disease, and for women>50 years of age. Residence in higher SES and lower Hispanic enclave neighborhoods were independently associated with higher incidence, with Hispanic enclave having a stronger association than SES.Compared with foreign-born, U.S.-born Hispanic women in California had higher prevalence of breast cancer risk factors, suggesting that incidence patterns largely reflect these differences in risk factors.Further research is needed to separate the effects of individual- and neighborhood-level factors that affect incidence in this large and growing population.

  View details for DOI 10.1158/1055-9965.EPI-10-0021

  View details for Web of Science ID 000278489800009

  View details for PubMedID 20447917

  View details for PubMedCentralID PMC2895619

• European Ancestry Is Positively Associated with Breast Cancer Risk in Mexican Women CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Fejerman, L., Romieu, I., John, E. M., Lazcano-Ponce, E., Huntsman, S., Beckman, K. B., Perez-Stable, E. J., Burchard, E. G., Ziv, E., Torres-Mejia, G. 2010; 19 (4): 1074-1082

  Abstract

  The incidence of breast cancer is 35% lower in Hispanic women living in the San Francisco Bay Area than in non-Hispanic White women. We have previously described a significant association between genetic ancestry and risk for breast cancer in a sample of U.S. Hispanics/Latinas. We retested the association in women residing in Mexico because of the possibility that the original finding may be confounded by U.S. specific unmeasured environmental exposures. We genotyped a set of 106 ancestry informative markers in 846 Mexican women with breast cancer and 1,035 unaffected controls and estimated genetic ancestry using a maximum likelihood method. Odds ratios and 95% confidence intervals (95% CI) for ancestry modeled as a categorical and continuous variable were estimated using logistic regression and adjusted for reproductive and other known risk factors. Greater European ancestry was associated with increased breast cancer risk in this new and independent sample of Mexican women residing in Mexico. Compared with women with 0% to 25% European ancestry, the risk was increased for women with 51% to 75% and 76% to 100% European ancestry [odds ratios, 1.35 (95% CI, 0.96-1.91) and 2.44 (95% CI, 0.94-6.35), respectively; P for trend = 0.044]. For every 25% increase in European ancestry (modeled as a continuous variable), there was a 20% increase in risk for breast cancer (95% CI, 1.03-1.41; P = 0.019). These results suggest that nongenetic factors play a crucial role in explaining the difference in breast cancer incidence between Latinas and non-Latina White women, and it also points out to the possibility of a genetic component to this difference.

  View details for DOI 10.1158/1055-9965.EPI-09-1193

  View details for Web of Science ID 000278484400027

  View details for PubMedID 20332279

  View details for PubMedCentralID PMC2852491

• Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study BREAST CANCER RESEARCH Milne, R. L., Gaudet, M. M., Spurdle, A. B., Fasching, P. A., Couch, F. J., Benitez, J., Arias Perez, J. I., Pilar Zamora, M., Malats, N., dos Santos Silva, I., Gibson, L. J., Fletcher, O., Johnson, N., Anton-Culver, H., Ziogas, A., Figueroa, J., Brinton, L., Sherman, M. E., Lissowska, J., Hopper, J. L., Dite, G. S., Apicella, C., Southey, M. C., Sigurdson, A. J., Linet, M. S., Schonfeld, S. J., Freedman, D. M., Mannermaa, A., Kosma, V., Kataja, V., Auvinen, P., Andrulis, I. L., Glendon, G., Knight, J. A., Weerasooriya, N., Cox, A., Reed, M. W., Cross, S. S., Dunning, A. M., Ahmed, S., Shah, M., Brauch, H., Ko, Y., Bruening, T., Lambrechts, D., Reumers, J., Smeets, A., Wang-Gohrke, S., Hall, P., Czene, K., Liu, J., Irwanto, A. K., Chenevix-Trench, G., Holland, H., Giles, G. G., Baglietto, L., Severi, G., Bojensen, S. E., Nordestgaard, B. G., Flyger, H., John, E. M., West, D. W., Whittemore, A. S., Vachon, C., Olson, J. E., Fredericksen, Z., Kosel, M., Hein, R., Vrieling, A., Flesch-Janys, D., Heinz, J., Beckmann, M. W., Heusinger, K., Ekici, A. B., Haeberle, L., Humphreys, M. K., Morrison, J., Easton, D. F., Pharoah, P. D., Garcia-Closas, M., Goode, E. L., Chang-Claude, J. 2010; 12 (6)

  Abstract

  Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium.We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects.These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar.The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified.

  View details for DOI 10.1186/bcr2797

  View details for Web of Science ID 000288751500021

  View details for PubMedID 21194473

  View details for PubMedCentralID PMC3046455

• A qualitative study evaluating parental attitudes towards the creation of a female youth cohort (LEGACY) in the Breast Cancer Family Registry PSYCHO-ONCOLOGY Glendon, G., Frost, C. J., Andrulis, I. L., Hanna, D., John, E. M., Phipps, A. I., Thompson, A., Venne, V., Ritvo, P. 2010; 19 (1): 93-101

  Abstract

  Expanding the existing Breast Cancer Family Registry (BCFR) to enrol daughters aged 6-17 years in a prospective cohort study named LEGACY (Lessons in Epidemiology and Genetics of Adult Cancer from Youth) offers the opportunity to study the effects of genetic and environmental exposures in youth on adult breast cancer risk. Few studies have assessed parents' willingness to enroll their daughters in genetic epidemiological cohort studies. Since BCFR parents are the gatekeepers of their daughters' future enrollment, it is important to explore their interests and attitudes towards LEGACY.Semi-structured telephone interviews were conducted with 85 BCFR participant parents at 3 BCFR sites in Ontario, Canada, and in Utah and Northern California. We explored parents' thoughts and feelings (interests and attitudes) regarding their daughters' enrollment in LEGACY and different data collection modalities. Qualitative analysis of audiotaped interviews was carried out utilizing an inductive content analysis.Parents' acceptance of three data collection modalities were 92% (78/85) for questionnaire data, 87% (74/85) for biological samples and 63% (46/73) for physical examination for pubertal staging. The parents' primary motivation for participation was altruistic. Their concerns regarding their daughters' participation centered on exacerbating awkward pubertal feelings, increasing cancer anxiety, respecting autonomy and maturity, privacy and future use of data and logistical impediments.Parents demonstrated a high level of interest in the creation of LEGACY. Their motivation to participate was balanced by their desire to protect daughters from undue harm. These interviews contributed valuable information for the design of LEGACY.

  View details for DOI 10.1002/pon.1543

  View details for Web of Science ID 000273693900012

  View details for PubMedID 19415783

• Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA) BRITISH JOURNAL OF CANCER Osorio, A., Milne, R. L., Pita, G., Peterlongo, P., Heikkinen, T., Simard, J., Chenevix-Trench, G., Spurdle, A. B., Beesley, J., Chen, X., Healey, S., Neuhausen, S. L., Ding, Y. C., Couch, F. J., Wang, X., Lindor, N., Manoukian, S., Barile, M., Viel, A., Tizzoni, L., SZABO, C. I., Foretova, L., Zikan, M., Claes, K., Greene, M. H., Mai, P., Rennert, G., Lejbkowicz, F., Barnett-Griness, O., Andrulis, I. L., Ozcelik, H., Weerasooriya, N., Gerdes, A., Thomassen, M., Cruger, D. G., Caligo, M. A., FRIEDMAN, E., Kaufman, B., Laitman, Y., Cohen, S., Kontorovich, T., Gershoni-Baruch, R., Dagan, E., Jernstrom, H., ASKMALM, M. S., Arver, B., Malmer, B., Domchek, S. M., Nathanson, K. L., Brunet, J., Ramon y Cajal, T., Yannoukakos, D., Hamann, U., Hogervorst, F. B., Verhoef, S., Gomez Garcia, E. B., Wijnen, J. T., Van den Ouweland, A., Easton, D. F., Peock, S., Cook, M., Oliver, C. T., Frost, D., Luccarini, C., Evans, D. G., Lalloo, F., Eeles, R., Pichert, G., Cook, J., HODGSON, S., Morrison, P. J., Douglas, F., Godwin, A. K., Sinilnikova, O. M., Barjhoux, L., Stoppa-Lyonnet, D., Moncoutier, V., Giraud, S., CASSINI, C., Olivier-Faivre, L., Revillion, F., Peyrat, J., Muller, D., Fricker, J., Lynch, H. T., John, E. M., Buys, S., Daly, M., Hopper, J. L., Terry, M. B., Miron, A., Yassin, Y., Goldgar, D., Singer, C. F., Gschwantler-Kaulich, D., Pfeiler, G., Spiess, A., Hansen, T. v., Johannsson, O. T., Kirchhoff, T., Offit, K., Kosarin, K., Piedmonte, M., RODRIGUEZ, G. C., Wakeley, K., Boggess, J. F., Basil, J., Schwartz, P. E., Blank, S. V., Toland, A. E., Montagna, M., Casella, C., Imyanitov, E. N., Allavena, A., Schmutzler, R. K., Versmold, B., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Niederacher, D., Deissler, H., Fiebig, B., Varon-Mateeva, R., Schaefer, D., Froster, U. G., Caldes, T., De la Hoya, M., McGuffog, L., Antoniou, A. C., Nevanlinna, H., Radice, P., Benitez, J. 2009; 101 (12): 2048-2054

  Abstract

  In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers.We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach.We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers.This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.

  View details for DOI 10.1038/sj.bjc.6605416

  View details for Web of Science ID 000272557800015

  View details for PubMedID 19920816

• Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers HUMAN MOLECULAR GENETICS Antoniou, A. C., Sinilnikova, O. M., McGuffog, L., Healey, S., Nevanlinna, H., Heikkinen, T., Simard, J., Spurdle, A. B., Beesley, J., Chen, X., Neuhausen, S. L., Ding, Y. C., Couch, F. J., Wang, X., Fredericksen, Z., Peterlongo, P., Peissel, B., Bonanni, B., Viel, A., Bernard, L., Radice, P., Szabo, C. I., Foretova, L., Zikan, M., Claes, K., Greene, M. H., Mai, P. L., Rennert, G., Lejbkowicz, F., Andrulis, I. L., Ozcelik, H., Glendon, G., Gerdes, A., Thomassen, M., Sunde, L., Caligo, M. A., Laitman, Y., Kontorovich, T., Cohen, S., Kaufman, B., Dagan, E., Baruch, R. G., friedman, e., Harbst, K., Barbany-Bustinza, G., Rantala, J., Ehrencrona, H., Karlsson, P., Domchek, S. M., Nathanson, K. L., Osorio, A., Blanco, I., Lasa, A., Benitez, J., Hamann, U., Hogervorst, F. B., Rookus, M. A., Collee, J. M., Devilee, P., Ligtenberg, M. J., van der Luijt, R. B., Aalfs, C. M., Waisfisz, Q., Wijnen, J., van Roozendaal, C. E., Peock, S., Cook, M., Frost, D., Oliver, C., Platte, R., Evans, D. G., Lalloo, F., Eeles, R., Izatt, L., Davidson, R., Chu, C., Eccles, D., Cole, T., Hodgson, S., Godwin, A. K., Stoppa-Lyonnet, D., Buecher, B., Leone, M., Bressac-de Paillerets, B., Remenieras, A., Caron, O., Lenoir, G. M., Sevenet, N., Longy, M., Ferrer, S. F., Prieur, F., Goldgar, D., Miron, A., John, E. M., Buys, S. S., Daly, M. B., Hopper, J. L., Terry, M. B., Yassin, Y., Singer, C., Gschwantler-Kaulich, D., Staudigl, C., Hansen, T. v., Barkardottir, R. B., Kirchhoff, T., Pal, P., Kosarin, K., Offit, K., Piedmonte, M., Rodriguez, G. C., Wakeley, K., Boggess, J. F., Basil, J., Schwartz, P. E., Blank, S. V., Toland, A. E., Montagna, M., Casella, C., Imyanitov, E. N., Allavena, A., Schmutzler, R. K., Versmold, B., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Niederacher, D., Deissler, H., Fiebig, B., Suttner, C., Schoenbuchner, I., Gadzicki, D., Caldes, T., de la Hoya, M., Pooley, K. A., Easton, D. F., Chenevix-Trench, G. 2009; 18 (22): 4442-4456

  Abstract

  Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.

  View details for DOI 10.1093/hmg/ddp372

  View details for Web of Science ID 000271107300019

  View details for PubMedID 19656774

• An Admixture Scan in 1,484 African American Women with Breast Cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Fejerman, L., Haiman, C. A., Reich, D., Tandon, A., Deo, R. C., John, E. M., Ingles, S. A., Ambrosone, C. B., Bovbjerg, D. H., Jandorf, L. H., Davis, W., Ciupak, G., Whittemore, A. S., Press, M. F., Ursin, G., Bernstein, L., Huntsman, S., Henderson, B. E., Ziv, E., Freedman, M. L. 2009; 18 (11): 3110-3117

  Abstract

  African American women with breast cancer present more commonly with aggressive tumors that do not express the estrogen receptor (ER) and progesterone receptor (PR) compared with European American women. Whether this disparity is the result of inherited factors has not been established. We did an admixture-based genome-wide scan to search for risk alleles for breast cancer that are highly differentiated in frequency between African American and European American women, and may contribute to specific breast cancer phenotypes, such as ER-negative (ER-) disease. African American women with invasive breast cancer (n = 1,484) were pooled from six population-based studies and typed at approximately 1,500 ancestry-informative markers. We investigated global genetic ancestry and did a whole genome admixture scan searching for breast cancer-predisposing loci in association with disease phenotypes. We found a significant difference in ancestry between ER+PR+ and ER-PR- women, with higher European ancestry among ER+PR+ individuals, after controlling for possible confounders (odds ratios for a 0 to 1 change in European ancestry proportion, 2.84; 95% confidence interval, 1.13-7.14; P = 0.026). Women with localized tumors had higher European ancestry than women with non-localized tumors (odds ratios, 2.65; 95% confidence interval, 1.11-6.35; P = 0.029). No genome-wide statistically significant associations were observed between European or African ancestry at any specific locus and breast cancer, or in analyses stratified by ER/PR status, stage, or grade. In summary, in African American women, genetic ancestry is associated with ER/PR status and disease stage. However, we found little evidence that genetic ancestry at any one region contributes significantly to breast cancer risk or hormone receptor status.

  View details for DOI 10.1158/1055-9965.EPI-09-0464

  View details for Web of Science ID 000271562600045

  View details for PubMedID 19843668

  View details for PubMedCentralID PMC2783219

• Rare, Evolutionarily Unlikely Missense Substitutions in ATM Confer Increased Risk of Breast Cancer AMERICAN JOURNAL OF HUMAN GENETICS Tavtigian, S. V., Oefner, P. J., Babikyan, D., Hartmann, A., Healey, S., Le Calvez-Kelm, F., Lesueur, F., Byrnes, G. B., Chuang, S., Forey, N., Feuchtinger, C., Gioia, L., Hall, J., Hashibe, M., Herte, B., McKay-Chopin, S., Thomas, A., Vallee, M. P., Voegele, C., Webb, P. M., Whiteman, D. C., Sangrajrang, S., Hopper, J. L., Southey, M. C., Andrulis, I. L., John, E. M., Chenevix-Trench, G. 2009; 85 (4): 427-446

  Abstract

  The susceptibility gene for ataxia telangiectasia, ATM, is also an intermediate-risk breast-cancer-susceptibility gene. However, the spectrum and frequency distribution of ATM mutations that confer increased risk of breast cancer have been controversial. To assess the contribution of rare variants in this gene to risk of breast cancer, we pooled data from seven published ATM case-control mutation-screening studies, including a total of 1544 breast cancer cases and 1224 controls, with data from our own mutation screening of an additional 987 breast cancer cases and 1021 controls. Using an in silico missense-substitution analysis that provides a ranking of missense substitutions from evolutionarily most likely to least likely, we carried out analyses of protein-truncating variants, splice-junction variants, and rare missense variants. We found marginal evidence that the combination of ATM protein-truncating and splice-junction variants contribute to breast cancer risk. There was stronger evidence that a subset of rare, evolutionarily unlikely missense substitutions confer increased risk. On the basis of subset analyses, we hypothesize that rare missense substitutions falling in and around the FAT, kinase, and FATC domains of the protein may be disproportionately responsible for that risk and that a subset of these may confer higher risk than do protein-truncating variants. We conclude that a comparison between the graded distributions of missense substitutions in cases versus controls can complement analyses of truncating variants and help identify susceptibility genes and that this approach will aid interpretation of the data emerging from new sequencing technologies.

  View details for DOI 10.1016/j.ajhg.2009.08.018

  View details for Web of Science ID 000270836000001

  View details for PubMedID 19781682

  View details for PubMedCentralID PMC2756555

• Socioeconomic status and prostate cancer incidence and mortality rates among the diverse population of California CANCER CAUSES & CONTROL Cheng, I., Witte, J. S., McClure, L. A., Shema, S. J., Cockburn, M. G., John, E. M., Clarke, C. A. 2009; 20 (8): 1431-1440

  Abstract

  The racial/ethnic disparities in prostate cancer rates are well documented, with the highest incidence and mortality rates observed among African-Americans followed by non-Hispanic Whites, Hispanics, and Asian/Pacific Islanders. Whether socioeconomic status (SES) can account for these differences in risk has been investigated in previous studies, but with conflicting results. Furthermore, previous studies have focused primarily on the differences between African-Americans and non-Hispanic Whites, and little is known for Hispanics and Asian/Pacific Islanders.To further investigate the relationship between SES and prostate cancer among African-Americans, non-Hispanic Whites, Hispanics, and Asian/Pacific Islanders, we conducted a large population-based cross-sectional study of 98,484 incident prostate cancer cases and 8,997 prostate cancer deaths from California.Data were abstracted from the California Cancer Registry, a population-based surveillance, epidemiology, and end results (SEER) registry. Each prostate cancer case and death was assigned a multidimensional neighborhood-SES index using the 2000 US Census data. SES quintile-specific prostate cancer incidence and mortality rates and rate ratios were estimated using SEER*Stat for each race/ethnicity categorized into 10-year age groups.For prostate cancer incidence, we observed higher levels of SES to be significantly associated with increased risk of disease [SES Q1 vs. Q5: relative risk (RR) = 1.28; 95% confidence interval (CI): 1.25-1.30]. Among younger men (45-64 years), African-Americans had the highest incidence rates followed by non-Hispanic Whites, Hispanics, and Asian/Pacific Islanders for all SES levels. Yet, among older men (75-84 years) Hispanics, following African-Americans, displayed the second highest incidence rates of prostate cancer. For prostate cancer deaths, higher levels of SES were associated with lower mortality rates of prostate cancer deaths (SES Q1 vs. Q5: RR = 0.88; 95% CI: 0.92-0.94). African-Americans had a twofold to fivefold increased risk of prostate cancer deaths in comparison to non-Hispanic Whites across all levels of SES.Our findings suggest that SES alone cannot account for the greater burden of prostate cancer among African-American men. In addition, incidence and mortality rates of prostate cancer display different age and racial/ethnic patterns across gradients of SES.

  View details for DOI 10.1007/s10552-009-9369-0

  View details for Web of Science ID 000270737900020

  View details for PubMedID 19526319

  View details for PubMedCentralID PMC2746891

• Identification of seven new prostate cancer susceptibility loci through a genome-wide association study NATURE GENETICS Eeles, R. A., Kote-Jarai, Z., Al Olama, A. A., Giles, G. G., Guy, M., Severi, G., Muir, K., Hopper, J. L., Henderson, B. E., Haiman, C. A., Schleutker, J., Hamdy, F. C., Neal, D. E., Donovan, J. L., Stanford, J. L., Ostrander, E. A., Ingles, S. A., John, E. M., Thibodeau, S. N., Schaid, D., Park, J. Y., Spurdle, A., Clements, J., Dickinson, J. L., Maier, C., Vogel, W., Doerk, T., Rebbeck, T. R., Cooney, K. A., Cannon-Albright, L., Chappuis, P. O., Hutter, P., Zeegers, M., Kaneva, R., Zhang, H., Lu, Y., Foulkes, W. D., English, D. R., Leongamornlert, D. A., Tymrakiewicz, M., Morrison, J., Ardern-Jones, A. T., Hall, A. L., O'Brien, L. T., Wilkinson, R. A., Saunders, E. J., Page, E. C., Sawyer, E. J., Edwards, S. M., Dearnaley, D. P., Horwich, A., Huddart, R. A., Khoo, V. S., Parker, C. C., Van As, N., Woodhouse, C. J., Thompson, A., Christmas, T., Ogden, C., Cooper, C. S., Southey, M. C., Lophatananon, A., Liu, J., Kolonel, L. N., Le Marchand, L., Wahlfors, T., Tammela, T. L., Auvinen, A., Lewis, S. J., Cox, A., FitzGerald, L. M., Koopmeiners, J. S., Karyadi, D. M., Kwon, E. M., Stern, M. C., Corral, R., Joshi, A. D., Shahabi, A., McDonnell, S. K., Sellers, T. A., Pow-Sang, J., Chambers, S., Aitken, J., Gardiner, R. A., Batra, J., Kedda, M. A., Lose, F., Polanowski, A., Patterson, B., Serth, J., Meyer, A., Luedeke, M., Stefflova, K., Ray, A. M., Lange, E. M., Farnham, J., Khan, H., Slavov, C., Mitkova, A., Cao, G., Easton, D. F. 2009; 41 (10): 1116-U97

  Abstract

  Prostate cancer (PrCa) is the most frequently diagnosed cancer in males in developed countries. To identify common PrCa susceptibility alleles, we previously conducted a genome-wide association study in which 541,129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and in 1,894 controls. We have now extended the study to evaluate promising associations in a second stage in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls and in a third stage involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to replicating previous associations, we identified seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11 and 22 (with P = 1.6 x 10(-8) to P = 2.7 x 10(-33)).

  View details for DOI 10.1038/ng.450

  View details for Web of Science ID 000270330400016

  View details for PubMedID 19767753

• Family history of breast cancer and all-cause mortality after breast cancer diagnosis in the Breast Cancer Family Registry BREAST CANCER RESEARCH AND TREATMENT Chang, E. T., Milne, R. L., Phillips, K., Figueiredo, J. C., Sangaramoorthy, M., Keegan, T. H., Andrulis, I. L., Hopper, J. L., Goodwin, P. J., O'Malley, F. P., Weerasooriya, N., Apicella, C., Southey, M. C., Friedlander, M. L., Giles, G. G., Whittemore, A. S., West, D. W., John, E. M. 2009; 117 (1): 167-176

  Abstract

  Although having a family history of breast cancer is a well established breast cancer risk factor, it is not known whether it influences mortality after breast cancer diagnosis. We studied 4,153 women with first primary incident invasive breast cancer diagnosed between 1991 and 2000, and enrolled in the Breast Cancer Family Registry through population-based sampling in Northern California, USA; Ontario, Canada; and Melbourne and Sydney, Australia. Cases were oversampled for younger age at diagnosis and/or family history of breast cancer. Carriers of germline mutations in BRCA1 or BRCA2 were excluded. Cases and their relatives completed structured questionnaires assessing breast cancer risk factors and family history of cancer. Cases were followed for a median of 6.5 years, during which 725 deaths occurred. Cox proportional hazards regression was used to evaluate associations between family history of breast cancer at the time of diagnosis and risk of all-cause mortality after breast cancer diagnosis, adjusting for established prognostic factors. The hazard ratios for all-cause mortality were 0.98 (95% confidence interval [CI] = 0.84-1.15) for having at least one first- or second-degree relative with breast cancer, and 0.85 (95% CI = 0.70-1.02) for having at least one first-degree relative with breast cancer, compared with having no such family history. Estimates did not vary appreciably when stratified by case or tumor characteristics. In conclusion, family history of breast cancer is not associated with all-cause mortality after breast cancer diagnosis for women without a known germline mutation in BRCA1 or BRCA2. Therefore, clinical management should not depend on family history of breast cancer.

  View details for DOI 10.1007/s10549-008-0255-3

  View details for Web of Science ID 000269005400020

  View details for PubMedID 19034644

  View details for PubMedCentralID PMC2728159

• Second Primary Breast Cancer Occurrence According to Hormone Receptor Status JOURNAL OF THE NATIONAL CANCER INSTITUTE Kurian, A. W., McClure, L. A., John, E. M., Horn-Ross, P. L., Ford, J. M., Clarke, C. A. 2009; 101 (15): 1058-1065

  Abstract

  Contralateral second primary breast cancers occur in 4% of female breast cancer survivors. Little is known about differences in risk for second primary breast cancers related to the estrogen and progesterone receptor (hormone receptor [HR]) status of the first tumor.We calculated standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for contralateral primary breast cancers among 4927 women diagnosed with a first breast cancer between January 1, 1992, and December 31, 2004, using the National Cancer Institute's Surveillance, Epidemiology, and End Results database.For women whose first breast tumors were HR positive, risk of contralateral primary breast cancer was elevated, compared with the general population, adjusted for age, race, and calendar year (SIR = 2.22, 95% CI = 2.15 to 2.29, absolute risk [AR] = 13 cases per 10 000 person-years [PY]), and was not related to the HR status of the second tumor. For women whose first breast tumors were HR negative, the risk of a contralateral primary tumor was statistically significantly higher than that for women whose first tumors were HR positive (SIR = 3.57, 95% CI = 3.38 to 3.78, AR = 18 per 10 000 PY), and it was associated with a much greater likelihood of an HR-negative second tumor (SIR for HR-positive second tumors = 1.94, 95% CI = 1.77 to 2.13, AR = 20 per 10 000 PY; SIR for HR-negative second tumors = 9.81, 95% CI = 9.00 to 10.7, AR = 24 per 10 000 PY). Women who were initially diagnosed with HR-negative tumors when younger than 30 years had greatly elevated risk of HR-negative contralateral tumors, compared with the general population (SIR = 169, 95% CI = 106 to 256, AR = 77 per 10 000 PY). Incidence rates for any contralateral primary cancer following an HR-negative or HR-positive tumor were higher in non-Hispanic blacks, Hispanics, and Asians or Pacific Islanders than in non-Hispanic whites.Risk for contralateral second primary breast cancers varies substantially by HR status of the first tumor, age, and race and/or ethnicity. Women with HR-negative first tumors have nearly a 10-fold elevated risk of developing HR-negative second tumors, compared with the general population. These findings warrant intensive surveillance for second breast cancers in women with HR-negative tumors.

  View details for DOI 10.1093/jnci/djp181

  View details for Web of Science ID 000268812900007

  View details for PubMedID 19590058

  View details for PubMedCentralID PMC2720990

• BRCA1 and BRCA2 mutation carriers in the Breast Cancer Family Registry: an open resource for collaborative research BREAST CANCER RESEARCH AND TREATMENT Neuhausen, S. L., Ozcelik, H., Southey, M. C., John, E. M., Godwin, A. K., Chung, W., Iriondo-Perez, J., Miron, A., Santella, R. M., Whittemore, A., Andrulis, I. L., Buys, S. S., Daly, M. B., Hopper, J. L., Seminara, D., Senie, R. T., Terry, M. B. 2009; 116 (2): 379-386

  Abstract

  The Breast Cancer Family Registry is a resource for interdisciplinary and translational studies of the genetic epidemiology of breast cancer. This resource is available to researchers worldwide for collaborative studies. Herein, we report the results of testing for germline mutations in BRCA1 and BRCA2. We have tested 4,531 probands for mutations in BRCA1 and 4,084 in BRCA2. Deleterious mutations in BRCA1 and BRCA2 were identified for 9.8% of probands tested [233/4,531 (5.1%) for BRCA1 and 193/4,084 (4.7%) for BRCA2]. Of 1,385 Ashkenazi Jewish women tested for only the three founder mutations, 17.4% carried a deleterious mutation. In total, from the proband and subsequent family testing, 1,360 female mutation carriers (788 in BRCA1, 566 in BRCA2, 6 in both BRCA1 and BRCA2) have been identified. The value of the resource has been greatly enhanced by determining the germline BRCA1 and BRCA2 mutation statuses of nearly 6,000 probands.

  View details for DOI 10.1007/s10549-008-0153-8

  View details for Web of Science ID 000266988000018

  View details for PubMedID 18704680

  View details for PubMedCentralID PMC2775077

• Prediagnosis Reproductive Factors and All-Cause Mortality for Women with Breast Cancer in the Breast Cancer Family Registry CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Phillips, K., Milne, R. L., West, D. W., Goodwin, P. J., Giles, G. G., Chang, E. T., Figueiredo, J. C., Friedlander, M. L., Keegan, T. H., Glendon, G., Apicella, C., O'Malley, F. P., Southey, M. C., Andrulis, I. L., John, E. M., Hopper, J. L. 2009; 18 (6): 1792-1797

  Abstract

  Studies have examined the prognostic relevance of reproductive factors before breast cancer diagnosis, but most have been small and their overall findings inconclusive. Associations between reproductive risk factors and all-cause mortality after breast cancer diagnosis were assessed with the use of a population-based cohort of 3,107 women of White European ancestry with invasive breast cancer (1,130 from Melbourne and Sydney, Australia; 1,441 from Ontario, Canada; and 536 from Northern California, United States). During follow-up with a median of 8.5 years, 567 deaths occurred. At recruitment, questionnaire data were collected on oral contraceptive use, number of full-term pregnancies, age at first full-term pregnancy, time from last full-term pregnancy to breast cancer diagnosis, breastfeeding, age at menarche, and menopause and menopausal status at breast cancer diagnosis. Hazard ratios for all-cause mortality were estimated with the use of Cox proportional hazards models with and without adjustment for age at diagnosis, study center, education, and body mass index. Compared with nulliparous women, those who had a child up to 2 years, or between 2 and 5 years, before their breast cancer diagnosis were more likely to die. The unadjusted hazard ratio estimates were 2.75 [95% confidence interval (95% CI), 1.98-3.83; P < 0.001] and 2.20 (95% CI, 1.65-2.94; P < 0.001), respectively, and the adjusted estimates were 2.25 (95% CI, 1.59-3.18; P < 0.001) and 1.82 (95% CI, 1.35-2.46; P < 0.001), respectively. When evaluating the prognosis of women recently diagnosed with breast cancer, the time since last full-term pregnancy should be routinely considered along with other established host and tumor prognostic factors, but consideration of other reproductive factors may not be warranted.

  View details for DOI 10.1158/1055-9965.EPI-08-1014

  View details for Web of Science ID 000266754100020

  View details for PubMedID 19505912

  View details for PubMedCentralID PMC2746957

• Description and Validation of High-Throughput Simultaneous Genotyping and Mutation Scanning by High-Resolution Melting Curve Analysis HUMAN MUTATION Nguyen-Dumont, T., Le Calvez-Kelm, F., Forey, N., McKay-Chopin, S., Garritano, S., Gioia-Patricola, L., De Silva, D., Weigel, R., Sangrajrang, S., Lesueur, F., Tavtigian, S. V., Breast Canc Family Registries BCFR, Kathleen Cuningham Fdn Consortium 2009; 30 (6): 884–90

  Abstract

  Mutation scanning using high-resolution melting curve analysis (HR-melt) is an effective and sensitive method to detect sequence variations. However, the presence of a common SNP within a mutation scanning amplicon may considerably complicate the interpretation of results and increase the number of samples flagged for sequencing by interfering with the clustering of samples according to melting profiles. A protocol describing simultaneous high-resolution gene scanning and genotyping has been reported. Here, we show that it can improve the sensitivity and the efficiency of large-scale case-control mutation screening. Two exons of ATM, both containing an SNP interfering with standard mutation scanning, were selected for screening of 1,356 subjects from an international breast cancer genetics study. Asymmetric PCR was performed in the presence of an SNP-specific unlabeled probe. Stratification of the samples according to their probe-target melting was aided by customized HR-melt software. This approach improved identification of rare known and unknown variants, while dramatically reducing the sequencing effort. It even allowed genotyping of tandem SNPs using a single probe. Hence, HR-melt is a rapid, efficient, and cost-effective tool that can be used for high-throughput mutation screening for research, as well as for molecular diagnostic and clinical purposes.

  View details for DOI 10.1002/humu.20949

  View details for Web of Science ID 000267635100005

  View details for PubMedID 19347964

  View details for PubMedCentralID PMC3478947

• Admixture Mapping of 15,280 African Americans Identifies Obesity Susceptibility Loci on Chromosomes 5 and X PLOS GENETICS Cheng, C., Kao, W. H., Patterson, N., Tandon, A., Haiman, C. A., Harris, T. B., Xing, C., John, E. M., Ambrosone, C. B., Brancati, F. L., Coresh, J., Press, M. F., Parekh, R. S., Klag, M. J., Meoni, L. A., Hsueh, W., Fejerman, L., Pawlikowska, L., Freedman, M. L., Jandorf, L. H., Bandera, E. V., Ciupak, G. L., Nalls, M. A., Akylbekova, E. L., Orwoll, E. S., Leak, T. S., Miljkovic, I., Li, R., Ursin, G., Bernstein, L., Ardlie, K., Taylor, H. A., Boerwinckle, E., Zmuda, J. M., Henderson, B. E., Wilson, J. G., Reich, D. 2009; 5 (5)

  Abstract

  The prevalence of obesity (body mass index (BMI) > or =30 kg/m(2)) is higher in African Americans than in European Americans, even after adjustment for socioeconomic factors, suggesting that genetic factors may explain some of the difference. To identify genetic loci influencing BMI, we carried out a pooled analysis of genome-wide admixture mapping scans in 15,280 African Americans from 14 epidemiologic studies. Samples were genotyped at a median of 1,411 ancestry-informative markers. After adjusting for age, sex, and study, BMI was analyzed both as a dichotomized (top 20% versus bottom 20%) and a continuous trait. We found that a higher percentage of European ancestry was significantly correlated with lower BMI (rho = -0.042, P = 1.6x10(-7)). In the dichotomized analysis, we detected two loci on chromosome X as associated with increased African ancestry: the first at Xq25 (locus-specific LOD = 5.94; genome-wide score = 3.22; case-control Z = -3.94); and the second at Xq13.1 (locus-specific LOD = 2.22; case-control Z = -4.62). Quantitative analysis identified a third locus at 5q13.3 where higher BMI was highly significantly associated with greater European ancestry (locus-specific LOD = 6.27; genome-wide score = 3.46). Further mapping studies with dense sets of markers will be necessary to identify the alleles in these regions of chromosomes X and 5 that may be associated with variation in BMI.

  View details for DOI 10.1371/journal.pgen.1000490

  View details for Web of Science ID 000267083000012

  View details for PubMedID 19461885

  View details for PubMedCentralID PMC2679192

• No association of TGFB1 L10P genotypes and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a multi-center cohort study BREAST CANCER RESEARCH AND TREATMENT Rebbeck, T. R., Antoniou, A. C., Caldes Llopis, T., Nevanlinna, H., Aittomaki, K., Simard, J., Spurdle, A. B., Couch, F. J., Pereira, L. H., Greene, M. H., Andrulis, I. L., Pasche, B., Kaklamani, V., Hamann, U., Szabo, C., Peock, S., Cook, M., Harrington, P. A., Donaldson, A., Male, A. M., Gardiner, C. A., Gregory, H., Side, L. E., Robinson, A. C., Emmerson, L., Ellis, I., Peyrat, J., Fournier, J., Vennin, P., Adenis, C., Muller, D., Fricker, J., Longy, M., Sinilnikova, O. M., Stoppa-Lyonnet, D., Schmutzler, R. K., Versmold, B., Engel, C., Meindl, A., Kast, K., Schaefer, D., Froster, U. G., Chenevix-Trench, G., Easton, D. F. 2009; 115 (1): 185-192

  Abstract

  The transforming growth factor beta-1 gene (TGFB1) is a plausible candidate for breast cancer susceptibility. The L10P variant of TGFB1 is associated with higher circulating levels and secretion of TGF-beta, and recent large-scale studies suggest strongly that this variant is associated with breast cancer risk in the general population.To evaluate whether TGFB1 L10P also modifies the risk of breast cancer in BRCA1 or BRCA2 mutation carriers, we undertook a multi-center study of 3,442 BRCA1 and 2,095 BRCA2 mutation carriers.We found no evidence of association between TGFB1 L10P and breast cancer risk in either BRCA1 or BRCA2 mutation carriers. The per-allele HR for the L10P variant was 1.01 (95%CI: 0.92-1.11) in BRCA1 carriers and 0.92 (95%CI: 0.81-1.04) in BRCA2 mutation carriers.These results do not support the hypothesis that TGFB1 L10P genotypes modify the risk of breast cancer in BRCA1 or BRCA2 mutation carriers.

  View details for DOI 10.1007/s10549-008-0064-8

  View details for Web of Science ID 000265440400021

  View details for PubMedID 18523885

  View details for PubMedCentralID PMC2700286

• UGT1A1 gene polymorphisms and plasma bilirubin levels in African American women Huo, D., Hong, A., Yu, Z., John, E., West, D., Whittemore, A., Olopade, O. AMER ASSOC CANCER RESEARCH. 2009

  View details for Web of Science ID 000209702802076

• Performance of Prediction Models for BRCA Mutation Carriage in Three Racial/Ethnic Groups: Findings from the Northern California Breast Cancer Family Registry CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Kurian, A. W., Gong, G. D., John, E. M., Miron, A., Felberg, A., Phipps, A. I., West, D. W., Whittemore, A. S. 2009; 18 (4): 1084-1091

  Abstract

  Patients with early-onset breast and/or ovarian cancer frequently wish to know if they inherited a mutation in one of the cancer susceptibility genes, BRCA1 or BRCA2. Accurate carrier prediction models are needed to target costly testing. Two widely used models, BRCAPRO and BOADICEA, were developed using data from non-Hispanic Whites (NHW), but their accuracies have not been evaluated in other racial/ethnic populations.We evaluated the BRCAPRO and BOADICEA models in a population-based series of African American, Hispanic, and NHW breast cancer patients tested for BRCA1 and BRCA2 mutations. We assessed model calibration by evaluating observed versus predicted mutations and attribute diagrams, and model discrimination using areas under the receiver operating characteristic curves.Both models were well-calibrated within each racial/ethnic group, with some exceptions. BOADICEA overpredicted mutations in African Americans and older NHWs, and BRCAPRO underpredicted in Hispanics. In all racial/ethnic groups, the models overpredicted in cases whose personal and family histories indicated >80% probability of carriage. The two models showed similar discrimination in each racial/ethnic group, discriminating least well in Hispanics. For example, BRCAPRO's areas under the receiver operating characteristic curves were 83% (95% confidence interval, 63-93%) for NHWs, compared with 74% (59-85%) for African Americans and 58% (45-70%) for Hispanics.The poor performance of the model for Hispanics may be due to model misspecification in this racial/ethnic group. However, it may also reflect racial/ethnic differences in the distributions of personal and family histories among breast cancer cases in the Northern California population.

  View details for DOI 10.1158/1055-9965.EPI-08-1090

  View details for PubMedID 19336551

• A pilot genome-wide association study of early-onset breast cancer BREAST CANCER RESEARCH AND TREATMENT Kibriya, M. G., Jasmine, F., Argos, M., Andrulis, I. L., John, E. M., Chang-Claude, J., Ahsan, H. 2009; 114 (3): 463-477

  Abstract

  High-density oligonucleotide microarrays containing a large number of single nucleotide polymorphisms (SNPs) have enabled genome-wide association (GWA) analysis to become a reality. We used the early access Affymetrix Mendel Nsp 250K chips in a GWA case-control pilot study to identify genomic regions associated with breast cancer. We included 30 randomly sampled incident invasive breast cancer cases aged <45 years without deleterious mutations in the BRCA1 or BRCA2 genes, and 30 population controls individually matched on age, ethnicity and geographical area. The overall genotype call rate was 97.13+/-1.33% for controls and 97.48+/-1.42% for cases. Comparison was made between cases and controls for 203,477 genotyped SNPs using (a) unconditional logistic regression (ULR), (b) conditional logistic regression (CLR) models with adjustment for the matched pairs, (c) allelic tests for single marker tests and (d) haplotype trend regression (HTR). Genomic control and EIGENSTRAT methods were used for correction of population stratification in appropriate models. We demonstrate the similarity and dissimilarity of results from different statistical analyses. We found several possible significant regions harboring biologically meaningful known candidate genes, such as genes encoding fibroblast growth factor, transforming growth factor, epidermal growth factor, and estrogen synthesis enzymes to be associated with early-onset breast cancer. In single marker analysis, none of the SNPs were statistically significant after correction for multiple testing. However, haplotype association tests, using 90730 tag-SNPs, suggested two regions in GLG1 and UGT1 genes retaining significance even after Bonferroni correction. Nevertheless, without systematic replication, findings from this pilot study, especially the associations of breast cancer in relation to specific SNPs, should be interpreted with great caution.

  View details for DOI 10.1007/s10549-008-0039-9

  View details for Web of Science ID 000263786300009

  View details for PubMedID 18463975

• Whole-Genome Amplification Enables Accurate Genotyping for Microarray-Based High-Density Single Nucleotide Polymorphism Array CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Jasmine, F., Ahsan, H., Andrulis, I. L., John, E. M., Chang-Claude, J., Kibriya, M. G. 2008; 17 (12): 3499-3508

  Abstract

  In large-scale genome-wide association studies based on high-density single nucleotide polymorphism (SNP) genotyping array, the quantity and quality of available genomic DNA (gDNA) is a practical problem. We examined the feasibility of using the Multiple Displacement Amplification (MDA) method of whole-genome amplification (WGA) for such a platform. The Affymetrix Early Access Mendel Nsp 250K GeneChip was used for genotyping 224,940 SNPs per sample for 28 DNA samples. We compared the call concordance using 14 gDNA samples and their corresponding 14 WGA samples. The overall mean genotype call rates in gDNA and the corresponding WGA samples were comparable at 97.07% [95% confidence interval (CI), 96.17-97.97] versus 97.77% (95% CI, 97.26-98.28; P = 0.154), respectively. Reproducibility of the platform, calculated as concordance in duplicate samples, was 99.45%. Overall genotypes for 97.74% (95% CI, 97.03-98.44) of SNPs were concordant between gDNA and WGA samples. When the analysis was restricted to well-performing SNPs (successful genotyping in gDNA and WGA in >90% of samples), 99.11% (95% CI, 98.80-99.42) of the SNPs, on average, were concordant, and overall a SNP showed a discordant call in 0.92% (95% CI, 0.90-0.94) of paired samples. In a pair of gDNA and WGA DNA, similar concordance was reproducible on Illumina's Infinium 610 Quad platform as well. Although copy number analysis revealed a total of seven small telomeric regions in six chromosomes with loss of copy number, the estimated genome representation was 99.29%. In conclusion, our study confirms that high-density oligonucleotide array-based genotyping can yield reproducible data and MDA-WGA DNA products can be effectively used for genome-wide SNP genotyping analysis.

  View details for DOI 10.1158/1055-9965.EPI-08-0482

  View details for Web of Science ID 000261724000030

  View details for PubMedID 19064567

  View details for PubMedCentralID PMC2871542

• Genetic Ancestry and Risk of Breast Cancer among US Latinas CANCER RESEARCH Fejerman, L., John, E. M., Huntsman, S., Beckman, K., Choudhry, S., Perez-Stable, E., Burchard, E. G., Ziv, E. 2008; 68 (23): 9723-9728

  Abstract

  U.S. Latinas have a lower incidence of breast cancer compared with non-Latina White women. This difference is partially explained by differences in the prevalence of known risk factors. Genetic factors may also contribute to this difference in incidence. Latinas are an admixed population with most of their genetic ancestry from Europeans and Indigenous Americans. We used genetic markers to estimate the ancestry of Latina breast cancer cases and controls and assessed the association with genetic ancestry, adjusting for reproductive and other risk factors. We typed a set of 106 ancestry informative markers in 440 Latina women with breast cancer and 597 Latina controls from the San Francisco Bay area and estimated genetic ancestry using a maximum likelihood method. Odds ratios (OR) and 95% confidence intervals (95% CI) for ancestry modeled as a continuous variable were estimated using logistic regression with known risk factors included as covariates. Higher European ancestry was associated with increased breast cancer risk. The OR for a 25% increase in European ancestry was 1.79 (95% CI, 1.28-2.79; P<0.001). When known risk factors and place of birth were adjusted for, the association with European ancestry was attenuated but remained statistically significant (OR, 1.39; 95% CI, 1.06-2.11; P=0.013). Further work is needed to determine if the association is due to genetic differences between populations or possibly due to environmental factors not measured.

  View details for DOI 10.1158/0008-5472.CAN-08-2039

  View details for Web of Science ID 000261488900022

  View details for PubMedID 19047150

  View details for PubMedCentralID PMC2674787

• 5-lipoxygenase and 5-lipoxygenase-activating protein gene polymorphisms, dietary linoleic acid, and risk for breast cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Wang, J., John, E. M., Ingles, S. A. 2008; 17 (10): 2748-2754

  Abstract

  The n-6 polyunsaturated fatty acid 5-lipoxygenase pathway has been shown to play a role in the carcinogenesis of breast cancer. We conducted a population-based case-control study among Latina, African-American, and White women from the San Francisco Bay area to examine the association of the 5-lipoxygenase gene (ALOX5) and 5-lipoxygenase-activating protein gene (ALOX5AP) with breast cancer risk. Three ALOX5AP polymorphisms [poly(A) microsatellite, -4900 A>G (rs4076128), and -3472 A>G (rs4073259)] and three ALOX5 polymorphisms [Sp1-binding site (-GGGCGG-) variable number of tandem repeat polymorphism, -1279 G>T (rs6593482), and 760 G>A (rs2228065)] were genotyped in 802 cases and 888 controls. We did not find significant main effects of ALOX5 and ALOX5AP genotypes on breast cancer risk that were consistent across race or ethnicity; however, there was a significant interaction between the ALOX5AP -4900 A>G polymorphism and dietary linoleic acid intake (P=0.03). Among women consuming a diet high in linoleic acid (top quartile of intake, >17.4 g/d), carrying the AA genotype was associated with higher breast cancer risk (age- and race-adjusted odds ratio, 1.8; 95% confidence interval, 1.2-2.9) compared with carrying genotypes AG or GG. Among women consuming

  View details for DOI 10.1158/1055-9965.EPI-08-0439

  View details for Web of Science ID 000260051000031

  View details for PubMedID 18843019

• Multiple novel prostate cancer predisposition loci confirmed by an international study: The PRACTICAL consortium CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Kote-Jarai, Z., Easton, D. F., Stanford, J. L., Ostrander, E. A., Schleutker, J., Ingles, S. A., Schaid, D., Thibodeau, S., Doerk, T., Neal, D., Cox, A., Maier, C., Vogel, W., Guy, M., Muir, K., Lophatananon, A., Kedda, M., Spurdle, A., Steginga, S., John, E. M., Giles, G., Hopper, J., Chappuis, P. O., Hutter, P., Foulkes, W. D., Hamel, N., Salinas, C. A., Koopmeiners, J. S., Karyadi, D. M., Johanneson, B., Wahlfors, T., Tammela, T. L., Stern, M. C., Corral, R., McDonnell, S. K., Schuermann, P., Meyer, A., Kuefer, R., Leongamornlert, D. A., Tymrakiewicz, M., Liu, J., O'Mara, T., Gardiner, R. A., Aitken, J., Joshi, A. D., Severi, G., English, D. R., Southey, M., Edwards, S. M., Al Olama, A. A., Eeles, R. A. 2008; 17 (8): 2052-2061

  Abstract

  A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10(-17)). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported [per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31)]. The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction.

  View details for DOI 10.1158/1055-9965.EPI-08-0317

  View details for Web of Science ID 000258800800032

  View details for PubMedID 18708398

  View details for PubMedCentralID PMC2776652

• Dietary fat, cooking fat, and breast cancer risk in a multiethnic population NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL Wang, J., John, E. M., Horn-Ross, P. L., Ingles, S. A. 2008; 60 (4): 492-504

  Abstract

  Our objective was to examine the association between dietary fat intake, cooking fat usage, and breast cancer risk in a population-based, multiethnic, case-control study conducted in the San Francisco Bay area. Intake of total fat and types of fat were assessed with a food frequency questionnaire among 1,703 breast cancer cases diagnosed between 1995 and 1999 and 2,045 controls. In addition, preferred use of fat for cooking was assessed. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). High fat intake was associated with increased risk of breast cancer (highest vs. lowest quartile, adjusted OR = 1.35, 95% CI = 1.10-1.65, P(trend) < 0.01). A positive association was found for oleic acid (OR = 1.55, 95% CI = 1.14-2.10, P(trend) < 0.01) but not for linoleic acid or saturated fat. Risk was increased for women cooking with hydrogenated fats (OR = 1.58, 95% CI = 1.20-2.10) or vegetable/corn oil (rich in linoleic acid; OR = 1.30, 95% CI = 1.06-1.58) compared to women using olive/canola oil (rich in oleic acid). Our results suggest that a low-fat diet may play a role in breast cancer prevention. We speculate that monounsaturated trans fats may have driven the discrepant associations between types of fat and breast cancer.

  View details for DOI 10.1080/01635580801956485

  View details for Web of Science ID 000257988700008

  View details for PubMedID 18584483

• Smoking and risk of breast cancer in carriers of mutations in BRCA1 or BRCA2 aged less than 50 years BREAST CANCER RESEARCH AND TREATMENT Anonymous 2008; 109 (1): 67-75

  Abstract

  Cigarette smoke contains compounds that may damage DNA, and the repair of damage may be impaired in women with germline mutations in BRCA1 or BRCA2. However, the effect of cigarette smoking on breast cancer risk in mutation carriers is the subject of conflicting reports. We have examined the relation between smoking and breast cancer risk in non-Hispanic white women under the age of 50 years who carry a deleterious mutation in BRCA1 or BRCA2.We conducted a case-control study using data from carriers of mutations in BRCA1 (195 cases and 302 controls) and BRCA2 (128 cases and 179 controls). Personal information, including smoking history, was collected using a common structured questionnaire by eight recruitment sites in four countries. Odds-ratios (OR) for breast cancer risk according to smoking were adjusted for age, family history, parity, alcohol use, and recruitment site.Compared to non-smokers, the OR for risk of breast cancer for women with five or more pack-years of smoking was 2.3 (95% confidence interval 1.6-3.5) for BRCA1 carriers and 2.6 (1.8-3.9) for BRCA2 carriers. Risk increased 7% per pack-year (p<0.001) in both groups.These results indicate that smoking is associated with increased risk of breast cancer before age 50 years in BRCA1 and BRCA2 mutation carriers. If confirmed, they provide a practical way for carriers to reduce their risks. Previous studies in prevalent mutation carriers have not shown smoking to increase risk of breast cancer, but are subject to bias, because smoking decreases survival after breast cancer.

  View details for DOI 10.1007/s10549-007-9621-9

  View details for Web of Science ID 000255031000008

  View details for PubMedID 17972172

• Genetic variation in IGFBP2 and IGFBP5 is associated with breast cancer in populations of African descent HUMAN GENETICS Garner, C. P., Ding, Y. C., John, E. M., Ingles, S. A., Olopade, O. I., Huo, D., Adebamowo, C., Ogundiran, T., Neuhausen, S. L. 2008; 123 (3): 247-255

  Abstract

  The insulin-like growth factor (IGF) signaling pathway is thought to play a major role in the etiology of breast cancer. Although incidence rates of breast cancer overall are lower in African Americans than in Caucasians, African-American women have a higher incidence under age 40 years, are diagnosed with more advanced disease, and have poorer prognosis. We investigated the association of breast cancer and genetic variants in genes in the IGF signaling pathway in a population-based case-control study of African-American women. We found significant associations at a locus encompassing parts of the IGFBP2 and IGFBP5 genes on chromosome 2q35, which we then replicated in a case-control study of Nigerian women. Based on those initial findings, we genotyped a total of 34 single nucleotide polymorphisms (SNPs) across the region in both study populations. Statistically significant associations with breast cancer were observed across approximately 50 kb of DNA sequence encompassing three exons in the 3' end of IGFBP2 and three exons in the 3' end of IGFBP5. SNPs were associated with breast cancer risk with P values as low as P = 0.0038 and P = 0.01 in African-Americans and Nigerians, respectively. This study is the first to report associations between genetic variants in IGFBP2 and IGFBP5 and breast cancer risk.

  View details for DOI 10.1007/s00439-008-0468-x

  View details for Web of Science ID 000254184700003

  View details for PubMedID 18210156

• Mitochondrial DNA G10398A variant is not associated with breast cancer in African-American women CANCER GENETICS AND CYTOGENETICS Setiawan, V. W., Chu, L., John, E. M., Ding, Y. C., Ingles, S. A., Bernstein, L., Press, M. F., Ursin, G., Haiman, C. A., Neuhausen, S. L. 2008; 181 (1): 16-19

  Abstract

  Mitochondria play important roles in cellular energy production, free radical generation, and apoptosis. In a previous report, the mitochondrial DNA (mtDNA) G10398A (Thr-->Ala) polymorphism was associated with breast cancer risk in African-American women [Cancer Res 2005;65:8028-33]. We sought to replicate the association by genotyping the G10398A polymorphism in multiple established population-based case-control studies of breast cancer in African-American women. The 10398A allele was not significantly associated with risk in any of the studies: San Francisco (542 cases, 282 controls, odds ratio OR = 1.73, 95% confidence interval CI = 0.87-3.47, P = 0.12); Multiethnic Cohort (391 cases, 460 controls, OR = 1.08, 95% CI = 0.62-1.86, P = 0.79); and CARE and LIFE (524 cases, 236 controls, OR = 0.81, 95% CI = 0.43-1.52, P = 0.50). With data pooled across the studies (1,456 cases and 978 controls), no significant association was observed with the 10398A allele (OR = 1.14, 95% CI = 0.80-1.62, P = 0.47, test for heterogeneity = 0.30). In analysis of advanced breast cancer cases (n = 674), there was also no significant association (OR = 1.18, 95% CI = 0.76-1.82, P = 0.46). Our results do not support the hypothesis that the mtDNA G10398A polymorphism is, as has previously been reported, a marker of breast cancer risk in African Americans.

  View details for DOI 10.1016/j.cancergencyto.2007.10.019

  View details for Web of Science ID 000253364800003

  View details for PubMedID 18262047

  View details for PubMedCentralID PMC3225405

• Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION John, E. M., Miron, A., Gong, G., Phipps, A. I., Felberg, A., Li, F. P., West, D. W., Whittemore, A. S. 2007; 298 (24): 2869-2876

  Abstract

  Information on the prevalence of pathogenic BRCA1 mutation carriers in racial/ethnic minority populations is limited.To estimate BRCA1 carrier prevalence in Hispanic, African American, and Asian American female breast cancer patients compared with non-Hispanic white patients with and without Ashkenazi Jewish ancestry.We estimated race/ethnicity-specific prevalence of BRCA1 in a population-based, multiethnic series of female breast cancer patients younger than 65 years at diagnosis who were enrolled at the Northern California site of the Breast Cancer Family Registry during the period 1996-2005. Race/ethnicity and religious ancestry were based on self-report. Weighted estimates of prevalence and 95% confidence intervals (CIs) were based on Horvitz-Thompson estimating equations.Estimates of BRCA1 prevalence.Estimates of BRCA1 prevalence were 3.5% (95% CI, 2.1%-5.8%) in Hispanic patients (n = 393), 1.3% (95% CI, 0.6%-2.6%) in African American patients (n = 341), and 0.5% (95% CI, 0.1%-2.0%) in Asian American patients (n = 444), compared with 8.3% (95% CI, 3.1%-20.1%) in Ashkenazi Jewish patients (n = 41) and 2.2% (95% CI, 0.7%-6.9%) in other non-Hispanic white patients (n = 508). Prevalence was particularly high in young (<35 years) African American patients (5/30 patients [16.7%]; 95% CI, 7.1%-34.3%). 185delAG was the most common mutation in Hispanics, found in 5 of 21 carriers (24%).Among African American, Asian American, and Hispanic patients in the Northern California Breast Cancer Family Registry, the prevalence of BRCA1 mutation carriers was highest in Hispanics and lowest in Asian Americans. The higher carrier prevalence in Hispanics may reflect the presence of unrecognized Jewish ancestry in this population.

  View details for Web of Science ID 000251816000019

  View details for PubMedID 18159056

• Sun exposure, vitamin D receptor gene polymorphisms, and breast cancer risk in a multiethnic population AMERICAN JOURNAL OF EPIDEMIOLOGY John, E. M., Schwartz, G. G., Koo, J., Wang, W., Ingles, S. A. 2007; 166 (12): 1409-1419

  Abstract

  Considerable evidence indicates that vitamin D may reduce the risk of several cancers, including breast cancer. This study examined associations of breast cancer with sun exposure, the principal source of vitamin D, and vitamin D receptor gene (VDR) polymorphisms (FokI, TaqI, BglI) in a population-based case-control study of Hispanic, African-American, and non-Hispanic White women aged 35-79 years from the San Francisco Bay Area of California (1995-2003). In-person interviews were obtained for 1,788 newly diagnosed cases and 2,129 controls. Skin pigmentation measurements were taken on the upper underarm (a sun-protected site that measures constitutive pigmentation) and on the forehead (a sun-exposed site) using reflectometry. Biospecimens were collected for a subset of the study population (814 cases, 910 controls). A high sun exposure index based on reflectometry was associated with reduced risk of advanced breast cancer among women with light constitutive skin pigmentation (odds ratio = 0.53, 95% confidence interval: 0.31, 0.91). The association did not vary with VDR genotype. No associations were found for women with medium or dark pigmentation. Localized breast cancer was not associated with sun exposure or VDR genotype. This study supports the hypothesis that sunlight exposure reduces risk of advanced breast cancer among women with light skin pigmentation.

  View details for DOI 10.1093/aje/kwm259

  View details for Web of Science ID 000251334400008

  View details for PubMedID 17934201

• Alcohol metabolism, alcohol intake, and breast cancer risk: A sister-set analysis using the breast cancer family registry BREAST CANCER RESEARCH AND TREATMENT Terry, M. B., Knight, J. A., Zablotska, L., Wang, Q., John, E. M., Andrulis, I. L., Senie, R. T., Daly, M., Ozcelik, H., Briollais, L., Santella, R. M. 2007; 106 (2): 281-288

  Abstract

  Moderate alcohol intake has been consistently associated with a modest (30-50%) increase in breast cancer risk, but it remains unclear if certain individuals have higher susceptibility to the harmful effects of alcohol intake. Individuals differ in their ability to metabolize alcohol through genetic differences in alcohol dehydrogenase (ADH), the enzyme that catalyzes the oxidation of approximately 80% of ethanol to acetaldehyde, a known carcinogen. Using data from the Breast Cancer Family Registry (n = 811 sister sets), we examined whether sisters with breast cancer differ with respect to alcohol consumption and alcohol metabolism (measured by polymorphisms in ADH1B and ADH1C) compared to their sisters without breast cancer. Neither alcohol drinking nor alcohol metabolizing ADH1B and ADH1C genotypes were associated with breast cancer risk. However, only 19% and 42% of sisters were discordant by ADH1B and ADH1C, respectively, and even fewer were discordant by both genotype and alcohol intake, making it difficult to detect differences if they existed.

  View details for DOI 10.1007/s10549-007-9498-7

  View details for Web of Science ID 000250579600014

  View details for PubMedID 17268812

• UDP-glucuronosyltransferase 1A1 gene polymorphisms and total bilirubin levels in an ethnically diverse cohort of women DRUG METABOLISM AND DISPOSITION Hong, A. L., Huo, D., Kim, H., Niu, Q., Fackenthal, D. L., Cummings, S. A., John, E. M., West, D. W., Whittemore, A. S., Das, S., Olopade, O. I. 2007; 35 (8): 1254-1261

  Abstract

  The objective of this study was to investigate variations in UGT1A1 polymorphisms and haplotypes among African-American and Caucasian women and to assess whether variants other than UGT1A1*28 are associated with total serum bilirubin levels. The (TA)(n) repeats and 14 single nucleotide polymorphisms (SNPs) in the UGT1A1 gene were genotyped in 335 African Americans and 181 Caucasians. Total serum bilirubin levels were available in a subset of 125 women. Allele frequencies of all SNPs and (TA)(n) repeats were significantly different between African Americans and Caucasians. In Caucasians, three common haplotypes accounted for 71.8% of chromosomes, whereas five common haplotypes accounted for only 46.6% of chromosomes in African Americans. Mean total serum bilirubin levels were significantly lower (p = 0.005) in African Americans (0.36 mg/dl) than in Caucasians (0.44 mg/dl). The (TA)(n) repeats explained a significant amount of variation in total bilirubin levels (R(2) = 0.27, p < 0.0001), whereas other SNPs were less correlative. Thus, significant variations in UGT1A1 haplotype structure exist between African Americans and Caucasians in this relatively large cohort of women. The correlation of UGT1A1 with total bilirubin levels was mainly due to (TA)(n) repeats in Caucasians but a clear correlation was not observed in African Americans because of the high diversity of haplotypes and the small sample size. These data have implications for the design of epidemiologic studies of cancer susceptibility and pharmacogenetic studies for adverse drug reactions in populations of African ancestry.

  View details for DOI 10.1124/dmd.106.014183

  View details for Web of Science ID 000248200000003

  View details for PubMedID 17478602

• Validation study of the LAMBDA model for predicting the BRCA1 or BRCA2 mutation carrier status of North American Ashkenazi Jewish women CLINICAL GENETICS Apicella, C., Dowty, J. G., Dite, G. S., Jenkins, M. A., Senle, R. T., Daly, M. B., Andrulis, I. L., John, E. M., Buys, S. S., Li, F. P., Glendon, G., Chung, W., Ozcelik, H., Miron, A., Kotar, K., Southey, M. C., Foulkes, W. D., Hopper, J. L. 2007; 72 (2): 87-97

  Abstract

  LAMBDA is a model that estimates the probability an Ashkenazi Jewish (AJ) woman carries an ancestral BRCA1 or BRCA2 mutation from her personal and family cancer history. LAMBDA is relevant to clinical practice, and its implementation does not require a computer. It was developed principally from Australian and UK data. We conducted a validation study using 1286 North American AJ women tested for the mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. Most had a personal or family history of breast cancer. We observed 197 carriers. The area under the receiver operator characteristic (ROC) curve (a measure of ranking) was 0.79 [95% confidence interval (CI) = 0.77-0.81], similar to that for the model-generating data (0.78; 95% CI = 0.75-0.82). LAMBDA predicted 232 carriers (18% more than observed; p = 0.002) and was overdispersed (p = 0.009). The Bayesian computer program BRCAPRO gave a similar area under the ROC curve (0.78; 95% CI = 0.76-0.80), but predicted 367 carriers (86% more than observed; p < 0.0001), and was substantially overdispersed (p < 0.0001). Therefore, LAMBDA is comparable to BRCAPRO for ranking AJ women according to their probability of being a BRCA1 or BRCA2 mutation carrier and is more accurate than brcapro which substantially overpredicts carriers in this population.

  View details for DOI 10.1111/j.1399-0004.2007.00841.x

  View details for Web of Science ID 000248533500004

  View details for PubMedID 17661812

• Medical radiation exposure and breast cancer risk: Findings from the Breast Cancer Family Registry INTERNATIONAL JOURNAL OF CANCER John, E. M., Phipps, A. I., Knight, J. A., Milne, R. L., Dite, G. S., Hopper, J. L., Andrulis, I. L., Southey, M., Giles, G. G., West, D. W., Whittemore, A. S. 2007; 121 (2): 386-394

  Abstract

  Moderate to high-dose radiotherapy is known to increase the risk of breast cancer. Uncertainties remain about the effects of low-dose chest X-rays, particularly in individuals at increased genetic risk. We analyzed case-control data from the Breast Cancer Family Registry. Self-reported data on therapeutic and diagnostic radiation exposures to the chest were available for 2,254 breast cancer cases and 3,431 controls (1,556 unaffected sisters and 1,875 unrelated population controls). We used unconditional logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with radiation exposure, after adjusting for age, study center, country of birth, and education. Increased risks for breast cancer were found for women who had radiotherapy for a previous cancer (OR=3.55, CI=1.47-8.54) and diagnostic chest X-rays for tuberculosis (OR=2.49, CI=1.82-3.40) or pneumonia (OR=2.19, CI=1.38-3.47). Risks were highest for women with a large number of exposures at a young age or exposed in earlier calendar years. There was no evidence of increased risk associated with other diagnostic chest X-rays (not including tuberculosis or pneumonia), both in women with and without indicators of increased genetic risk (i.e., diagnosed at age <40 years or family history of breast cancer). Given the widespread and increasing use of medical diagnostic radiation, continued surveillance of breast cancer risk is warranted, particularly in women at specific genetic risk, such as those carrying mutations in BRCA1 or BRCA2.

  View details for DOI 10.1002/ijc.22668

  View details for Web of Science ID 000247155000021

  View details for PubMedID 17372900

• Sun exposure and prostate cancer risk: Evidence for a protective effect of early-life exposure CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION John, E. M., Koo, J., Schwartz, G. G. 2007; 16 (6): 1283-1286

  Abstract

  Mounting experimental and epidemiologic evidence supports the hypothesis that vitamin D reduces the risk of prostate cancer. Some evidence suggests that prostate cancer risk may be influenced by sun exposure early in life. We analyzed data from the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study to examine associations of prostate cancer risk with early-life and adult residential sun exposure and adult sun exposures that were assessed through self-report, physician report, and dermatologic examination. We used solar radiation in the state of birth as a measure of sun exposure in early life. Follow-up from 1971 to 1975 (baseline) to 1992 identified 161 prostate cancer cases (102 nonfatal and 59 fatal) among non-Hispanic white men for whom sun exposure data were available. Significant inverse associations were found for men born in a region of high solar radiation (relative risk, 0.49, 95% confidence interval, 0.27-0.90 for high versus low solar radiation), with a slightly greater reduction for fatal than for nonfatal prostate cancer. Frequent recreational sun exposure in adulthood was associated with a significantly reduced risk of fatal prostate cancer only (relative risk, 0.47; 95% confidence interval, 0.23-0.99). These findings suggest that, in addition to sun exposure in adulthood, sun exposure in early life protects against prostate cancer.

  View details for DOI 10.1158/1055-9965.EPI-06-1053

  View details for Web of Science ID 000247163100038

  View details for PubMedID 17548698

• Multiple regions within 8q24 independently affect risk for prostate cancer NATURE GENETICS Haiman, C. A., Patterson, N., Freedman, M. L., Myers, S. R., Pike, M. C., Waliszewska, A., Neubauer, J., Tandon, A., Schirmer, C., McDonald, G. J., Greenway, S. C., Stram, D. O., Le Marchand, L., Kolonel, L. N., Frasco, M., Wong, D., Pooler, L. C., Ardlie, K., Oakley-Girvan, I., Whittemore, A. S., Cooney, K. A., John, E. M., Ingles, S. A., Altshuler, D., Henderson, B. E., Reich, D. 2007; 39 (5): 638-644

  Abstract

  After the recent discovery that common genetic variation in 8q24 influences inherited risk of prostate cancer, we genotyped 2,973 SNPs in up to 7,518 men with and without prostate cancer from five populations. We identified seven risk variants, five of them previously undescribed, spanning 430 kb and each independently predicting risk for prostate cancer (P = 7.9 x 10(-19) for the strongest association, and P < 1.5 x 10(-4) for five of the variants, after controlling for each of the others). The variants define common genotypes that span a more than fivefold range of susceptibility to cancer in some populations. None of the prostate cancer risk variants aligns to a known gene or alters the coding sequence of an encoded protein.

  View details for DOI 10.1038/ng2015

  View details for Web of Science ID 000245971300019

  View details for PubMedID 17401364

  View details for PubMedCentralID PMC2638766

• A variant in the cytochrome P450 oxidoreductase gene is associated with breast cancer risk in African Americans CANCER RESEARCH Haiman, C. A., Setiawan, V. W., Xia, L. Y., Le Marchand, L., Ingles, S. A., Ursin, G., Press, M. F., Bernstein, L., John, E. M., Henderson, B. E. 2007; 67 (8): 3565-3568

  Abstract

  Variation in the cytochrome P450 oxidoreductase (POR) gene, a key regulator of type II cytochrome P450 enzymes, may affect exposure to endogenous steroid hormones and breast cancer risk. We sequenced the POR locus and tested candidate polymorphisms G5G and A503V for association with breast cancer risk among women in the Multiethnic Cohort Study (1,615 cases and 1,962 controls). The single nucleotide polymorphism (SNP) A503V was common in all racial/ethnic populations (minor allele frequency, > or =0.05) but was not associated with risk. SNP G5G (A --> G nucleotide change), which lies in a suggestive exonic splicing enhancer motif in exon 1, was common only in African Americans (minor allele frequency, 0.21) and the homozygous state was modestly associated with increased breast risk among all cases [345 cases and 426 controls; odds ratio (OR), 1.64; 95% confidence interval (CI), 0.89-3.04; P = 0.12] and among cases with advanced disease (95 cases: OR, 3.08; 95% CI, 1.42-6.70; P = 0.005). In an attempt to replicate this association, we genotyped SNP G5G in additional African American case-control studies (747 cases and 468 controls). Nonsignificant positive associations were noted with the GG genotype class in all studies. In the pooled analysis (1,038 cases and 877 controls with genotype data), the association was statistically significant among all cases (OR, 1.58; 95% CI, 1.04-2.41; P = 0.03) and stronger in those with advanced disease (411 cases and 877 controls; OR, 2.60; 95% CI, 1.56-4.34; P = 0.0002). These data suggest that African Americans harbor an allele at the POR locus that may increase breast cancer risk.

  View details for DOI 10.1158/0008-5472.CAN-06-4801

  View details for Web of Science ID 000245779600015

  View details for PubMedID 17440066

• Recent changes in breast cancer incidence and risk factor prevalence in San Francisco Bay area and California women: 1988 to 2004 BREAST CANCER RESEARCH Keegan, T. H., Chang, E. T., John, E. M., Horn-Ross, P. L., Wrensch, M. R., Glaser, S. L., Clarke, C. A. 2007; 9 (5)

  Abstract

  Historically, the incidence rate of breast cancer among non-Hispanic white women living in the San Francisco Bay area (SFBA) of California has been among the highest in the world. Substantial declines in breast cancer incidence rates have been documented in the United States and elsewhere during recent years. In light of these reports, we examined recent changes in breast cancer incidence and risk factor prevalence among non-Hispanic white women in the SFBA and other regions of California.Annual age-adjusted breast cancer incidence and mortality rates (1988 to 2004) were obtained from the California Cancer Registry and analyzed using Joinpoint regression. Population-based risk factor prevalences were calculated using two data sources: control subjects from four case-control studies (1989 to 1999) and the 2001 and 2003 California Health Interview Surveys.In the SFBA, incidence rates of invasive breast cancer increased 1.3% per year (95% confidence interval [CI], 0.7% to 2.0%) in 1988-1999 and decreased 3.6% per year (95% CI, 1.6% to 5.6%) in 1999-2004. In other regions of California, incidence rates of invasive breast cancer increased 0.8% per year (95% CI, 0.4% to 1.1%) in 1988-2001 and decreased 4.4% per year (95% CI, 1.4% to 7.3%) in 2001-2004. In both regions, recent (2000-2001 to 2003-2004) decreases in invasive breast cancer occurred only in women 40 years old or older and in women with all histologic subtypes and tumor sizes, hormone receptor-defined types, and all stages except distant disease. Mortality rates declined 2.2% per year (95% CI, 1.8% to 2.6%) from 1988 to 2004 in the SFBA and the rest of California. Use of estrogen-progestin hormone therapy decreased significantly from 2001 to 2003 in both regions. In 2003-2004, invasive breast cancer incidence remained higher (4.2%) in the SFBA than in the rest of California, consistent with the higher distributions of many established risk factors, including advanced education, nulliparity, late age at first birth, and alcohol consumption.Ongoing surveillance of breast cancer occurrence patterns in this high-risk population informs breast cancer etiology through comparison of trends with lower-risk populations and by highlighting the importance of examining how broad migration patterns influence the geographic distribution of risk factors.

  View details for DOI 10.1186/bcr1768

  View details for Web of Science ID 000253285800011

  View details for PubMedID 20210979

  View details for PubMedCentralID PMC2829782

• Multiple regions within 8q24 independently affect risk for prostate cancer Nat Genet Haiman CA, Patterson N, Freedman ML, Myers SR, Pike MC, Waliszewska A, Neubauer J, Tandon A, Schirmer C, McDonald GJ, Greenway SC, Stram DO, Le Marchand L, Kolonel LN, Frasco M, Wong D, Pooler LC, Ardlie K, Oakley-Girvan I, Whittemore AS, Cooney KA, John EM, Ingles SA, Altschuler D, Henderson BE, Reich D 2007; 39 (5): 638-44
• Medical radiation exposure and breast cancer risk: Findings from the Breast Cancer Family Registry. Int J Cancer John EM, Phipps AI, Knight JA, Milne RL, Dite GS, Hopper JL, Andrulis IL, Southey M, Giles GG, West DW, Whittemore AS 2007; 15 (121): 386-94
• BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays AMERICAN JOURNAL OF SURGICAL PATHOLOGY Bane, A. L., Beck, J. C., Bleiweiss, I., Buys, S. S., Catalano, E., Daly, M. B., Giles, G., Godwin, A. K., Hibshoosh, H., Hopper, J. L., John, E. M., Layfield, L., Longacre, T., Miron, A., Senie, R., Southey, M. C., West, D. W., Whittemore, A. S., Wu, H., Andrulis, I. L., O'Malley, F. P. 2007; 31 (1): 121-128

  Abstract

  A distinct morphologic and molecular phenotype has been reported for BRCA1-associated breast cancers; however, the phenotype of BRCA2-associated breast cancers is less certain. To comprehensively characterize BRCA2-associated breast cancers we performed a retrospective case control study using tumors accrued through the Breast Cancer Family Registry. We examined the tumor morphology and hormone receptor status in 157 hereditary breast cancers with germline mutations in BRCA2 and 314 control tumors negative for BRCA1 and BRCA2 mutations that were matched for age and ethnicity. Tissue microarrays were constructed from 64 BRCA2-associated and 185 control tumors. Tissue microarray sections were examined for HER2/neu protein overexpression, p53 status and the expression of basal markers, luminal markers, cyclin D1, bcl2, and MIB1 by immunohistochemistry. The majority of BRCA2-associated tumors and control tumors were invasive ductal, no special-type tumors. In contrast to control tumors, BRCA2-associated cancers were more likely to be high grade (P<0.0001) and to have pushing tumor margins (P=0.0005). Adjusting for grade, BRCA2-associated tumors were more often estrogen receptor positive (P=0.008) and exhibited a luminal phenotype (P=0.003). They were less likely than controls to express the basal cytokeratin CK5 (P=0.03) or to overexpress HER2/neu protein (P=0.06). There was no difference in p53, bcl2, MIB1, or cyclin D1 expression between BRCA2-associated and control tumors. We have demonstrated, in the largest series of BRCA2-associated breast cancers studied to date, that these tumors are predominantly high-grade invasive ductal carcinomas of no special type and they demonstrate a luminal phenotype despite their high histologic grade.

  View details for Web of Science ID 000243236000015

  View details for PubMedID 17197928

• Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T > G and c.1066-6T > G (IVS10-6T > G) from the breast cancer family registry HUMAN MUTATION Bernstein, J. L., Teraoka, S., Southey, M. C., Jenkins, M. A., Andrulis, I. L., Knight, J. A., John, E. M., Lapinski, R., Wolitzer, A. L., Whittemore, A. S., West, D., Seminara, D., Olson, E. R., Spurdle, A. B., Chenevix-Trench, G., Giles, G. G., Hopper, J. L., Concannon, P. 2006; 27 (11): 1122-1128

  Abstract

  The ATM gene variants segregating in ataxia-telangiectasia families are associated with increased breast cancer risk, but the contribution of specific variants has been difficult to estimate. Previous small studies suggested two functional variants, c.7271T>G and c.1066-6T>G (IVS10-6T>G), are associated with increased risk. Using population-based blood samples we found that 7 out of 3,743 breast cancer cases (0.2%) and 0 out of 1,268 controls were heterozygous for the c.7271T>G allele (P=0.1). In cases, this allele was more prevalent in women with an affected mother (odds ratio [OR]=5.5, 95% confidence interval [CI]=1.2-25.5; P=0.04) and delayed child-bearing (OR=5.1; 95% CI=1.0-25.6; P=0.05). The estimated cumulative breast cancer risk to age 70 years (penetrance) was 52% (95% CI=28-80%; hazard ratio [HR]=8.6; 95% CI=3.9-18.9; P<0.0001). In contrast, 13 of 3,757 breast cancer cases (0.3%) and 10 of 1,268 controls (0.8%) were heterozygous for the c.1066-6T>G allele (OR=0.4; 95% CI=0.2-1.0; P=0.05), and the penetrance was not increased (P=0.5). These findings suggest that although the more common c.1066-6T>G variant is not associated with breast cancer, the rare ATM c.7271T>G variant is associated with a substantially elevated risk. Since c.7271T>G is only one of many rare ATM variants predicted to have deleterious consequences on protein function, an effective means of identifying and grouping these variants is essential to assess the contribution of ATM variants to individual risk and to the incidence of breast cancer in the population.

  View details for DOI 10.1002/humu.20415

  View details for Web of Science ID 000241529500007

  View details for PubMedID 16958054

• BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50 CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Haile, R. W., Thomas, D. C., McGuire, V., Felberg, A., John, E. M., Milne, R. L., Hopper, J. L., Jenkins, M. A., Levine, A. J., Daly, M. M., Buys, S. S., Senie, R. T., Andrulis, I. L., Knight, J. A., Godwin, A. K., Southey, M., McCredie, M. R., Giles, G. G., Andrews, L., Tucker, K., Miron, A., Apicella, C., Tesoriero, A., Bane, A., Pike, M. C., Whittemore, A. S. 2006; 15 (10): 1863-1870

  Abstract

  Understanding the effect of oral contraceptives on risk of breast cancer in BRCA1 or BRCA2 mutation carriers is important because oral contraceptive use is a common, modifiable practice.We studied 497 BRCA1 and 307 BRCA2 mutation carriers, of whom 195 and 128, respectively, had been diagnosed with breast cancer. Case-control analyses were conducted using unconditional logistic regression with adjustments for family history and familial relationships and were restricted to subjects with a reference age under 50 years.For BRCA1 mutation carriers, there was no significant association between risk of breast cancer and use of oral contraceptives for at least 1 year [odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.53-1.12] or duration of oral contraceptive use (P(trend) = 0.62). For BRCA2 mutation carriers, there was no association with use of oral contraceptives for at least 1 year (OR, 1.62; 95% CI, 0.90-2.92); however, there was an association of elevated risk with oral contraceptive use for at least 5 years (OR, 2.06; 95% CI, 1.08-3.94) and with duration of use (OR(trend) per year of use, 1.08; P = 0.008). Similar results were obtained when we considered only use of oral contraceptives that first started in 1975 or later.We found no evidence overall that use of oral contraceptives for at least 1 year is associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers before age 50. For BRCA2 mutation carriers, use of oral contraceptives may be associated with an increased risk of breast cancer among women who use them for at least 5 years. Further studies reporting results separately for BRCA1 and BRCA2 mutation carriers are needed to resolve this important issue.

  View details for DOI 10.1158/1055-9965.EPI-06-0258

  View details for Web of Science ID 000241616800019

  View details for PubMedID 17021353

• Genetic ancestry and risk factors for breast cancer among Latinas in the San Francisco Bay Area CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ziv, E., John, E. M., Choudhry, S., Kho, J., Lorizio, W., Perez-Stable, E. J., Burchard, E. G. 2006; 15 (10): 1878-1885

  Abstract

  Genetic association studies using case-control designs are susceptible to false-positive and false-negative results if there are differences in genetic ancestry between cases and controls. We measured genetic ancestry among Latinas in a population-based case-control study of breast cancer and tested the association between ancestry and known breast cancer risk factors. We reasoned that if genetic ancestry is associated with known breast cancer risk factors, then the results of genetic association studies would be confounded.We used 44 ancestry informative markers to estimate individuals' genetic ancestry in 563 Latina participants. To test whether ancestry is a predictor of hormone therapy use, parity, and body mass index (BMI), we used multivariate logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (95% CI) associated with a 25% increase in Indigenous American ancestry, adjusting for age, education, and the participant's and grandparents' place of birth.Hormone therapy use was significantly less common among women with higher Indigenous American ancestry (OR, 0.78; 95% CI, 0.63-0.96). Higher Indigenous American ancestry was also significantly associated with overweight (BMI, 25-29.9 versus <25) and obesity (BMI, > or =30 versus <25), but only among foreign-born Latina women (OR, 3.44; 95% CI, 1.97-5.99 and OR, 1.95; 95% CI, 1.24-3.06, respectively).Some breast cancer risk factors are associated with genetic ancestry among Latinas in the San Francisco Bay Area. Therefore, case-control genetic association studies for breast cancer should directly measure genetic ancestry to avoid potential confounding.

  View details for DOI 10.1158/1055-9965.EPI-06-0092

  View details for Web of Science ID 000241616800021

  View details for PubMedID 17035394

• Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Freedman, M. L., Haiman, C. A., Patterson, N., McDonald, G. J., Tandon, A., Waliszewska, A., Penney, K., Steen, R. G., Ardlie, K., John, E. M., Clakley-Girvan, I., Whitternore, A. S., Cooney, K. A., Ingles, S. A., Altshuler, D., Henderson, B. E., Reich, D. 2006; 103 (38): 14068-14073

  Abstract

  A whole-genome admixture scan in 1,597 African Americans identified a 3.8 Mb interval on chromosome 8q24 as significantly associated with susceptibility to prostate cancer [logarithm of odds (LOD) = 7.1]. The increased risk because of inheriting African ancestry is greater in men diagnosed before 72 years of age (P < 0.00032) and may contribute to the epidemiological observation that the higher risk for prostate cancer in African Americans is greatest in younger men (and attenuates with older age). The same region was recently identified through linkage analysis of prostate cancer, followed by fine-mapping. We strongly replicated this association (P < 4.2 x 10(-9)) but find that the previously described alleles do not explain more than a fraction of the admixture signal. Thus, admixture mapping indicates a major, still-unidentified risk gene for prostate cancer at 8q24, motivating intense work to find it.

  View details for DOI 10.1073/pnas.0605832103

  View details for Web of Science ID 000240746600031

  View details for PubMedID 16945910

  View details for PubMedCentralID PMC1599913

• No increased risk of breast cancer associated with alcohol consumption among carriers of BRCA1 and BRCA2 mutations ages < 50 years CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION McGuire, V., John, E. M., Felberg, A., Haile, R. W., Boyd, N. F., Thomas, D. C., Jenkins, M. A., Milne, R. L., Daly, M. B., Ward, J., Terry, M. B., Andrulis, I. L., Knight, J. A., Godwin, A. K., Giles, G. G., Southey, M., West, D. W., Hopper, J. L., Whittemore, A. S. 2006; 15 (8): 1565-1567

  View details for DOI 10.1158/1055-9965.EPI-06-0323

  View details for PubMedID 16896052

• The role of self-defined race/ethnicity in population structure control ANNALS OF HUMAN GENETICS Liu, X., Paterson, A. D., John, E. M., Knight, J. A. 2006; 70: 496-505

  Abstract

  Population-based association studies are powerful tools for the genetic mapping of complex diseases. However, this method is sensitive to potential confounding by population structure. While statistical methods that use genetic markers to detect and control for population structure have been the focus of current literature, the utility of self-defined race/ethnicity in controlling for population structure has been controversial. In this study of 1334 individuals, who self-identified as either African American, European American or Hispanic, we demonstrated that when the true underlying genetic structure and the self-defined racial/ethnic groups were roughly in agreement with each other, the self-defined race/ethnicity information was useful in the control of population structure.

  View details for DOI 10.1111/j.1469-1809.2005.00255.x

  View details for Web of Science ID 000237811500006

  View details for PubMedID 16759181

• The CHEK2*1100de/C allelic variant and risk of breast cancer: Screening results from the breast cancer family registry CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Bernstein, J. L., Teraoka, S. N., John, E. M., Andrulis, I. L., Knight, J. A., Lapinski, R., Olson, E. R., Wolitzer, A. L., Seminara, D., Whittemore, A. S., Concannon, P. 2006; 15 (2): 348-352

  Abstract

  CHEK2, a serine-threonine kinase, is activated in response to agents, such as ionizing radiation, which induce DNA double-strand breaks. Activation of CHEK2 can result in cell cycle checkpoint arrest or apoptosis. One specific variant, CHEK2*1100delC, has been associated with an increased risk of breast cancer. In this population-based study, we screened 2,311 female breast cancer cases and 496 general population controls enrolled in the Ontario and Northern California Breast Cancer Family Registries for this variant (all controls were Canadian). Overall, 30 cases and one control carried the 1100delC allele. In Ontario, the weighted mutation carrier frequency among cases and controls was 1.34% and 0.20%, respectively [odds ratio (OR), 6.65; 95% confidence interval (95% CI), 2.37-18.68]. In California, the weighted population mutation carrier frequency in cases was 0.40%. Across all cases, 1 of 524 non-Caucasians (0.19%) and 29 of 1,775 Caucasians (1.63%) were mutation carriers (OR, 0.12; 95% CI, 0.02-0.89). Among Caucasian cases >45 years age at diagnosis, carrier status was associated with history of benign breast disease (OR, 3.18; 95% CI, 1.30-7.80) and exposure to diagnostic ionizing radiation (excluding mammography; OR, 3.21; 95% CI, 1.13-9.14); compared with women without exposure to ionizing radiation, the association was strongest among women exposed >15 years before diagnosis (OR, 4.28; 95% CI, 1.50-12.20) and among those who received two or more chest X-rays (OR, 3.63; 95% CI, 1.25-10.52). These data supporting the biological relevance of CHEK2 in breast carcinogenesis suggest that further studies examining the joint roles of CHEK2*1100delC carrier status and radiation exposure may be warranted.

  View details for DOI 10.1158/1055-9965.EPI-05-0557

  View details for Web of Science ID 000235587200024

  View details for PubMedID 16492927

• Breast and ovarian cancer in relatives of cancer patients, with and without BRCA mutations CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Lee, J. S., John, E. M., McGuire, V., Felberg, A., Ostrow, K. L., DiCioccio, R. A., Li, F. P., Miron, A., West, D. W., Whittemore, A. S. 2006; 15 (2): 359-363

  Abstract

  First-degree relatives of patients with breast or ovarian cancer have increased risks for these cancers. Little is known about how their risks vary with the patient's cancer site, carrier status for predisposing genetic mutations, or age at cancer diagnosis.We evaluated breast and ovarian cancer incidence in 2,935 female first-degree relatives of non-Hispanic White female patients with incident invasive cancers of the breast (n = 669) or ovary (n = 339) who were recruited from a population-based cancer registry in northern California. Breast cancer patients were tested for BRCA1 and BRCA2 mutations. Ovarian cancer patients were tested for BRCA1 mutations. We estimated standardized incidence ratios (SIR) and 95% confidence intervals (95% CI) for breast and ovarian cancer among the relatives according to the patient's mutation status, cancer site, and age at cancer diagnosis.In families of patients who were negative or untested for BRCA1 or BRCA2 mutations, risks were elevated only for the patient's cancer site. The breast cancer SIR was 1.5 (95% CI, 1.2-1.8) for relatives of breast cancer patients, compared with 1.1 (95% CI, 0.8-1.6) for relatives of ovarian cancer patients (P = 0.12 for difference by patient's cancer site). The ovarian cancer SIR was 0.9 (95% CI, 0.5-1.4) for relatives of breast cancer patients, compared with 1.9 (95% CI, 1.0-4.0) for relatives of ovarian cancer patients (P = 0.04 for difference by site). In families of BRCA1-positive patients, relatives' risks also correlated with the patient's cancer site. The breast cancer SIR was 10.6 (95% CI, 5.2-21.6) for relatives of breast cancer patients, compared with 3.3 (95% CI, 1.4-7.3) for relatives of ovarian cancer patients (two-sided P = 0.02 for difference by site). The ovarian cancer SIR was 7.9 (95% CI, 1.2-53.0) for relatives of breast cancer patients, compared with 11.3 (3.6-35.9) for relatives of ovarian cancer patients (two-sided P = 0.37 for difference by site). Relatives' risks were independent of patients' ages at diagnosis, with one exception: In families ascertained through a breast cancer patient without BRCA mutations, breast cancer risks were higher if the patient had been diagnosed before age 40 years.In families of patients with and without BRCA1 mutations, breast and ovarian cancer risks correlate with the patient's cancer site. Moreover, in families of breast cancer patients without BRCA mutations, breast cancer risk depends on the patient's age at diagnosis. These patterns support the presence of genes that modify risk specific to cancer site, in both carriers and noncarriers of BRCA1 and BRCA2 mutations.

  View details for DOI 10.1158/1055-9965.EPI-05-0687

  View details for PubMedID 16492929

• An inverse association between ovarian cysts and breast cancer in the Breast Cancer Family Registry INTERNATIONAL JOURNAL OF CANCER Knight, J. A., John, E. M., Milne, R. L., Dite, G. S., Balbuena, R., Shi, E. J., Giles, G. G., Ziogas, A., Andrulis, I. L., Whittemore, A. S., Hopper, J. L. 2006; 118 (1): 197-202

  Abstract

  Ovarian cysts of several types are common in women of reproductive age. Their etiology is not well understood but is likely related to perturbations in the hypothalamic-pituitary-gonadal axis. The relationship of ovarian cysts to breast cancer risk is not known, although a negative association with polycystic ovarian syndrome has been reported. Incident, invasive female breast cancer cases, population-based controls and unaffected sisters of cases were studied from 3 countries participating in the Breast Cancer Family Registry: Melbourne and Sydney, Australia; the San Francisco Bay Area, USA; and Ontario, Canada. Using the same questionnaire, information was collected on self-reported history of ovarian cysts and other risk factors. Analyses were based on 3,049 cases, 2,344 population controls and 1,934 sister controls from all sites combined. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using both unconditional and conditional logistic regression using an offset term to account for sampling fractions at 2 of the sites. A significantly reduced risk of breast cancer was observed for women reporting a history of ovarian cysts (OR = 0.70, 95% CI 0.59-0.82, among all cases and all controls). This risk estimate was similar regardless of control group used, within all 3 sites and in both premenopausal and postmenopausal women (ORs ranging from 0.68-0.75, all 95% CI excluded 1.00). A self-reported history of ovarian cysts was strongly and consistently associated with a reduced risk of breast cancer. Further study of ovarian cysts may increase our understanding of hormonal and other mechanisms of breast cancer etiology.

  View details for DOI 10.1002/ijc.21298

  View details for Web of Science ID 000233376000027

  View details for PubMedID 16032703

• The AIB1 polyglutamine repeat does not modify breast cancer risk in BRCA1 and BRCA2 mutation carriers CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Spurdle, A. B., Antoniou, A. C., Kelemen, L., Holland, H., Peock, S., Cook, M. R., Smith, P. L., Greene, M. H., Simard, J., Plourde, M., Southey, M. C., Godwin, A. K., Beck, J., Miron, A., Daly, M. B., Santella, R. M., Hopper, J. L., John, E. M., Andrulis, I. L., Durocher, F., Struewing, J. P., Easton, D. F., Chenevix-Trench, G. 2006; 15 (1): 76-79

  Abstract

  This is by far the largest study of its kind to date, and further suggests that AIB1 does not play a substantial role in modifying the phenotype of BRCA1 and BRCA2 carriers. The AIB1 gene encodes the AIB1/SRC-3 steroid hormone receptor coactivator, and amplification of the gene and/or protein occurs in breast and ovarian tumors. A CAG/CAA repeat length polymorphism encodes a stretch of 17 to 29 glutamines in the HR-interacting carboxyl-terminal region of the protein which is somatically unstable in tumor tissues and cell lines. There is conflicting evidence regarding the role of this polymorphism as a modifier of breast cancer risk in BRCA1 and BRCA2 carriers. To further evaluate the evidence for an association between AIB1 glutamine repeat length and breast cancer risk in BRCA1 and BRCA2 mutation carriers, we have genotyped this polymorphism in 1,090 BRCA1 and 661 BRCA2 mutation carriers from Australia, Europe, and North America. There was no evidence for an increased risk associated with AIB1 glutamine repeat length. Given the large sample size, with more than adequate power to detect previously reported effects, we conclude that the AIB1 glutamine repeat does not substantially modify risk of breast cancer in BRCA1 and BRCA2 mutation carriers.

  View details for DOI 10.1158/1055-9965.EPI-05-0709

  View details for Web of Science ID 000234866200015

  View details for PubMedID 16434590

• Migration history, acculturation, and breast cancer risk in Hispanic women CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION John, E. M., Phipps, A. I., Davis, A., Koo, J. 2005; 14 (12): 2905-2913

  Abstract

  Migrant studies have shown that breast cancer risk increases in women who move from countries with low incidence rates to countries with high rates. We examined the influence of migration history and acculturation on breast cancer risk in Hispanic women ages 35 to 79 years.In a population-based case-control study conducted in the San Francisco Bay Area, information on migration history, language usage, and other risk factors for breast cancer was collected through an in-person interview for 991 cases and 1,285 controls.Breast cancer risk was 50% lower in foreign-born Hispanics than U.S.-born Hispanics. Risk increased with increasing duration of residence in the United States, decreasing age at migration, and increasing acculturation. Among long-term foreign-born residents, risk was lower among Hispanics who moved to the United States at age > or =20 years and those who spoke mostly Spanish. The difference in risk between third-generation or higher-generation Hispanics and recent migrants from rural areas was approximately 6-fold in postmenopausal women and 4-fold in premenopausal women. Adjustment for differences in the distribution of breast cancer risk factors greatly attenuated the associations with migration patterns in premenopausal women; reduced risks remained only in those who resided in the United States for <10 years or migrated at age > or =30 years. In postmenopausal women, a 25% to 30% lower risk remained among long-term residents and those who migrated to the United States before age 20 years.These findings suggest the importance of yet unidentified protective factors among both recent premenopausal migrants and postmenopausal migrants.

  View details for DOI 10.1158/1055-9965.EPI-05-0483

  View details for Web of Science ID 000234055600014

  View details for PubMedID 16365008

• Androgen receptor and prostate-specific antigen gene polymorphisms and breast cancer in African-American women CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Wang, W., John, E. M., Ingles, S. A. 2005; 14 (12): 2990-2994

  Abstract

  Several previous studies have found the CAG repeat polymorphism in exon 1 of the androgen receptor (AR) gene to be associated with breast cancer risk among some groups of Caucasian and Asian women. In a population-based case-control study of 488 African-American women (239 cases and 249 controls), we examined this polymorphism along with a polymorphism (-158 G/A) in an androgen-regulated gene (PSA) whose expression has been correlated with breast cancer prognosis. Overall, we did not observe any significant association between the CAG repeat polymorphism and breast cancer risk. However, among women with a first-degree family history of breast cancer, longer CAG repeats were associated with a significantly increased risk. Women carrying at least one longer allele [(CAG)n > or = 22] had a 3-fold increased risk compared to those with two shorter alleles (odds ratio, 3.18; 95% confidence interval, 1.08-9.36). There was no significant association between the PSA gene polymorphism and breast cancer risk, nor was there significant gene-gene interaction. In summary, our results further support that shorter CAG repeats (stronger AR transactivation activity) may reduce the risk of breast cancer, at least among some groups of women. Our data, however, are unable to provide evidence that PSA is the pathway through which the protective effect of androgens operates.

  View details for DOI 10.1158/1055-9965.EPI-05-0310

  View details for Web of Science ID 000234055600029

  View details for PubMedID 16365023

• Obesity before age 30 years and risk of advanced prostate cancer AMERICAN JOURNAL OF EPIDEMIOLOGY Robinson, W. R., Stevens, J., Gammon, M. D., John, E. M. 2005; 161 (12): 1107-1114

  Abstract

  Adult obesity has shown little association with prostate cancer risk, but obesity at younger ages may be associated with reduced risk. In 1997-2000, the relation between obesity before age 30 years and incident advanced prostate cancer was investigated in a population-based case-control study of African-American and White men (568 cases, 544 controls) in California. Unconditional logistic regression was used to estimate odds ratios and 95% confidence intervals, adjusted for age, race, family history of prostate cancer, and saturated fat intake. Measures of obesity for age 10 years tended to be inversely associated with prostate cancer (odds ratio (OR) = 0.79, 95% confidence interval (CI): 0.46, 1.38 for selecting the "obese" pictogram and OR = 0.76, 95% CI: 0.52, 1.11 for reporting being heavier than peers). The decreased risk was more pronounced at ages 20-29 years (OR = 0.53, 95% CI: 0.28, 1.00 for the "obese" drawing, OR = 0.59, 95% CI: 0.40, 0.88 for being heavier than peers, and OR = 0.40, 95% CI: 0.20, 0.81 for body mass index > or =30 kg/m(2)). In addition, both "obese" and small waist size at ages 20-29 years showed inverse trends. This research implicating early-life body size in prostate cancer development helps to elucidate causal mechanisms, such as altered sex hormone profiles during critical developmental periods, potentially involved in development of the disease.

  View details for DOI 10.1093/aje/kwi150

  View details for Web of Science ID 000229700300003

  View details for PubMedID 15937019

• Sun exposure, vitamin D receptor gene polymorphisms, and risk of advanced prostate cancer CANCER RESEARCH John, E. M., Schwartz, G. G., Koo, J., Van Den Berg, D., Ingles, S. A. 2005; 65 (12): 5470-5479

  Abstract

  Substantial experimental evidence indicates that the hormonal form of vitamin D promotes the differentiation and inhibits the proliferation, invasiveness, and metastasis of human prostatic cancer cells. Results from epidemiologic studies of vitamin D status and/or vitamin D receptor (VDR) polymorphisms and prostate cancer risk have been mixed. We conducted a population-based, case-control study of advanced prostate cancer among men ages 40 to 79 years from the San Francisco Bay area. Interview data on lifetime sun exposure and other risk factors were collected for 905 non-Hispanic White men (450 cases and 455 controls). Using a reflectometer, we measured constitutive skin pigmentation on the upper underarm (a sun-protected site) and facultative pigmentation on the forehead (a sun-exposed site) and calculated a sun exposure index from these measurements. Biospecimens were collected for 426 cases and 440 controls. Genotyping was done for VDR polymorphisms in the 5' regulatory region (Cdx-2), exon 2 (FokI), and the 3' region (TaqI and BglI). Reduced risk of advanced prostate cancer was associated with high sun exposure determined by reflectometry [odds ratio (OR), 0.51; 95% confidence interval (95% CI), 0.33-0.80] and high occupational outdoor activity (OR, 0.73; 95% CI, 0.48-1.11). Significant risk reductions with the high-activity alleles FokI FF or Ff, TaqI tt, and BglI BB genotypes and a nonsignificant reduction with Cdx-2 AG or AA genotype were observed in the presence of high sun exposure, with ORs ranging from 0.46 to 0.67. Our findings support the hypothesis that sun exposure and VDR polymorphisms together play important roles in the etiology of prostate cancer.

  View details for Web of Science ID 000229734300064

  View details for PubMedID 15958597

• Oral contraceptive use and risk of early-onset breast cancer in carriers and noncarriers of BRCA1 and BRCA2 mutations CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Milne, R. L., Knight, J. A., John, E. M., Dite, G. S., Balbuena, R., Ziogas, A., Andrulis, I. L., West, D. W., Li, F. P., Southey, M. C., Giles, G. G., McCredie, M. R., Hopper, J. L., Whittemore, A. S. 2005; 14 (2): 350-356

  Abstract

  Recent oral contraceptive use has been associated with a small increase in breast cancer risk and a substantial decrease in ovarian cancer risk. The effects on risks for women with germ line mutations in BRCA1 or BRCA2 are unclear.Subjects were population-based samples of Caucasian women that comprised 1,156 incident cases of invasive breast cancer diagnosed before age 40 (including 47 BRCA1 and 36 BRCA2 mutation carriers) and 815 controls from the San Francisco Bay area, California, Ontario, Canada, and Melbourne and Sydney, Australia. Relative risks by carrier status were estimated using unconditional logistic regression, comparing oral contraceptive use in case groups defined by mutation status with that in controls.After adjustment for potential confounders, oral contraceptive use for at least 12 months was associated with decreased breast cancer risk for BRCA1 mutation carriers [odds ratio (OR), 0.22; 95% confidence interval (CI), 0.10-0.49; P < 0.001], but not for BRCA2 mutation carriers (OR, 1.02; 95% CI, 0.34-3.09) or noncarriers (OR, 0.93; 95% CI, 0.69-1.24). First use during or before 1975 was associated with increased risk for noncarriers (OR, 1.52 per year of use before 1976; 95% CI, 1.22-1.91; P < 0.001).There was no evidence that use of current low-dose oral contraceptive formulations increases risk of early-onset breast cancer for mutation carriers, and there may be a reduced risk for BRCA1 mutation carriers. Because current formulations of oral contraceptives may reduce, or at least not exacerbate, ovarian cancer risk for mutation carriers, they should not be contraindicated for a woman with a germ line mutation in BRCA1 or BRCA2.

  View details for Web of Science ID 000227113800010

  View details for PubMedID 15734957

• Prevalence of BRCA1 mutation carriers among US non-Hispanic Whites CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Whittemore, A. S., Gong, G., John, E. M., McGuire, V., Li, F. P., Ostrow, K. L., DiCioccio, R., Felberg, A., West, D. W. 2004; 13 (12): 2078-2083

  Abstract

  Data from several countries indicate that 1% to 2% of Ashkenazi Jews carry a pathogenic ancestral mutation of the tumor suppressor gene BRCA1. However, the prevalence of BRCA1 mutations among non-Ashkenazi Whites is uncertain. We estimated mutation carrier prevalence in U.S. non-Hispanic Whites, specific for Ashkenazi status, using data from two population-based series of San Francisco Bay Area patients with invasive cancers of the breast or ovary, and data on breast and ovarian cancer risks in Ashkenazi and non-Ashkenazi carriers. Assuming that 90% of the BRCA1 mutations were detected, we estimate a carrier prevalence of 0.24% (95% confidence interval, 0.15-0.39%) in non-Ashkenazi Whites, and 1.2% (95% confidence interval, 0.5-2.6%) in Ashkenazim. When combined with U.S. White census counts, these prevalence estimates suggest that approximately 550,513 U.S. Whites (506,206 non-Ashkenazim and 44,307 Ashkenazim) carry germ line BRCA1 mutations. These estimates may be useful in guiding resource allocation for genetic testing and genetic counseling and in planning preventive interventions.

  View details for PubMedID 15598764

• Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations BRITISH JOURNAL OF CANCER Whittemore, A. S., Balise, R. R., Pharoah, P. D., DiCioccio, R. A., Oakley-Girvan, I., Ramus, S. J., Daly, M., Usinowicz, M. B., Garlinghouse-Jones, K., Ponder, B. A., Buys, S., Senie, R., Andrulis, I., John, E., Hopper, J. L., Piver, M. S. 2004; 91 (11): 1911-1915

  Abstract

  Women with mutations of the genes BRCA1 or BRCA2 are at increased risk of ovarian cancer. Oral contraceptives protect against ovarian cancer in general, but it is not known whether they protect against the disease in carriers of these mutations. We obtained self-reported lifetime histories of oral contraceptive use from 451 women who carried mutations of BRCA1 or BRCA2. We used conditional logistic regression to estimate the odds ratios associated with oral contraceptive use, comparing the histories of 147 women with ovarian cancer (cases) to those of 304 women without ovarian cancer (controls) who were matched to cases on year of birth, country of residence and gene (BRCA1 vs BRCA2). Reference ages for controls had to exceed the ages at diagnosis of their matched cases. After adjusting for parity, the odds-ratio for ovarian cancer associated with use of oral contraceptives for at least 1 year was 0.85 (95 percent confidence interval, 0.53-1.36). The risk decreased by 5% (1-9%) with each year of use (P for trend=0.01). Use for 6 or more years was associated with an odds-ratio of 0.62 (0.35-1.09). These data support the hypothesis that long-term oral contraceptive use reduces the risk of ovarian cancer among women who carry mutations of BRCA1 or BRCA2.

  View details for DOI 10.1038/sj.bjc.6602239

  View details for PubMedID 15545966

• Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations AMERICAN JOURNAL OF EPIDEMIOLOGY McGuire, V., Felberg, A., Mills, M., Ostrow, K. L., DiCioccio, R., John, E. M., West, D. W., Whittemore, A. S. 2004; 160 (7): 613-618

  Abstract

  In the general population, ovarian cancer risk is inversely associated with oral contraceptive use, tubal ligation, and childbearing. Among carriers of BRCA1 gene mutations, the data are conflicting. The authors identified women diagnosed with incident invasive epithelial ovarian cancer in the San Francisco Bay Area of California from March 1997 through July 2001. They compared the contraceptive and reproductive histories of 36 carrier cases and 381 noncarrier cases with those of 568 controls identified by random digit dialing who were frequency matched to cases on age and race/ethnicity. In both carriers and noncarriers, reduced risk was associated with ever use of oral contraceptives (odds ratio = 0.54 (95% confidence interval (CI): 0.26, 1.13) for carriers and 0.55 (95% CI: 0.41, 0.73) for noncarriers), duration of oral contraceptive use (risk reduction per year = 13% (p = 0.01) for carriers and 6% (p < 0.001) for noncarriers), history of tubal ligation (odds ratio = 0.68 (95% CI: 0.25, 1.90) for carriers and 0.65 (95% CI: 0.45, 0.95) for noncarriers), and increasing parity (risk reduction per childbirth = 16% (p = 0.26) for carriers and 24% (p < 0.001) for noncarriers). These data suggest that BRCA1 mutation carriers and noncarriers have similar risk reductions associated with oral contraceptive use, tubal ligation, and parity.

  View details for PubMedID 15383404

• Residential sunlight exposure is associated with a decreased risk of prostate cancer JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY John, E. M., Dreon, D. M., Koo, J., Schwartz, G. G. 2004; 89-90 (1-5): 549-552

  Abstract

  The possibility that exposure to sunlight reduces the risk of clinical prostate cancer has been strongly suggested by ecologic data. However, data on prostate cancer risk in relation to sunlight exposure in individuals are sparse. We analyzed data from the First National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study in order to test the hypothesis that residential sunlight exposure reduces the risk of prostate cancer. We identified 153 men with incident prostate cancer from a cohort of 3414 white men who completed the baseline interview and dermatologic examination in 1971-1975 and were followed up to 1992. We used Cox proportional hazards modeling to estimate relative risks (RR) and 95% confidence intervals (CI) for measures of residential sunlight exposure, adjusting for age, family history of prostate cancer, and dietary intake of fat and calcium. Residence in the South at baseline (RR = 0.68, CI = 0.41-1.13), state of longest residence in the South (RR = 0.62, CI = 0.40-0.95), and high solar radiation in the state of birth (RR = 0.49, CI = 0.30-0.79) were associated with significant and substantial reductions in prostate cancer risk. These data support the hypothesis that sunlight exposure reduces the risk of prostate cancer and have important implications for prostate cancer prevention.

  View details for DOI 10.1016/j.jsbmb.2004.03.067

  View details for Web of Science ID 000222852500100

  View details for PubMedID 15225836

• The Breast Cancer Family Registry: an infrastructure for cooperative multinational, interdisciplinary and translational studies of the genetic epidemiology of breast cancer BREAST CANCER RESEARCH John, E. M., Hopper, J. L., Beck, J. C., Knight, J. A., Neuhausen, S. L., Senie, R. T., Ziogas, A., Andrulis, I. L., Anton-Culver, H., Boyd, N., Buys, S. S., Daly, M. B., O'Malley, F. P., Santella, R. M., Southey, M. C., Venne, V. L., Venter, D. J., West, D. W., Whittemore, A. S., Seminara, D. 2004; 6 (4): R375-R389

  Abstract

  The etiology of familial breast cancer is complex and involves genetic and environmental factors such as hormonal and lifestyle factors. Understanding familial aggregation is a key to understanding the causes of breast cancer and to facilitating the development of effective prevention and therapy. To address urgent research questions and to expedite the translation of research results to the clinical setting, the National Cancer Institute (USA) supported in 1995 the establishment of a novel research infrastructure, the Breast Cancer Family Registry, a collaboration of six academic and research institutions and their medical affiliates in the USA, Canada, and Australia.The sites have developed core family history and epidemiology questionnaires, data dictionaries, and common protocols for biospecimen collection and processing and pathology review. An Informatics Center has been established to collate, manage, and distribute core data.As of September 2003, 9116 population-based and 2834 clinic-based families have been enrolled, including 2346 families from minority populations. Epidemiology questionnaire data are available for 6779 affected probands (with a personal history of breast cancer), 4116 unaffected probands, and 16,526 relatives with or without a personal history of breast or ovarian cancer. The biospecimen repository contains blood or mouthwash samples for 6316 affected probands, 2966 unaffected probands, and 10,763 relatives, and tumor tissue samples for 4293 individuals.This resource is available to internal and external researchers for collaborative, interdisciplinary, and translational studies of the genetic epidemiology of breast cancer. Detailed information can be found at the URL http://www.cfr.epi.uci.edu/.

  View details for DOI 10.1186/bcr801

  View details for Web of Science ID 000222828200022

  View details for PubMedID 15217505

  View details for PubMedCentralID PMC468645

• Lifetime physical activity and breast cancer risk in a multiethnic population: The San Francisco Bay area breast cancer study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION John, E. M., Horn-Ross, P. L., Koo, J. 2003; 12 (11): 1143-1152

  Abstract

  Considerable epidemiological data have accumulated in support of a lower risk of breast cancer among physically active women. Few studies, however, have examined the relation with lifetime physical activity from all sources, and moderate activity in particular. We conducted a population-based case-control study of breast cancer in Latinas, African Americans, and whites aged 35-79 years to assess the association with lifetime histories of moderate and vigorous physical activity, including recreational activity, walking, bicycling, household and outdoor chores, and occupation. Patients diagnosed with invasive breast cancer between 1995 and 1998 were identified through the cancer registry in the San Francisco Bay area, and a random sample of women without breast cancer was identified through random-digit dialing. A structured questionnaire administered in-person was completed by 403 premenopausal cases and 483 controls and 847 postmenopausal cases and 1065 controls. Summing activities from all sources over an individual's lifetime, we found reduced breast cancer risk in both pre- and postmenopausal women with the highest versus lowest tertile of average lifetime activity (premenopausal: multivariate adjusted odds ratio = 0.74, 95% confidence interval = 0.52-1.05; postmenopausal: odds ratio = 0.81, 95% confidence interval = 0.64-1.02), with similar reductions in the three racial/ethnic groups. In premenopausal women, risk reductions were similar for different types of activities, whereas in postmenopausal women, they were limited to occupational activity. Considering the intensity of activities, risk reductions were similar for moderate and vigorous activities. Because few of the currently known risk factors for breast cancer are modifiable, these results underline the public health importance of promoting physically active lifestyles.

  View details for Web of Science ID 000187001700004

  View details for PubMedID 14652273

• Phytoestrogen intake and endometrial cancer risk JOURNAL OF THE NATIONAL CANCER INSTITUTE Horn-Ross, P. L., John, E. M., Canchola, A. J., Stewart, S. L., Lee, M. M. 2003; 95 (15): 1158-1164

  Abstract

  The development of endometrial cancer is largely related to prolonged exposure to unopposed estrogens. Phytoestrogens (i.e., weak estrogens found in plant foods) may have antiestrogenic effects. We evaluated the associations between dietary intake of seven specific compounds representing three classes of phytoestrogens (isoflavones, coumestans, and lignans) and the risk of endometrial cancer.In a case-control study from the greater San Francisco Bay Area, we collected dietary information from 500 African American, Latina, and white women aged 35-79 years who were diagnosed with endometrial cancer between 1996 and 1999 and from 470 age- and ethnicity-matched control women identified through random-digit dialing. Unconditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).Isoflavone (OR = 0.59, 95% CI = 0.37 to 0.93 for the highest versus lowest quartile of exposure) and lignan (OR = 0.68, 95% CI = 0.44 to 1.1) consumptions were inversely related to the risk of endometrial cancer. These associations were slightly stronger in postmenopausal women (OR = 0.44, 95% CI = 0.26 to 0.77 and OR = 0.57, 95% CI = 0.34 to 0.97 for isoflavones and lignans, respectively). Obese postmenopausal women consuming relatively low amounts of phytoestrogens had the highest risk of endometrial cancer (OR = 6.9, 95% CI = 3.3 to 14.5 compared with non-obese postmenopausal women consuming relatively high amounts of isoflavones); however, the interaction between obesity and phytoestrogen intake was not statistically significant.Some phytoestrogenic compounds, at the levels consumed in the typical American-style diet, are associated with reduced risk of endometrial cancer.

  View details for DOI 10.1093/jnci/djg015

  View details for Web of Science ID 000184710300011

  View details for PubMedID 12902445

• Segregation analysis of prostate cancer in 1719 white, African-American and Asian-American families in the United States and Canada CANCER CAUSES & CONTROL Gong, G., Oakley-Girvan, I., Wu, A. H., Kolonel, L. N., John, E. M., West, D. W., Felberg, A., Gallagher, R. P., Whittemore, A. S. 2002; 13 (5): 471-482

  Abstract

  Some data suggest that brothers of prostate cancer patients have higher disease risk than their fathers, supporting an X-linked or recessive mode of inheritance. However, higher observed frequencies in brothers than fathers may merely reflect the strong temporal changes in US incidence rates.(a) to evaluate the fit of X-linked, recessive, and dominant modes of inheritance to prostate cancer incidence, specific for calendar year, age, and race, in population-based samples of US and Canadian families; and (b) to evaluate a simple multifactorial model for familial aggregation of prostate cancer due to shared low-penetrance variants of many genes or shared lifestyle factors.The data consist of reported prostate cancer incidence in first-degree relatives of 1,719 white, African-American, and Asian-American men with and without prostate cancer at ages <70 years. Model parameters were estimated by maximizing a pseudo-likelihood function of the data, and goodness of model fit was assessed by evaluating discrepancies between observed and expected numbers of pairs of relatives with prostate cancer.After adjusting for temporal trends in prostate cancer incidence rates we found that the X-linked model fit poorly. underpredicting the observed number of affected father-son pairs. This also was true of the recessive model, although the evidence for poor fit did not achieve statistical significance. In contrast, the dominant model provided adequate fit to the data. In this model the race-specific penetrance estimates for carriers of deleterious genotypes were similar among African-Americans and whites, but lower among Asian-Americans: risk by age 80 years for carriers born in 1900 was estimated as 75.3% for African-Americans and whites, and 44.4% for Asian-Americans. None of the Mendelian models fit the data better than did the simple multifactorial model.The good fit of the multifactorial model suggests that multiple genes, each having low penetrance, may be responsible for most inherited prostate cancer susceptibility, and that the contribution of rare highly penetrant mutations is small.

  View details for PubMedID 12146852

• Phytoestrogen consumption and breast cancer risk in a multiethnic population - The Bay Area Breast Cancer Study AMERICAN JOURNAL OF EPIDEMIOLOGY Horn-Ross, P. L., John, E. M., Lee, M., Stewart, S. L., Koo, J., Sakoda, L. C., Shiau, A. G., Goldstein, J., Davis, P., Perez-Stable, E. J. 2001; 154 (5): 434-441

  Abstract

  Research on the relation between phytoestrogens and breast cancer risk has been limited in scope. Most epidemiologic studies have involved Asian women and have examined the effects of traditional soy foods (e.g., tofu), soy protein, or urinary excretion of phytoestrogens. The present study extends this research by examining the effects of a spectrum of phytoestrogenic compounds on breast cancer risk in non-Asian US women. African-American, Latina, and White women aged 35-79 years, who were diagnosed with breast cancer between 1995 and 1998, were compared with women selected from the general population via random digit dialing. Interviews were conducted with 1,326 cases and 1,657 controls. Usual intake of specific phytoestrogenic compounds was assessed via a food frequency questionnaire and a newly developed nutrient database. Phytoestrogen intake was not associated with breast cancer risk (odds ratio = 1.0, 95% confidence interval: 0.80, 1.3 for the highest vs. lowest quartile). Results were similar for pre- and postmenopausal women, for women in each ethnic group, and for all seven phytoestrogenic compounds studied. Phytoestrogens appear to have little effect on breast cancer risk at the levels commonly consumed by non-Asian US women: an average intake equivalent to less than one serving of tofu per week.

  View details for Web of Science ID 000171019700007

  View details for PubMedID 11532785

• Lifestyle determinants of 5 alpha-reductase metabolites in older African-American, white, and Asian-American men CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Wu, A. H., Whittemore, A. S., Kolonel, L. N., Stanczyk, F. Z., John, E. M., Gallagher, R. P., West, D. W. 2001; 10 (5): 533-538

  Abstract

  Men with higher endogenous 5alpha-reductase activity may have higher prostate cancer risk. This hypothesis raises two questions: (a) Could racial differences in 5alpha-reductase activity explain the observed racial differences in prostate cancer risk? and (b) Could a man reduce his activity level by modifying his lifestyle? To address these questions, we measured two hormonal indices of 5alpha-reductase activity [serum levels of androstane-3alpha-17beta-diol glucuronide (3alpha-diol G) and androsterone glucuronide (AG)] in healthy, older African-American, white, and Asian-American men, who are at high, intermediate, and low prostate cancer risk, respectively. We also examined associations between these metabolite levels and such lifestyle characteristics as body size and physical activity as well as select aspects of medical history and family history of prostate cancer. Men included in this cross-sectional analysis (n = 1054) had served as control subjects in a population-based case-control study of prostate cancer we conducted in California, Hawaii, and Vancouver, Canada and provided information on certain personal attributes and donated blood between March 1990 and March 1992. In this study, concentrations of 3alpha-diol G declined significantly with age and increased significantly with body mass index. Mean levels of 3alpha-diol G, adjusted for age and body mass index, were 6.1 ng/ml in African-Americans, 6.9 ng/ml in whites and 4.8 ng/ml in Asian-Americans. These differences were statistically significant (African-Americans versus whites: P < 0.01; whites versus Asian-Americans: P < 0.001). Concentrations of AG decreased significantly with age, but only in whites, and were unrelated to any of the reported personal attributes. Mean levels of AG, adjusted for age, were 44.1 ng/ml in African-Americans, 44.9 ng/ml in whites, and 37.5 ng/ml in Asian-Americans (Asian-Americans versus whites, P < 0.001). In conclusion, older African-American and white men have similar levels of these two indices of 5alpha-reductase activity, and these levels are higher than those of older Asian-American men. This difference may be related to the lower prostate cancer risk in Asian-Americans.

  View details for Web of Science ID 000168737800016

  View details for PubMedID 11352865

• Successful transformation of cryopreserved lymphocytes: A resource for epidemiological studies CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Beck, J. C., Beiswanger, C. M., John, E. M., Satariano, E., West, D. 2001; 10 (5): 551-554

  View details for Web of Science ID 000168737800018

  View details for PubMedID 11352867

• Vegetables, fruits, legumes and prostate cancer: A multiethnic case-control study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Kolonel, L. N., Hankin, J. H., Whittemore, A. S., Wu, A. H., Gallagher, R. P., Wilkens, L. R., John, E. M., Howe, G. R., Dreon, D. M., West, D. W., Paffenbarger, R. S. 2000; 9 (8): 795-804

  Abstract

  The evidence for a protective effect of vegetables, fruits, and legumes against prostate cancer is weak and inconsistent. We examined the relationship of these food groups and their constituent foods to prostate cancer risk in a multicenter case-control study of African-American, white, Japanese, and Chinese men. Cases (n = 1619) with histologically confirmed prostate cancer were identified through the population-based tumor registries of Hawaii, San Francisco, and Los Angeles in the United States and British Columbia and Ontario in Canada. Controls (n = 1618) were frequency-matched to cases on ethnicity, age, and region of residence of the case, in a ratio of approximately 1:1. Dietary and other information was collected by in-person home interview; a blood sample was obtained from control subjects for prostate-specific antigen determination. Odds ratios (OR) were estimated using logistic regression, adjusting for age, geographic location, education, calories, and when indicated, ethnicity. Intake of legumes (whether total legumes, soyfoods specifically, or other legumes) was inversely related to prostate cancer (OR for highest relative to lowest quintile for total legumes = 0.62; P for trend = 0.0002); results were similar when restricted to prostate-specific antigen-normal controls or to advanced cases. Intakes of yellow-orange and cruciferous vegetables were also inversely related to prostate cancer, especially for advanced cases, among whom the highest quintile OR for yellow-orange vegetables = 0.67 (P for trend = 0.01) and the highest quintile OR for cruciferous vegetables = 0.61 (P for trend = 0.006). Intake of tomatoes and of fruits was not related to risk. Findings were generally consistent across ethnic groups. These results suggest that legumes (not limited to soy products) and certain categories of vegetables may protect against prostate cancer.

  View details for Web of Science ID 000088719500005

  View details for PubMedID 10952096

• Assessing phytoestrogen exposure in epidemiologic studies: development of a database (United States) CANCER CAUSES & CONTROL Horn-Ross, P. L., Barnes, S., Lee, M., Coward, L., Mandel, J. E., Koo, J., John, E. M., Smith, M. 2000; 11 (4): 289-298

  Abstract

  Phytoestrogens (weak estrogens found in plants or derived from plant precursors by human metabolism) have been hypothesized to reduce the risk of a number of cancers. However, epidemiologic studies addressing this issue are hampered by the lack of a comprehensive phytoestrogen database for quantifying exposure. The purpose of this research was to develop such a database for use with food-frequency questionnaires in large epidemiologic studies.The database is based on consumption patterns derived from semistructured interviews with 118 African-American, Latina, and white women residing in California's San Francisco Bay Area. HPLC-mass spectrometry was used to determine the content of seven specific phytoestrogenic compounds (i.e. the isoflavones: genistein, daidzein, biochanin A, and formononetin; the coumestan: coumestrol; and the plant lignans: matairesinol and secoisolariciresinol) in each of 112 food items/groups.Traditional soy-based foods were found to contain high levels of genistein and daidzein, as expected, as well as substantial amounts of coumestrol. A wide variety of "hidden" sources of soy (that is, soy protein isolate, soy concentrate, or soy flour added to foods) was observed. Several other foods (such as various types of sprouts and dried fruits, garbanzo beans, asparagus, garlic, and licorice) were also found to be substantial contributors of one or more of the phytoestrogens analyzed.Databases, such as the one described here, are important in assessing the relationship between phytoestrogen exposure and cancer risk in epidemiologic studies. Agencies, such as the United States Department of Agriculture (USDA), that routinely provide data on food composition, on which epidemiologic investigations into dietary health effects are based, should consider instituting programs for the analysis of phytochemicals, including the phytoestrogens.

  View details for Web of Science ID 000087586700001

  View details for PubMedID 10843440

• Sources of phytoestrogen exposure among non-Asian women in California, USA CANCER CAUSES & CONTROL Horn-Ross, P. L., Lee, M., John, E. M., Koo, J. 2000; 11 (4): 299-302

  Abstract

  We recently described the development of a comprehensive database for assessing phytoestrogen exposure in epidemiologic studies. This paper describes the first application of this database and the primary sources of phytoestrogen consumption in non-Asian women.Four hundred and forty-seven randomly selected African-American, Latina, and white women, ages 50-79 years, residing in California's San Francisco Bay Area and participating as controls in an ongoing population-based case-control study of breast cancer, were included in the present analysis. Average daily consumption of each of seven phytoestrogenic compounds was determined for each woman by combining the values from the new database with food consumption reported on a food-frequency questionnaire.Phytoestrogens in the non-Asian Bay Area diet appear to come primarily from: (1) traditional soy-based foods (e.g. tofu and soy milk); (2) "hidden" sources of soy (e.g. foods containing added soy protein isolate, soy concentrate, or soy flour, e.g. many brands of doughnuts and white bread); and (3) a variety of foods which contain only low to moderate amounts of phytoestrogens per 100 grams but which are frequently consumed (e.g. coffee and orange juice).In the absence of a comprehensive assessment of various phytoestrogens in a wide variety of foods, epidemiologic studies could suffer from the effects of uncontrolled confounding by unmeasured sources of phytoestrogen exposure potentially leading to biased estimates of effect and misinterpretation of findings.

  View details for Web of Science ID 000087586700002

  View details for PubMedID 10843441

• Vitamin D and breast cancer risk: The NHANES I Epidemiologic Follow-up Study, 1971-1975 to 1992 CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION John, E. M., Schwartz, G. G., Dreon, D. M., Koo, J. 1999; 8 (5): 399-406

  Abstract

  We analyzed data from the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study to test the hypothesis that vitamin D from sunlight exposure, diet, and supplements reduces the risk of breast cancer. We identified 190 women with incident breast cancer from a cohort of 5009 white women who completed the dermatological examination and 24-h dietary recall conducted from 1971-1974 and who were followed up to 1992. Using Cox proportional hazards regression, we estimated relative risks (RRs) for breast cancer and 95% confidence intervals, adjusting for age, education, age at menarche, age at menopause, body mass index, alcohol consumption, and physical activity. Several measures of sunlight exposure and dietary vitamin D intake were associated with reduced risk of breast cancer, with RRs ranging from 0.67-0.85. The associations with vitamin D exposures, however, varied by region of residence. The risk reductions were highest for women who lived in United States regions of high solar radiation, with RRs ranging from 0.35-0.75. No reductions in risk were found for women who lived in regions of low solar radiation. Although limited by the relatively small size of the case population, the protective effects of vitamin D observed in this prospective study are consistent for several independent measures of vitamin D. These data support the hypothesis that sunlight and dietary vitamin D reduce the risk of breast cancer.

  View details for Web of Science ID 000080300400001

  View details for PubMedID 10350434

• Recreational and occupational physical activities and risk of breast cancer JOURNAL OF THE NATIONAL CANCER INSTITUTE Gammon, M. D., John, M., Britton, J. A. 1998; 90 (2): 100-117

  Abstract

  Physical activity has been hypothesized to reduce breast cancer risk, but an inverse association has not been consistently reported. In this review, we critically evaluate for coherence, validity, and bias the epidemiologic studies on recreational or occupational physical activity, discuss the biologic plausibility of the association, and identify areas for future research. Results from seven of nine studies suggest that higher levels of occupational physical activity may be associated with a reduction in risk, at least among a subgroup of women. Eleven of 16 investigations on recreational exercise reported a 12%-60% decrease in risk among premenopausal and postmenopausal women, although a dose-response trend was not evident in most of the studies. The reduction in risk associated with exercise was more likely to be observed in case-control studies than in cohort studies. Most investigations incompletely assessed physical activity, which contributed to conflicting findings on the optimal time period, duration, frequency, or intensity of activity to minimize risk. Physical activity may exert its effects through changes in menstrual characteristics, reduced body size, or alterations in immune function. In summary, most epidemiologic studies of physical activity reported a reduction in the risk of breast cancer among physically active women. Future research studies should focus on using a cohort design to rule out recall bias as a possible explanation for the decrease in risk associated with exercise, on improving assessment of lifetime physical activity from all sources to clarify whether there is a dose-response relation or an optimal time period, duration, frequency, or intensity of activity, and on elucidating the underlying mechanisms for the inverse association.

  View details for Web of Science ID 000165537400009

  View details for PubMedID 9450570

• Serum levels of prostate-specific antigen among Japanese-American and native Japanese men JOURNAL OF THE NATIONAL CANCER INSTITUTE Shibata, A., Whittemore, A. S., Imai, K., Kolonel, L. N., Wu, A. H., John, E. H., Stamey, T. A., Paffenbarger, R. S. 1997; 89 (22): 1716-1720

  Abstract

  Fourfold to sixfold higher prostate cancer rates in Japanese-American men in the United States compared with Japanese men in Japan have been cited to support a role for environmental risk factors in the etiology of the disease. To examine the hypothesis that part or all of the elevated prostate cancer rates in Japanese-American men may reflect more intensive prostate cancer screening in the United States than in Japan, we compared prostate-specific antigen (PSA) levels in community-based samples of serum from men without prostate cancer.Japanese-American men aged 40-85 years and native Japanese men aged 40-89 years with no history of prostate cancer provided sera, respectively, in the United States from March 1990 through March 1992 (n = 237) or in Japan from January 1992 through December 1993 (n = 3522). Age-specific PSA levels were used to estimate the prevalences of undetected prostate cancer in the two populations.Age-specific mean PSA levels were significantly lower in Japanese-Americans than in native Japanese (two-sided P<.001). The prevalence of an elevated PSA level increased with age in both populations and exceeded 5% among men aged 60 years or more. Combined with data on prevalence of detected prostate cancer in the two populations, our data suggest that some 10.0% of Japanese-Americans aged 75 years have prostate cancer, with 31% of that fraction remaining undiagnosed. The corresponding estimates in Japan are a total cancer prevalence of 5.4%, of which 81% has not been detected clinically.The total cancer prevalence ratio 10.0/5.4 = 1.9 (95% confidence interval = 1.5-2.3) in Japanese-American men compared with Japanese men in Japan suggests an increased risk for Japanese-American men, but of less magnitude than the fourfold to sixfold increase indicated by the incidence data.

  View details for PubMedID 9390541

• SERUM ANDROGENS AND SEX HORMONE-BINDING GLOBULINS IN RELATION TO LIFE-STYLE FACTORS IN OLDER AFRICAN-AMERICAN, WHITE, AND ASIAN MEN IN THE UNITED-STATES AND CANADA CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Wu, A. H., Whittemore, A. S., Kolonel, L. N., John, E. M., Gallagher, R. P., West, D. W., Hankin, J., Teh, C. Z., Dreon, D. M., Paffenbarger, R. S. 1995; 4 (7): 735-741

  Abstract

  Differences in endogenous androgen levels have been hypothesized to explain ethnic differences in prostate cancer risk. To examine this hypothesis, we gathered data on serum concentrations of androgens and sex hormone-binding globulin (SHBG) in healthy older men from four ethnic groups at different levels of prostate cancer risk. As part of a population-based case-control study of prostate cancer we conducted in California, Hawaii, and Vancouver, Canada, 1127 African-American, white, Chinese-American, and Japanese-American control men, mostly ages 60 years or older (mean age, 69.9 years) provided information on various lifestyle factors and donated an early morning fasting blood sample between March 1990 and March 1992. We used these data to examine the distributions of serum androgens [testosterone (total, free, and bioavailable), dihydrotestosterone (DHT)], the ratio of DHT to total testosterone (DHT:testosterone ratio), and SHBG in these four ethnic groups. We also assessed correlations between concentrations of these measures with age, body size, physical activity, and other personal characteristics, and we evaluated ethnic differences in concentrations of androgens and SHBG after adjusting for these characteristics. In each of the four ethnic groups, concentrations of free and bioavailable testosterone declined with age, whereas SHBG concentrations increased with age. Age-adjusted concentrations of all androgen measures and SHBG decreased with increasing levels of Quetelet's index. After adjustment for age and Quetelet's index, androgens and SHBG showed no clear and consistent relationships to physical activity, alcohol consumption, or tobacco use. DHT:testosterone ratio was higher in men reporting a history of benign prostate disease than in men without such a history, and higher in vasectomized men than in nonvasectomized men. SHBG concentrations were higher in men reporting one or more first-degree relatives with prostate cancer than in men without such a family history. After adjustment for age and Quetelet's index, the levels of total and bioavailable testosterone were highest in Asian-Americans, intermediate in African-Americans, and lowest in whites. However, the DHT:testosterone ratio was highest in African-Americans, intermediate in whites, and lowest in Asian-Americans, corresponding to the respective incidence rates in these groups and providing indirect evidence for ethnic differences in 5alpha-reductase enzyme activity.

  View details for Web of Science ID A1995RZ11000007

  View details for PubMedID 8672990

• PROSTATE-CANCER IN RELATION TO DIET, PHYSICAL-ACTIVITY, AND BODY-SIZE IN BLACKS, WHITES, AND ASIANS IN THE UNITED-STATES AND CANADA JOURNAL OF THE NATIONAL CANCER INSTITUTE Whittemore, A. S., Kolonel, L. N., Wu, A. H., John, E. M., Gallagher, R. P., Howe, G. R., Burch, J. D., Hankin, J., Dreon, D. M., West, D. W., Teh, C. Z., Paffenbarger, R. S. 1995; 87 (9): 652-661

  Abstract

  International and interethnic differences in prostate cancer incidence suggest an environmental, potentially modifiable etiology for the disease.We conducted a population-based case-control study of prostate cancer among blacks (very high risk), whites (high risk), and Asian-Americans (low risk) in Los Angeles, San Francisco, Hawaii, Vancouver, and Toronto. Our aim was to evaluate the roles of diet, physical activity patterns, body size, and migration characteristics on risk in these ethnic groups and to assess how much of the interethnic differences in risk might be attributed to interethnic differences in such lifestyle characteristics.We used a common protocol and questionnaire to administer personal interviews to 1655 black, white, Chinese-American, and Japanese-American case patients diagnosed during 1987-1991 with histologically confirmed prostate carcinoma and to 1645 population-based control subjects matched to case patients by age, ethnicity, and region of residence. Sera collected from 1127 control subjects were analyzed for levels of prostate-specific antigen (PSA) to permit comparison of case patients with control subjects lacking serological evidence of prostate disease. Odds ratios were estimated using conditional logistic regression. We estimated the proportion of prostate cancer attributable to certain risk factors and the proportion of interethnic risk differences attributable to interethnic differences in risk-factor prevalence.A positive statistically significant association of prostate cancer risk and total fat intake was found for all ethnic groups combined. This association was attributable to energy from saturated fats; after adjusting for saturated fat, risk was associated only weakly with monounsaturated fat and was unrelated to protein, carbohydrate, polyunsaturated fat, and total food energy. Saturated fat intake was associated with higher risks for Asian-Americans than for blacks and whites. In all ethnic groups combined, the risk tended to be higher when only case patients with advanced disease were compared with control subjects with normal PSA levels. Among foreign-born Asian-Americans, risk increased independently with years of residence in North America and with saturated fat intake. Crude estimates suggest that differences in saturated fat intake account for about 10% of black-white differences and about 15% of white-Asian-American differences in prostate cancer incidence. Risk was not consistently associated with intake of any micronutrients, body mass, or physical activity patterns.These data support a causal role in prostate cancer for saturated fat intake but suggest that other factors are largely responsible for interethnic differences in risk.

  View details for PubMedID 7752270

• VASECTOMY AND PROSTATE-CANCER - RESULTS FROM A MULTIETHNIC CASE-CONTROL STUDY JOURNAL OF THE NATIONAL CANCER INSTITUTE John, E. M., Whittemore, A. S., Wu, A. H., Kolonel, L. N., Hislop, T. G., Howe, G. R., West, D. W., Hankin, J., Dreon, D. M., Teh, C. Z., Burch, J. D., PAFFENBARGER, S. 1995; 87 (9): 662-669

  Abstract

  Vasectomy, a widely used form of contraception, has been associated in some studies with increased prostate cancer risk.We assessed this association on the basis of data collected in a large multiethnic case-control study of prostate cancer that was conducted in the United States (Los Angeles, San Francisco, and Hawaii) and Canada (Toronto and Vancouver).In home interviews conducted with newly diagnosed prostate cancer case patients and population control subjects, we obtained information on the participants' medical history, including a history of vasectomy and the age at which the procedure was performed, as well as other potential risk factors. Blood samples were collected from control subjects only and were assayed for concentration of sex hormones and sex hormone-binding globulin.The present analysis was based on 1642 prostate cancer patients and 1636 control subjects. A history of vasectomy was not significantly associated with prostate cancer risk among all racial/ethnic groups combined (odds ratio [OR] = 1.1; 95% confidence interval [CI] = 0.83-1.3), whites (OR = 0.94; 95% CI = 0.69-1.3), blacks (OR = 1.0; 95% CI = 0.59-1.8), or Chinese-Americans (OR = 0.96; 95% CI = 0.42-2.2). Among Japanese-Americans, the OR was 1.8 (95% CI = 0.97-3.4), but the statistically nonsignificant elevation in risk was limited to more educated men and those with localized cancers. ORs did not vary significantly by age at vasectomy or years since vasectomy. We found a lower serum concentration of sex hormone-binding globulin and a higher ratio of dihydrotestosterone to testosterone among vasectomized control subjects than among nonvasectomized control subjects.The findings of this study do not support previous reports of increased prostate cancer risk associated with vasectomy. However, the altered endocrine profiles of vasectomized control subjects seen in this cross-sectional comparison warrant further evaluation in longitudinal studies.

  View details for PubMedID 7538594

• FAMILY HISTORY AND PROSTATE-CANCER RISK IN BLACK, WHITE, AND ASIAN MEN IN THE UNITED-STATES AND CANADA AMERICAN JOURNAL OF EPIDEMIOLOGY Whittemore, A. S., Wu, A. H., Kolonel, L. N., John, E. M., Gallagher, R. P., Howe, G. R., West, D. W., Teh, C. Z., Stamey, T. 1995; 141 (8): 732-740

  Abstract

  Increased risk of prostate cancer in men with a family history of the disease has been observed consistently in epidemiologic studies. However, most studies have been confined to white men; little is known about familial aggregation of prostate cancer in populations with unusually high incidence, such as African Americans, or in populations with low incidence, such as Asian-Americans. The authors report results from a population-based case-control study of prostate cancer among blacks, whites, and Asian-Americans in the United States and Canada. Controls were matched to cases on age (5-year groups), ethnicity (black, white, Chinese-American, Japanese-American), and region of residence (Los Angeles, San Francisco, Hawaii, Vancouver, Toronto). In the combined group of participants, 5% of controls and 13% of cases reported a father, brother, or son with prostate cancer. These prevalences were somewhat lower among Asian-Americans than among blacks or whites. A positive family history was associated with a statistically significant two- to threefold increase in risk in each of the three ethnic groups. The overall odds ratio associated with such a family history, adjusted for age and ethnicity, was 2.5 (95% confidence interval 1.9-3.3). This odds ratio varied by neither ethnicity nor age of the participants. Sera from 1,087 controls were used to examine the relations between family history and serum concentrations of androgens and prostate-specific antigen. The concentrations of sex hormone-binding globulin were slightly higher in men with than without a positive family history. Prostate-specific antigen concentrations were unrelated to family history.

  View details for PubMedID 7535977

• Effect of a monetary incentive on response to a mail survey. Annals of epidemiology John, E. M., Savitz, D. A. 1994; 4 (3): 231-235

  Abstract

  We assessed the effect of a $1 incentive on response to a two-page questionnaire which was sent to 8356 female cosmetologists between 22 and 36 years old. The study population was randomly assigned to one of three groups in which a $1 incentive was enclosed with either the first or second mailing, or with none of the mailings. Ten percent of questionnaires were returned by the postal service because of an incorrect address or death of the addressee and were omitted from response calculations. Of the remaining questionnaires, 79% were completed and returned after up to three mailings. The cumulative response was highest among cosmetologists who received a $1 incentive with the first mailing, (81%; 95% confidence interval (CI), 80 to 82), intermediate among those who received $1 with the second mailing (78%, 95% CI, 77 to 79), and lowest among cosmetologists who received no incentive (74%; 95% CI, 70 to 78). Characteristics of cosmetologists who responded after having received a "41 incentive were similar to those who responded without having received an incentive. The higher costs per response incurred by the use of an incentive must be weighed against the benefit of higher response.

  View details for PubMedID 8055124

• SPONTANEOUS-ABORTIONS AMONG COSMETOLOGISTS EPIDEMIOLOGY John, E. M., Savitz, D. A., Shy, C. M. 1994; 5 (2): 147-155

  Abstract

  To examine the relation between adverse pregnancy outcomes and work in cosmetology during pregnancy, we conducted a mail survey in North Carolina among 8,356 licensed female cosmetologists 22-36 years of age. We identified pregnancies between 1983 and 1988 by a brief screening questionnaire, followed by a more detailed mail questionnaire. Seventy-four per cent of eligible cosmetologists responded to each inquiry. We restricted the main analysis to 96 cosmetologists with a spontaneous abortion and 547 cosmetologists with a single livebirth who worked full-time in cosmetology or in other jobs during the first trimester of pregnancy. With adjusted odds ratios ranging from 1.4 to 2.0, we found associations between spontaneous abortion and the number of hours worked per day in cosmetology, the number of chemical services performed per week, the use of formaldehyde-based disinfectants, and work in salons where nail sculpturing was performed by other employees. We found no important associations among full-time cosmetologists who performed few chemical services and among cosmetologists who worked less than 35 hours per week.

  View details for Web of Science ID A1994MZ61300004

  View details for PubMedID 8172989

• LACTATION AND THE RISK OF BREAST-CANCER NEW ENGLAND JOURNAL OF MEDICINE Kelsey, J. L., John, E. M. 1994; 330 (2): 136-137

  View details for Web of Science ID A1994MQ67000010

  View details for PubMedID 8259169

• CHARACTERISTICS RELATING TO OVARIAN-CANCER RISK - COLLABORATIVE ANALYSIS OF 7 UNITED-STATES CASE-CONTROL STUDIES - EPITHELIAL OVARIAN-CANCER IN BLACK-WOMEN JOURNAL OF THE NATIONAL CANCER INSTITUTE John, E. M., Whittemore, A. S., Harris, R., ITNYRE, J. 1993; 85 (2): 142-147

  Abstract

  Previous epidemiologic studies of ovarian cancer have focused chiefly on White women, who have a higher incidence of ovarian cancer than Black women. No study has previously examined risk factors for ovarian cancer among Black women.This study was designed to evaluate the risk of epithelial ovarian cancer in Black women in relation to reproductive characteristics such as pregnancy, oral contraceptive use, and breast-feeding, and to determine whether differences in reproductive factors between Black and White women account for differences in ovarian cancer incidence.Combining interview data from seven case-control studies, we compared reproductive characteristics of 110 Black case subjects with a diagnosis of epithelial ovarian cancer between 1971 and 1986 with characteristics of 251 Black population control subjects and 114 Black hospital control subjects. We also compared the prevalence of reproductive factors in 246 Black population control subjects and 4378 White population control subjects and estimated the fraction of Black-White differences in ovarian cancer incidence attributable to racial differences in prevalence of these characteristics.Decreased risks of epithelial ovarian cancer in Black women were associated with parity of four or higher (odds ratio [OR] = 0.53; 95% confidence interval [CI] = 0.25-1.1), breast-feeding for 6 months or longer (OR = 0.85; 95% CI = 0.36-2.0), and use of oral contraceptives for 6 years or longer (OR = 0.62; 95% CI = 0.24-1.6). A greater proportion of Black women (48%) than White women (27%) reported four or more term pregnancies, and Black women (62%) were more likely than White women (53%) to have breast-fed their children. Oral contraceptive use was more common among White women (59%) than Black women (51%).Differences in the prevalence of other factors related to ovarian cancer risk or differences in genetic susceptibility must explain most of the Black-White differences in incidence of ovarian cancer.

  View details for PubMedID 8418303

• USE OF NHANES DATA TO ASSIGN NUTRIENT DENSITIES TO FOOD GROUPS IN A MULTIETHNIC DIET HISTORY QUESTIONNAIRE NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL Dreon, D. M., John, E. M., DICICCIO, Y., Whittemore, A. S. 1993; 20 (3): 223-230

  Abstract

  In epidemiological studies of diet and chronic disease, a brief yet comprehensive diet history questionnaire must aggregate some foods into food groups. A nutrient density is assigned to each food group by averaging the densities of its constituent foods. A person's intake of a given nutrient is then estimated by multiplying the reported consumption of each food group by its average nutrient density and summing over food groups. These calculations could introduce bias in multiethnic studies, if the average nutrient densities assigned to food groups are inappropriate for some ethnic populations. This issue is examined here for intakes of total fat, saturated fat, and vitamin A for U.S. blacks and whites. We used 24-hour diet recall data from the Second National Health and Nutrition Examination Survey (NHANES II) to assess black-white differences in relative frequency of consumption of foods within food groups of a diet history questionnaire. We also calculated ethnic-specific average nutrient densities for each food group by weighting the densities of its foods in proportion to their frequency of consumption by black and white NHANES II participants. We found black-white differences in the frequency of consumption of foods within 14 food groups. However, blacks and whites had different average total fat densities for only 1 of the 14 food groups, no difference in saturated fat densities for any food group, and different vitamin A densities for 2 food groups. Among blacks and whites, there is no advantage to calculating ethnic-specific average nutrient densities for food groups comprised of foods with similar densities.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for PubMedID 8108272

• REPRODUCTIVE FACTORS AND BREAST-CANCER EPIDEMIOLOGIC REVIEWS Kelsey, J. L., Gammon, M. D., John, E. M. 1993; 15 (1): 36-47

  View details for PubMedID 8405211

• RECENT ETIOLOGIC HYPOTHESES CONCERNING BREAST-CANCER EPIDEMIOLOGIC REVIEWS Gammon, M. D., John, E. M. 1993; 15 (1): 163-168

  Abstract

  A few studies have noted moderate elevation in the risk of breast cancer among women with residential exposure to electromagnetic fields, among women without a history of much strenuous physical activity, and among women with in utero exposures that may indicate high levels of maternal estrogen. The relative risk for each of these associations has generally been less than 2, with little adjustment for possible confounding factors. Also, several studies have not been able to confirm these relations. Currently there is scant or no evidence that silicone breast implants or psychological factors increase the risk of breast cancer. Despite the limited number of studies, the inconsistent results, and the difficulty of measuring several of these exposures, the plausible biologic mechanisms for each indicate that more research on these hypotheses is warranted.

  View details for Web of Science ID A1993LV35100015

  View details for PubMedID 8405199

• RADIATION AND OTHER ENVIRONMENTAL EXPOSURES AND BREAST-CANCER EPIDEMIOLOGIC REVIEWS John, E. M., Kelsey, J. L. 1993; 15 (1): 157-162

  View details for PubMedID 8405198

• ASSOCIATION OF PATERNAL ALCOHOL-USE WITH GESTATIONAL-AGE AND BIRTH-WEIGHT TERATOLOGY Savitz, D. A., Zhang, J., Schwingl, P., John, E. M. 1992; 46 (5): 465-471

  Abstract

  Paternal alcohol use has been associated with a number of adverse reproductive outcomes in laboratory animals and there is one epidemiologic report of a detrimental effect on infant birth weight. To expand the epidemiologic evidence, data from the Child Health and Development Studies were analyzed. Data collected from the onset of prenatal care in 10,232 women enrolled in the Kaiser Foundation Health Plan and residing in the San Francisco East Bay area between June 1959 and September 1966 were available, including information on the mother's report of paternal alcohol consumption and a number of potential confounders. Pregnancy outcomes included preterm delivery (< 37 weeks completed gestation), moderately low birth weight (1,501-2,500 g), very low birth weight (< or = 1,500 g), small-for-gestational-age (< 10th percentile of weight for gestational age), and mean birth weight. Paternal alcohol use, analyzed in intervals from 0 to 2.0 or more drinks per day, showed no association with any of the outcomes of interest. Adjusted prevalence odds ratios ranged from 0.7 to 1.5, with no indication of a monotonic dose-response gradient. Mean birth weight was also virtually unrelated to paternal alcohol use. Compared with the earlier report, this population had a very modest level of alcohol consumption. Nonetheless, within the range that was studied there appears to be no association between paternal alcohol use and birth outcome.

  View details for Web of Science ID A1992JV80300009

  View details for PubMedID 1462251

• USE OF A JOB-EXPOSURE MATRIX TO EVALUATE PARENTAL OCCUPATION AND CHILDHOOD-CANCER CANCER CAUSES & CONTROL FEINGOLD, L., Savitz, D. A., John, E. M. 1992; 3 (2): 161-169

  Abstract

  We examined the association between parental occupation and childhood cancer among 252 incident cases of childhood cancer (ages 0-14, diagnosed 1976-83) and 222 controls selected by random digit dialing in Denver, Colorado (USA). A job-exposure matrix was used to assign parental exposures based on job titles, emphasizing chemicals that were implicated in previous studies. All cancers, acute lymphocytic leukemia (ALL), and brain cancer were examined in relation to parental occupation during the year prior to the birth of the child. Elevated odds ratios (OR), all with confidence intervals extending below the null, were found for maternal exposure to benzene (OR = 1.9), petroleum/coke pitch/tar (OR = 2.2), and soot (OR = 3.3) in relation to total cancers. The ORs for total cancer and paternal exposure to all hydrocarbons combined was 1.0. Results for individual hydrocarbons and ALL showed larger odds ratios, including aniline (OR = 2.1), benzene (OR = 1.6), and petroleum/coke pitch/tar (OR = 1.6). Potential exposure to creosote was strongly associated with brain cancer (OR = 3.7) based on five exposed cases (95 percent confidence interval = 0.8-16.6). Control for other potential childhood cancer risk factors did not alter the results substantially. In spite of uncertainties due to small numbers and errors in exposure classification, results tend to corroborate past research that suggests an association between specific parental occupational exposures and childhood cancer.

  View details for Web of Science ID A1992HJ57100007

  View details for PubMedID 1562706

• PRENATAL EXPOSURE TO PARENTS SMOKING AND CHILDHOOD-CANCER AMERICAN JOURNAL OF EPIDEMIOLOGY John, E. M., Savitz, D. A., Sandler, D. P. 1991; 133 (2): 123-132

  Abstract

  The relation between parents' tobacco smoking prior to birth and cancer in the offspring was investigated with the use of data from a case-control study. Incident cases included all children (aged 0-14 years) diagnosed in Denver, Colorado from 1976 to 1983. Controls were selected through random digit dialing, and matched to cases on age, sex, and geographic area. Information on smoking by parents and other household members was obtained by personal interview for 223 cases and 196 controls. After adjustment for father's education, mother's smoking during the first trimester of pregnancy was associated with an increased risk for all cancers combined (odds ratio (OR) = 1.3, 95% confidence interval (CI) 0.7-2.1), acute lymphocytic leukemia (OR = 1.9, 95% CI 0.9-4.1), and lymphomas (OR = 2.3, 95% CI 0.8-7.1). Adjusting for father's education, associations with father's smoking in the absence of mother's smoking were found for all cancers combined (OR = 1.2, 95% CI 0.8-2.1), acute lymphocytic leukemia (OR = 1.4, 95% CI 0.6-3.1), lymphomas (OR = 1.6, 95% 0.5-5.4), and brain cancer (OR = 1.6, 95% CI 0.7-3.5). In spite of imprecision resulting from small numbers of cases in diagnostic subgroups, these results are suggestive of a possible influence of parents' smoking on childhood cancer.

  View details for Web of Science ID A1991ET75500004

  View details for PubMedID 1822074

• MAGNETIC-FIELD EXPOSURE FROM ELECTRIC APPLIANCES AND CHILDHOOD-CANCER AMERICAN JOURNAL OF EPIDEMIOLOGY Savitz, D. A., John, E. M., Kleckner, R. C. 1990; 131 (5): 763-773

  Abstract

  The effect on childhood cancer of prolonged exposure to 60-H magnetic fields from electric appliances was examined using interview data from a recently completed case-control study. Exposures of children aged 0-14 years whose incident cancers were diagnosed between 1976 and 1983 and who resided in the Denver, Colorado, Standard Metropolitan Statistical Area were compared with those of controls selected by random digit dialing, matched on age, sex, and telephone exchange area. Parents of 252 cases and 222 controls were interviewed at home about the use of electric appliances by the mother during pregnancy (prenatal exposure) and by the child (postnatal exposure). After adjustment for income, prenatal electric blanket exposure was associated with a small increase in the incidence of childhood cancers (odds ratio (OR) = 1.3, 95% confidence interval (CI) 0.7-2.2) that was more pronounced for leukemia (OR = 1.7, 95% CI 0.8-3.6) and brain cancer (OR = 2.5, 95% CI 1.1-5.5). Postnatal exposure to electric blankets was also weakly associated with childhood cancer (OR = 1.5, 95% CI 0.6-3.4), with a larger but imprecise association with acute lymphocytic leukemia (OR = 1.9, 95% CI 0.6-6.5). Water beds and bedside electric clocks were unrelated to childhood cancer incidence. Results are limited by nonresponse and imprecision resulting from the rarity of appliance use, especially for subgroups of cases. Nonetheless, electric blankets, one of the principal sources of prolonged magnetic field exposure, were weakly associated with childhood cancer and warrant a more thorough evaluation.

  View details for Web of Science ID A1990CY88600003

  View details for PubMedID 2321620

• CASE-CONTROL STUDY OF CHILDHOOD-CANCER AND EXPOSURE TO 60-HZ MAGNETIC-FIELDS AMERICAN JOURNAL OF EPIDEMIOLOGY Savitz, D. A., Wachtel, H., Barnes, F. A., John, E. M., TVRDIK, J. G. 1988; 128 (1): 21-38

  Abstract

  Concern with health effects of extremely low frequency magnetic fields has been raised by epidemiologic studies of childhood cancer in relation to proximity to electric power distribution lines. This case-control study was designed to assess the relation between residential exposure to magnetic fields and the development of childhood cancer. Eligible cases consisted of all 356 residents of the five-county 1970 Denver, Colorado Standard Metropolitan Statistical Area aged 0-14 years who were diagnosed with any form of cancer between 1976 and 1983. Controls were selected by random digit dialing to approximate the case distribution by age, sex, and telephone exchange area. Exposure was characterized through in-home electric and magnetic field measurements under low and high power use conditions and wire configuration codes, a surrogate measure of long-term magnetic field levels. Measured magnetic fields under low power use conditions had a modest association with cancer incidence; a cutoff score of 2.0 milligauss resulted in an odds ratio of 1.4 (95% confidence interval (CI) = 0.6-2.9) for total cancers and somewhat larger odds ratios (ORs) for leukemias (OR = 1.9), lymphomas (OR = 2.2), and soft tissue sarcomas (OR = 3.3). Neither magnetic fields (OR = 1.0) nor electric fields (OR = 0.9) under high power use conditions were related to total cancers. Wire codes associated with higher magnetic fields were more common among case than control homes. The odds ratio to contrast very high and high to very low, low, and buried wire codes was 1.5 (95% CI = 1.0-2.3) for total cases, with consistency across cancer subgroups except for brain cancer (OR = 2.0) and lymphomas (OR = 0.8). Contrasts of very high to buried wire code homes produced larger, less precise odds ratios of 2.3 for total cases, 2.9 for leukemias, and 3.3 for lymphomas. Adjusted estimates for measured fields and wire codes did not differ from crude results, indicating an absence of confounding. Limitations to the study are nonresponse (especially for field measurements), differential mobility of cases and controls, and a presumably nondifferential exposure misclassification from the use of imperfect surrogates for long-term magnetic field exposure history. In spite of these concerns, the results encourage further examination of the carcinogenic potential from this form of nonionizing radiation.

  View details for Web of Science ID A1988P034600003

  View details for PubMedID 3164167

• Physicians' attitude to after-hours callers: A five year study in a university-based family practice center Int J Fam Pract John EM, Curtis P 1988; 5: 168-73
• Geographic variation in the onset of decline of ischemic heart disease mortality in the United States. Am J Public Health Wing S, Hayes C, Heiss G, John E, Knowles M, Riggan W, Tyroler HA. 1986; 76 (12): 1404-8