Esther M. John

All Publications

• Evaluation of multiple breast cancer polygenic risk score panels in women of Latin American heritage. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Huang, X., Lott, P. C., Hu, D., Zavala, V. A., Jamal, Z. N., Vidaurre, T., Casavilca-Zambrano, S., Navarro Vásquez, J., Castañeda, C. A., Valencia, G., Morante, Z., Calderón, M., Abugattas, J. E., Fuentes, H. A., Liendo-Picoaga, R., Cotrina, J. M., Neciosup, S. P., Rioja Viera, P., Salinas, L. A., Galvez-Nino, M., Huntsman, S., Sanchez, S. E., Williams, M. A., Gelaye, B., Estrada-Florez, A. P., Polanco-Echeverry, G., Echeverry, M., Velez, A., Carmona-Valencia, J. A., Bohorquez-Lozano, M. E., Torres, J., Cruz, M., Ho, W. K., Teo, S. H., Tai, M. C., John, E. M., Haiman, C. A., Conti, D. V., Chen, F., Torres-Mejía, G., Kushi, L. H., Neuhausen, S. L., Ziv, E., Carvajal-Carmona, L. G., Fejerman, L. 2024

  Abstract

  A substantial portion of the genetic predisposition for breast cancer is explained by multiple common genetic variants of relatively small effect. A subset of these variants, which have been identified mostly in individuals of European and Asian ancestry, have been combined to construct a polygenic risk score (PRS) to predict breast cancer risk, but the prediction accuracy of existing PRSs in Hispanic/Latinx individuals (H/L) remain relatively low. We assessed the performance of several existing PRS panels with and without addition of H/L specific variants among self-reported H/L women.PRS performance was evaluated using multivariable logistic regression and the area under the receiver operating characteristic curve (AUC).Both European and Asian PRSs performed worse in H/L samples compared to original reports. The best European PRS performed better than the best Asian PRS in pooled H/L samples. European PRSs had decreased performance with increasing Indigenous American (IA) ancestry while Asian PRSs had increased performance with increasing IA ancestry. The addition of 2 H/L SNPs increased performance for all PRSs, most notably in the samples with high IA ancestry and did not impact the performance of PRSs in individuals with lower IA ancestry.A single PRS that incorporates risk variants relevant to the multiple ancestral components of individuals from Latin America, instead of a set of ancestry specific panels, could be used in clinical practice.Results highlight the importance of population-specific discovery and suggest a straightforward approach to integrate ancestry specific variants into PRS for clinical application.

  View details for DOI 10.1158/1055-9965.EPI-24-1247

  View details for PubMedID 39625644

• Pathogenic variants in cancer susceptibility genes predispose to Ductal Carcinoma In situ of the breast. Clinical cancer research : an official journal of the American Association for Cancer Research Huang, H., Couch, R. E., Karam, R., Hu, C., Boddicker, N., Polley, E. C., Na, J., Ambrosone, C. B., Yao, S., Trentham-Dietz, A., Eliassen, A. H., Penney, K., Brantley, K., Bodelon, C., Teras, L. R., Hodge, J., Patel, A., Haiman, C. A., John, E. M., Neuhausen, S. L., Martinez, E., Lacey, J. V., O'Brien, K. M., Sandler, D. P., Weinberg, C. R., Palmer, J. R., Bertrand, K. A., Vachon, C. M., Olson, J. E., Ruddy, K. E., Anton-Culver, H., Ziogas, A., Goldgar, D. E., Nathanson, K. L., Domchek, S. M., Weitzel, J. N., Kraft, P., Dolinsky, J. S., Pesaran, T., Richardson, M. E., Yadav, S., Couch, F. J. 2024

  Abstract

  To determine the relationship between germline pathogenic variants (PVs) in cancer predisposition genes and the risk of ductal carcinoma in situ (DCIS).Germline PV frequencies in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, PALB2, RAD51C, and RAD51D) were compared between DCIS cases and unaffected controls, and between DCIS and infiltrating ductal carcinoma (IDC) cases from a clinical-testing cohort (n=9,887), a population-based cohort (n=3,876) and the UK Biobank (n=2421). The risk of contralateral breast cancer for DCIS cases with PVs was estimated in the population-based cohort.Germline PVs were observed in 6.5% and 4.6% of women with DCIS in the clinical-testing and population-based cohorts, respectively. BRCA1, BRCA2, and PALB2 PVs frequencies were significantly lower among women with DCIS than IDC (clinical cohort: 2.8% vs. 5.7%; population-based cohort: 1.7% vs. 3.7%), whereas the PV frequencies for ATM and CHEK2 were similar. ATM, BRCA1, BRCA2, CHEK2, and PALB2 PVs were significantly associated with an increased risk of DCIS (OR>2.0), but only BRCA2 PVs were associated with high-risk (OR>4) in both cohorts. The cumulative incidence of contralateral breast cancer among carriers of PVs in high penetrance genes with DCIS was 23% over 15 years.The enrichment of PVs in ATM, BRCA1, BRCA2, CHEK2 and PALB2 among women with DCIS suggests that multigene panel testing may be appropriate for women with DCIS. Elevated risks of contralateral breast cancer in carriers of PVs in high penetrance genes with DCIS confirmed the utility of testing for surgical decision-making.

  View details for DOI 10.1158/1078-0432.CCR-24-1884

  View details for PubMedID 39513960

• A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer. Nature communications Srinivasan, S., Kryza, T., Bock, N., Tse, B. W., Sokolowski, K. A., Janaththani, P., Fernando, A., Moya, L., Stephens, C., Dong, Y., Röhl, J., Alinezhad, S., Vela, I., Perry-Keene, J. L., Buzacott, K., Nica, R., Gago-Dominguez, M., Schleutker, J., Maier, C., Muir, K., Tangen, C. M., Gronberg, H., Pashayan, N., Albanes, D., Wolk, A., Stanford, J. L., Berndt, S. I., Mucci, L. A., Koutros, S., Cussenot, O., Sorensen, K. D., Grindedal, E. M., Travis, R. C., Haiman, C. A., MacInnis, R. J., Vega, A., Wiklund, F., Neal, D. E., Kogevinas, M., Penney, K. L., Nordestgaard, B. G., Brenner, H., John, E. M., Gamulin, M., Claessens, F., Melander, O., Dahlin, A., Stattin, P., Hallmans, G., Häggström, C., Johansson, R., Thysell, E., Rönn, A. C., Li, W., Brown, N., Dimeski, G., Shepherd, B., Dadaev, T., Brook, M. N., Spurdle, A. B., Stenman, U. H., Koistinen, H., Kote-Jarai, Z., Klein, R. J., Lilja, H., Ecker, R. C., Eeles, R., Clements, J., Batra, J. 2024; 15 (1): 9587

  Abstract

  Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility in men. The non-synonymous KLK3 single nucleotide polymorphism (SNP), rs17632542 (c.536 T > C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity mediates prostate cancer pathogenesis. The 'Thr' PSA variant leads to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displays higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterisation of this PSA variant demonstrates markedly reduced proteolytic activity that correlates with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele have reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.

  View details for DOI 10.1038/s41467-024-52472-6

  View details for PubMedID 39505858

  View details for PubMedCentralID 10894656

• Trends in Hepatocellular Carcinoma Mortality Rates in the US and Projections Through 2040. JAMA network open Qiu, S., Cai, J., Yang, Z., He, X., Xing, Z., Zu, J., Xie, E., Henry, L., Chong, C. R., John, E. M., Cheung, R., Ji, F., Nguyen, M. H. 2024; 7 (11): e2445525

  Abstract

  Importance: The burden of liver cancer varies worldwide. An upward trend in both hepatocellular carcinoma (HCC) incidence and mortality in the past 2 decades has been observed.Objective: To assess observed HCC-related age-standardized mortality rates (ASMRs) in the US for 2006 to 2022 and provide ASMR projections through 2040.Design, Setting, and Participants: This cross-sectional study used data from the National Vital Statistics System, which is accessible through the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research website. Data on deaths attributed to HCC (from January 1, 2006, to December 31, 2022) were obtained for adults 25 years or older and were stratified by liver disease etiology, age, sex, and race and ethnicity. Etiologies included alcohol-associated liver disease (ALD), hepatitis B virus (HBV), hepatitis C virus (HCV), and metabolic dysfunction-associated steatotic liver disease (MASLD).Main Outcomes and Measures: The main outcomes were (1) observed ASMRs of HCC per 100 000 persons using Joinpoint regression (National Cancer Institute) to assess trends during 2006 to 2022 and (2) ASMRs projected for 2023 to 2040 using Prophet and AutoARIMA modeling.Results: This study included 188 280 HCC-related deaths from 2006 to 2022. Most deaths occurred among males (77.4%). The annual percentage change was 4.1% (95% CI, 2.2% to 7.7%) for 2006 to 2009 and decreased to 1.8% (95% CI, 0.7% to 2.0%) for 2009 to 2022, with an overall observed ASMR of 5.03 per 100 000 persons in 2022 and a projected ASMR of 6.39 per 100 000 persons by 2040, with consistent trends for both sexes. By etiology, ASMRs decreased for HCV- and HBV-related mortality but increased for ALD- and MASLD-related mortality. In 2022, MASLD surpassed HBV as the third-leading cause of HCC-related death and was projected to overtake HCV in 2032 as the second-leading cause; ALD was projected to be the leading cause of HCC-related death in 2026. In 2022, the ASMR was higher among individuals aged 65 years or older compared with those aged 25 to 64 years (18.37 vs 1.79 per 100 000 persons). The American Indian or Alaska Native population had the largest increase in projected ASMR by 2040 (14.71 per 100 000 persons) compared with the Asian population (3.03 per 100 000 persons).Conclusions and Relevance: In this cross-sectional study, ASMRs for ALD- and MASLD-related HCC death increased rapidly from 2006 to 2022; ALD-related HCC was projected to be the leading cause by 2026, with MASLD as the second-leading cause by 2032. These findings may serve as a reference for public health decision-making and timely identification of groups at high risk of HCC death.

  View details for DOI 10.1001/jamanetworkopen.2024.45525

  View details for PubMedID 39556395

• 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

• Risk of Subsequent Melanoma in Patients with Primary Cutaneous or Ocular Melanoma in the United States between 2000-2020: A Surveillance, Epidemiology, and End Results (SEER) Analysis Chang, M., Cai, Z. R., Mruthyunjaya, P., Swetter, S. M., John, E. M., Linos, E. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2024

  View details for Web of Science ID 001312227706200

• 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

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• 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

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• 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

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• 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.,