Alice S Whittemore

All Publications

• p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study. The journal of pathology. Clinical research Köbel, M., Kang, E. Y., Weir, A., Rambau, P. F., Lee, C. H., Nelson, G. S., Ghatage, P., Meagher, N. S., Riggan, M. J., Alsop, J., Anglesio, M. S., Beckmann, M. W., Bisinotto, C., Boisen, M., Boros, J., Brand, A. H., Brooks-Wilson, A., Carney, M. E., Coulson, P., Courtney-Brooks, M., Cushing-Haugen, K. L., Cybulski, C., Deen, S., El-Bahrawy, M. A., Elishaev, E., Erber, R., Fereday, S., Fischer, A., Gayther, S. A., Barquin-Garcia, A., Gentry-Maharaj, A., Gilks, C. B., Gronwald, H., Grube, M., Harnett, P. R., Harris, H. R., Hartkopf, A. D., Hartmann, A., Hein, A., Hendley, J., Hernandez, B. Y., Huang, Y., Jakubowska, A., Jimenez-Linan, M., Jones, M. E., Kennedy, C. J., Kluz, T., Koziak, J. M., Lesnock, J., Lester, J., Lubiński, J., Longacre, T. A., Lycke, M., Mateoiu, C., McCauley, B. M., McGuire, V., Ney, B., Olawaiye, A., Orsulic, S., Osorio, A., Paz-Ares, L., Ramón Y Cajal, T., Rothstein, J. H., Ruebner, M., Schoemaker, M. J., Shah, M., Sharma, R., Sherman, M. E., Shvetsov, Y. B., Singh, N., Steed, H., Storr, S. J., Talhouk, A., Traficante, N., Wang, C., Whittemore, A. S., Widschwendter, M., Wilkens, L. R., Winham, S. J., Benitez, J., Berchuck, A., Bowtell, D. D., Candido Dos Reis, F. J., Campbell, I., Cook, L. S., DeFazio, A., Doherty, J. A., Fasching, P. A., Fortner, R. T., García, M. J., Goodman, M. T., Goode, E. L., Gronwald, J., Huntsman, D. G., Karlan, B. Y., Kelemen, L. E., Kommoss, S., Le, N. D., Martin, S. G., Menon, U., Modugno, F., Pharoah, P. D., Schildkraut, J. M., Sieh, W., Staebler, A., Sundfeldt, K., Swerdlow, A. J., Ramus, S. J., Brenton, J. D. 2023

  Abstract

  Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

  View details for DOI 10.1002/cjp2.311

  View details for PubMedID 36948887

• Lifetime ovulatory years and risk of epithelial ovarian cancer: a multinational pooled analysis. Journal of the National Cancer Institute Fu, Z., Brooks, M. M., Irvin, S., Jordan, S., Aben, K. K., Anton-Culver, H., Bandera, E. V., Beckmann, M. W., Berchuck, A., Brooks-Wilson, A., Chang-Claude, J., Cook, L. S., Cramer, D. W., Cushing-Haugen, K. L., Doherty, J. A., Ekici, A. B., Fasching, P. A., Fortner, R. T., Gayther, S. A., Gentry-Maharaj, A., Giles, G. G., Goode, E. L., Goodman, M. T., Harris, H. R., Hein, A., Kaaks, R., Kiemeney, L. A., Köbel, M., Kotsopoulos, J., Kotsopoulos, J., Le, N. D., Lee, A. W., Matsuo, K., McGuire, V., McLaughlin, J. R., Menon, U., Milne, R. L., Moysich, K. B., Pearce, C. L., Pike, M. C., Qin, B., Ramus, S. J., Riggan, M. J., Rothstein, J. H., Schildkraut, J. M., Sieh, W., Sutphen, R., Terry, K. L., Thompson, P. J., Titus, L., van Altena, A. M., White, E., Whittemore, A. S., Wu, A. H., Zheng, W., Ziogas, A., Taylor, S. E., Tang, L., Songer, T., Wentzensen, N., Webb, P. M., Risch, H. A., Modugno, F. 2023

  Abstract

  The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive (OC) use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC.LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26,204 controls and 21,267 cases from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models to expected estimates assuming one year of ovulation suppression has the same effect regardless of source.LOY was associated with increased EOC risk (ORs per year increase: 1.014 (95%CI 1.009-1.020) to 1.044 (95%CI 1.041-1.048)). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for OC use and pregnancies were 4.45 times and 12-15 fold greater than expected, respectively. LOY was associated with high-grade serous (HGSOC), low-grade serous (LGSOC), endometrioid, and clear cell histotypes (ORs per year increase: 1.054, 1.040, 1.065, and 1.098, respectively), but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for HGSOC but larger than expected for LGSOC, endometrioid, and clear cell histotypes.LOY is positively associated with non-mucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC.

  View details for DOI 10.1093/jnci/djad011

  View details for PubMedID 36688720

• MiXcan: a framework for cell-type-aware transcriptome-wide association studies with an application to breast cancer. Nature communications Song, X., Ji, J., Rothstein, J. H., Alexeeff, S. E., Sakoda, L. C., Sistig, A., Achacoso, N., Jorgenson, E., Whittemore, A. S., Klein, R. J., Habel, L. A., Wang, P., Sieh, W. 2023; 14 (1): 377

  Abstract

  Human bulk tissue samples comprise multiple cell types with diverse roles in disease etiology. Conventional transcriptome-wide association study approaches predict genetically regulated gene expression at the tissue level, without considering cell-type heterogeneity, and test associations of predicted tissue-level expression with disease. Here we develop MiXcan, a cell-type-aware transcriptome-wide association study approach that predicts cell-type-level expression, identifies disease-associated genes via combination of cell-type-level association signals for multiple cell types, and provides insight into the disease-critical cell type. As a proof of concept, we conducted cell-type-aware analyses of breast cancer in 58,648 women and identified 12 transcriptome-wide significant genes using MiXcan compared with only eight genes using conventional approaches. Importantly, MiXcan identified genes with distinct associations in mammary epithelial versus stromal cells, including three new breast cancer susceptibility genes. These findings demonstrate that cell-type-aware transcriptome-wide analyses can reveal new insights into the genetic and cellular etiology of breast cancer and other diseases.

  View details for DOI 10.1038/s41467-023-35888-4

  View details for PubMedID 36690614

• Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci. Journal of the National Cancer Institute DeVries, A. A., Dennis, J., Tyrer, J. P., Peng, P., Coetzee, S. G., Reyes, A. L., Plummer, J. T., Davis, B. D., Chen, S. S., Dezem, F. S., Aben, K. K., Anton-Culver, H., Antonenkova, N. N., Beckmann, M. W., Beeghly-Fadiel, A., Berchuck, A., Bogdanova, N. V., Bogdanova-Markov, N., Brenton, J. D., Butzow, R., Campbell, I., Chang-Claude, J., Chenevix-Trench, G., Cook, L. S., DeFazio, A., Doherty, J. A., Dork, T., Eccles, D. M., Eliassen, A. H., Fasching, P. A., Fortner, R. T., Giles, G. G., Goode, E. L., Goodman, M. T., Gronwald, J., OPAL Study Group, AOCS Group, Hakansson, N., Hildebrandt, M. A., Huff, C., Huntsman, D. G., Jensen, A., Kar, S., Karlan, B. Y., Khusnutdinova, E. K., Kiemeney, L. A., Kjaer, S. K., Kupryjanczyk, J., Labrie, M., Lambrechts, D., Le, N. D., Lubinski, J., May, T., Menon, U., Milne, R. L., Modugno, F., Monteiro, A. N., Moysich, K. B., Odunsi, K., Olsson, H., Pearce, C. L., Pejovic, T., Ramus, S. J., Riboli, E., Riggan, M. J., Romieu, I., Sandler, D. P., Schildkraut, J. M., Setiawan, V. W., Sieh, W., Song, H., Sutphen, R., Terry, K. L., Thompson, P. J., Titus, L., Tworoger, S. S., Van Nieuwenhuysen, E., Edwards, D. V., Webb, P. M., Wentzensen, N., Whittemore, A. S., Wolk, A., Wu, A. H., Ziogas, A., Freedman, M. L., Lawrenson, K., Pharoah, P. D., Easton, D. F., Gayther, S. A., Jones, M. R., Webb, P., DeFazio, A., Friedlander, M., Obermair, A., Grant, P., Nagle, C., Beesley, V., Chevenix-Trench, G., Bowtell, D., Blomfield, P., Brand, A., Davis, A., Leung, Y., Nicklin, J., Quinn, M., Livingstone, K., O'Neill, H., Williams, M., Black, A., Hadley, A., Glasgow, A., Garrett, A., Rao, A., Shannon, C., Steer, C., Allen, D., Neesham, D., Otton, G., Au-Yeung, G., Goss, G., Wain, G., Gard, G., Robertson, G., Lombard, J., Tan, J., McNeilage, J., Power, J., Coward, J., Miller, J., Carter, J., Lamont, J., Wong, K. M., Reid, K., Perrin, L., Milishkin, L., Nascimento, M., Buck, M., Bunting, M., Harrison, M., Chetty, N., Hacker, N., McNally, O., Harnett, P., Beale, P., Awad, R., Mohan, R., Farrell, R., McIntosh, R., Rome, R., Sayer, R., Houghton, R., Hogg, R., Land, R., Baron-Hay, S., Paramasivum, S., Pather, S., Hyde, S., Salfinger, S., Valmadre, S., Jobling, T., Manolitsas, T., Bonaventura, T., Arora, V., Bowtell, D., Chenevix-Trench, G., Green, A., Webb, P., DeFazio, A., Gertig, D., Traficante, N., Fereday, S., Moore, S., Hung, J., Harrap, K., Sadkowsky, T., Pandeya, N., Malt, M., Robertson, R., Bergh, T. V., Jones, M., McKenzie, P., Maidens, J., Nattress, K., Chiew, Y. E., Stenlake, A., Sullivan, H., Alexander, B., Ashover, P., Brown, S., Corrish, T., Green, L., Jackman, L., Ferguson, K., Martin, K., Martyn, A., Ranieri, B., White, J., Jayde, V., Bowes, L., Mamers, P., Galletta, L., Giles, D., Hendley, J., Alsop, K., Schmidt, T., Shirley, H., Ball, C., Young, C., Viduka, S., Tran, H., Bilic, S., Glavinas, L., Brooks, J., Stuart-Harris, R., Kirsten, F., Rutovitz, J., Clingan, P., Glasgow, A., Proietto, A., Braye, S., Otton, G., Shannon, J., Bonaventura, T., Stewart, J., Begbie, S. 2022

  Abstract

  BACKGROUND: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort.METHODS: Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer-related cell types.RESULTS: We identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC=1.60E-21; OREOC=8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC]=5.5E-4; odds ratio [OR]HGSOC=5.74 del), and BRCA2 (PHGSOC=7.0E-4; ORHGSOC=3.31 deletion). Four suggestive associations (P<.001) were identified for rare CNVs. Risk-associated CNVs were enriched (P<.05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types.CONCLUSIONS: CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.

  View details for DOI 10.1093/jnci/djac160

  View details for PubMedID 36210504

• 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

• Outdoor ambient air pollution and breast cancer survival among California participants of the Multiethnic Cohort Study. Environment international Cheng, I., Yang, J., Tseng, C., Wu, J., Conroy, S. M., Shariff-Marco, S., Lin Gomez, S., Whittemore, A. S., Stram, D. O., Le Marchand, L., Wilkens, L. R., Ritz, B., Wu, A. H. 1800; 161: 107088

  Abstract

  BACKGROUND: Within the Multiethnic Cohort (MEC), we examined the association between air pollution and mortality among African American, European American, Japanese American, and Latina American women diagnosed with breast cancer.METHODS: We used a land use regression (LUR) model and kriging interpolation to estimate nitrogen oxides (NOx , NO2) and particulate matter (PM2.5, PM10) exposures for 3,089 breast cancer cases in the MEC, who were diagnosed from 1993 through 2013 and resided largely in Los Angeles County, California. Cox proportional hazards models were used to examine the association of time-varying air pollutants with all-cause, breast cancer, cardiovascular disease (CVD), and non-breast cancer/non-CVD mortality, accounting for key covariates.RESULTS: We identified 1,125 deaths from all causes (474 breast cancer, 272 CVD, 379 non-breast cancer/non-CVD deaths) among the 3,089 breast cancer cases with 8.1years of average follow-up. LUR and kriged NOX (per 50ppb) and NO2 (per 20ppb), PM2.5 (per 10g/m3), and PM10 (per 10g/m3) were positively associated with risks of all-cause (Hazard Ratio (HR) range=1.13-1.25), breast cancer (HR range=1.19-1.45), and CVD mortality (HR range=1.37-1.60). Associations were statistically significant for LUR NOX and CVD mortality (HR=1.60; 95% CI: 1.08-2.37) and kriged NO2 and breast cancer mortality (HR=1.45; 95% CI 1.02-2.07). Gaseous and PM pollutants were positively associated with breast cancer mortality across racial/ethnic group.CONCLUSION: In this study, air pollutants have a harmful impact on breast cancer survival. Additional studies should evaluate potential confounding by socioeconomic factors. These data support maintaining clean air laws to improve survival for women with breast cancer.

  View details for DOI 10.1016/j.envint.2022.107088

  View details for PubMedID 35063793

• 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

• Identification of 31 loci for mammographic density phenotypes and their associations with breast cancer risk. Nature communications Sieh, W., Rothstein, J. H., Klein, R. J., Alexeeff, S. E., Sakoda, L. C., Jorgenson, E., McBride, R. B., Graff, R. E., McGuire, V., Achacoso, N., Acton, L., Liang, R. Y., Lipson, J. A., Rubin, D. L., Yaffe, M. J., Easton, D. F., Schaefer, C., Risch, N., Whittemore, A. S., Habel, L. A. 2020; 11 (1): 5116

  Abstract

  Mammographic density (MD) phenotypes are strongly associated with breast cancer risk and highly heritable. In this GWAS meta-analysis of 24,192 women, we identify 31 MD loci at P<5*10-8, tripling the number known to 46. Seventeen identified MD loci also are associated with breast cancer risk in an independent meta-analysis (P<0.05). Mendelian randomization analyses show that genetic estimates of dense area (DA), nondense area (NDA), and percent density (PD) are all significantly associated with breast cancer risk (P<0.05). Pathway analyses reveal distinct biological processes involving DA, NDA and PD loci. These findings provide additional insights into the genetic basis of MD phenotypes and their associations with breast cancer risk.

  View details for DOI 10.1038/s41467-020-18883-x

  View details for PubMedID 33037222

• Reply to Comment on: Racial, Ethnic, and Socioeconomic Disparities in Retinoblastoma Enucleation: A Population-Based Study, SEER 18 2000-2014 AMERICAN JOURNAL OF OPHTHALMOLOGY Rajeshuni, N., Whittemore, A. S., Ludwig, C. A., Mruthyunjaya, P., Moshfeghi, D. M. 2020; 217: 351

  View details for Web of Science ID 000574918000040

• Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer. European urology Schaid, D. J., McDonnell, S. K., FitzGerald, L. M., DeRycke, L., Fogarty, Z., Giles, G. G., MacInnis, R. J., Southey, M. C., Nguyen-Dumont, T., Cancel-Tassin, G., Cussenot, O., Whittemore, A. S., Sieh, W., Ioannidis, N. M., Hsieh, C., Stanford, J. L., Schleutker, J., Cropp, C. D., Carpten, J., Hoegel, J., Eeles, R., Kote-Jarai, Z., Ackerman, M. J., Klein, C. J., Mandal, D., Cooney, K. A., Bailey-Wilson, J. E., Helfand, B., Catalona, W. J., Wiklund, F., Riska, S., Bahetti, S., Larson, M. C., Cannon Albright, L., Teerlink, C., Xu, J., Isaacs, W., Ostrander, E. A., Thibodeau, S. N. 2020

  Abstract

  BACKGROUND: Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease.OBJECTIVE: To detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa.DESIGN, SETTING, AND PARTICIPANTS: A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Frequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls.RESULTS AND LIMITATIONS: Eleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa.CONCLUSIONS: Our approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease.PATIENT SUMMARY: Multiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa.

  View details for DOI 10.1016/j.eururo.2020.07.038

  View details for PubMedID 32800727

• Reply to Comment on: Racial, Ethnic, and Socioeconomic Disparities in Retinoblastoma Enucleation: A Population-Based Study, SEER 18 2000-2014. American journal of ophthalmology Rajeshuni, N., Whittemore, A. S., Ludwig, C. A., Mruthyunjaya, P., Moshfeghi, D. M. 2020

  View details for DOI 10.1016/j.ajo.2020.04.038

  View details for PubMedID 32660706

• Association between outdoor air pollution and breast cancer survival: The Multiethnic Cohort Study Cheng, I., Yang, J., Tseng, C., Wu, J., Conroy, S. M., Shariff-Marco, S., Gomez, S., Whittemore, A., Stram, D. O., Le Marchand, L., Wilkens, L. R., Ritz, B., Wu, A. H. AMER ASSOC CANCER RESEARCH. 2020

  View details for DOI 10.1158/1538-7755.DISP19-C050

  View details for Web of Science ID 000580647800285

• Alcohol and tobacco use in relation to mammographic density in 23,456 women. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology McBride, R. B., Fei, K., Rothstein, J. H., Alexeeff, S. E., Song, X., Sakoda, L. C., McGuire, V., Achacoso, N., Acton, L., Liang, R. Y., Lipson, J. A., Yaffe, M. J., Rubin, D. L., Whittemore, A. S., Habel, L. A., Sieh, W. 2020

  Abstract

  BACKGROUND: Percent density (PD) is a strong risk factor for breast cancer that is potentially modifiable by lifestyle factors. PD is a composite of the dense (DA) and nondense (NDA) areas of a mammogram, representing predominantly fibroglandular or fatty tissues, respectively. Alcohol and tobacco use have been associated with increased breast cancer risk. However, their effects on mammographic density (MD) phenotypes are poorly understood.METHODS: We examined associations of alcohol and tobacco use with PD, DA and NDA in a population-based cohort of 23,456 women screened using full-field digital mammography machines manufactured by Hologic or General Electric (GE). MD was measured using Cumulus. Machine-specific effects were estimated using linear regression, and combined using random effects meta-analysis.RESULTS: Alcohol use was positively associated with PD (ptrend=0.01), unassociated with DA (ptrend=0.23), and inversely associated with NDA (ptrend=0.02) adjusting for age, BMI, reproductive factors, physical activity, and family history of breast cancer. In contrast, tobacco use was inversely associated with PD (ptrend=0.0008), unassociated with DA (ptrend=0.93), and positively associated with NDA (ptrend<0.0001). These trends were stronger in normal and overweight women than in obese women.CONCLUSIONS: These findings suggest that associations of alcohol and tobacco use with PD result more from their associations with NDA than DA.IMPACT: PD and NDA may mediate the association of alcohol drinking, but not tobacco smoking, with increased breast cancer risk. Further studies are needed to elucidate the modifiable lifestyle factors that influence breast tissue composition, and the important role of the fatty tissues on breast health.

  View details for DOI 10.1158/1055-9965.EPI-19-0348

  View details for PubMedID 32066618

• Association between ambient air pollution and breast cancer risk: The multiethnic cohort study INTERNATIONAL JOURNAL OF CANCER Cheng, I., Tseng, C., Wu, J., Yang, J., Conroy, S. M., Shariff-Marco, S., Li, L., Hertz, A., Gomez, S., Le Marchand, L., Whittemore, A. S., Stram, D. O., Ritz, B., Wu, A. H. 2020; 146 (3): 699–711

  View details for DOI 10.1002/ijc.32308

  View details for Web of Science ID 000531411900012

• Alcohol and tobacco use in relation to mammographic density in 23,456 women McBride, R. B., Fei, K., Rothstein, J. H., Alexeeff, S. E., Song, X., Sakoda, L. C., McGuire, V., Achacoso, N., Acton, L., Liang, R. Y., Lipson, J. A., Yaffe, M. J., Rubin, D. L., Whittemore, A. S., Habel, L. A., Sieh, W. AMER ASSOC CANCER RESEARCH. 2020

  View details for DOI 10.1158/1538-7445.SABCS19-P2-08-01

  View details for Web of Science ID 000527012501030

• Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium. British journal of cancer Martins, F. C., Couturier, D. L., Paterson, A. n., Karnezis, A. N., Chow, C. n., Nazeran, T. M., Odunsi, A. n., Gentry-Maharaj, A. n., Vrvilo, A. n., Hein, A. n., Talhouk, A. n., Osorio, A. n., Hartkopf, A. D., Brooks-Wilson, A. n., DeFazio, A. n., Fischer, A. n., Hartmann, A. n., Hernandez, B. Y., McCauley, B. M., Karpinskyj, C. n., de Sousa, C. B., Høgdall, C. n., Tiezzi, D. G., Herpel, E. n., Taran, F. A., Modugno, F. n., Keeney, G. n., Nelson, G. n., Steed, H. n., Song, H. n., Luk, H. n., Benitez, J. n., Alsop, J. n., Koziak, J. M., Lester, J. n., Rothstein, J. H., de Andrade, J. M., Lundvall, L. n., Paz-Ares, L. n., Robles-Díaz, L. n., Wilkens, L. R., Garcia, M. J., Intermaggio, M. P., Alcaraz, M. L., Brett, M. A., Beckmann, M. W., Jimenez-Linan, M. n., Anglesio, M. n., Carney, M. E., Schneider, M. n., Traficante, N. n., Pejovic, N. n., Singh, N. n., Le, N. n., Sinn, P. n., Ghatage, P. n., Erber, R. n., Edwards, R. n., Vierkant, R. n., Ness, R. B., Leung, S. n., Orsulic, S. n., Brucker, S. Y., Kaufmann, S. H., Fereday, S. n., Gayther, S. n., Winham, S. J., Kommoss, S. n., Pejovic, T. n., Longacre, T. A., McGuire, V. n., Rhenius, V. n., Sieh, W. n., Shvetsov, Y. B., Whittemore, A. S., Staebler, A. n., Karlan, B. Y., Rodriguez-Antona, C. n., Bowtell, D. D., Goode, E. L., Høgdall, E. n., Candido Dos Reis, F. J., Gronwald, J. n., Chang-Claude, J. n., Moysich, K. B., Kelemen, L. E., Cook, L. S., Goodman, M. T., Fasching, P. A., Crawford, R. n., Deen, S. n., Menon, U. n., Huntsman, D. G., Köbel, M. n., Ramus, S. J., Pharoah, P. D., Brenton, J. D. 2020

  Abstract

  PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study.Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests.Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016).PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.

  View details for DOI 10.1038/s41416-020-0900-0

  View details for PubMedID 32555365

• Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma. Nature communications Sarin, K. Y., Lin, Y. n., Daneshjou, R. n., Ziyatdinov, A. n., Thorleifsson, G. n., Rubin, A. n., Pardo, L. M., Wu, W. n., Khavari, P. A., Uitterlinden, A. n., Nijsten, T. n., Toland, A. E., Olafsson, J. H., Sigurgeirsson, B. n., Thorisdottir, K. n., Jorgensen, E. n., Whittemore, A. S., Kraft, P. n., Stacey, S. N., Stefansson, K. n., Asgari, M. M., Han, J. n. 2020; 11 (1): 820

  Abstract

  Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers in the United States. Previous genome-wide association studies (GWAS) have identified 14 single nucleotide polymorphisms (SNPs) associated with cutaneous SCC. Here, we report the largest cutaneous SCC meta-analysis to date, representing six international cohorts and totaling 19,149 SCC cases and 680,049 controls. We discover eight novel loci associated with SCC, confirm all previously associated loci, and perform fine mapping of causal variants. The novel SNPs occur within skin-specific regulatory elements and implicate loci involved in cancer development, immune regulation, and keratinocyte differentiation in SCC susceptibility.

  View details for DOI 10.1038/s41467-020-14594-5

  View details for PubMedID 32041948

• 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

• Expanding our understanding of ovarian cancer risk: the role of incomplete pregnancies. Journal of the National Cancer Institute Lee, A. W., Rosenzweig, S. n., Wiensch, A. n., Ramus, S. J., Menon, U. n., Gentry-Maharaj, A. n., Ziogas, A. n., Anton-Culver, H. n., Whittemore, A. S., Sieh, W. n., Rothstein, J. H., McGuire, V. n., Wentzensen, N. n., Bandera, E. V., Qin, B. n., Terry, K. L., Cramer, D. W., Titus, L. n., Schildkraut, J. M., Berchuck, A. n., Goode, E. L., Kjaer, S. K., Jensen, A. n., Jordan, S. J., Ness, R. B., Modugno, F. n., Moysich, K. n., Thompson, P. J., Goodman, M. T., Carney, M. E., Chang-Claude, J. n., Rossing, M. A., Harris, H. R., Doherty, J. A., Risch, H. A., Khoja, L. n., Alimujiang, A. n., Phung, M. T., Brieger, K. n., Mukherjee, B. n., Pharoah, P. D., Wu, A. H., Pike, M. C., Webb, P. M., Pearce, C. L. 2020

  Abstract

  Parity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated.A pooled analysis of 10,470 invasive epithelial ovarian cancer cases and 16,942 controls was conducted. Odds ratios and 95% confidence intervals for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race/ethnicity, age, and education level, and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses.Ever having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (two-sided Ptrend <.001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer.Incomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk.

  View details for DOI 10.1093/jnci/djaa099

  View details for PubMedID 32766851

• Cross-cancer genome-wide association study of endometrial cancer and epithelial ovarian cancer identifies genetic risk regions associated with risk of both cancers. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Glubb, D. M., Thompson, D. J., Aben, K. K., Alsulimani, A. n., Amant, F. n., Annibali, D. n., Attia, J. n., Barricarte, A. n., Beckmann, M. W., Berchuck, A. n., Bermisheva, M. n., Bernardini, M. Q., Bischof, K. n., Bjørge, L. n., Bodelon, C. n., Brand, A. H., Brenton, J. D., Brinton, L. A., Bruinsma, F. n., Buchanan, D. D., Burghaus, S. n., Bützow, R. n., Cai, H. n., Carney, M. E., Chanock, S. J., Chen, C. n., Chen, X. n., Chen, Z. n., Cook, L. S., Cunningham, J. M., De Vivo, I. n., DeFazio, A. n., Doherty, J. A., Dork, T. n., du Bois, A. n., Dunning, A. M., Durst, M. n., Edwards, T. n., Edwards, R. P., Ekici, A. B., Ewing, A. n., Fasching, P. A., Ferguson, S. n., Flanagan, J. M., Fostira, F. n., Fountzilas, G. n., Friedenreich, C. M., Gao, B. n., Gaudet, M. M., Gawełko, J. n., Gentry-Maharaj, A. n., Giles, G. G., Glasspool, R. n., Goodman, M. T., Gronwald, J. n., Harris, H. R., Harter, P. n., Hein, A. n., Heitz, F. n., Hildebrandt, M. A., Hillemanns, P. n., Høgdall, E. n., Høgdall, C. K., Holliday, E. G., Huntsman, D. G., Huzarski, T. n., Jakubowska, A. n., Jensen, A. n., Jones, M. E., Karlan, B. Y., Karnezis, A. n., Kelley, J. L., Khusnutdinova, E. n., Killeen, J. L., Kjaer, S. K., Klapdor, R. n., Köbel, M. n., Konopka, B. n., Konstantopoulou, I. n., Kopperud, R. K., Koti, M. n., Kraft, P. n., Kupryjanczyk, J. n., Lambrechts, D. n., Larson, M. C., Le Marchand, L. n., Lele, S. n., Lester, J. n., Li, A. J., Liang, D. n., Liebrich, C. n., Lipworth, L. n., Lissowska, J. n., Lu, L. n., Lu, K. H., Macciotta, A. n., Mattiello, A. n., May, T. n., McAlpine, J. N., McGuire, V. n., McNeish, I. A., Menon, U. n., Modugno, F. n., Moysich, K. B., Nevanlinna, H. n., Odunsi, K. n., Olsson, H. n., Orsulic, S. n., Osorio, A. n., Palli, D. n., Park-Simon, T. W., Pearce, C. L., Pejovic, T. n., Permuth, J. B., Podgorska, A. n., Ramus, S. J., Rebbeck, T. R., Riggan, M. J., Risch, H. A., Rothstein, J. H., Runnebaum, I. B., Scott, R. J., Sellers, T. A., Senz, J. n., Setiawan, V. W., Siddiqui, N. n., Sieh, W. n., Spiewankiewicz, B. n., Sutphen, R. n., Swerdlow, A. J., Szafron, L. M., Teo, S. H., Thompson, P. J., Thomsen, L. C., Titus, L. n., Tone, A. n., Tumino, R. n., Turman, C. n., Vanderstichele, A. n., Velez Edwards, D. n., Vergote, I. n., Vierkant, R. A., Wang, Z. n., Wang-Gohrke, S. n., Webb, P. M., White, E. n., Whittemore, A. S., Winham, S. J., Wu, X. n., Wu, A. H., Yannoukakos, D. n., Spurdle, A. B., O'Mara, T. A. 2020

  Abstract

  Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e. inverse-variance meta-analysis, co-localization, and M-values), and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10-5). We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10-9). In addition, four novel sub-genome wide regions at 7p22.2, 7q22.1, 9p12 and 11q13.3 were identified (P < 5 × 10-7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines, and expression quantitative trait loci (eQTL) data highlighted candidate target genes for further investigation.Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.

  View details for DOI 10.1158/1055-9965.EPI-20-0739

  View details for PubMedID 33144283

• 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

• Racial, Ethnic, and Socioeconomic Disparities in Retinoblastoma Enucleation: A Population-Based Study, SEER 18 2000-2014 AMERICAN JOURNAL OF OPHTHALMOLOGY Rajeshuni, N., Whittemore, A. S., Ludwig, C. A., Mruthyunjaya, P., Moshfeghi, D. M. 2019; 207: 215–23

  View details for DOI 10.1016/j.ajo.2019.04.015

  View details for Web of Science ID 000504341100022

• Reproductive Factors and Mammographic Density: Associations Among 24,840 Women and Comparison of Studies Using Digitized Film-Screen Mammography and Full-Field Digital Mammography AMERICAN JOURNAL OF EPIDEMIOLOGY Alexeeff, S. E., Odo, N. U., McBride, R., McGuire, V., Achacoso, N., Rothstein, J. H., Lipson, J. A., Liang, R. Y., Acton, L., Yaffe, M. J., Whittemore, A. S., Rubin, D. L., Sieh, W., Habel, L. A. 2019; 188 (6): 1144–54

  View details for DOI 10.1093/aje/kwz033

  View details for Web of Science ID 000473760200018

• Data-adaptive multi-locus association testing in subjects with arbitrary genealogical relationships STATISTICAL APPLICATIONS IN GENETICS AND MOLECULAR BIOLOGY Gong, G., Wang, W., Hsieh, C., Van Den Berg, D. J., Haiman, C., Oakley-Girvan, I., Whittemore, A. S. 2019; 18 (3)

  View details for DOI 10.1515/sagmb-2018-0030

  View details for Web of Science ID 000467578400002

• A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants INTERNATIONAL JOURNAL OF CANCER Kim, S., Wang, M., Tyrer, J. P., Jensen, A., Wiensch, A., Liu, G., Lee, A. W., Ness, R. B., Salvatore, M., Tworoger, S. S., Whittemore, A. S., Anton-Culver, H., Sieh, W., Olson, S. H., Berchuck, A., Goode, E. L., Goodman, M. T., Doherty, J., Chenevix-Trench, G., Rossing, M., Webb, P. M., Giles, G. G., Terry, K. L., Ziogas, A., Fortner, R. T., Menon, U., Gayther, S. A., Wu, A. H., Song, H., Brooks-Wilson, A., Bandera, E., Cook, L. S., Cramer, D. W., Milne, R. L., Winham, S. J., Kjaer, S. K., Modugno, F., Thompson, P. J., Chang-Claude, J., Harris, H. R., Schildkraut, J. M., Le, N. D., Wentzensen, N., Trabert, B., Hogdall, E., Huntsman, D., Pike, M. C., Pharoah, P. P., Pearce, C., Mukherjee, B. 2019; 144 (9): 2192–2205

  View details for DOI 10.1002/ijc.32029

  View details for Web of Science ID 000460343700016

• Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women CANCER MEDICINE Grant, D. J., Manichaikul, A., Alberg, A. J., Bandera, E., Barnholtz-Sloan, J., Bondy, M., Cote, M. L., Funkhouser, E., Moorman, P. G., Peres, L. C., Peters, E. S., Schwartz, A. G., Terry, P. D., Wang, X., Keku, T. O., Hoyo, C., Berchuck, A., Sandler, D. P., Taylor, J. A., O'Brien, K. M., Edwards, D., Edwards, T. L., Beeghly-Fadiel, A., Wentzensen, N., Pearce, C., Wu, A. H., Whittemore, A. S., McGuire, V., Sieh, W., Rothstein, J. H., Modugno, F., Ness, R., Moysich, K., Rossing, M., Doherty, J. A., Sellers, T. A., Permuth-Way, J. B., Monteiro, A. N., Levine, D. A., Setiawan, V., Haiman, C. A., LeMarchand, L., Wilkens, L. R., Karlan, B. Y., Menon, U., Ramus, S., Gayther, S., Gentry-Maharaj, A., Terry, K. L., Cramer, D. W., Goode, E. L., Larson, M. C., Kaufmann, S. H., Cannioto, R., Odunsi, K., Etter, J. L., Huang, R., Bernardini, M. Q., Tone, A. A., May, T., Goodman, M. T., Thompson, P. J., Carney, M. E., Tworoger, S. S., Poole, E. M., Lambrechts, D., Vergote, I., Vanderstichele, A., Van Nieuwenhuysen, E., Anton-Culver, H., Ziogas, A., Brenton, J. D., Bjorge, L., Salvensen, H. B., Kiemeney, L. A., Massuger, L. G., Pejovic, T., Bruegl, A., Moffitt, M., Cook, L., Le, N. D., Brooks-Wilson, A., Kelemen, L. E., Pharoah, P. P., Song, H., Campbe, I., Eccles, D., DeFazio, A., Kennedy, C. J., Schildkraut, J. M. 2019; 8 (5): 2503–13

  View details for DOI 10.1002/cam4.1996

  View details for Web of Science ID 000469272500052

• Data-adaptive multi-locus association testing in subjects with arbitrary genealogical relationships. Statistical applications in genetics and molecular biology Gong, G., Wang, W., Hsieh, C., Van Den Berg, D. J., Haiman, C., Oakley-Girvan, I., Whittemore, A. S. 2019

  Abstract

  Genome-wide sequencing enables evaluation of associations between traits and combinations of variants in genes and pathways. But such evaluation requires multi-locus association tests with good power, regardless of the variant and trait characteristics. And since analyzing families may yield more power than analyzing unrelated individuals, we need multi-locus tests applicable to both related and unrelated individuals. Here we describe such tests, and we introduce SKAT-X, a new test statistic that uses genome-wide data obtained from related or unrelated subjects to optimize power for the specific data at hand. Simulations show that: a) SKAT-X performs well regardless of variant and trait characteristics; and b) for binary traits, analyzing affected relatives brings more power than analyzing unrelated individuals, consistent with previous findings for single-locus tests. We illustrate the methods by application to rare unclassified missense variants in the tumor suppressor gene BRCA2, as applied to combined data from prostate cancer families and unrelated prostate cancer cases and controls in the Multi-ethnic Cohort (MEC). The methods can be implemented using open-source code for public use as the R-package GATARS (Genetic Association Tests for Arbitrarily Related Subjects) .

  View details for PubMedID 30956231

• 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

• Association between ambient air pollution and breast cancer risk: The Multiethnic Cohort Study. International journal of cancer Cheng, I., Tseng, C., Wu, J., Yang, J., Conroy, S. M., Shariff-Marco, S., Li, L., Hertz, A., Gomez, S. L., Le Marchand, L., Whittemore, A., Stram, D. O., Ritz, B., Wu, A. H. 2019

  Abstract

  Previous studies using different exposure methods to assess air pollution and breast cancer risk among primarily whites have been inconclusive. Air pollutant exposures of particulate matter and oxides of nitrogen were estimated by kriging (NOx , NO2 , PM10 , PM2.5 ), land use regression (LUR, NOx , NO2 ), and California Line Source Dispersion Model (CALINE4, NOx , PM2.5 ) for 57,589 females from the Multiethnic Cohort, residing largely in Los Angeles County from recruitment (1993-1996) through 2010. Cox proportional hazards models were used to examine the associations between time-varying air pollution and breast cancer incidence adjusting for confounding factors. Stratified analyses were conducted by race/ethnicity and distance to major roads. Among all women, breast cancer risk was positively but not significantly associated with NOx (per 50 parts per billion (ppb)) and NO2 (per 20 ppb) determined by kriging and LUR and with PM2.5 and PM10 (per 10 mug/m3 ) determined by kriging. However, among women who lived within 500 meters of major roads, significant increased risks were observed with NOx (Hazard Ratio (HR)=1.35, 95% CI: 1.02-1.79), NO2 (HR=1.44, 95% CI: 1.04-1.99), PM10 (HR=1.29, 95% CI: 1.07-1.55) and PM2.5 (HR=1.85, 95% CI: 1.15-2.99) determined by kriging and NOx (HR=1.21, 95% CI:1.01-1.45) and NO2 (HR=1.26, 95% CI: 1.00-1.59) determined by LUR. No overall associations were observed with exposures assessed by CALINE4. Subgroup analyses suggested stronger associations of NOx and NO2 among African Americans and Japanese Americans. Further studies of multiethnic populations to confirm the effects of air pollution, particularly near roadway exposures, on risk of breast cancer is warranted. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30924138

• 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

• Reproductive Factors and Mammographic Density: Associations Among 24,840 Women and Comparison of Studies Using Digitized Film-Screen Mammography and Full-Field Digital Mammography. American journal of epidemiology Alexeeff, S. E., Odo, N. U., McBride, R., McGuire, V., Achacoso, N., Rothstein, J. H., Lipson, J. A., Liang, R. Y., Acton, L., Yaffe, M. J., Whittemore, A. S., Rubin, D. L., Sieh, W., Habel, L. A. 2019

  Abstract

  Breast density is a modifiable factor that is strongly associated with breast cancer risk. We sought to understand the influence of newer technologies of full-field digital mammography (FFDM) on breast density research and to determine whether results are comparable across studies using FFDM and previous studies using traditional film-screen mammography. We studied 24,840 screening-age (40-74 years) non-Hispanic white women who were participants in the Research Program on Genes, Environment and Health of Kaiser Permanente Northern California and underwent screening mammography with either Hologic (Hologic, Inc., Marlborough, Massachusetts) or General Electric (General Electric Company, Boston, Massachusetts) FFDM machines between 2003 and 2013. We estimated the associations of parity, age at first birth, age at menarche, and menopausal status with percent density and dense area as measured by a single radiological technologist using Cumulus software (Canto Software, Inc., San Francisco, California). We found that associations between reproductive factors and mammographic density measured using processed FFDM images were generally similar in magnitude and direction to those from prior studies using film mammography. Estimated associations for both types of FFDM machines were in the same direction. There was some evidence of heterogeneity in the magnitude of the effect sizes by machine type, which we accounted for using random-effects meta-analysis when combining results. Our findings demonstrate the robustness of quantitative mammographic density measurements across FFDM and film mammography platforms.

  View details for PubMedID 30865217

• 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

• 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

• Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus CANCER RESEARCH Buckley, M. A., Woods, N. T., Tyrer, J. P., Mendoza-Fandino, G., Lawrenson, K., Hazelett, D. J., Najafabadi, H. S., Gjyshi, A., Carvalho, R. S., Lyra, P. C., Coetzee, S. G., Shen, H. C., Yang, A. W., Earp, M. A., Yoder, S. J., Risch, H., Chenevix-Trench, G., Ramus, S. J., Phelan, C. M., Coetzee, G. A., Noushmehr, H., Hughes, T. R., Sellers, T. A., Goode, E. L., Pharoah, P. D., Gayther, S. A., Monteiro, A. A., Chen, Y., Fridley, B. L., Aben, K. H., Kiemeney, L. A., Anton-Culver, H., Ziogas, A., Bruinsma, F., Milne, R. L., Bandera, E. V., Giles, G. G., Bean, Y. T., Pejovic, T., Beckmann, M. W., Hein, A., Bjorge, L., Fasching, P. A., Thomsen, L. V., Kopperud, R. K., Bischof, K., Bogdanova, N., Doek, T., Hillemanns, P., Brinton, L. A., Wentzensen, N., Yang, H., Brooks-Wilson, A., Bunker, C. H., Butzow, R., Nevanlinna, H., Pelttari, L. M., Campbell, I. G., Southey, M. C., Modugno, F., Carty, K., Glasspool, R., McNeish, I., Paul, J., Siddiqui, N., Chang-Claude, J., Rudolph, A., Chang-Claude, J., Cook, L. S., Cramer, D. W., Terry, K. L., Cunningham, J. M., Cybulski, C., Gronwald, J., Jakubowska, A., Lubinski, J., Dansonka-Mieszkowska, A., Kupryjanczyk, J., Rzepecka, I. K., du Bois, A., Harter, P., Dicks, E., Song, H., Doherty, J. A., Rossing, M., Duerst, M., Easton, D. F., Eccles, D. M., Edwards, R. P., Ekici, A. B., Fasching, P. A., Gao, Y., Milne, R. L., Gentry-Maharaj, A., Giles, G. G., Goodman, M. T., Thompson, P. J., Hasmad, H. N., Teo, S., Hildebrandt, M. T., Wu, X., Hogdall, E., Jensen, A., Kjaer, S. K., Hogdall, E., Iversen, E. S., Karlan, B. Y., Lester, J., Orsulic, S., Walsh, C. S., Kelley, J. L., Lambrechts, D., Lambrechts, S., Vergote, I., Lee, A. W., Levine, D. A., Liang, D., Lissowska, J., Lu, K., Lundvall, L., Kjaer, S. K., Massuger, L. G., van Altena, A. M., Matsuo, K., McGuire, V., McLaughlin, J. R., Menon, U., Moysich, K. B., Ness, R. B., Odunsi, K., Olson, S. H., Orlow, I., Pike, M. C., Pearce, C. L., Wu, A. H., Permuth, J. B., Tsai, Y., Tworoger, S. S., Poole, E. M., Rosen, B., Shu, X., Shvetsov, Y. B., Wilkens, L. R., Sieh, W., Spiewankiewicz, B., Sucheston-Campbell, L., Thomsen, L., Wang-Gohrke, S., Whittemore, A. S., Woo, Y., Zheng, W., Berchuck, A., Chenevix-Trench, G., Schildkraut, J. M., Kelemen, L. E., Freedman, M. L., Ovarian Canc Asso Consortium, AOCS Management Grp 2019; 79 (3): 467–81

  Abstract

  : Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer. SIGNIFICANCE: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene.See related commentary by Choi and Brown, p. 439.

  View details for DOI 10.1158/0008-5472.CAN-17-3864

  View details for Web of Science ID 000457394600008

  View details for PubMedID 30487138

  View details for PubMedCentralID PMC6359979

• 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

• 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

• Racial, Ethnic, and Socioeconomic Disparities in Retinoblastoma Enucleation: A Population-Based Study, SEER 18 2000-2014. American journal of ophthalmology Rajeshuni, N. n., Whittemore, A. S., Ludwig, C. A., Mruthyunjaya, P. n., Moshfeghi, D. M. 2019

  Abstract

  To determine the effect of race, ethnicity, and census-tract-level composite socioeconomic status (SES) on retinoblastoma enucleation. This study augments Truong et al., providing multivariate analyses combining sociodemographic and clinical characteristics with more accurate SES measures. We hypothesized children from non-white, Hispanic, and lower socioeconomic backgrounds would have increased adjusted odds of enucleation.Retrospective cohort analysis.Setting: Multicenter population-based study using the Surveillance, Epidemiology, and End Results (SEER) 18 Registries.Children aged 18 and under diagnosed with retinoblastoma between 2000-2014. Subjects were identified using International Classification of Diseases Oncology (ICD-O) site and morphology codes.Enucleation Odds Ratios and 95% Confidence Intervals RESULTS: Analysis of 959 retinoblastoma patients revealed that 70.8% were enucleated. Adjusted analyses showed associations between enucleation and Asian (Odds Ratio (OR) 2.00, Confidence Interval (CI) 1.08-3.71) or Black (2.42, 1.41-4.16) race, Hispanic ethnicity (1.69, 1.16-2.46), and low SES (1.68, 1.09-2.58). Significantly increased enucleation risk was associated with older age at diagnosis (Age 1-2 years 2.55, 1.80-3.61; >2 years 4.88, 2.57-9.25), unilateral disease (5.00, 3.45-7.14), and advanced stage (Regional 4.71, 2.51-8.84; Distant 3.15, 1.63-6.08). No interactions were observed between race, ethnicity, SES, and stage at diagnosis. Enucleation rates decreased over time across all racial, ethnic, and socioeconomic groups.Children from non-white, Hispanic, and lower socioeconomic backgrounds are more likely to receive enucleation. These associations are independent of stage of diagnosis, suggesting larger systemic disparities in retinoblastoma care. The origin of these differences requires further study and attention by clinicians and policy-makers.

  View details for PubMedID 31077666

• Identification of novel epithelial ovarian cancer loci in Women of African Ancestry. International journal of cancer Manichaikul, A. n., Peres, L. C., Wang, X. Q., Barnard, M. E., Chyn, D. n., Sheng, X. n., Du, Z. n., Tyrer, J. n., Dennis, J. n., Schwartz, A. G., Cote, M. L., Peters, E. n., Moorman, P. G., Bondy, M. n., Barnholtz-Sloan, J. S., Terry, P. n., Alberg, A. J., Bandera, E. V., Funkhouser, E. n., Wu, A. H., Pearce, C. L., Pike, M. n., Setiawan, V. W., Haiman, C. A., Palmer, J. R., LeMarchand, L. n., Wilkens, L. R., Berchuck, A. n., Doherty, J. A., Modugno, F. n., Ness, R. n., Moysich, K. n., Karlan, B. Y., Whittemore, A. S., McGuire, V. n., Sieh, W. n., Lawrenson, K. n., Gayther, S. n., Sellers, T. A., Pharoah, P. n., Schildkraut, J. M. 2019

  Abstract

  Women of African Ancestry have lower incidence of epithelial ovarian cancer (EOC) yet worse survival compared to women of European Ancestry. We conducted a genome-wide association study (GWAS) in African ancestry women with 755 EOC cases, including 537 high-grade serous ovarian carcinomas (HGSOC), and 1,235 controls. We identified four novel loci with suggestive evidence of association with EOC (P < 1x10-6 ), including rs4525119 (intronic to AKR1C3), rs7643459 (intronic to LOC101927394), rs4286604 (12 kb 3' of UGT2A2), and rs142091544 (5 kb 5' of WWC1). For HGSOC, we identified six loci with suggestive evidence of association including rs37792 (132 kb 5' of FST), rs57403204 (81 kb 3' of MAGEC1), rs79079890 (LOC105376360 intronic), rs66459581 (5 kb 5' of PRPSAP1), rs116046250 (GABRG3 intronic), and rs192876988 (32 kb 3' of GK2). Among the identified variants, two are near genes known to regulate hormones and diseases of the ovary (AKR1C3 and FST), and two are linked to cancer (AKR1C3 and MAGEC1). In follow-up studies of the 10 identified variants, the GK2 region SNP, rs192876988, showed an inverse association with EOC in European ancestry women (P = 0.002), increased risk of ER positive breast cancer in African ancestry women (P = 0.027), and decreased expression of GK2 in HGSOC tissue from African ancestry women (P = 0.004). A European ancestry-derived polygenic risk score showed positive associations with EOC and HGSOC in women of African ancestry suggesting shared genetic architecture. Our investigation presents evidence of variants for EOC shared among European and African ancestry women and identifies novel EOC risk loci in women of African ancestry. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ijc.32653

  View details for PubMedID 31469419

• 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

• 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

• Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women. Cancer medicine Grant, D. J., Manichaikul, A. n., Alberg, A. J., Bandera, E. V., Barnholtz-Sloan, J. n., Bondy, M. n., Cote, M. L., Funkhouser, E. n., Moorman, P. G., Peres, L. C., Peters, E. S., Schwartz, A. G., Terry, P. D., Wang, X. Q., Keku, T. O., Hoyo, C. n., Berchuck, A. n., Sandler, D. P., Taylor, J. A., O'Brien, K. M., Velez Edwards, D. R., Edwards, T. L., Beeghly-Fadiel, A. n., Wentzensen, N. n., Pearce, C. L., Wu, A. H., Whittemore, A. S., McGuire, V. n., Sieh, W. n., Rothstein, J. H., Modugno, F. n., Ness, R. n., Moysich, K. n., Rossing, M. A., Doherty, J. A., Sellers, T. A., Permuth-Way, J. B., Monteiro, A. N., Levine, D. A., Setiawan, V. W., Haiman, C. A., LeMarchand, L. n., Wilkens, L. R., Karlan, B. Y., Menon, U. n., Ramus, S. n., Gayther, S. n., Gentry-Maharaj, A. n., Terry, K. L., Cramer, D. W., Goode, E. L., Larson, M. C., Kaufmann, S. H., Cannioto, R. n., Odunsi, K. n., Etter, J. L., Huang, R. Y., Bernardini, M. Q., Tone, A. A., May, T. n., Goodman, M. T., Thompson, P. J., Carney, M. E., Tworoger, S. S., Poole, E. M., Lambrechts, D. n., Vergote, I. n., Vanderstichele, A. n., Van Nieuwenhuysen, E. n., Anton-Culver, H. n., Ziogas, A. n., Brenton, J. D., Bjorge, L. n., Salvensen, H. B., Kiemeney, L. A., Massuger, L. F., Pejovic, T. n., Bruegl, A. n., Moffitt, M. n., Cook, L. n., Le, N. D., Brooks-Wilson, A. n., Kelemen, L. E., Pharoah, P. D., Song, H. n., Campbell, I. n., Eccles, D. n., DeFazio, A. n., Kennedy, C. J., Schildkraut, J. M. 2019

  Abstract

  An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 1.2 × 10-6 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6-3.4, P = 1.6 × 10-5 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 2.3 × 10-5 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.

  View details for PubMedID 31001917

• 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

• 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

• A Prediction Tool to Facilitate Risk-Stratified Screening for SquamousCellSkin Cancer. The Journal of investigative dermatology Wang, W., Jorgenson, E., Ioannidis, N. M., Asgari, M. M., Whittemore, A. S. 2018; 138 (12): 2589–94

  Abstract

  Cutaneous squamous cell cancers (cSCCs) present an under-recognized health issue among non-Hispanic whites, one that is likely to increase as populations age. cSCC risks vary considerably among non-Hispanic whites, and this heterogeneity indicates the need for risk-stratified screening strategies that are guided by patients' personal characteristics and clinical histories. Here we describe cSCCscore, a prediction tool that uses patients' covariates and clinical histories to assign them personal probabilities of developing cSCCs within 3 years after risk assessment. cSCCscore uses a statistical model for the occurrence and timing of a patient's cSCCs, whose parameters we estimated using cohort data from 66,995 patients in the Kaiser Permanente Northern California healthcare system. We found that patients' covariates and histories explained approximately 75% of their interpersonal cSCC risk variation. Using cross-validated performance measures, we also found cSCCscore's predictions to be moderately well calibrated to the patients' observed cSCC incidence. Moreover, cSCCscore discriminated well between patients who subsequently did and did not develop a new primary cSCC within 3 years after risk assignment, with area under the receiver operating characteristic curve of approximately 85%. Thus, cSCCscore can facilitate more informed management of non-Hispanic white patients at cSCC risk. cSCCscore's predictions are available at https://researchapps.github.io/cSCCscore/.

  View details for PubMedID 30472995

• A Comprehensive Gene-Environment Interaction Analysis in Ovarian Cancer using Genome-wide Significant Common Variants. International journal of cancer Kim, S., Wang, M., Tyrer, J. P., Jensen, A., Wiensch, A., Liu, G., Lee, A. W., Ness, R. B., Salvatore, M., Tworoger, S. S., Whittemore, A. S., Anton-Culver, H., Sieh, W., Olson, S. H., Berchuck, A., Goode, E. L., Goodman, M. T., Doherty, J. A., Chenevix-Trench, G., Rossing, M. A., Webb, P. M., Giles, G. G., Terry, K. L., Ziogas, A., Fortner, R. T., Menon, U., Gayther, S. A., Wu, A. H., Song, H., Brooks-Wilson, A., Bandera, E. V., Cook, L. S., Cramer, D. W., Milne, R. L., Winham, S. J., Kjaer, S. K., Modugno, F., Thompson, P. J., Chang-Claude, J., Harris, H. R., Schildkraut, J. M., Le, N. D., Wentzensen, N., Trabert, B., Hogdall, E., Huntsman, D., Pike, M. C., Pharoah, P. D., Pearce, C. L., Mukherjee, B. 2018

  Abstract

  As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), this study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9,971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs never) and rs13255292 (P-value = 3.48 x 10-4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI=0.46-0.60) compared to 0.71 (95%CI=0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30499236

• Gene expression imputation identifies candidate genes and susceptibility loci associated with cutaneous squamous cell carcinoma. Nature communications Ioannidis, N. M., Wang, W., Furlotte, N. A., Hinds, D. A., 23andMe Research Team, Bustamante, C. D., Jorgenson, E., Asgari, M. M., Whittemore, A. S., Agee, M., Alipanahi, B., Auton, A., Bell, R. K., Bryc, K., Elson, S. L., Fontanillas, P., Huber, K. E., Kleinman, A., Litterman, N. K., McCreight, J. C., McIntyre, M. H., Mountain, J. L., Noblin, E. S., Northover, C. A., Pitts, S. J., Sathirapongsasuti, J. F., Sazonova, O. V., Shelton, J. F., Shringarpure, S., Tian, C., Tung, J. Y., Vacic, V., Wilson, C. H. 2018; 9 (1): 4264

  Abstract

  Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer with genetic susceptibility loci identified in recent genome-wide association studies (GWAS). Transcriptome-wide association studies (TWAS) using imputed gene expression levels can identify additional gene-levelassociations. Here we impute gene expression levels in 6891cSCC cases and 54,566controls in the Kaiser Permanente Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort and 25,558self-reported cSCC cases and 673,788controls from 23andMe. In a discovery-validation study, we identify 19 loci containing 33 genes whose imputed expression levels are associated with cSCC at false discovery rate<10% in the GERA cohort and validate 15 of these candidate genes at Bonferroni significance in the 23andMe dataset, including eight genes in five novel susceptibility loci and seven genes in four previously associated loci. These results suggest genetic mechanisms contributing to cSCC risk and illustrate advantages and disadvantages of TWAS as a supplement to traditional GWAS analyses.

  View details for PubMedID 30323283

• Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study JOURNAL OF PATHOLOGY CLINICAL RESEARCH Rambau, P. F., Vierkant, R. A., Intermaggio, M. P., Kelemen, L. E., Goodman, M. T., Herpel, E., Pharoah, P. D., Kommoss, S., Jimenez-Linan, M., Karlan, B. Y., Gentry-Maharaj, A., Menon, U., Polo, S., Candido dos Reis, F. J., Doherty, J., Gayther, S. A., Sharma, R., Larson, M. C., Harnett, P. R., Hatfield, E., de Andrade, J. M., Nelson, G. S., Steed, H., Schildkraut, J. M., Carney, M. E., Hogdall, E., Whittemore, A. S., Widschwendter, M., Kennedy, C. J., Wang, F., Wang, Q., Wang, C., Armasu, S. M., Daley, F., Coulson, P., Jones, M. E., Anglesio, M. S., Chow, C., de Fazio, A., Garcia-Closas, M., Brucker, S. Y., Cybulski, C., Harris, H. R., Hartkopf, A. D., Huzarski, T., Jensen, A., Lubinski, J., Oszurek, O., Benitez, J., Mina, F., Staebler, A., Taran, F., Pasternak, J., Talhouk, A., Rossing, M., Hendley, J., Edwards, R. P., Fereday, S., Modugno, F., Ness, R. B., Sieh, W., El-Bahrawy, M. A., Winham, S. J., Lester, J., Kjaer, S. K., Gronwald, J., Sinn, P., Fasching, P. A., Chang-Claude, J., Moysich, K. B., Bowtell, D. D., Hernandez, B. Y., Luk, H., Behrens, S., Shah, M., Jung, A., Ghatage, P., Alsop, J., Alsop, K., Garcia-Donas, J., Thompson, P. J., Swerdlow, A. J., Karpinskyj, C., Cazorla-Jimenez, A., Garcia, M. J., Deen, S., Wilkens, L. R., Palacios, J., Berchuck, A., Koziak, J. M., Brenton, J. D., Cook, L. S., Goode, E. L., Huntsman, D. G., Ramus, S. J., Koebel, M., AOCS Group 2018; 4 (4): 250–61

  Abstract

  We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.

  View details for PubMedID 30062862

• rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Kelemen, L. E., Earp, M., Fridley, B. L., Chenevix-Trench, G., Fasching, P. A., Beckmann, M. W., Ekici, A. B., Hein, A., Lambrechts, D., Lambrechts, S., Van Nieuwenhuysen, E., Vergote, I., Rossing, M., Doherty, J. A., Chang-Claude, J., Behrens, S., Moysich, K. B., Cannioto, R., Lele, S., Odunsi, K., Goodman, M. T., Shvetsov, Y. B., Thompson, P. J., Wilkens, L. R., Doerk, T., Antonenkova, N., Bogdanova, N., Hillemanns, P., Runnebaum, I. B., du Bois, A., Harter, P., Heitz, F., Schwaab, I., Butzow, R., Pelttari, L. M., Nevanlinna, H., Modugno, F., Edwards, R. P., Kelley, J. L., Ness, R. B., Karlan, B. Y., Lester, J., Orsulic, S., Walsh, C., Kjaer, S. K., Jensen, A., Cunningham, J. M., Vierkant, R. A., Giles, G. G., Bruinsma, F., Southey, M. C., Hildebrandt, M. T., Liang, D., Lu, K., Wu, X., Sellers, T. A., Levine, D. A., Schildkraut, J. M., Iversen, E. S., Terry, K. L., Cramer, D. W., Tworoger, S. S., Poole, E. M., Bandera, E. V., Olson, S. H., Orlow, I., Thomsen, L., Bjorge, L., Krakstad, C., Tangen, I. L., Kiemeney, L. A., Aben, K. H., Massuger, L. G., van Altena, A. M., Pejovic, T., Bean, Y., Kellar, M., Cook, L. S., Le, N. D., Brooks-Wilson, A., Gronwald, J., Cybulski, C., Jakubowska, A., Lubinski, J., Wentzensen, N., Brinton, L. A., Lissowska, J., Hogdall, E., Engelholm, S., Hogdall, C., Lundvall, L., Nedergaard, L., Pharoah, P. P., Dicks, E., Song, H., Tyrer, J. P., McNeish, I., Siddiqui, N., Carty, K., Glasspool, R., Paul, J., Campbell, I. G., Eccles, D., Whittemore, A. S., McGuire, V., Rothstein, J. H., Sieh, W., Narod, S. A., Phelan, C. M., McLaughlin, J. R., Risch, H. A., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S. A., Gentry-Maharaj, A., Ramus, S. J., Wu, A. H., Pearce, C., Lee, A. W., Pike, M. C., Kupryjanczyk, J., Podgorska, A., Plisiecka-Halasa, J., Sawicki, W., Goode, E. L., Berchuck, A., Australian Ovarian Canc Study Grp, Ovarian Cancr Assoc Consortium 2018; 19 (9)

  Abstract

  Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97⁻1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03⁻1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10-28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.

  View details for PubMedID 30134598

• 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

• Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility PLOS ONE Earp, M., Tyrer, J. P., Winham, S. J., Lin, H., Chornokur, G., Dennis, J., Aben, K. H., Anton-Culver, H., Antonenkova, N., Bandera, E. V., Bean, Y. T., Beckmann, M. W., Bjorge, L., Bogdanova, N., Brinton, L. A., Brooks-Wilson, A., Bruinsma, F., Bunker, C. H., Butzow, R., Campbell, I. G., Carty, K., Chang-Claude, J., Cook, L. S., Cramer, D. W., Cunningham, J. M., Cybulski, C., Dansonka-Mieszkowska, A., Despierre, E., Doherty, J. A., Doerk, T., du Bois, A., Duerst, M., Easton, D. F., Eccles, D. M., Edwards, R. P., Ekici, A. B., Fasching, P. A., Fridley, B. L., Gentry-Maharaj, A., Giles, G. G., Glasspool, R., Goodman, M. T., Gronwald, J., Harter, P., Hein, A., Heitz, F., Hildebrandt, M. T., Hillemanns, P., Hogdall, C. K., Hogdall, E., Hosono, S., Iversen, E. S., Jakubowska, A., Jensen, A., Ji, B., Jung, A. Y., Karlan, B. Y., Kellar, M., Kiemeney, L. A., Lim, B., Kjaer, S. K., Krakstad, C., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N. D., Lele, S., Lester, J., Levine, D. A., Li, Z., Liang, D., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L. G., Matsuo, K., McGuire, V., McLaughlin, J. R., McNeish, I., Menon, U., Milne, R. L., Modugno, F., Moysich, K. B., Ness, R. B., Nevanlinna, H., Odunsi, K., Olson, S. H., Orlow, I., Orsulic, S., Paul, J., Pejovic, T., Pelttari, L. M., Permuth, J. B., Pike, M. C., Poole, E. M., Rosen, B., Rossing, M., Rothstein, J. H., Runnebaum, I. B., Rzepecka, I. K., Schernhammer, E., Schwaab, I., Shu, X., Shvetsov, Y. B., Siddiqui, N., Sieh, W., Song, H., Southey, M. C., Spiewankiewicz, B., Sucheston-Campbell, L., Tangen, I. L., Teo, S., Terry, K. L., Thompson, P. J., Thomsen, L., Tworoger, S. S., van Altena, A. M., Vergote, I., Thomsen, L., Vierkant, R. A., Walsh, C. S., Wang-Gohrke, S., Wentzensen, N., Whittemore, A. S., Wicklund, K. G., Wilkens, L. R., Woo, Y., Wu, A. H., Wu, X., Xiang, Y., Yang, H., Zheng, W., Ziogas, A., Lee, A. W., Pearce, C. L., Berchuck, A., Schildkraut, J. M., Ramus, S. J., Monteiro, A. A., Narod, S. A., Sellers, T. A., Gayther, S. A., Kelemen, L. E., Chenevix-Trench, G., Risch, H. A., Pharoah, P. P., Goode, E. L., Phelan, C. M. 2018; 13 (7): e0197561

  Abstract

  Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.

  View details for PubMedID 29979793

• 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

• Genetic variants in the HLA class II region associated with risk of cutaneous squamous cell carcinoma. Cancer immunology, immunotherapy : CII Wang, W., Ollila, H. M., Whittemore, A. S., Demehri, S., Ioannidis, N. M., Jorgenson, E., Mignot, E., Asgari, M. M. 2018

  Abstract

  BACKGROUND: The immune system has been implicated in the pathophysiology of cutaneous squamous cell carcinoma (cSCC) as evidenced by the substantially increased risk of cSCC in immunosuppressed individuals. Associations between cSCC risk and single nucleotide polymorphisms (SNPs) in the HLA region have been identified by genome-wide association studies (GWAS). The translation of the associated HLA SNPs to structural amino acids changes in HLA molecules has not been previously elucidated.METHODS: Using data from a GWAS that included 7238 cSCC cases and 56,961 controls of non-Hispanic white ancestry, we imputed classical alleles and corresponding amino acid changes in HLA genes. Logistic regression models were used to examine associations between cSCC risk and genotyped or imputed SNPs, classical HLA alleles, and amino acid changes.RESULTS: Among the genotyped SNPs, cSCC risk was associated with rs28535317 (OR=1.20, p=9.88*10-11) corresponding to an amino-acid change from phenylalanine to leucine at codon 26 of HLA-DRB1 (OR=1.17, p=2.48*10-10). An additional independent association was observed for a threonine to isoleucine change at codon 107 of HLA-DQA1 (OR=1.14, p=2.34*10-9). Among the classical HLA alleles, cSCC was associated with DRB1*01 (OR=1.18, p=5.86*10-10). Conditional analyses revealed additional independent cSCC associations with DQA1*05:01 and DQA1*05:05. Extended haplotype analysis was used to complement the imputed haplotypes, which identified three extended haplotypes in the HLA-DR and HLA-DQ regions.CONCLUSIONS: Associations with specific HLA-DR and -DQ alleles are likely to explain previously observed GWAS signals in the HLA region associated with cSCC risk.

  View details for PubMedID 29754218

• 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

• 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

• Racial/ethnic differences in the epidemiology of ovarian cancer: a pooled analysis of 12 case-control studies INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Peres, L. C., Risch, H., Terry, K. L., Webb, P. M., Goodman, M. T., Wu, A. H., Alberg, A. J., Bandera, E. V., Barnholtz-Sloan, J., Bondy, M. L., Cote, M. L., Funkhouser, E., Moorman, P. G., Peters, E. S., Schwartz, A. G., Terry, P. D., Manichaikul, A., Abbott, S. E., Camacho, F., Jordan, S. J., Nagle, C. M., Rossing, M., Doherty, J. A., Modugno, F., Moysich, K., Ness, R., Berchuck, A., Cook, L., Nhu Le, Brooks-Wilson, A., Sieh, W., Whittemore, A., McGuire, V., Rothstein, J., Anton-Culver, H., Ziogas, A., Pearce, C. L., Tseng, C., Pike, M., Schildkraut, J. M., Australian Ovarian Canc Study Grp, African Amer Canc Epidemiology Stu, Ovarian Canc Assoc Consortium 2018; 47 (2): 460–72

  Abstract

  Ovarian cancer incidence differs substantially by race/ethnicity, but the reasons for this are not well understood. Data were pooled from the African American Cancer Epidemiology Study (AACES) and 11 case-control studies in the Ovarian Cancer Association Consortium (OCAC) to examine racial/ethnic differences in epidemiological characteristics with suspected involvement in epithelial ovarian cancer (EOC) aetiology.We used multivariable logistic regression to estimate associations for 17 reproductive, hormonal and lifestyle characteristics and EOC risk by race/ethnicity among 10 924 women with invasive EOC (8918 Non-Hispanic Whites, 433 Hispanics, 911 Blacks, 662 Asian/Pacific Islanders) and 16 150 controls (13 619 Non-Hispanic Whites, 533 Hispanics, 1233 Blacks, 765 Asian/Pacific Islanders). Likelihood ratio tests were used to evaluate heterogeneity in the risk factor associations by race/ethnicity.We observed statistically significant racial/ethnic heterogeneity for hysterectomy and EOC risk (P = 0.008), where the largest odds ratio (OR) was observed in Black women [OR = 1.64, 95% confidence interval (CI) = 1.34-2.02] compared with other racial/ethnic groups. Although not statistically significant, the associations for parity, first-degree family history of ovarian or breast cancer, and endometriosis varied by race/ethnicity. Asian/Pacific Islanders had the greatest magnitude of association for parity (≥3 births: OR = 0.38, 95% CI = 0.28-0.54), and Black women had the largest ORs for family history (OR = 1.77, 95% CI = 1.42-2.21) and endometriosis (OR = 2.42, 95% CI = 1.65-3.55).Although racial/ethnic heterogeneity was observed for hysterectomy, our findings support the validity of EOC risk factors across all racial/ethnic groups, and further suggest that any racial/ethnic population with a higher prevalence of a modifiable risk factor should be targeted to disseminate information about prevention.

  View details for PubMedID 29211900

  View details for PubMedCentralID PMC5913601

• Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study BRITISH JOURNAL OF CANCER Dixon-Suen, S. C., Nagle, C. M., Thrift, A. P., Pharoah, P. P., Ewing, A., Pearce, C., Zheng, W., Chenevix-Trench, G., Fasching, P. A., Beckmann, M. W., Lambrechts, D., Vergote, I., Lambrechts, S., Van Nieuwenhuysen, E., Rossing, M., Doherty, J. A., Wicklund, K. G., Chang-Claude, J., Jung, A. Y., Moysich, K. B., Odunsi, K., Goodman, M. T., Wilkens, L. R., Thompson, P. J., Shvetsov, Y. B., Doerk, T., Park-Simon, T., Hillemanns, P., Bogdanova, N., Butzow, R., Nevanlinna, H., Pelttari, L. M., Leminen, A., Modugno, F., Ness, R. B., Edwards, R. P., Kelley, J. L., Heitz, F., du Bois, A., Harter, P., Schwaab, I., Karlan, B. Y., Lester, J., Orsulic, S., Rimel, B. J., Kjaer, S. K., Hogdall, E., Jensen, A., Goode, E. L., Fridley, B. L., Cunningham, J. M., Winham, S. J., Giles, G. G., Bruinsma, F., Milne, R. L., Southey, M. C., Hildebrandt, M. T., Wu, X., Lu, K. H., Liang, D., Levine, D. A., Bisogna, M., Schildkraut, J. M., Berchuck, A., Cramer, D. W., Terry, K. L., Bandera, E. V., Olson, S. H., Salvesen, H. B., Thomsen, L., Kopperud, R. K., Bjorge, L., Kiemeney, L. A., Massuger, L. G., Pejovic, T., Bruegl, A., Cook, L. S., Le, N. D., Swenerton, K. D., Brooks-Wilson, A., Kelemen, L. E., Lubinski, J., Huzarski, T., Gronwald, J., Menkiszak, J., Wentzensen, N., Brinton, L., Yang, H., Lissowska, J., Hogdall, C. K., Lundvall, L., Song, H., Tyrer, J. P., Campbell, I., Eccles, D., Paul, J., Glasspool, R., Siddiqui, N., Whittemore, A. S., Sieh, W., McGuire, V., Rothstein, J. H., Narod, S. A., Phelan, C., Risch, H. A., McLaughlin, J. R., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S. A., Ramus, S. J., Gentry-Maharaj, A., Wu, A. H., Pike, M. C., Tseng, C., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Budzilowska, A., Rzepecka, I. K., Webb, P. M., Australian Ovarian Canc Study Grp, Ovarian Canc Assoc Consortium 2018; 118 (8): 1123–29

  Abstract

  Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias.We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis.Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours.Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.

  View details for PubMedID 29555990

• Susceptibility Loci-Associated Cutaneous Squamous Cell Carcinoma Invasiveness JOURNAL OF INVESTIGATIVE DERMATOLOGY Wang, W., Jorgenson, E., Whittemore, A. S., Asgari, M. M. 2018; 138 (3): 557–61

  Abstract

  Genome-wide association studies have identified genetic loci associated with cutaneous squamous cell carcinoma (cSCC) risk, but single-nucleotide polymorphism associations with cSCC invasiveness have not been investigated. We examined associations between cSCC invasiveness and 23 reported single-nucleotide polymorphisms among 67,833 non-Hispanic white subjects. Additionally, we performed a genome-wide scan and identified one SNP with significantly different frequencies in 5,724 subjects with at least one invasive tumor and 1,943 subjects with in situ tumors only. We then compared genotype frequencies among the invasive and in situ groups with those of 60,166 control subjects. The genome-wide scan identified that the T allele in single-nucleotide polymorphism rs41269979 in the class II human leukocyte antigen region was more frequent in the invasive than the in situ group (P = 4.93 × 10-8). Single-nucleotide polymorphisms in five of the 23 previously associated loci showed odds ratio heterogeneity between the in situ and invasive groups: rs447510 in HLA-DQA1 (Phet = 2.93 × 10-3), rs12203592 in IRF4 (Phet = 3.94 × 10-4), rs1805007 in MC1R (Phet = 7.71 × 10-3), and two SNPs in DEF8 (rs4268748, Phet = 1.09 × 10-4 and rs8063761, Phet = 1.40 × 10-4). These findings may provide new insight into the genetic basis of cSCC invasiveness and may help identify individuals at higher risk for developing clinically aggressive cSCC.

  View details for PubMedID 29054604

• MyD88 and TLR4 Expression in Epithelial Ovarian Cancer. Mayo Clinic proceedings Block, M. S., Vierkant, R. A., Rambau, P. F., Winham, S. J., Wagner, P., Traficante, N., Tołoczko, A., Tiezzi, D. G., Taran, F. A., Sinn, P., Sieh, W., Sharma, R., Rothstein, J. H., Ramón Y Cajal, T., Paz-Ares, L., Oszurek, O., Orsulic, S., Ness, R. B., Nelson, G., Modugno, F., Menkiszak, J., McGuire, V., McCauley, B. M., Mack, M., Lubiński, J., Longacre, T. A., Li, Z., Lester, J., Kennedy, C. J., Kalli, K. R., Jung, A. Y., Johnatty, S. E., Jimenez-Linan, M., Jensen, A., Intermaggio, M. P., Hung, J., Herpel, E., Hernandez, B. Y., Hartkopf, A. D., Harnett, P. R., Ghatage, P., García-Bueno, J. M., Gao, B., Fereday, S., Eilber, U., Edwards, R. P., de Sousa, C. B., de Andrade, J. M., Chudecka-Głaz, A., Chenevix-Trench, G., Cazorla, A., Brucker, S. Y., Alsop, J., Whittemore, A. S., Steed, H., Staebler, A., Moysich, K. B., Menon, U., Koziak, J. M., Kommoss, S., Kjaer, S. K., Kelemen, L. E., Karlan, B. Y., Huntsman, D. G., Høgdall, E., Gronwald, J., Goodman, M. T., Gilks, B., García, M. J., Fasching, P. A., de Fazio, A., Deen, S., Chang-Claude, J., Candido Dos Reis, F. J., Campbell, I. G., Brenton, J. D., Bowtell, D. D., Benítez, J., Pharoah, P. D., Köbel, M., Ramus, S. J., Goode, E. L. 2018; 93 (3): 307-320

  Abstract

  To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival.We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong).Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29-0.84] and 0.44 [0.21-0.89], respectively; P=.009 and P=.02, respectively).Results are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes.

  View details for DOI 10.1016/j.mayocp.2017.10.023

  View details for PubMedID 29502561

  View details for PubMedCentralID PMC5870793

• MyD88 and TLR4 Expression in Epithelial Ovarian Cancer MAYO CLINIC PROCEEDINGS Block, M. S., Vierkant, R. A., Rambau, P. F., Winham, S. J., Wagner, P., Traficante, N., Toloczko, A., Tiezzi, D. G., Taran, F., Sinn, P., Sieh, W., Sharma, R., Rothstein, J. H., Ramon y Cajal, T., Paz-Ares, L., Oszurek, O., Orsulic, S., Ness, R. B., Nelson, G., Modugno, F., Menkiszak, J., McGuire, V., McCauley, B. M., Mack, M., Lubinski, J., Longacre, T. A., Li, Z., Lester, J., Kennedy, C. J., Kalli, K. R., Jung, A. Y., Johnatty, S. E., Jimenez-Linan, M., Jensen, A., Intermaggio, M. P., Hung, J., Herpel, E., Hernandez, B. Y., Hartkopf, A. D., Harnett, P. R., Ghatage, P., Garcia-Bueno, J. M., Gao, B., Fereday, S., Eilber, U., Edwards, R. P., de Sousa, C. B., de Andrade, J. M., Chudecka-Glaz, A., Chenevix-Trench, G., Cazorla, A., Brucker, S. Y., Alsop, J., Whittemore, A. S., Steed, H., Staebler, A., Moysich, K. B., Menon, U., Koziak, J. M., Kommoss, S., Kjaer, S. K., Kelemen, L. E., Karlan, B. Y., Huntsman, D. G., Hogdall, E., Gronwald, J., Goodman, M. T., Gilks, B., Jose Garcia, M., Fasching, P. A., de Fazio, A., Deen, S., Chang-Claude, J., dos Reis, F., Campbell, I. G., Brenton, J. D., Bowtell, D. D., Benitez, J., Pharoah, P. P., Kobel, M., Ramus, S. J., Goode, E. L., Australian Ovarian Canc Study Grp 2018; 93 (3): 307–20

  View details for DOI 10.1016/j.mayocp.2017.10.023

  View details for Web of Science ID 000426558100011

• Persistent Postoperative Opioid Use in Older Head and Neck Cancer Patients. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery Saraswathula, A. n., Chen, M. M., Mudumbai, S. C., Whittemore, A. S., Divi, V. n. 2018: 194599818778276

  Abstract

  Objectives Despite the epidemic of opioid overuse among American patients, there are limited data regarding the prevalence of such use among patients with head and neck cancer (HNC). Here, we report on the prevalence of persistent postoperative opioid (PPO) use and its risk factors among older patients with HNC undergoing surgery. Study Design Retrospective cohort study. Setting Surveillance, Epidemiology, and End Results (SEER)-Medicare linked cancer registry-claims database. Subjects and Methods We identified patients aged 66 years or older who were diagnosed with HNC from 2008 to 2013, underwent primary surgical resection for their cancers, and met certain insurance and discharge criteria. The primary outcome was PPO use, defined as new opioid prescriptions 90 to 180 days postoperatively. We used multivariable logistic regression to evaluate associations between PPO use and factors such as demographics and postoperative treatment. Results Of the 1190 eligible patients with HNC, 866 (72.8%) received opioid prescriptions attributable to their surgery. Among these 866 patients, the prevalence of PPO use was 33.3% overall; it was 48.3% among the 428 patients with preoperative opioid use compared to 18.5% among the 438 opioid-naive patients (adjusted odds ratio [OR], 3.96; 95% confidence interval [CI], 2.80-5.59). Other factors associated with PPO use include postoperative radiotherapy (OR, 1.99; 95%, CI 1.33-2.98) and Charlson comorbidity index (OR, 1.20; 95% CI, 1.03-1.41). Postoperative chemotherapy (OR, 1.19; 95% CI, 0.73-1.95) was not significantly associated with PPO use. Conclusions PPO use is a substantial problem in older surgical patients with HNC, one that warrants consideration of alternative treatment strategies and continued examination of prescription guidelines for patients with HNC.

  View details for PubMedID 29807503

• 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

• Circulating sex hormones in relation to anthropometric, sociodemographic and behavioural factors in an international dataset of 12,300 men PLOS ONE Watts, E. L., Appleby, P. N., Albanese, D., Black, A., Chan, J. M., Chen, C., Cirillo, P. M., Cohn, B. A., Cook, M. B., Donovan, J. L., Ferrucci, L., Garland, C. F., Giles, G. G., Goodman, P. J., Habel, L. A., Haiman, C. A., Holly, J. P., Hoover, R. N., Kaaks, R., Knekt, P., Kolonel, L. N., Kubo, T., Le Marchand, L., Luostarinen, T., Maclnnis, R. J., Maenpaa, H. O., Mannisto, S., Metter, E., Milne, R. L., Nomura, A. Y., Oliver, S. E., Parsons, J., Peeters, P. H., Platz, E. A., Riboli, E., Ricceri, F., Rinaldi, S., Rissanen, H., Sawada, N., Schaefer, C. A., Schenk, J. M., Stanczyk, F. Z., Stampfer, M., Stattin, P., Stenman, U., Tjonneland, A., Trichopoulou, A., Thompson, I. M., Tsugane, S., Vatten, L., Whittemore, A. S., Ziegler, R. G., Allen, N. E., Key, T. J., Travis, R. C. 2017; 12 (12): e0187741

  Abstract

  Sex hormones have been implicated in the etiology of a number of diseases. To better understand disease etiology and the mechanisms of disease-risk factor associations, this analysis aimed to investigate the associations of anthropometric, sociodemographic and behavioural factors with a range of circulating sex hormones and sex hormone-binding globulin.Statistical analyses of individual participant data from 12,330 male controls aged 25-85 years from 25 studies involved in the Endogenous Hormones Nutritional Biomarkers and Prostate Cancer Collaborative Group. Analysis of variance was used to estimate geometric means adjusted for study and relevant covariates.Older age was associated with higher concentrations of sex hormone-binding globulin and dihydrotestosterone and lower concentrations of dehydroepiandrosterone sulfate, free testosterone, androstenedione, androstanediol glucuronide and free estradiol. Higher body mass index was associated with higher concentrations of free estradiol, androstanediol glucuronide, estradiol and estrone and lower concentrations of dihydrotestosterone, testosterone, sex hormone-binding globulin, free testosterone, androstenedione and dehydroepiandrosterone sulfate. Taller height was associated with lower concentrations of androstenedione, testosterone, free testosterone and sex hormone-binding globulin and higher concentrations of androstanediol glucuronide. Current smoking was associated with higher concentrations of androstenedione, sex hormone-binding globulin and testosterone. Alcohol consumption was associated with higher concentrations of dehydroepiandrosterone sulfate, androstenedione and androstanediol glucuronide. East Asians had lower concentrations of androstanediol glucuronide and African Americans had higher concentrations of estrogens. Education and marital status were modestly associated with a small number of hormones.Circulating sex hormones in men are strongly associated with age and body mass index, and to a lesser extent with smoking status and alcohol consumption.

  View details for PubMedID 29281666

• 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

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• Dose-Response Association of CD8(+) Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer JAMA ONCOLOGY Goode, E. L., Block, M. S., Kalli, K. R., Vierkant, R. A., Chen, W., Fogarty, Z. C., Gentry-Maharaj, A., Toloczko, A., Hein, A., Bouligny, A. L., Jensen, A., Osorio, A., Hartkopf, A. D., Ryan, A., Chudecka-Glaz, A., Magliocco, A. M., Hartmann, A., Jung, A. Y., Gao, B., Hernandez, B. Y., Fridley, B. L., McCauley, B. M., Kennedy, C. J., Wang, C., Karpinskyj, C., de Sousa, C. B., Tiezzi, D. G., Wachter, D. L., Herpel, E., Taran, F., Modugno, F., Nelson, G., Lubinski, J., Menkiszak, J., Alsop, J., Lester, J., Garcia-Donas, J., Nation, J., Hung, J., Palacios, J., Rothstein, J. H., Kelley, J. L., de Andrade, J. M., Robles-Diaz, L., Intermaggio, M. P., Widschwendter, M., Beckmann, M. W., Ruebner, M., Jimenez-Linan, M., Singh, N., Oszurek, O., Harnett, P. R., Rambau, P. F., Sinn, P., Wagner, P., Ghatage, P., Sharma, R., Edwards, R. P., Ness, R. B., Orsulic, S., Brucker, S. Y., Johnatty, S. E., Longacre, T. A., Eilber, U., McGuire, V., Sieh, W., Natanzon, Y., Li, Z., Whittemore, A. S., deFazio, A., Staebler, A., Karlan, B. Y., Gilks, B., Bowtell, D. D., Hogdall, E., Candido dos Reis, F. J., Steed, H., Campbell, I. G., Gronwald, J., Benitez, J., Koziak, J. M., Chang-Claude, J., Moysich, K. B., Kelemen, L. E., Cook, L. S., Goodman, M. T., Jose Garcia, M., Fasching, P. A., Kommoss, S., Deen, S., Kjaer, S. K., Menon, U., Brenton, J. D., Pharoah, P. P., Chenevix-Trench, G., Huntsman, D. G., Winham, S. J., Kobel, M., Ramus, S. J., Ovarian Tumor Tissue Analysis OTTA 2017; 3 (12): e173290

  Abstract

  Cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors.To define the prognostic role of CD8+ TILs in epithelial ovarian cancer.This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years.Following immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines.Overall survival time.The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form.This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.

  View details for PubMedID 29049607

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• 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

• Age at Menarche and Late Adolescent Adiposity Associated with Mammographic Density on Processed Digital Mammograms in 24,840 Women CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Alexeeff, S. E., Odo, N. U., Lipson, J. A., Achacosol, N., Rothstein, J. H., Yaffe, M. J., Liang, R. Y., Acton, L., McGuire, V., Whittemore, A. S., Rubin, D. L., Sieh, W., Habel, L. A. 2017; 26 (9): 1450–58

  Abstract

  Background: High mammographic density is strongly associated with increased breast cancer risk. Some, but not all, risk factors for breast cancer are also associated with higher mammographic density.Methods: The study cohort (N = 24,840) was drawn from the Research Program in Genes, Environment and Health of Kaiser Permanente Northern California and included non-Hispanic white females ages 40 to 74 years with a full-field digital mammogram (FFDM). Percent density (PD) and dense area (DA) were measured by a radiological technologist using Cumulus. The association of age at menarche and late adolescent body mass index (BMI) with PD and DA were modeled using linear regression adjusted for confounders.Results: Age at menarche and late adolescent BMI were negatively correlated. Age at menarche was positively associated with PD (P value for trend <0.0001) and DA (P value for trend <0.0001) in fully adjusted models. Compared with the reference category of ages 12 to 13 years at menarche, menarche at age >16 years was associated with an increase in PD of 1.47% (95% CI, 0.69-2.25) and an increase in DA of 1.59 cm2 (95% CI, 0.48-2.70). Late adolescent BMI was inversely associated with PD (P < 0.0001) and DA (P < 0.0001) in fully adjusted models.Conclusions: Age at menarche and late adolescent BMI are both associated with Cumulus measures of mammographic density on processed FFDM images.Impact: Age at menarche and late adolescent BMI may act through different pathways. The long-term effects of age at menarche on cancer risk may be mediated through factors besides mammographic density. Cancer Epidemiol Biomarkers Prev; 26(9); 1450-8. ©2017 AACR.

  View details for PubMedID 28698185

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• Germline whole exome sequencing and large-scale replication identifies FANCM as a likely high grade serous ovarian cancer susceptibility gene. Oncotarget Dicks, E., Song, H., Ramus, S. J., Oudenhove, E. V., Tyrer, J. P., Intermaggio, M. P., Kar, S., Harrington, P., Bowtell, D. D., Group, A. S., Cicek, M. S., Cunningham, J. M., Fridley, B. L., Alsop, J., Jimenez-Linan, M., Piskorz, A., Goranova, T., Kent, E., Siddiqui, N., Paul, J., Crawford, R., Poblete, S., Lele, S., Sucheston-Campbell, L., Moysich, K. B., Sieh, W., McGuire, V., Lester, J., Odunsi, K., Whittemore, A. S., Bogdanova, N., Dürst, M., Hillemanns, P., Karlan, B. Y., Gentry-Maharaj, A., Menon, U., Tischkowitz, M., Levine, D., Brenton, J. D., Dörk, T., Goode, E. L., Gayther, S. A., Pharoah, D. P. 2017; 8 (31): 50930-50940

  Abstract

  We analyzed whole exome sequencing data in germline DNA from 412 high grade serous ovarian cancer (HGSOC) cases from The Cancer Genome Atlas Project and identified 5,517 genes harboring a predicted deleterious germline coding mutation in at least one HGSOC case. Gene-set enrichment analysis showed enrichment for genes involved in DNA repair (p = 1.8×10-3). Twelve DNA repair genes - APEX1, APLF, ATX, EME1, FANCL, FANCM, MAD2L2, PARP2, PARP3, POLN, RAD54L and SMUG1 - were prioritized for targeted sequencing in up to 3,107 HGSOC cases, 1,491 cases of other epithelial ovarian cancer (EOC) subtypes and 3,368 unaffected controls of European origin. We estimated mutation prevalence for each gene and tested for associations with disease risk. Mutations were identified in both cases and controls in all genes except MAD2L2, where we found no evidence of mutations in controls. In FANCM we observed a higher mutation frequency in HGSOC cases compared to controls (29/3,107 cases, 0.96 percent; 13/3,368 controls, 0.38 percent; P=0.008) with little evidence for association with other subtypes (6/1,491, 0.40 percent; P=0.82). The relative risk of HGSOC associated with deleterious FANCM mutations was estimated to be 2.5 (95% CI 1.3 - 5.0; P=0.006). In summary, whole exome sequencing of EOC cases with large-scale replication in case-control studies has identified FANCM as a likely novel susceptibility gene for HGSOC, with mutations associated with a moderate increase in risk. These data may have clinical implications for risk prediction and prevention approaches for high-grade serous ovarian cancer in the future and a significant impact on reducing disease mortality.

  View details for DOI 10.18632/oncotarget.15871

  View details for PubMedID 28881617

  View details for PubMedCentralID PMC5584218

• 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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• ERRATUM. The Prostate Whittemore, A. S. 2017; 77 (8): 934

  View details for DOI 10.1002/pros.23345

  View details for PubMedID 28429423

• 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

• 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

• No Evidence That Genetic Variation in the Myeloid-Derived Suppressor Cell Pathway Influences Ovarian Cancer Survival. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Sucheston-Campbell, L. E., Cannioto, R., Clay, A. I., Etter, J. L., Eng, K. H., Liu, S., Battaglia, S., Hu, Q., Szender, J. B., Minlikeeva, A., Joseph, J. M., Mayor, P., Abrams, S. I., Segal, B. H., Wallace, P. K., Soh, K. T., Zsiros, E., Anton-Culver, H., Bandera, E. V., Beckmann, M. W., Berchuck, A., Bjorge, L., Bruegl, A., Campbell, I. G., Campbell, S. P., Chenevix-Trench, G., Cramer, D. W., Dansonka-Mieszkowska, A., Dao, F., Diergaarde, B., Doerk, T., Doherty, J. A., du Bois, A., Eccles, D., Engelholm, S. A., Fasching, P. A., Gayther, S. A., Gentry-Maharaj, A., Glasspool, R. M., Goodman, M. T., Gronwald, J., Harter, P., Hein, A., Heitz, F., Hillemmanns, P., Høgdall, C., Høgdall, E. V., Huzarski, T., Jensen, A., Johnatty, S. E., Jung, A., Karlan, B. Y., Klapdor, R., Kluz, T., Konopka, B., Kjær, S. K., Kupryjanczyk, J., Lambrechts, D., Lester, J., Lubinski, J., Levine, D. A., Lundvall, L., McGuire, V., McNeish, I. A., Menon, U., Modugno, F., Ness, R. B., Orsulic, S., Paul, J., Pearce, C. L., Pejovic, T., Pharoah, P., Ramus, S. J., Rothstein, J., Rossing, M. A., Rübner, M., Schildkraut, J. M., Schmalfeldt, B., Schwaab, I., Siddiqui, N., Sieh, W., Sobiczewski, P., Song, H., Terry, K. L., van Nieuwenhuysen, E., Vanderstichele, A., Vergote, I., Walsh, C. S., Webb, P. M., Wentzensen, N., Whittemore, A. S., Wu, A. H., Ziogas, A., Odunsi, K., Chang-Claude, J., Goode, E. L., Moysich, K. B. 2017; 26 (3): 420-424

  Abstract

  Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses.Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival.Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (P < 3.5 × 10(-5)), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival.Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes.Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev; 26(3); 420-4. ©2016 AACR.

  View details for DOI 10.1158/1055-9965.EPI-16-0631

  View details for PubMedID 27677730

• gsSKAT: Rapid gene set analysis and multiple testing correction for rare-variant association studies using weighted linear kernels. Genetic epidemiology Larson, N. B., McDonnell, S., Cannon Albright, L., Teerlink, C., Stanford, J., Ostrander, E. A., Isaacs, W. B., Xu, J., Cooney, K. A., Lange, E., Schleutker, J., Carpten, J. D., Powell, I., Bailey-Wilson, J. E., Cussenot, O., Cancel-Tassin, G., Giles, G. G., MacInnis, R. J., Maier, C., Whittemore, A. S., Hsieh, C., Wiklund, F., Catolona, W. J., Foulkes, W., Mandal, D., Eeles, R., Kote-Jarai, Z., Ackerman, M. J., Olson, T. M., Klein, C. J., Thibodeau, S. N., Schaid, D. J. 2017

  Abstract

  Next-generation sequencing technologies have afforded unprecedented characterization of low-frequency and rare genetic variation. Due to low power for single-variant testing, aggregative methods are commonly used to combine observed rare variation within a single gene. Causal variation may also aggregate across multiple genes within relevant biomolecular pathways. Kernel-machine regression and adaptive testing methods for aggregative rare-variant association testing have been demonstrated to be powerful approaches for pathway-level analysis, although these methods tend to be computationally intensive at high-variant dimensionality and require access to complete data. An additional analytical issue in scans of large pathway definition sets is multiple testing correction. Gene set definitions may exhibit substantial genic overlap, and the impact of the resultant correlation in test statistics on Type I error rate control for large agnostic gene set scans has not been fully explored. Herein, we first outline a statistical strategy for aggregative rare-variant analysis using component gene-level linear kernel score test summary statistics as well as derive simple estimators of the effective number of tests for family-wise error rate control. We then conduct extensive simulation studies to characterize the behavior of our approach relative to direct application of kernel and adaptive methods under a variety of conditions. We also apply our method to two case-control studies, respectively, evaluating rare variation in hereditary prostate cancer and schizophrenia. Finally, we provide open-source R code for public use to facilitate easy application of our methods to existing rare-variant analysis results.

  View details for DOI 10.1002/gepi.22036

  View details for PubMedID 28211093

• Predicting Prostate Cancer Recurrence After Radical Prostatectomy PROSTATE Jeffers, A., Sochat, V., Kattan, M. W., Yu, C., Melcon, E., Yamoah, K., Rebbeck, T. R., Whittemore, A. S. 2017; 77 (3): 291-298

  View details for DOI 10.1002/pros.23268

  View details for Web of Science ID 000393893600006

• Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci. British journal of cancer Kar, S. P., Adler, E., Tyrer, J., Hazelett, D., Anton-Culver, H., Bandera, E. V., Beckmann, M. W., Berchuck, A., Bogdanova, N., Brinton, L., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Cook, L. S., Cramer, D. W., Cunningham, J. M., Dansonka-Mieszkowska, A., Doherty, J. A., Dörk, T., Dürst, M., Eccles, D., Fasching, P. A., Flanagan, J., Gentry-Maharaj, A., Glasspool, R., Goode, E. L., Goodman, M. T., Gronwald, J., Heitz, F., Hildebrandt, M. A., Høgdall, E., Høgdall, C. K., Huntsman, D. G., Jensen, A., Karlan, B. Y., Kelemen, L. E., Kiemeney, L. A., Kjaer, S. K., Kupryjanczyk, J., Lambrechts, D., Levine, D. A., Li, Q., Lissowska, J., Lu, K. H., Lubinski, J., Massuger, L. F., McGuire, V., McNeish, I., Menon, U., Modugno, F., Monteiro, A. N., Moysich, K. B., Ness, R. B., Nevanlinna, H., Paul, J., Pearce, C. L., Pejovic, T., Permuth, J. B., Phelan, C., Pike, M. C., Poole, E. M., Ramus, S. J., Risch, H. A., Rossing, M. A., Salvesen, H. B., Schildkraut, J. M., Sellers, T. A., Sherman, M., Siddiqui, N., Sieh, W., Song, H., Southey, M., Terry, K. L., Tworoger, S. S., Walsh, C., Wentzensen, N., Whittemore, A. S., Wu, A. H., Yang, H., Zheng, W., Ziogas, A., Freedman, M. L., Gayther, S. A., Pharoah, P. D., Lawrenson, K. 2017; 116 (4): 524-535

  Abstract

  Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis.All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals).The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10(-5) (including six with P<5 × 10(-8)). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation.Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.

  View details for DOI 10.1038/bjc.2016.426

  View details for PubMedID 28103614

• Cutaneous squamous cell cancer (cSCC) risk and the human leukocyte antigen (HLA) system. Human immunology Yesantharao, P., Wang, W., Ioannidis, N. M., Demehri, S., Whittemore, A. S., Asgari, M. M. 2017

  Abstract

  Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer among Caucasians in the United States, with rising incidence over the past decade. Treatment for non-melanoma skin cancer, including cSCC, in the United States was estimated to cost $4.8 billion in 2014. Thus, an understanding of cSCC pathogenesis could have important public health implications. Immune function impacts cSCC risk, given that cSCC incidence rates are substantially higher in patients with compromised immune systems. We report a systematic review of published associations between cSCC risk and the human leukocyte antigen (HLA) system. This review includes studies that analyze germline class I and class II HLA allelic variation as well as HLA cell-surface protein expression levels associated with cSCC risk. We propose biological mechanisms for these HLA-cSCC associations based on known mechanisms of HLA involvement in other diseases. The review suggests that immunity regulates the development of cSCC and that HLA-cSCC associations differ between immunocompetent and immunosuppressed patients. This difference may reflect the presence of viral co-factors that affect tumorigenesis in immunosuppressed patients. Finally, we highlight limitations in the literature on HLA-cSCC associations, and suggest directions for future research aimed at understanding, preventing and treating cSCC.

  View details for DOI 10.1016/j.humimm.2017.02.002

  View details for PubMedID 28185865

  View details for PubMedCentralID PMC5428079

• Breast Cancer Risk and Mammographic Density Assessed with Semiautomated and Fully Automated Methods and BI-RADS. Radiology Jeffers, A. M., Sieh, W., Lipson, J. A., Rothstein, J. H., McGuire, V., Whittemore, A. S., Rubin, D. L. 2017; 282 (2): 348-355

  Abstract

  Purpose To compare three metrics of breast density on full-field digital mammographic (FFDM) images as predictors of future breast cancer risk. Materials and Methods This institutional review board-approved study included 125 women with invasive breast cancer and 274 age- and race-matched control subjects who underwent screening FFDM during 2004-2013 and provided informed consent. The percentage of density and dense area were assessed semiautomatically with software (Cumulus 4.0; University of Toronto, Toronto, Canada), and volumetric percentage of density and dense volume were assessed automatically with software (Volpara; Volpara Solutions, Wellington, New Zealand). Clinical Breast Imaging Reporting and Data System (BI-RADS) classifications of breast density were extracted from mammography reports. Odds ratios and 95% confidence intervals (CIs) were estimated by using conditional logistic regression stratified according to age and race and adjusted for body mass index, parity, and menopausal status, and the area under the receiver operating characteristic curve (AUC) was computed. Results The adjusted odds ratios and 95% CIs for each standard deviation increment of the percentage of density, dense area, volumetric percentage of density, and dense volume were 1.61 (95% CI: 1.19, 2.19), 1.49 (95% CI: 1.15, 1.92), 1.54 (95% CI: 1.12, 2.10), and 1.41 (95% CI: 1.11, 1.80), respectively. Odds ratios for women with extremely dense breasts compared with those with scattered areas of fibroglandular density were 2.06 (95% CI: 0.85, 4.97) and 2.05 (95% CI: 0.90, 4.64) for BI-RADS and Volpara density classifications, respectively. Clinical BI-RADS was more accurate (AUC, 0.68; 95% CI: 0.63, 0.74) than Volpara (AUC, 0.64; 95% CI: 0.58, 0.70) and continuous measures of percentage of density (AUC, 0.66; 95% CI: 0.60, 0.72), dense area (AUC, 0.66; 95% CI: 0.60, 0.72), volumetric percentage of density (AUC, 0.64; 95% CI: 0.58, 0.70), and density volume (AUC, 0.65; 95% CI: 0.59, 0.71), although the AUC differences were not statistically significant. Conclusion Mammographic density on FFDM images was positively associated with breast cancer risk by using the computer assisted methods and BI-RADS. BI-RADS classification was as accurate as computer-assisted methods for discrimination of patients from control subjects. (©) RSNA, 2016.

  View details for DOI 10.1148/radiol.2016152062

  View details for PubMedID 27598536

• Cigarette smoking is associated with adverse survival among women with ovarian cancer: Results from a pooled analysis of 19 studies. International journal of cancer Praestegaard, C., Jensen, A., Jensen, S. M., Nielsen, T. S., Webb, P. M., Nagle, C. M., deFazio, A., Høgdall, E., Rossing, M. A., Doherty, J. A., Wicklund, K. G., Goodman, M. T., Modugno, F., Moysich, K., Ness, R. B., Edwards, R., Matsuo, K., Hosono, S., Goode, E. L., Winham, S. J., Fridley, B. L., Cramer, D. W., Terry, K. L., Schildkraut, J. M., Berchuck, A., Bandera, E. V., Paddock, L. E., Massuger, L. F., Wentzensen, N., Pharoah, P., Song, H., Whittemore, A., McGuire, V., Sieh, W., Rothstein, J., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S. A., Ramus, S. J., Gentry-Maharaj, A., Wu, A. H., Pearce, C. L., Pike, M., Lee, A. W., Sutphen, R., Chang-Claude, J., Risch, H. A., Kjaer, S. K. 2017

  Abstract

  Cigarette smoking is associated with an increased risk of developing mucinous ovarian tumors but whether it is associated with ovarian cancer survival overall or for the different histotypes is unestablished. Furthermore, it is unknown whether the association between cigarette smoking and survival differs according to strata of ovarian cancer stage at diagnosis. In a large pooled analysis, we evaluated the association between various measures of cigarette smoking and survival among women with epithelial ovarian cancer. We obtained data from 19 case-control studies in the Ovarian Cancer Association Consortium (OCAC), including 9,114 women diagnosed with ovarian cancer. Cox regression models were used to estimate adjusted study-specific hazard ratios (HRs), which were combined into pooled hazard ratios (pHR) with corresponding 95% confidence intervals (CIs) under random effects models. Overall, 5,149 (57%) women died during a median follow-up period of 7.0 years. Among women diagnosed with ovarian cancer, both current (pHR = 1.17, 95% CI: 1.08-1.28) and former smokers (pHR = 1.10, 95% CI: 1.02-1.18) had worse survival compared with never smoking women. In histotype-stratified analyses, associations were observed for mucinous (current smoking: pHR = 1.91, 95% CI: 1.01-3.65) and serous histotypes (current smoking: pHR = 1.11, 95% CI: 1.00-1.23; former smoking: pHR = 1.12, 95% CI: 1.04-1.20). Further, our results suggested that current smoking has a greater impact on survival among women with localized than disseminated disease. The identification of cigarette smoking as a modifiable factor associated with survival has potential clinical importance as a focus area to improve ovarian cancer prognosis.

  View details for DOI 10.1002/ijc.30600

  View details for PubMedID 28063166

• FIRE: functional inference of genetic variants that regulate gene expression. Bioinformatics (Oxford, England) Ioannidis, N. M., Davis, J. R., DeGorter, M. K., Larson, N. B., McDonnell, S. K., French, A. J., Battle, A. J., Hastie, T. J., Thibodeau, S. N., Montgomery, S. B., Bustamante, C. D., Sieh, W. n., Whittemore, A. S. 2017; 33 (24): 3895–3901

  Abstract

  Interpreting genetic variation in noncoding regions of the genome is an important challenge for personal genome analysis. One mechanism by which noncoding single nucleotide variants (SNVs) influence downstream phenotypes is through the regulation of gene expression. Methods to predict whether or not individual SNVs are likely to regulate gene expression would aid interpretation of variants of unknown significance identified in whole-genome sequencing studies.We developed FIRE (Functional Inference of Regulators of Expression), a tool to score both noncoding and coding SNVs based on their potential to regulate the expression levels of nearby genes. FIRE consists of 23 random forests trained to recognize SNVs in cis-expression quantitative trait loci (cis-eQTLs) using a set of 92 genomic annotations as predictive features. FIRE scores discriminate cis-eQTL SNVs from non-eQTL SNVs in the training set with a cross-validated area under the receiver operating characteristic curve (AUC) of 0.807, and discriminate cis-eQTL SNVs shared across six populations of different ancestry from non-eQTL SNVs with an AUC of 0.939. FIRE scores are also predictive of cis-eQTL SNVs across a variety of tissue types.FIRE scores for genome-wide SNVs in hg19/GRCh37 are available for download at https://sites.google.com/site/fireregulatoryvariation/.nilah@stanford.edu.Supplementary data are available at Bioinformatics online.

  View details for PubMedID 28961785

• Does radiotherapy still have a role in unresected biliary tract cancer? Cancer medicine Pollom, E. L., Alagappan, M., Park, L. S., Whittemore, A. S., Koong, A. C., Chang, D. T. 2017; 6 (1): 129-141

  Abstract

  The benefits of radiotherapy for inoperable biliary tract cancer remain unclear due to the lack of randomized data. We evaluated the impact of radiotherapy on survival in elderly patients using the SEER-Medicare database. Patients in the SEER-Medicare database with inoperable biliary tract tumors diagnosed between 1998 and 2011 were included. We used multivariate logistic regression to evaluate factors associated with treatment selection, and multivariate Cox regression and propensity score matching to evaluate treatment selection in relation to subsequent survival. Of the 2343 patients included, 451 (19%) received radiotherapy within 4 months of diagnosis. The use of radiotherapy declined over time, and was influenced by receipt of chemotherapy and patient age, race, marital status, poverty status, and tumor stage and type. Median survival was 9.3 (95% CI 8.7-9.7) months among patients who did not receive radiation and 10.0 (95% CI 9.1-11.3) months among those who received radiation, conditional on having survived 4 months. In patients who received chemotherapy (n = 1053), receipt of radiation was associated with improved survival, with an adjusted hazard ratio of 0.82 (95% 0.70-0.97, P = 0.02). In patients who did not receive chemotherapy (n = 1290), receipt of radiation was not associated with improved survival, with an adjusted hazard ratio of 1.09 (95% 0.91-1.30, P = 0.34). Propensity-scored matched analyses showed similar results. Despite the survival benefit associated with the addition of radiotherapy to chemotherapy, the use of radiation for unresectable biliary tract cancers has declined over time.

  View details for DOI 10.1002/cam4.975

  View details for PubMedID 27891822

• Evaluating disease prediction models using a cohort whose covariate distribution differs from that of the target population. Statistical methods in medical research Powers, S., McGuire, V., Bernstein, L., Canchola, A. J., Whittemore, A. S. 2017: 962280217723945

  Abstract

  Personal predictive models for disease development play important roles in chronic disease prevention. The performance of these models is evaluated by applying them to the baseline covariates of participants in external cohort studies, with model predictions compared to subjects' subsequent disease incidence. However, the covariate distribution among participants in a validation cohort may differ from that of the population for which the model will be used. Since estimates of predictive model performance depend on the distribution of covariates among the subjects to which it is applied, such differences can cause misleading estimates of model performance in the target population. We propose a method for addressing this problem by weighting the cohort subjects to make their covariate distribution better match that of the target population. Simulations show that the method provides accurate estimates of model performance in the target population, while un-weighted estimates may not. We illustrate the method by applying it to evaluate an ovarian cancer prediction model targeted to US women, using cohort data from participants in the California Teachers Study. The methods can be implemented using open-source code for public use as the R-package RMAP (Risk Model Assessment Package) available at http://stanford.edu/~ggong/rmap/ .

  View details for PubMedID 28812439

• Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration ONCOTARGET Permuth, J. B., Reid, B., Earp, M., Chen, Y. A., Monteiro, A. N., Chen, Z., Chenevix-Trench, G., Fasching, P. A., Beckmann, M. W., Lambrechts, D., Vanderstichele, A., Van Niewenhuyse, E., Vergote, I., Rossing, M. A., Doherty, J. A., Chang-Claude, J., Moysich, K., Odunsi, K., Goodman, M. T., Shvetsov, Y. B., Wilkens, L. R., Thompson, P. J., Doerk, T., Bogdanova, N., Butzow, R., Nevanlinna, H., Pelttari, L., Leminen, A., Modugno, F., Edwards, R. P., Ness, R. B., Kelley, J., Heitz, F., Karlan, B., Lester, J., Kjaer, S. K., Jensen, A., Giles, G., Hildebrandt, M., Liang, D., Lu, K. H., Wu, X., Levine, D. A., Bisogna, M., Berchuck, A., Cramer, D. W., Terry, K. L., Tworoger, S. S., Poole, E. M., Bandera, E. V., Fridley, B., Cunningham, J., Winham, S. J., Olson, S. H., Orlow, I., Bjorge, L., Kiemeney, L. A., Massuger, L., Pejovic, T., Moffitt, M., Le, N., Cook, L. S., Brooks-Wilson, A., Kelemen, L. E., Gronwald, J., Lubinski, J., Wentzensen, N., Brinton, L. A., Lissowska, J., Yang, H., Hogdall, E., Hogdall, C., Lundvall, L., Pharoah, P. D., Song, H., Campbell, I., Eccles, D., McNeish, I., Whittemore, A., McGuire, V., Sieh, W., Rothstein, J., Phelan, C. M., Risch, H., Narod, S., McLaughlin, J., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S., Ramus, S. J., Gentry-Maharaj, A., Pearce, C. L., Wu, A. H., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Schildkraut, J. M., Cheng, J. Q., Goode, E. L., Sellers, T. A. 2016; 7 (45): 72381-72394

  Abstract

  RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for European ancestry. We conducted gene-level analyses using the Admixture Maximum Likelihood (AML) test and the Sequence-Kernel Association test for common and rare variants (SKAT-CR). Association analysis revealed top risk-associated SNP rs77027562 (OR (95% CI)= 1.39 (1.17-1.64), P=1.0x10-4) in ADAR3 and rs185455523 in SND1 (OR (95% CI)= 0.68 (0.56-0.83), P=2.0x10-4). When restricting to serous histology (n=6,500), the magnitude of association strengthened for rs185455523 (OR=0.60, P=1.0x10-4). Gene-level analyses revealed that variation in ADAR was associated (P<0.05) with EOC susceptibility, with PAML=0.022 and PSKAT-CR=0.020. Expression quantitative trait locus analysis in EOC tissue revealed significant associations (P<0.05) with ADAR expression for several SNPs in ADAR, including rs1127313 (G/A), a SNP in the 3' untranslated region. In summary, germline variation involving RNA editing genes may influence EOC susceptibility, warranting further investigation of inherited and acquired alterations affecting RNA editing.

  View details for DOI 10.18632/oncotarget.10546

  View details for PubMedID 27911851

• A GWAS of Cutaneous Squamous Cell Carcinoma-Letter. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Whittemore, A. S., Wang, W., Jorgenson, E., Asgari, M. M. 2016; 25 (11): 1534

  View details for DOI 10.1158/1055-9965.EPI-16-0502

  View details for PubMedID 27803070

  View details for PubMedCentralID PMC5113720

• Predicting Prostate Cancer Recurrence After Radical Prostatectomy. Prostate Jeffers, A., Sochat, V., Kattan, M. W., Yu, C., Melcon, E., Yamoah, K., Rebbeck, T. R., Whittemore, A. S. 2016

  Abstract

  Prostate cancer prognosis is variable, and management decisions involve balancing patients' risks of recurrence and recurrence-free death. Moreover, the roles of body mass index (BMI) and race in risk of recurrence are controversial [1,2]. To address these issues, we developed and cross-validated RAPS (Risks After Prostate Surgery), a personal prediction model for biochemical recurrence (BCR) within 10 years of radical prostatectomy (RP) that includes BMI and race as possible predictors, and recurrence-free death as a competing risk.RAPS uses a patient's risk factors at surgery to assign him a recurrence probability based on statistical learning methods applied to a cohort of 1,276 patients undergoing RP at the University of Pennsylvania. We compared the performance of RAPS to that of an existing model with respect to calibration (by comparing observed and predicted outcomes), and discrimination (using the area under the receiver operating characteristic curve (AUC)).RAPS' cross-validated BCR predictions provided better calibration than those of an existing model that underestimated patients' risks. Discrimination was similar for the two models, with BCR AUCs of 0.793, 95% confidence interval (0.766-0.820) for RAPS, and 0.780 (0.745-0.815) for the existing model. RAPS' most important BCR predictors were tumor grade, preoperative prostate-specific antigen (PSA) level and BMI; race was less important [3]. RAPS' predictions can be obtained online at https://predict.shinyapps.io/raps.RAPS' cross-validated BCR predictions were better calibrated than those of an existing model, and BMI information contributed substantially to these predictions. RAPS predictions for recurrence-free death were limited by lack of co-morbidity data; however the model provides a simple framework for extension to include such data. Its use and extension should facilitate decision strategies for post-RP prostate cancer management. Prostate 77:291-298, 2017. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/pros.23268

  View details for PubMedID 27775165

• Risk Prediction for Epithelial Ovarian Cancer in 11 United States-Based Case-Control Studies: Incorporation of Epidemiologic Risk Factors and 17 Confirmed Genetic Loci AMERICAN JOURNAL OF EPIDEMIOLOGY Clyde, M. A., Weber, R. P., Iversen, E. S., Poole, E. M., Doherty, J. A., Goodman, M. T., Ness, R. B., Risch, H. A., Rossing, M. A., Terry, K. L., Wentzensen, N., Whittemore, A. S., Anton-Culver, H., Bandera, E. V., Berchuck, A., Carney, M. E., Cramer, D. W., Cunningham, J. M., Cushing-Haugen, K. L., Edwards, R. P., Fridley, B. L., Goode, E. L., Lurie, G., McGuire, V., Modugno, F., Moysich, K. B., Olson, S. H., Pearce, C. L., Pike, M. C., Rothstein, J. H., Sellers, T. A., Sieh, W., Stram, D., Thompson, P. J., Vierkant, R. A., Wicklund, K. G., Wu, A. H., Ziogas, A., Tworoger, S. S., Schildkraut, J. M. 2016; 184 (8): 555-569

  Abstract

  Previously developed models for predicting absolute risk of invasive epithelial ovarian cancer have included a limited number of risk factors and have had low discriminatory power (area under the receiver operating characteristic curve (AUC) < 0.60). Because of this, we developed and internally validated a relative risk prediction model that incorporates 17 established epidemiologic risk factors and 17 genome-wide significant single nucleotide polymorphisms (SNPs) using data from 11 case-control studies in the United States (5,793 cases; 9,512 controls) from the Ovarian Cancer Association Consortium (data accrued from 1992 to 2010). We developed a hierarchical logistic regression model for predicting case-control status that included imputation of missing data. We randomly divided the data into an 80% training sample and used the remaining 20% for model evaluation. The AUC for the full model was 0.664. A reduced model without SNPs performed similarly (AUC = 0.649). Both models performed better than a baseline model that included age and study site only (AUC = 0.563). The best predictive power was obtained in the full model among women younger than 50 years of age (AUC = 0.714); however, the addition of SNPs increased the AUC the most for women older than 50 years of age (AUC = 0.638 vs. 0.616). Adapting this improved model to estimate absolute risk and evaluating it in prospective data sets is warranted.

  View details for DOI 10.1093/aje/kww091

  View details for Web of Science ID 000386552900001

  View details for PubMedCentralID PMC5065620

• Risk Prediction for Epithelial Ovarian Cancer in 11 United States-Based Case-Control Studies: Incorporation of Epidemiologic Risk Factors and 17 Confirmed Genetic Loci. American journal of epidemiology Clyde, M. A., Palmieri Weber, R., Iversen, E. S., Poole, E. M., Doherty, J. A., Goodman, M. T., Ness, R. B., Risch, H. A., Rossing, M. A., Terry, K. L., Wentzensen, N., Whittemore, A. S., Anton-Culver, H., Bandera, E. V., Berchuck, A., Carney, M. E., Cramer, D. W., Cunningham, J. M., Cushing-Haugen, K. L., Edwards, R. P., Fridley, B. L., Goode, E. L., Lurie, G., McGuire, V., Modugno, F., Moysich, K. B., Olson, S. H., Pearce, C. L., Pike, M. C., Rothstein, J. H., Sellers, T. A., Sieh, W., Stram, D., Thompson, P. J., Vierkant, R. A., Wicklund, K. G., Wu, A. H., Ziogas, A., Tworoger, S. S., Schildkraut, J. M. 2016; 184 (8): 579-589

  Abstract

  Previously developed models for predicting absolute risk of invasive epithelial ovarian cancer have included a limited number of risk factors and have had low discriminatory power (area under the receiver operating characteristic curve (AUC) < 0.60). Because of this, we developed and internally validated a relative risk prediction model that incorporates 17 established epidemiologic risk factors and 17 genome-wide significant single nucleotide polymorphisms (SNPs) using data from 11 case-control studies in the United States (5,793 cases; 9,512 controls) from the Ovarian Cancer Association Consortium (data accrued from 1992 to 2010). We developed a hierarchical logistic regression model for predicting case-control status that included imputation of missing data. We randomly divided the data into an 80% training sample and used the remaining 20% for model evaluation. The AUC for the full model was 0.664. A reduced model without SNPs performed similarly (AUC = 0.649). Both models performed better than a baseline model that included age and study site only (AUC = 0.563). The best predictive power was obtained in the full model among women younger than 50 years of age (AUC = 0.714); however, the addition of SNPs increased the AUC the most for women older than 50 years of age (AUC = 0.638 vs. 0.616). Adapting this improved model to estimate absolute risk and evaluating it in prospective data sets is warranted.

  View details for PubMedID 27698005

• REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants AMERICAN JOURNAL OF HUMAN GENETICS Ioannidis, N. M., Rothstein, J. H., Pejaver, V., Middha, S., McDonnell, S. K., Baheti, S., Musolf, A., Li, Q., Holzinger, E., Karyadi, D., Cannon-Albright, L. A., Teerlink, C. C., Stanford, J. L., Isaacs, W. B., Xu, J., Cooney, K. A., Lange, E. M., Schleutker, J., Carpten, J. D., Powell, I. J., Cussenot, O., Cancel-Tassin, G., Giles, G. G., MacInnis, R. J., Maier, C., Hsieh, C., Wiklund, F., Catalona, W. J., Foulkes, W. D., Mandal, D., Eeles, R. A., Kote-Jarai, Z., Bustamante, C. D., Schaid, D. J., Hastie, T., Ostrander, E. A., Bailey-Wilson, J. E., Radivojac, P., Thibodeau, S. N., Whittemore, A. S., Sieh, W. 2016; 99 (4): 877-885

  Abstract

  The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons. REVEL was trained with recently discovered pathogenic and rare neutral missense variants, excluding those previously used to train its constituent tools. When applied to two independent test sets, REVEL had the best overall performance (p < 10(-12)) as compared to any individual tool and seven ensemble methods: MetaSVM, MetaLR, KGGSeq, Condel, CADD, DANN, and Eigen. Importantly, REVEL also had the best performance for distinguishing pathogenic from rare neutral variants with allele frequencies <0.5%. The area under the receiver operating characteristic curve (AUC) for REVEL was 0.046-0.182 higher in an independent test set of 935 recent SwissVar disease variants and 123,935 putatively neutral exome sequencing variants and 0.027-0.143 higher in an independent test set of 1,953 pathogenic and 2,406 benign variants recently reported in ClinVar than the AUCs for other ensemble methods. We provide pre-computed REVEL scores for all possible human missense variants to facilitate the identification of pathogenic variants in the sea of rare variants discovered as sequencing studies expand in scale.

  View details for DOI 10.1016/j.ajhg.2016.08.016

  View details for PubMedID 27666373

• 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

• Geographic variation in Medicare treatment costs and outcomes for advanced head and neck cancer ORAL ONCOLOGY Divi, V., Tao, L., Whittemore, A., Oakley-Girvan, I. 2016; 61: 83-88

  Abstract

  Advanced head and neck cancer (HNC) is a complex group of diseases that requires the input and coordination of multiple providers. While there are general guidelines for treatment, there is also considerable variation in how patients are treated, and how long they survive after treatment. It is unclear how the treatment variations relate to treatment costs and survival.We identified 3678 Medicare patients with advanced HNC treated in 12 US regions between 2004 and 2009 using the linked database containing Medicare and Surveillance Epidemiology and End Results (SEER) data. We calculated average cost per patient during the period three months before to 12months after diagnosis for each region. Costs included inpatient hospital, outpatient, physician, and durable medical equipment charges. We also calculated three-year overall survival for each of the regions.The mean cost-per-patient varied substantially among the regions, ranging from $51,857 for Utah to $82,181 for Detroit. Utah incurred the lowest total costs within one year of advanced HNC diagnosis ($51,857 per patient, 95% CI $42,285-$61,429), whereas Detroit had the highest costs ($82,181 per patient, 95% CI $74,752-$89,610). Overall survival also varied among the regions, ranging from 45months in Kentucky to 58months in Washington. There was little correlation between expenditures and length of survival, with correlation coefficient of 0.0088.Despite significant variation in both expenditures and survival among the regions, we found no correlation between costs and mean survival time, suggesting that more costly care did not lead to improved outcomes.

  View details for DOI 10.1016/j.oraloncology.2016.08.018

  View details for Web of Science ID 000384695400013

  View details for PubMedID 27688109

• Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Ong, J., Cuellar-Partida, G., Lu, Y., Fasching, P. A., Hein, A., Burghaus, S., Beckmann, M. W., Lambrechts, D., van Nieuwenhuysen, E., Vergote, I., Vanderstichele, A., Doherty, J. A., Rossing, M. A., Chang-Claude, J., Eilber, U., Rudolph, A., Wang-Gohrke, S., Goodman, M. T., Bogdanova, N., Dork, T., Durst, M., Hillemanns, P., Runnebaum, I. B., Antonenkova, N., Butzow, R., Leminen, A., Nevanlinna, H., Pelttari, L. M., Edwards, R. P., Kelley, J. L., Modugno, F., Moysich, K. B., Ness, R. B., Cannioto, R., Hogdall, E., Hogdall, C. K., Jensen, A., Giles, G. G., Bruinsma, F., Kjaer, S. K., Hildebrandt, M. A., Liang, D., Lu, K. H., Wu, X., Bisogna, M., Dao, F., Levine, D. A., Cramer, D. W., Terry, K. L., Tworoger, S. S., Stampfer, M., Missmer, S., Bjorge, L., Salvesen, H. B., Kopperud, R. K., Bischof, K., Aben, K. K., Kiemeney, L. A., Massuger, L. F., Brooks-Wilson, A., Olson, S. H., McGuire, V., Rothstein, J. H., Sieh, W., Whittemore, A. S., Cook, L. S., Le, N. D., Gilks, C. B., Gronwald, J., Jakubowska, A., Lubinski, J., Kluz, T., Song, H., Tyrer, J. P., Wentzensen, N., Brinton, L., Trabert, B., Lissowska, J., McLaughlin, J. R., Narod, S. A., Phelan, C., Anton-Culver, H., Ziogas, A., Eccles, D., Campbell, I., Gayther, S. A., Gentry-Maharaj, A., Menon, U., Ramus, S. J., Wu, A. H., Dansonka-Mieszkowska, A., Kupryjanczyk, J., Timorek, A., Szafron, L., Cunningham, J. M., Fridley, B. L., Winham, S. J., Bandera, E. V., Poole, E. M., Morgan, T. K., Risch, H. A., Goode, E. L., Schildkraut, J. M., Pearce, C. L., Berchuck, A., Pharoah, P. D., Chenevix-Trench, G., Gharahkhani, P., Neale, R. E., Webb, P. M., Macgregor, S. 2016; 45 (5): 1619-1630

  Abstract

  In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer.We employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases).The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01).Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.

  View details for DOI 10.1093/ije/dyw207

  View details for Web of Science ID 000393184400034

  View details for PubMedCentralID PMC5100621

• PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. Journal of medical genetics Southey, M. C., Goldgar, D. E., Winqvist, R., Pylkäs, K., Couch, F., Tischkowitz, M., Foulkes, W. D., Dennis, J., Michailidou, K., Van Rensburg, E. J., Heikkinen, T., Nevanlinna, H., Hopper, J. L., Dörk, T., Claes, K. B., Reis-Filho, J., Teo, Z. L., Radice, P., Catucci, I., Peterlongo, P., Tsimiklis, H., Odefrey, F. A., Dowty, J. G., Schmidt, M. K., Broeks, A., Hogervorst, F. B., Verhoef, S., Carpenter, J., Clarke, C., Scott, R. J., Fasching, P. A., Haeberle, L., Ekici, A. B., Beckmann, M. W., Peto, J., Dos-Santos-Silva, I., Fletcher, O., Johnson, N., Bolla, M. K., Sawyer, E. J., Tomlinson, I., Kerin, M. J., Miller, N., Marme, F., Burwinkel, B., Yang, R., Guénel, P., Truong, T., Menegaux, F., Sanchez, M., Bojesen, S., Nielsen, S. F., Flyger, H., Benitez, J., Zamora, M. P., Perez, J. I., Menéndez, P., Anton-Culver, H., Neuhausen, S., Ziogas, A., Clarke, C. A., Brenner, H., Arndt, V., Stegmaier, C., Brauch, H., Brüning, T., Ko, Y., Muranen, T. A., Aittomäki, K., Blomqvist, C., Bogdanova, N. V., Antonenkova, N. N., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V., Hartikainen, J. M., Spurdle, A. B., Investigators, K., Wauters, E., Smeets, D., Beuselinck, B., Floris, G., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Olson, J. E., Vachon, C., Pankratz, V. S., McLean, C., Haiman, C. A., Henderson, B. E., Schumacher, F., Le Marchand, L., Kristensen, V., Alnæs, G. G., Zheng, W., Hunter, D. J., Lindstrom, S., Hankinson, S. E., Kraft, P., Andrulis, I., Knight, J. A., Glendon, G., Mulligan, A. M., Jukkola-Vuorinen, A., Grip, M., Kauppila, S., Devilee, P., Tollenaar, R. A., Seynaeve, C., Hollestelle, A., Garcia-Closas, M., Figueroa, J., Chanock, S. J., Lissowska, J., Czene, K., Darabi, H., Eriksson, M., Eccles, D. M., Rafiq, S., Tapper, W. J., Gerty, S. M., Hooning, M. J., Martens, J. W., Collée, J. M., Tilanus-Linthorst, M., Hall, P., Li, J., Brand, J. S., Humphreys, K., Cox, A., Reed, M. W., Luccarini, C., Baynes, C., Dunning, A. M., Hamann, U., Torres, D., Ulmer, H. U., Rüdiger, T., Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Slager, S., Toland, A. E., Ambrosone, C. B., Yannoukakos, D., Swerdlow, A., Ashworth, A., Orr, N., Jones, M., González-Neira, A., Pita, G., Alonso, M. R., Álvarez, N., Herrero, D., Tessier, D. C., Vincent, D., Bacot, F., Simard, J., Dumont, M., Soucy, P., Eeles, R., Muir, K., Wiklund, F., Gronberg, H., Schleutker, J., Nordestgaard, B. G., Weischer, M., Travis, R. C., Neal, D., Donovan, J. L., Hamdy, F. C., Khaw, K., Stanford, J. L., Blot, W. J., Thibodeau, S., Schaid, D. J., Kelley, J. L., Maier, C., Kibel, A. S., Cybulski, C., Cannon-Albright, L., Butterbach, K., Park, J., Kaneva, R., Batra, J., Teixeira, M. R., Kote-Jarai, Z., Olama, A. A., Benlloch, S., Renner, S. P., Hartmann, A., Hein, A., Ruebner, M., Lambrechts, D., van Nieuwenhuysen, E., Vergote, I., Lambretchs, S., Doherty, J. A., Rossing, M. A., Nickels, S., Eilber, U., Wang-Gohrke, S., Odunsi, K., Sucheston-Campbell, L. E., Friel, G., Lurie, G., Killeen, J. L., Wilkens, L. R., Goodman, M. T., Runnebaum, I., Hillemanns, P. A., Pelttari, L. M., Butzow, R., Modugno, F., Edwards, R. P., Ness, R. B., Moysich, K. B., du Bois, A., Heitz, F., Harter, P., Kommoss, S., Karlan, B. Y., Walsh, C., Lester, J., Jensen, A., Kjaer, S. K., Høgdall, E., Peissel, B., Bonanni, B., Bernard, L., Goode, E. L., Fridley, B. L., Vierkant, R. A., Cunningham, J. M., Larson, M. C., Fogarty, Z. C., Kalli, K. R., Liang, D., Lu, K. H., Hildebrandt, M. A., Wu, X., Levine, D. A., Dao, F., Bisogna, M., Berchuck, A., Iversen, E. S., Marks, J. R., Akushevich, L., Cramer, D. W., Schildkraut, J., Terry, K. L., Poole, E. M., Stampfer, M., Tworoger, S. S., Bandera, E. V., Orlow, I., Olson, S. H., Bjorge, L., Salvesen, H. B., van Altena, A. M., Aben, K. K., Kiemeney, L. A., Massuger, L. F., Pejovic, T., Bean, Y., Brooks-Wilson, A., Kelemen, L. E., Cook, L. S., Le, N. D., Górski, B., Gronwald, J., Menkiszak, J., Høgdall, C. K., Lundvall, L., Nedergaard, L., Engelholm, S. A., Dicks, E., Tyrer, J., Campbell, I., McNeish, I., Paul, J., Siddiqui, N., Glasspool, R., Whittemore, A. S., Rothstein, J. H., McGuire, V., Sieh, W., Cai, H., Shu, X., Teten, R. T., Sutphen, R., McLaughlin, J. R., Narod, S. A., Phelan, C. M., Monteiro, A. N., Fenstermacher, D., Lin, H., Permuth, J. B., Sellers, T. A., Chen, Y. A., Tsai, Y., Chen, Z., Gentry-Maharaj, A., Gayther, S. A., Ramus, S. J., Menon, U., Wu, A. H., Pearce, C. L., Van Den Berg, D., Pike, M. C., Dansonka-Mieszkowska, A., Plisiecka-Halasa, J., Moes-Sosnowska, J., Kupryjanczyk, J., Pharoah, P. D., Song, H., Winship, I., Chenevix-Trench, G., Giles, G. G., Tavtigian, S. V., Easton, D. F., Milne, R. L. 2016

  Abstract

  The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10(-5)), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10(-8)) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

  View details for DOI 10.1136/jmedgenet-2016-103839

  View details for PubMedID 27595995

• Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study. International journal of epidemiology Ong, J., Cuellar-Partida, G., Lu, Y., Ovarian Cancer Study, A., Fasching, P. A., Hein, A., Burghaus, S., Beckmann, M. W., Lambrechts, D., van Nieuwenhuysen, E., Vergote, I., Vanderstichele, A., Anne Doherty, J., Anne Rossing, M., Chang-Claude, J., Eilber, U., Rudolph, A., Wang-Gohrke, S., Goodman, M. T., Bogdanova, N., Dörk, T., Dürst, M., Hillemanns, P., Runnebaum, I. B., Antonenkova, N., Butzow, R., Leminen, A., Nevanlinna, H., Pelttari, L. M., Edwards, R. P., Kelley, J. L., Modugno, F., Moysich, K. B., Ness, R. B., Cannioto, R., Høgdall, E., Høgdall, C. K., Jensen, A., Giles, G. G., Bruinsma, F., Kjaer, S. K., Hildebrandt, M. A., Liang, D., Lu, K. H., Wu, X., Bisogna, M., Dao, F., Levine, D. A., Cramer, D. W., Terry, K. L., Tworoger, S. S., Stampfer, M., Missmer, S., Bjorge, L., Salvesen, H. B., Kopperud, R. K., Bischof, K., Aben, K. K., Kiemeney, L. A., Massuger, L. F., Brooks-Wilson, A., Olson, S. H., McGuire, V., Rothstein, J. H., Sieh, W., Whittemore, A. S., Cook, L. S., Le, N. D., Blake Gilks, C., Gronwald, J., Jakubowska, A., Lubinski, J., Kluz, T., Song, H., Tyrer, J. P., Wentzensen, N., Brinton, L., Trabert, B., Lissowska, J., McLaughlin, J. R., Narod, S. A., Phelan, C., Anton-Culver, H., Ziogas, A., Eccles, D., Campbell, I., Gayther, S. A., Gentry-Maharaj, A., Menon, U., Ramus, S. J., Wu, A. H., Dansonka-Mieszkowska, A., Kupryjanczyk, J., Timorek, A., Szafron, L., Cunningham, J. M., Fridley, B. L., Winham, S. J., Bandera, E. V., Poole, E. M., Morgan, T. K., Risch, H. A., Goode, E. L., Schildkraut, J. M., Pearce, C. L., Berchuck, A., Pharoah, P. D., Chenevix-Trench, G., Gharahkhani, P., Neale, R. E., Webb, P. M., Macgregor, S. 2016

  Abstract

  In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer.We employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases).The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01).Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.

  View details for PubMedID 27594614

• Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types CANCER DISCOVERY Kar, S. P., Beesley, J., Al Olama, A. A., Michailidou, K., Tyrer, J., Kote-Jarai, Z. A., Lawrenson, K., Lindstrom, S., Ramus, S. J., Thompson, D. J., Kibel, A. S., Dansonka-Mieszkowska, A., Michael, A., Dieffenbach, A. K., Gentry-Maharaj, A., Whittemore, A. S., Wolk, A., Monteiro, A., Peixoto, A., Kierzek, A., Cox, A., Rudolph, A., Gonzalez-Neira, A., Wu, A. H., Lindblom, A., Swerdlow, A., Ziogas, A., Ekici, A. B., Burwinkel, B., Karlan, B. Y., Nordestgaard, B. G., Blomqvist, C., Phelan, C., McLean, C., Pearce, C. L., Vachon, C., Cybulski, C., Slavov, C., Stegmaier, C., Maier, C., Ambrosone, C. B., Hogdall, C. K., Teerlink, C. C., Kang, D., Tessier, D. C., Schaid, D. J., Stram, D. O., Cramer, D. W., Neal, D. E., Eccles, D., Flesch-Janys, D., Edwards, D. R., Wokozorczyk, D., Levine, D. A., Yannoukakos, D., Sawyer, E. J., Bandera, E. V., Poole, E. M., Goode, E. L., Khusnutdinova, E., Hogdall, E., Song, F., Bruinsma, F., Heitz, F., Modugno, F., Hamdy, F. C., Wiklund, F., Giles, G. G., Olsson, H., Wildiers, H., Ulmer, H., Pandha, H., Risch, H. A., Darabi, H., Salvesen, H. B., Nevanlinna, H., Gronberg, H., Brenner, H., Brauch, H., Anton-Culver, H., Song, H., Lim, H., McNeish, I., Campbell, I., Vergote, I., Gronwald, J., Lubinski, J., Stanford, J. L., Bentez, J., Doherty, J. A., Permuth, J. B., Chang-Claude, J., Donovan, J. L., Dennis, J., Schildkraut, J. M., Schleutker, J., Hopper, J. L., Kupryjanczyk, J., Park, J. Y., Figueroa, J., Clements, J. A., Knight, J. A., Peto, J., Cunningham, J. M., Pow-Sang, J., Batra, J., Czene, K., Lu, K. H., Herkommer, K., Khaw, K., Matsuo, K., Muir, K., Offitt, K., Chen, K., Moysich, K. B., Aittomaki, K., Odunsi, K., Kiemeney, L. A., Massuger, L. F., FitzGerald, L. M., Cook, L. S., Cannon-Albright, L., Hooning, M. J., Pike, M. C., Bolla, M. K., Luedeke, M., Teixeira, M. R., Goodman, M. T., Schmidt, M. K., Riggan, M., Aly, M., Rossing, M. A., Beckmann, M. W., Moisse, M., Sanderson, M., Southey, M. C., Jones, M., Lush, M., Hildebrandt, M. A., Hou, M., Schoemaker, M. J., Garcia-Closas, M., Bogdanova, N., Rahman, N., Le, N. D., Orr, N., Wentzensen, N., Pashayan, N., Peterlongo, P., Guenel, P., Brennan, P., Paulo, P., Webb, P. M., Broberg, P., Fasching, P. A., Devilee, P., Wang, Q., Cai, Q., Li, Q., Kaneva, R., Butzow, R., Kopperud, R. K., Schmutzler, R. K., Stephenson, R. A., MacInnis, R. J., Hoover, R. N., Winqvist, R., Ness, R., Milne, R. L., Travis, R. C., Benlloch, S., Olson, S. H., McDonnell, S. K., Tworoger, S. S., Maia, S. A., Berndt, S., Lee, S. C., Teo, S., Thibodeau, S. N., Bojesen, S. E., Gapstur, S. M., Kjaer, S. K., Pejovic, T., Tammela, T. L., Doerk, T., Bruening, T., Wahlfors, T., Key, T. J., Edwards, T. L., Menon, U., Hamann, U., Mitev, V., Kosma, V., Setiawan, V. W., Kristensen, V., Arndt, V., Vogel, W., Zheng, W., Sieh, W., Blot, W. J., Kluzniak, W., Shu, X., Gao, Y., Schumacher, F., Freedman, M. L., Berchuck, A., Dunning, A. M., Simard, J., Haiman, C. A., Spurdle, A., Sellers, T. A., Hunter, D. J., Henderson, B. E., Kraft, P., Chanock, S. J., Couch, F. J., Hall, P., Gayther, S. A., Easton, D. F., Chenevix-Trench, G., Eeles, R., Pharoah, P. D., Lambrechts, D. 2016; 6 (9): 1052-1067

  Abstract

  Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis.We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

  View details for DOI 10.1158/2159-8290.CD-15-1227

  View details for Web of Science ID 000383356400028

  View details for PubMedCentralID PMC5010513

• Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations CANCER RESEARCH Fehringer, G., Kraft, P., Pharoah, P. D., Eeles, R. A., Chatterjee, N., Schumacher, F. R., Schildkraut, J. M., Lindstrom, S., Brennan, P., Bickeboller, H., Houlston, R. S., Landi, M. T., Caporaso, N., Risch, A., Al Olama, A. A., Berndt, S. I., Giovannucci, E. L., Gronberg, H., Kote-Jarai, Z., Ma, J., Muir, K., Stampfer, M. J., Stevens, V. L., Wiklund, F., Willett, W. C., Goode, E. L., Permuth, J. B., Risch, H. A., Reid, B. M., Bezieau, S., Brenner, H., Chan, A. T., Chang-Claude, J., Hudson, T. J., Kocarnik, J. K., Newcomb, P. A., Schoen, R. E., Slattery, M. L., White, E., Adank, M. A., Ahsan, H., Aittomaki, K., Baglietto, L., Blomquist, C., Canzian, F., Czene, K., Dos-Santos-Silva, I., Eliassen, A. H., Figueroa, J. D., Flesch-Janys, D., Fletcher, O., Garcia-Closas, M., Gaudet, M. M., Johnson, N., Hall, P., Hazra, A., Hein, R., Hofman, A., Hopper, J. L., Irwanto, A., Johansson, M., Kaaks, R., Kibriya, M. G., Lichtner, P., Liu, J., Lund, E., Makalic, E., Meindl, A., Muller-Myhsok, B., Muranen, T. A., Nevanlinna, H., Peeters, P. H., Peto, J., Prentice, R. L., Rahman, N., Sanchez, M. J., Schmidt, D. F., Schmutzler, R. K., Southey, M. C., Tamimi, R., Travis, R. C., Turnbull, C., Uitterlinden, A. G., Wang, Z., Whittemore, A. S., Yang, X. R., Zheng, W., Buchanan, D. D., Casey, G., Conti, D. V., Edlund, C. K., Gallinger, S., Haile, R. W., Jenkins, M., Le Marchand, L., Li, L., Lindor, N. M., Schmit, S. L., Thibodeau, S. N., Woods, M. O., Rafnar, T., Gudmundsson, J., Stacey, S. N., Stefansson, K., Sulem, P., Chen, Y. A., Tyrer, J. P., Christiani, D. C., Wei, Y., Shen, H., Hu, Z., Shu, X., Shiraishi, K., Takahashi, A., Bosse, Y., Obeidat, M., Nickle, D., Timens, W., Freedman, M. L., Li, Q., Seminara, D., Chanock, S. J., Gong, J., Peters, U., Gruber, S. B., Amos, C. I., Sellers, T. A., Easton, D. F., Hunter, D. J., Haiman, C. A., Henderson, B. E., Hung, R. J. 2016; 76 (17): 5103-5114

  Abstract

  Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103-14. ©2016 AACR.

  View details for DOI 10.1158/0008-5472.CAN-15-2980

  View details for Web of Science ID 000382298900020

  View details for PubMedCentralID PMC5010493

• Post hoc Analysis for Detecting Individual Rare Variant Risk Associations Using Probit Regression Bayesian Variable Selection Methods in Case-Control Sequencing Studies GENETIC EPIDEMIOLOGY Larson, N. B., McDonnell, S., Albright, L. C., Teerlink, C., Stanford, J., Ostrander, E. A., Isaacs, W. B., Xu, J., Cooney, K. A., Lange, E., Schleutker, J., Carpten, J. D., Powell, I., Bailey-Wilson, J., Cussenot, O., Cancel-Tassin, G., Giles, G., MacInnis, R., Maier, C., Whittemore, A. S., Hsieh, C., Wiklund, F., Catolona, W. J., Foulkes, W., Mandal, D., Eeles, R., Kote-Jarai, Z., Ackerman, M. J., Olson, T. M., Klein, C. J., Thibodeau, S. N., Schaid, D. J. 2016; 40 (6): 461-469

  Abstract

  Rare variants (RVs) have been shown to be significant contributors to complex disease risk. By definition, these variants have very low minor allele frequencies and traditional single-marker methods for statistical analysis are underpowered for typical sequencing study sample sizes. Multimarker burden-type approaches attempt to identify aggregation of RVs across case-control status by analyzing relatively small partitions of the genome, such as genes. However, it is generally the case that the aggregative measure would be a mixture of causal and neutral variants, and these omnibus tests do not directly provide any indication of which RVs may be driving a given association. Recently, Bayesian variable selection approaches have been proposed to identify RV associations from a large set of RVs under consideration. Although these approaches have been shown to be powerful at detecting associations at the RV level, there are often computational limitations on the total quantity of RVs under consideration and compromises are necessary for large-scale application. Here, we propose a computationally efficient alternative formulation of this method using a probit regression approach specifically capable of simultaneously analyzing hundreds to thousands of RVs. We evaluate our approach to detect causal variation on simulated data and examine sensitivity and specificity in instances of high RV dimensionality as well as apply it to pathway-level RV analysis results from a prostate cancer (PC) risk case-control sequencing study. Finally, we discuss potential extensions and future directions of this work.

  View details for DOI 10.1002/gepi.21983

  View details for Web of Science ID 000386036300002

  View details for PubMedID 27312771

  View details for PubMedCentralID PMC5063501

• Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types. Cancer discovery Kar, S. P., Beesley, J., Amin Al Olama, A., Michailidou, K., Tyrer, J., Kote-Jarai, Z., Lawrenson, K., Lindstrom, S., Ramus, S. J., Thompson, D. J., Kibel, A. S., Dansonka-Mieszkowska, A., Michael, A., Dieffenbach, A. K., Gentry-Maharaj, A., Whittemore, A. S., Wolk, A., Monteiro, A., Peixoto, A., Kierzek, A., Cox, A., Rudolph, A., Gonzalez-Neira, A., Wu, A. H., Lindblom, A., Swerdlow, A., Ziogas, A., Ekici, A. B., Burwinkel, B., Karlan, B. Y., Nordestgaard, B. G., Blomqvist, C., Phelan, C., McLean, C., Pearce, C. L., Vachon, C., Cybulski, C., Slavov, C., Stegmaier, C., Maier, C., Ambrosone, C. B., Høgdall, C. K., Teerlink, C. C., Kang, D., Tessier, D. C., Schaid, D. J., Stram, D. O., Cramer, D. W., Neal, D. E., Eccles, D., Flesch-Janys, D., Edwards, D. R., Wokozorczyk, D., Levine, D. A., Yannoukakos, D., Sawyer, E. J., Bandera, E. V., Poole, E. M., Goode, E. L., Khusnutdinova, E., Høgdall, E., Song, F., Bruinsma, F., Heitz, F., Modugno, F., Hamdy, F. C., Wiklund, F., Giles, G. G., Olsson, H., Wildiers, H., Ulmer, H., Pandha, H., Risch, H. A., Darabi, H., Salvesen, H. B., Nevanlinna, H., Gronberg, H., Brenner, H., Brauch, H., Anton-Culver, H., Song, H., Lim, H., McNeish, I., Campbell, I., Vergote, I., Gronwald, J., Lubinski, J., Stanford, J. L., Benítez, J., Doherty, J. A., Permuth, J. B., Chang-Claude, J., Donovan, J. L., Dennis, J., Schildkraut, J. M., Schleutker, J., Hopper, J. L., Kupryjanczyk, J., Park, J. Y., Figueroa, J., Clements, J. A., Knight, J. A., Peto, J., Cunningham, J. M., Pow-Sang, J., Batra, J., Czene, K., Lu, K. H., Herkommer, K., Khaw, K., Matsuo, K., Muir, K., Offitt, K., Chen, K., Moysich, K. B., Aittomäki, K., Odunsi, K., Kiemeney, L. A., Massuger, L. F., FitzGerald, L. M., Cook, L. S., Cannon-Albright, L., Hooning, M. J., Pike, M. C., Bolla, M. K., Luedeke, M., Teixeira, M. R., Goodman, M. T., Schmidt, M. K., Riggan, M., Aly, M., Rossing, M. A., Beckmann, M. W., Moisse, M., Sanderson, M., Southey, M. C., Jones, M., Lush, M., Hildebrandt, M. A., Hou, M., Schoemaker, M. J., Garcia-Closas, M., Bogdanova, N., Rahman, N., Le, N. D., Orr, N., Wentzensen, N., Pashayan, N., Peterlongo, P., Guénel, P., Brennan, P., Paulo, P., Webb, P. M., Broberg, P., Fasching, P. A., Devilee, P., Wang, Q., Cai, Q., Li, Q., Kaneva, R., Butzow, R., Kopperud, R. K., Schmutzler, R. K., Stephenson, R. A., MacInnis, R. J., Hoover, R. N., Winqvist, R., Ness, R., Milne, R. L., Travis, R. C., Benlloch, S., Olson, S. H., McDonnell, S. K., Tworoger, S. S., Maia, S., Berndt, S., Lee, S. C., Teo, S., Thibodeau, S. N., Bojesen, S. E., Gapstur, S. M., Kjær, S. K., Pejovic, T., Tammela, T. L., Dörk, T., Brüning, T., Wahlfors, T., Key, T. J., Edwards, T. L., Menon, U., Hamann, U., Mitev, V., Kosma, V., Setiawan, V. W., Kristensen, V., Arndt, V., Vogel, W., Zheng, W., Sieh, W., Blot, W. J., Kluzniak, W., Shu, X., Gao, Y., Schumacher, F., Freedman, M. L., Berchuck, A., Dunning, A. M., Simard, J., Haiman, C. A., Spurdle, A., Sellers, T. A., Hunter, D. J., Henderson, B. E., Kraft, P., Chanock, S. J., Couch, F. J., Hall, P., Gayther, S. A., Easton, D. F., Chenevix-Trench, G., Eeles, R., Pharoah, P. D., Lambrechts, D. 2016; 6 (9): 1052-1067

  Abstract

  Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis.We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

  View details for DOI 10.1158/2159-8290.CD-15-1227

  View details for PubMedID 27432226

• Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations. Cancer research Fehringer, G., Kraft, P., Pharoah, P. D., Eeles, R. A., Chatterjee, N., Schumacher, F. R., Schildkraut, J. M., Lindström, S., Brennan, P., Bickeböller, H., Houlston, R. S., Landi, M. T., Caporaso, N., Risch, A., Amin Al Olama, A., Berndt, S. I., Giovannucci, E. L., Grönberg, H., Kote-Jarai, Z., Ma, J., Muir, K., Stampfer, M. J., Stevens, V. L., Wiklund, F., Willett, W. C., Goode, E. L., Permuth, J. B., Risch, H. A., Reid, B. M., Bezieau, S., Brenner, H., Chan, A. T., Chang-Claude, J., Hudson, T. J., Kocarnik, J. K., Newcomb, P. A., Schoen, R. E., Slattery, M. L., White, E., Adank, M. A., Ahsan, H., Aittomäki, K., Baglietto, L., Blomquist, C., Canzian, F., Czene, K., Dos-Santos-Silva, I., Eliassen, A. H., Figueroa, J. D., Flesch-Janys, D., Fletcher, O., Garcia-Closas, M., Gaudet, M. M., Johnson, N., Hall, P., Hazra, A., Hein, R., Hofman, A., Hopper, J. L., Irwanto, A., Johansson, M., Kaaks, R., Kibriya, M. G., Lichtner, P., Liu, J., Lund, E., Makalic, E., Meindl, A., Müller-Myhsok, B., Muranen, T. A., Nevanlinna, H., Peeters, P. H., Peto, J., Prentice, R. L., Rahman, N., Sanchez, M. J., Schmidt, D. F., Schmutzler, R. K., Southey, M. C., Tamimi, R., Travis, R. C., Turnbull, C., Uitterlinden, A. G., Wang, Z., Whittemore, A. S., Yang, X. R., Zheng, W., Buchanan, D. D., Casey, G., Conti, D. V., Edlund, C. K., Gallinger, S., Haile, R. W., Jenkins, M., Le Marchand, L., Li, L., Lindor, N. M., Schmit, S. L., Thibodeau, S. N., Woods, M. O., Rafnar, T., Gudmundsson, J., Stacey, S. N., Stefansson, K., Sulem, P., Chen, Y. A., Tyrer, J. P., Christiani, D. C., Wei, Y., Shen, H., Hu, Z., Shu, X., Shiraishi, K., Takahashi, A., Bossé, Y., Obeidat, M., Nickle, D., Timens, W., Freedman, M. L., Li, Q., Seminara, D., Chanock, S. J., Gong, J., Peters, U., Gruber, S. B., Amos, C. I., Sellers, T. A., Easton, D. F., Hunter, D. J., Haiman, C. A., Henderson, B. E., Hung, R. J. 2016; 76 (17): 5103-5114

  Abstract

  Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103-14. ©2016 AACR.

  View details for DOI 10.1158/0008-5472.CAN-15-2980

  View details for PubMedID 27197191

• 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

• Two-stage sampling designs for external validation of personal risk models. Statistical methods in medical research Whittemore, A. S., Halpern, J. 2016; 25 (4): 1313-1329

  Abstract

  We propose a cost-effective sampling design and estimating procedure for validating personal risk models using right-censored cohort data. Validation involves using each subject's covariates, as ascertained at cohort entry, in a risk model (specified independently of the data) to assign him/her a probability of an adverse outcome within a future time period. Subjects are then grouped according to the magnitudes of their assigned risks, and within each group, the mean assigned risk is compared with the probability of outcome occurrence as estimated using the follow-up data. Such validation presents two complications. First, in the presence of right-censoring, estimating the probability of developing the outcomes before death requires competing risk analysis. Second, for rare outcomes, validation using the full cohort requires assembling covariates and assigning risks to thousands of subjects. This can be costly when some covariates involve analyzing biological specimens. A two-stage sampling design addresses this problem by assembling covariates and assigning risks only to those subjects most informative for estimating key parameters. We use this design to estimate the outcome probabilities needed to evaluate model performance and we provide theoretical and bootstrap estimates of their variances. We also describe how to choose two-stage designs with minimal efficiency loss for a parameter of interest when the quantities determining optimality are unknown at the time of design. We illustrate these methods by using subjects in the California Teachers Study to validate ovarian cancer risk models. We find that a design with optimal efficiency for one performance parameter need not be so for others, and trade-offs will be required. A two-stage design that samples all outcome-positive subjects and more outcome-negative than censored subjects will perform well in most circumstances. The methods are implemented in Risk Model Assessment Program, an R program freely available at http://med.stanford.edu/epidemiology/two-stage.html.

  View details for DOI 10.1177/0962280213480420

  View details for PubMedID 23592716

• 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

• 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

• The impact of body mass index on treatment outcomes for patients with low-intermediate risk prostate cancer BMC CANCER Yamoah, K., Zeigler-Johnson, C. M., Jeffers, A., Malkowicz, B., Spangler, E., Park, J. Y., Whittemore, A., Rebbeck, T. R. 2016; 16

  Abstract

  Little is known about the relationship between preoperative body mass index and need for adjuvant radiation therapy (RT) following radical prostatectomy. The goal of this study was to evaluate the utility of body mass index in predicting adverse clinical outcomes which require adjuvant RT among men with organ-confined prostate cancer (PCa).We used a prospective cohort of 1,170 low-intermediate PCa risk men who underwent radical prostatectomy and evaluated the effect of body mass index on adverse pathologic features and freedom from biochemical failure (FFbF). Clinical and pathologic variables were compared across the body mass index groups using an analysis of variance model for continuous variables or χ(2) for categorical variables. Factors related to adverse pathologic features were examined using logistic regression models. Time to biochemical recurrence was compared across the groups using a log-rank survivorship analysis. Multivariable analysis predicting biochemical recurrence was conducted with a Cox proportional hazards model.Patients with elevated body mass index (defined as body mass index ≥25 kg/m(2)) had greater extraprostatic extension (p = 0.004), and positive surgical margins (p = 0.01). Elevated body mass index did not correlate with preoperative risk groupings (p = 0.94). However, when compared with non-obese patients (body mass index <30 kg/m(2)), obese patients (body mass index ≥30 kg/m(2)) were much more likely to have higher rate of adverse pathologic features (p = 0.006). In patients with low- and intermediate- risk disease, obesity was strongly associated with rate of pathologic upgrading of tumors (p = 0.01 and p = 0.02), respectively. After controlling for known preoperative risk factors, body mass index was independently associated with ≥2 adverse pathologic features (p = 0.002), an indicator for adjuvant RT as well as FFbF (p = 0.001).Body mass index of ≥30 kg/m(2) is independently associated with adverse pathologic features, which is an indicator for additional RT, particularly in patients with low-intermediate risk disease. Future studies may determine if this select group of patients may be best treated with definitive RT to reduce toxicity from additional RT following radical prostatectomy. We propose including body mass index in clinical decision-making for appropriate treatment recommendation for patients with low-intermediate risk PCa.

  View details for DOI 10.1186/s12885-016-2572-y

  View details for Web of Science ID 000381215200001

  View details for PubMedID 27473687

  View details for PubMedCentralID PMC4966583

• Assessing the genetic architecture of epithelial ovarian cancer histological subtypes HUMAN GENETICS Cuellar-Partida, G., Lu, Y., Dixon, S. C., Fasching, P. A., Hein, A., Burghaus, S., Beckmann, M. W., Lambrechts, D., van Nieuwenhuysen, E., Vergote, I., Vanderstichele, A., Doherty, J. A., Rossing, M. A., Chang-Claude, J., Rudolph, A., Wang-Gohrke, S., Goodman, M. T., Bogdanova, N., Doerk, T., Duerst, M., Hillemanns, P., Runnebaum, I. B., Antonenkova, N., Butzow, R., Leminen, A., Nevanlinna, H., Pelttari, L. M., Edwards, R. P., Kelley, J. L., Modugno, F., Moysich, K. B., Ness, R. B., Cannioto, R., Hogdall, E., Hogdall, C., Jensen, A., Giles, G. G., Bruinsma, F., Kjaer, S. K., Hildebrandt, M. A., Liang, D., Lu, K. H., Wu, X., Bisogna, M., Dao, F., Levine, D. A., Cramer, D. W., Terry, K. L., Tworoger, S. S., Stampfer, M., Missmer, S., Bjorge, L., Salvesen, H. B., Kopperud, R. K., Bischof, K., Aben, K. K., Kiemeney, L. A., Massuger, L. F., Brooks-Wilson, A., Olson, S. H., McGuire, V., Rothstein, J. H., Sieh, W., Whittemore, A. S., Cook, L. S., Le, N. D., Gilks, C. B., Gronwald, J., Jakubowska, A., Lubinski, J., Kluz, T., Song, H., Tyrer, J. P., Wentzensen, N., Brinton, L., Trabert, B., Lissowska, J., McLaughlin, J. R., Narod, S. A., Phelan, C., Anton-Culver, H., Ziogas, A., Eccles, D., Campbell, I., Gayther, S. A., Gentry-Maharaj, A., Menon, U., Ramus, S. J., Wu, A. H., Dansonka-Mieszkowska, A., Kupryjanczyk, J., Timorek, A., Szafron, L., Cunningham, J. M., Fridley, B. L., Winham, S. J., Bandera, E. V., Poole, E. M., Morgan, T. K., Goode, E. L., Schildkraut, J. M., Pearce, C. L., Berchuck, A., Pharoah, P. D., Webb, P. M., Chenevix-Trench, G., Risch, H. A., Macgregor, S. 2016; 135 (7): 741-756

  Abstract

  Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

  View details for DOI 10.1007/s00439-016-1663-9

  View details for PubMedID 27075448

• Parity and Oral Contraceptive Use in Relation to Ovarian Cancer Risk in Older Women CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION McGuire, V., Hartge, P., Liao, L. M., Sinha, R., Bernstein, L., Canchola, A. J., Anderson, G. L., Stefanick, M. L., Whittemore, A. S. 2016; 25 (7): 1059-1063

  Abstract

  Several studies have suggested that the ovarian cancer risk reductions associated with parity and oral contraceptive use are weaker in postmenopausal than premenopausal women, yet little is known about the persistence of these reductions as women age. This question gains importance with the increasing numbers of older women in the population.We addressed the question using data from three large U.S. cohort studies involving 310,290 white women aged 50+ years at recruitment, of whom 1,815 developed subsequent incident invasive epithelial ovarian cancer. We used Cox regression, stratified by cohort, to examine age-related trends in the HRs per full-term pregnancy and per year of oral contraceptive use.The parity-associated risk reductions waned with age (Ptrend < 0.001 in HR with increasing age), particularly among women aged 75 years or more, for whom we observed no association with parity. However, we observed no such attenuation in the oral contraceptive-associated risk reductions (P = 0.79 for trend in HR with increasing age).These findings suggest that prior oral contraceptive use is important for ovarian cancer risk assessment among women of all ages, while the benefits of parity wane as women age.This information, if duplicated in other studies, will be useful to preventive counseling and risk prediction, particularly for women at increased ovarian cancer risk due to a personal history of breast cancer or a family history of ovarian cancer. Cancer Epidemiol Biomarkers Prev; 25(7); 1059-63. ©2016 AACR.

  View details for DOI 10.1158/1055-9965.EPI-16-0011

  View details for Web of Science ID 000380072700007

  View details for PubMedID 27197274

  View details for PubMedCentralID PMC4930714

• Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer. Oncotarget Hampras, S. S., Sucheston-Campbell, L. E., Cannioto, R., Chang-Claude, J., Modugno, F., Dörk, T., Hillemanns, P., Preus, L., Knutson, K. L., Wallace, P. K., Hong, C., Friel, G., Davis, W., Nesline, M., Pearce, C. L., Kelemen, L. E., Goodman, M. T., Bandera, E. V., Terry, K. L., Schoof, N., Eng, K. H., Clay, A., Singh, P. K., Joseph, J. M., Aben, K. K., Anton-Culver, H., Antonenkova, N., Baker, H., Bean, Y., Beckmann, M. W., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L. A., Brooks-Wilson, A., Bruinsma, F., Butzow, R., Campbell, I. G., Carty, K., Cook, L. S., Cramer, D. W., Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Despierre, E., Dicks, E., Doherty, J. A., du Bois, A., Dürst, M., Easton, D., Eccles, D., Edwards, R. P., Ekici, A. B., Fasching, P. A., Fridley, B. L., Gao, Y., Gentry-Maharaj, A., Giles, G. G., Glasspool, R., Gronwald, J., Harrington, P., Harter, P., Hasmad, H. N., Hein, A., Heitz, F., Hildebrandt, M. A., Hogdall, C., Hogdall, E., Hosono, S., Iversen, E. S., Jakubowska, A., Jensen, A., Ji, B., Karlan, B. Y., Kellar, M., Kelley, J. L., Kiemeney, L. A., Klapdor, R., Kolomeyevskaya, N., Krakstad, C., Kjaer, S. K., Kruszka, B., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N. D., Lee, A. W., Lele, S., Leminen, A., Lester, J., Levine, D. A., Liang, D., Lissowska, J., Liu, S., Lu, K., Lubinski, J., Lundvall, L., Massuger, L. F., Matsuo, K., McGuire, V., McLaughlin, J. R., McNeish, I., Menon, U., Moes-Sosnowska, J., Narod, S. A., Nedergaard, L., Nevanlinna, H., Nickels, S., Olson, S. H., Orlow, I., Weber, R. P., Paul, J., Pejovic, T., Pelttari, L. M., Perkins, B., Permuth-Wey, J., Pike, M. C., Plisiecka-Halasa, J., Poole, E. M., Risch, H. A., Rossing, M. A., Rothstein, J. H., Rudolph, A., Runnebaum, I. B., Rzepecka, I. K., Salvesen, H. B., Schernhammer, E., Schmitt, K., Schwaab, I., Shu, X., Shvetsov, Y. B., Siddiqui, N., Sieh, W., Song, H., Southey, M. C., Tangen, I. L., Teo, S., Thompson, P. J., Timorek, A., Tsai, Y., Tworoger, S. S., Tyrer, J., van Altena, A. M., Vergote, I., Vierkant, R. A., Walsh, C., Wang-Gohrke, S., Wentzensen, N., Whittemore, A. S., Wicklund, K. G., Wilkens, L. R., Wu, A. H., Wu, X., Woo, Y., Yang, H., Zheng, W., Ziogas, A., Gayther, S. A., Ramus, S. J., Sellers, T. A., Schildkraut, J. M., Phelan, C. M., Berchuck, A., Chenevix-Trench, G., Cunningham, J. M., Pharoah, P. P., Ness, R. B., Odunsi, K., Goode, E. L., Moysich, K. B. 2016

  Abstract

  Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer.In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients.The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively).Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

  View details for DOI 10.18632/oncotarget.10215

  View details for PubMedID 27533245

• Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study. International journal of epidemiology Dixon, S. C., Nagle, C. M., Thrift, A. P., Pharoah, P. D., Pearce, C. L., Zheng, W., Painter, J. N., Chenevix-Trench, G., Fasching, P. A., Beckmann, M. W., Lambrechts, D., Vergote, I., Lambrechts, S., van Nieuwenhuysen, E., Rossing, M. A., Doherty, J. A., Wicklund, K. G., Chang-Claude, J., Rudolph, A., Moysich, K. B., Odunsi, K., Goodman, M. T., Wilkens, L. R., Thompson, P. J., Shvetsov, Y. B., Dörk, T., Park-Simon, T., Hillemanns, P., Bogdanova, N., Butzow, R., Nevanlinna, H., Pelttari, L. M., Leminen, A., Modugno, F., Ness, R. B., Edwards, R. P., Kelley, J. L., Heitz, F., Karlan, B. Y., Kjær, S. K., Høgdall, E., Jensen, A., Goode, E. L., Fridley, B. L., Cunningham, J. M., Winham, S. J., Giles, G. G., Bruinsma, F., Milne, R. L., Southey, M. C., Hildebrandt, M. A., Wu, X., Lu, K. H., Liang, D., Levine, D. A., Bisogna, M., Schildkraut, J. M., Berchuck, A., Cramer, D. W., Terry, K. L., Bandera, E. V., Olson, S. H., Salvesen, H. B., Thomsen, L. C., Kopperud, R. K., Bjorge, L., Kiemeney, L. A., Massuger, L. F., Pejovic, T., Cook, L. S., Le, N. D., Swenerton, K. D., Brooks-Wilson, A., Kelemen, L. E., Lubinski, J., Huzarski, T., Gronwald, J., Menkiszak, J., Wentzensen, N., Brinton, L., Yang, H., Lissowska, J., Høgdall, C. K., Lundvall, L., Song, H., Tyrer, J. P., Campbell, I., Eccles, D., Paul, J., Glasspool, R., Siddiqui, N., Whittemore, A. S., Sieh, W., McGuire, V., Rothstein, J. H., Narod, S. A., Phelan, C., Risch, H. A., McLaughlin, J. R., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S. A., Ramus, S. J., Gentry-Maharaj, A., Wu, A. H., Pike, M. C., Tseng, C., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Budzilowska, A., Spiewankiewicz, B., Webb, P. M. 2016; 45 (3): 884-895

  Abstract

  Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC.We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis.Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81).Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.

  View details for DOI 10.1093/ije/dyw158

  View details for PubMedID 27401727

• 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

• Case-control study of mammographic density and breast cancer risk using processed digital mammograms BREAST CANCER RESEARCH Habel, L. A., Lipson, J. A., Achacoso, N., Rothstein, J. H., Yaffe, M. J., Liang, R. Y., Acton, L., McGuire, V., Whittemore, A. S., Rubin, D. L., Sieh, W. 2016; 18

  Abstract

  Full-field digital mammography (FFDM) has largely replaced film-screen mammography in the US. Breast density assessed from film mammograms is strongly associated with breast cancer risk, but data are limited for processed FFDM images used for clinical care.We conducted a case-control study nested among non-Hispanic white female participants of the Research Program in Genes, Environment and Health of Kaiser Permanente Northern California who were aged 40 to 74 years and had screening mammograms acquired on Hologic FFDM machines. Cases (n = 297) were women with a first invasive breast cancer diagnosed after a screening FFDM. For each case, up to five controls (n = 1149) were selected, matched on age and year of FFDM and image batch number, and who were still under follow-up and without a history of breast cancer at the age of diagnosis of the matched case. Percent density (PD) and dense area (DA) were assessed by a radiological technologist using Cumulus. Conditional logistic regression was used to estimate odds ratios (ORs) for breast cancer associated with PD and DA, modeled continuously in standard deviation (SD) increments and categorically in quintiles, after adjusting for body mass index, parity, first-degree family history of breast cancer, breast area, and menopausal hormone use.Median intra-reader reproducibility was high with a Pearson's r of 0.956 (range 0.902 to 0.983) for replicate PD measurements across 23 image batches. The overall mean was 20.02 (SD, 14.61) for PD and 27.63 cm(2) (18.22 cm(2)) for DA. The adjusted ORs for breast cancer associated with each SD increment were 1.70 (95 % confidence interval, 1.41-2.04) for PD, and 1.54 (1.34-1.77) for DA. The adjusted ORs for each quintile were: 1.00 (ref.), 1.49 (0.91-2.45), 2.57 (1.54-4.30), 3.22 (1.91-5.43), 4.88 (2.78-8.55) for PD, and 1.00 (ref.), 1.43 (0.85-2.40), 2.53 (1.53-4.19), 2.85 (1.73-4.69), 3.48 (2.14-5.65) for DA.PD and DA measured using Cumulus on processed FFDM images are positively associated with breast cancer risk, with similar magnitudes of association as previously reported for film-screen mammograms. Processed digital mammograms acquired for routine clinical care in a general practice setting are suitable for breast density and cancer research.

  View details for DOI 10.1186/s13058-016-0715-3

  View details for Web of Science ID 000377273200001

  View details for PubMedID 27209070

  View details for PubMedCentralID PMC4875652

• No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer GYNECOLOGIC ONCOLOGY Hollestelle, A., van der Baan, F. H., Berchuck, A., Johnatty, S. E., Aben, K. K., Agnarsson, B. A., Aittomaki, K., Alducci, E., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Antoniou, A. C., Apicella, C., Arndt, V., Arnold, N., Arun, B. K., Arver, B., Ashworth, A., Baglietto, L., Balleine, R., Bandera, E. V., Barrowdale, D., Bean, Y. T., Beckmann, L., Beckmann, M. W., Benitez, J., Berger, A., Berger, R., Beuselinck, B., Bisogna, M., Bjorge, L., Blomqvist, C., Bogdanova, N. V., Bojesen, A., Bojesen, S. E., Bolla, M. K., Bonanni, B., Brand, J. S., Brauch, H., Brenner, H., Brinton, L., Brooks-Wilson, A., Bruinsma, F., Brunet, J., Bruning, T., Budzilowska, A., Bunker, C. H., Burwinkel, B., Butzow, R., Buys, S. S., Caligo, M. A., Campbell, I., Carter, J., Chang-Claude, J., Chanock, S. J., Claes, K. B., Collee, J. M., Cook, L. S., Couch, F. J., Cox, A., Cramer, D., Cross, S. S., Cunningham, J. M., Cybulski, C., Czene, K., Damiola, F., Dansonka-Mieszkowska, A., Darabi, H., de la Hoya, M., deFazio, A., Dennis, J., Devilee, P., Dicks, E. M., Diez, O., Doherty, J. A., Domchek, S. M., Dorfling, C. M., Dork, T., dos Santos Silva, I., du Bois, A., Dumont, M., Dunning, A. M., Duran, M., Easton, D. F., Eccles, D., Edwards, R. P., Ehrencrona, H., Ejlertsen, B., Ekici, A. B., Ellis, S. D., Engel, C., Eriksson, M., Fasching, P. A., Feliubadalo, L., Figueroa, J., Flesch-Janys, D., Fletcher, O., Fontaine, A., Fortuzzi, S., Fostira, F., Fridley, B. L., Friebel, T., friedman, e., Friel, G., Frost, D., Garber, J., Garcia-Closas, M., Gayther, S. A., Gentry-Maharaj, A., Gerdes, A., Giles, G. G., Glasspool, R., Glendon, G., Godwin, A. K., Goodman, M. T., Gore, M., Greene, M. H., Grip, M., Gronwald, J., Kaulich, D. G., Guenel, P., Guzman, S. R., Haeberle, L., Haiman, C. A., Hall, P., Halverson, S. L., Hamann, U., Hansen, T. v., Harter, P., Hartikainen, J. M., Healey, S., Hein, A., Heitz, F., Henderson, B. E., Herzog, J., Hildebrandt, M. A., Bogdan, C. K., Hogdall, E., Hogervorst, F. B., Hopper, J. L., Humphreys, K., Huzarski, T., Imyanitov, E. N., Isaacs, C., Jakubowska, A., Janavicius, R., Jaworska, K., Jensen, A., Jensen, U. B., Johnson, N., Jukkola-Vuorinen, A., Kabisch, M., Karlan, B. Y., Kataja, V., Kauff, N., Kelemen, L. E., Kerin, M. J., Kiemeney, L. A., Kjaer, S. K., Knight, J. A., Knol-Bout, J. P., Konstantopoulou, I., Kosma, V., Krakstad, C., Kristensen, V., Kuchenbaecker, K. B., Kupryjanczyk, J., Laitman, Y., Lambrechts, D., Lambrechts, S., Larson, M. C., Lasa, A., Laurent-Puig, P., Lazaro, C., Le, N. D., Le Marchand, L., Leminen, A., Lester, J., Levine, D. A., Li, J., Liang, D., Lindblom, A., Lindor, N., Lissowska, J., Long, J., Lu, K. H., Lubinski, J., Lundvall, L., Lurie, G., Mai, P. L., Mannermaa, A., Margolin, S., Mariette, F., Marme, F., Martens, J. W., Massuger, L. F., Maugard, C., Mazoyer, S., McGuffog, L., McGuire, V., McLean, C., McNeish, L., Meindi, A., Menegaux, F., Menendez, P., Menkiszak, J., Menon, U., Mensenkamp, A. R., Miller, N., Milne, R. L., Modugno, F., Montagna, M., Moysich, K. B., Mueller, H., Mulligan, A. M., Muranen, T. A., Narod, S. A., Nathanson, K. L., Ness, R. B., Neuhausen, S. L., Nevanlinna, H., Neven, P., Nielsen, F. C., Nielsen, S. F., Nordestgaard, B. G., Nussbaum, R. L., Odunsi, K., Offit, K., Olah, E., Olopade, O. I., Olson, J. E., Olson, S. H., Oosterwijk, J. C., Orlow, I., Orr, N., Orsulic, S., Osorio, A., Ottini, L., Paul, J., Pearce, C. L., Pedersen, I. S., Peissel, B., Pejovic, T., Pelttari, L. M., Perkins, J., Permuth-Wey, J., Peterlongo, P., Peto, J., Phelan, C. M., Phillips, K., Piedmonte, M., Pike, M. C., Platte, R., Plisiecka-Halasa, J., Poole, E. M., Poppe, B., Pylkas, K., Radice, P., Ramus, S. J., Rebbeck, T. R., Reed, M. W., Rennert, G., Risch, H. A., Robson, M., Rodriguez, G. C., Romero, A., Rossing, M. A., Rothstein, J. H., Rudolph, A., Runnebaum, I., Salani, R., Salvesen, H. B., Sawyer, E. J., Schildkraut, J. M., Schmidt, M. K., Schmutzler, R. K., Schneeweiss, A., Schoemaker, M. J., Schrauder, M. G., Schumacher, F., Schwaab, I., Scuvera, G., Sellers, T. A., Severi, G., Seynaeve, C. M., Shah, M., Shrubsole, M., Siddiqui, N., Sieh, W., Simard, J., Singer, C. F., Sinilnikova, O. M., Smeets, D., Sohn, C., Soller, M., Song, H., Soucy, P., Southey, M. C., Stegmaier, C., Stoppa-Lyonnet, D., Sucheston, L., Swerdlow, A., Tangen, I. L., Tea, M., Teixeira, M. R., Terry, K. L., Terry, M. B., Thomassen, M., Thompson, P. J., Tihomirova, L., Tischkowitz, M., Toland, A. E., Tollenaar, R. A., Tomlinson, I., Torres, D., Truong, T., Tsimiklis, H., Tung, N., Tworoger, S. S., Tyrer, J. P., Vachon, C. M., van 't Veer, L. J., van Altena, A. M., van Asperen, C. J., Van Den Berg, D., van den Ouweland, A. M., Van Doom, H. C., van Nieuwenhuysen, E., Van Rensburg, E. J., Vergote, I., Verhoef, S., Vierkant, R. A., Vijai, J., Vitonis, A. F., von Wachenfeldt, A., Walsh, C., Wang, Q., Wang-Gohrke, S., Wappenschmidt, B., Weischer, M., Weitzel, J. N., Weltens, C., Wentzensen, N., Whittemore, A. S., Wilkens, L. R., Winqvist, R., Wu, A. H., Wu, X., Yang, H. P., Zaffaroni, D., Zamora, M. P., Zheng, W., Ziogas, A., Chenevix-Trench, G., Pharoah, P. D., Rookus, M. A., Hooning, M. J., Goode, E. L. 2016; 141 (2): 386-401

  Abstract

  Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370.Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers).We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations.rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.

  View details for DOI 10.1016/j.ygyno.2015.04.034

  View details for PubMedID 25940428

• 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

• Identification of Susceptibility Loci for Cutaneous Squamous Cell Carcinoma JOURNAL OF INVESTIGATIVE DERMATOLOGY Asgari, M. M., Wang, W., Ioannidis, N. M., Itnyre, J., Hoffmann, T., Jorgenson, E., Whittemore, A. S. 2016; 136 (5): 930-937

  Abstract

  We report a genome-wide association study of cutaneous squamous cell carcinoma conducted among non-Hispanic white members of the Kaiser Permanente Northern California health care system. The study includes a genome-wide screen of 61,457 members (6,891 cases and 54,566 controls) genotyped on the Affymetrix Axiom European array and a replication phase involving an independent set of 6,410 additional members (810 cases and 5,600 controls). Combined analysis of screening and replication phases identified 10 loci containing single-nucleotide polymorphisms (SNPs) with P-values < 5 × 10(-8). Six loci contain genes in the pigmentation pathway; SNPs at these loci appear to modulate squamous cell carcinoma risk independently of the pigmentation phenotypes. Another locus contains HLA class II genes studied in relation to elevated squamous cell carcinoma risk following immunosuppression. SNPs at the remaining three loci include an intronic SNP in FOXP1 at locus 3p13, an intergenic SNP at 3q28 near TP63, and an intergenic SNP at 9p22 near BNC2. These findings provide insights into the genetic factors accounting for inherited squamous cell carcinoma susceptibility.

  View details for DOI 10.1016/j.jid.2016.01.013

  View details for Web of Science ID 000375980600013

  View details for PubMedID 26829030

  View details for PubMedCentralID PMC4842155

• 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

• Assessment of Multifactor Gene-Environment Interactions and Ovarian Cancer Risk: Candidate Genes, Obesity, and Hormone-Related Risk Factors CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Usset, J. L., Raghavan, R., Tyrer, J. P., McGuire, V., Sieh, W., Webb, P., Chang-Claude, J., Rudolph, A., Anton-Culver, H., Berchuck, A., Brinton, L., Cunningham, J. M., deFazio, A., Doherty, J. A., Edwards, R. P., Gayther, S. A., Gentry-Maharaj, A., Goodman, M. T., Hogdall, E., Jensen, A., Johnatty, S. E., Kiemeney, L. A., Kjaer, S. K., Larson, M. C., Lurie, G., Massuger, L., Menon, U., Modugno, F., Moysich, K. B., Ness, R. B., Pike, M. C., Ramus, S. J., Rossing, M. A., Rothstein, J., Song, H., Thompson, P. J., Van den Berg, D. J., Vierkant, R. A., Wang-Gohrke, S., Wentzensen, N., Whittemore, A. S., Wilkens, L. R., Wu, A. H., Yang, H., Pearce, C. L., Schildkraut, J. M., Pharoah, P., Goode, E. L., Fridley, B. L. 2016; 25 (5): 780-790

  Abstract

  Many epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene-environment interactions related to hormone-related risk factors could differ between obese and non-obese women.We considered interactions between 11,441 SNPs within 80 candidate genes related to hormone biosynthesis and metabolism and insulin-like growth factors with six hormone-related factors (oral contraceptive use, parity, endometriosis, tubal ligation, hormone replacement therapy, and estrogen use) and assessed whether these interactions differed between obese and non-obese women. Interactions were assessed using logistic regression models and data from 14 case-control studies (6,247 cases; 10,379 controls). Histotype-specific analyses were also completed.SNPs in the following candidate genes showed notable interaction: IGF1R (rs41497346, estrogen plus progesterone hormone therapy, histology = all, P = 4.9 × 10(-6)) and ESR1 (rs12661437, endometriosis, histology = all, P = 1.5 × 10(-5)). The most notable obesity-gene-hormone risk factor interaction was within INSR (rs113759408, parity, histology = endometrioid, P = 8.8 × 10(-6)).We have demonstrated the feasibility of assessing multifactor interactions in large genetic epidemiology studies. Follow-up studies are necessary to assess the robustness of our findings for ESR1, CYP11A1, IGF1R, CYP11B1, INSR, and IGFBP2 Future work is needed to develop powerful statistical methods able to detect these complex interactions.Assessment of multifactor interaction is feasible, and, here, suggests that the relationship between genetic variants within candidate genes and hormone-related risk factors may vary EOC susceptibility. Cancer Epidemiol Biomarkers Prev; 25(5); 780-90. ©2016 AACR.

  View details for PubMedID 26976855

• The association between socioeconomic status and tumour stage at diagnosis of ovarian cancer: A pooled analysis of 18 case-control studies CANCER EPIDEMIOLOGY Praestegaard, C., Kjaer, S. K., Nielsen, T. S., Jensen, S. M., Webb, P. M., Nagle, C. M., Hogdall, E., Risch, H. A., Rossing, M. A., Doherty, J. A., Wicklund, K. G., Goodman, M. T., Modugno, F., Moysich, K., Ness, R. B., Edwards, R. P., Goode, E. L., Winham, S. J., Fridley, B. L., Cramer, D. W., Terry, K. L., Schildkraut, J. M., Berchuck, A., Bandera, E. V., Paddock, L., Kiemeney, L. A., Massuger, L. F., Wentzensen, N., Pharoah, P., Song, H., Whittemore, A. S., McGuire, V., Sieh, W., Rothstein, J., Anton-Culver, H., Ziogas, A., Menon, U., Gayther, S. A., Ramus, S. J., Gentry-Maharaj, A., Wu, A. H., Pearce, C. L., Pike, M. C., Lee, A. W., Chang-Claude, J., Jensen, A. 2016; 41: 71-79

  Abstract

  Socioeconomic status (SES) is a known predictor of survival for several cancers and it has been suggested that SES differences affecting tumour stage at diagnosis may be the most important explanatory factor for this. However, only a limited number of studies have investigated SES differences in tumour stage at diagnosis of ovarian cancer. In a pooled analysis, we investigated whether SES as represented by level of education is predictive for advanced tumour stage at diagnosis of ovarian cancer, overall and by histotype. The effect of cigarette smoking and body mass index (BMI) on the association was also evaluated.From 18 case-control studies, we obtained information on 10,601 women diagnosed with epithelial ovarian cancer. Study specific odds ratios (ORs) with corresponding 95% confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio (pOR) using a random effects model.Overall, women who completed ≤high school had an increased risk of advanced tumour stage at diagnosis compared with women who completed >high school (pOR 1.15; 95% CI 1.03-1.28). The risk estimates for the different histotypes of ovarian cancer resembled that observed for ovarian cancers combined but did not reach statistical significance. Our results were unchanged when we included BMI and cigarette smoking.Lower level of education was associated with an increased risk of advanced tumour stage at diagnosis of ovarian cancer. The observed socioeconomic difference in stage at diagnosis of ovarian cancer calls for further studies on how to reduce this diagnostic delay.

  View details for DOI 10.1016/j.canep.2016.01.012

  View details for PubMedID 26851750

• PPM1D Mosaic Truncating Variants in Ovarian Cancer Cases May Be Treatment-Related Somatic Mutations JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Pharoah, P. D., Song, H., Dicks, E., Intermaggio, M. P., Harrington, P., Baynes, C., Alsop, K., Bogdanova, N., Cicek, M. S., Cunningham, J. M., Fridley, B. L., Gentry-Maharaj, A., Hillemanns, P., Lele, S., Lester, J., McGuire, V., Moysich, K. B., Poblete, S., Sieh, W., Sucheston-Campbell, L., Widschwendter, M., Whittemore, A. S., Doerk, T., Menon, U., Odunsi, K., Goode, E. L., Karlan, B. Y., Bowtell, D. D., Gayther, S. A., Ramus, S. J. 2016; 108 (3)

  View details for DOI 10.1093/jnci/djv347

  View details for Web of Science ID 000372589400013

• PPM1D Mosaic Truncating Variants in Ovarian Cancer Cases May Be Treatment-Related Somatic Mutations. Journal of the National Cancer Institute Pharoah, P. D., Song, H., Dicks, E., Intermaggio, M. P., Harrington, P., Baynes, C., Alsop, K., Bogdanova, N., Cicek, M. S., Cunningham, J. M., Fridley, B. L., Gentry-Maharaj, A., Hillemanns, P., Lele, S., Lester, J., McGuire, V., Moysich, K. B., Poblete, S., Sieh, W., Sucheston-Campbell, L., Widschwendter, M., Whittemore, A. S., Dörk, T., Menon, U., Odunsi, K., Goode, E. L., Karlan, B. Y., Bowtell, D. D., Gayther, S. A., Ramus, S. J. 2016; 108 (3)

  Abstract

  Mosaic truncating mutations in the protein phosphatase, Mg(2+)/Mn(2+)-dependent, 1D (PPM1D) gene have recently been reported with a statistically significantly greater frequency in lymphocyte DNA from ovarian cancer case patients compared with unaffected control patients. Using massively parallel sequencing (MPS) we identified truncating PPM1D mutations in 12 of 3236 epithelial ovarian cancer (EOC) case patients (0.37%) but in only one of 3431 unaffected control patients (0.03%) (P = .001). All statistical tests were two-sided. A combination of Sanger sequencing, pyrosequencing, and MPS data suggested that 12 of the 13 mutations were mosaic. All mutations were identified in post-chemotherapy treatment blood samples from case patients (n = 1827) (average 1234 days post-treatment in carriers) rather than from cases collected pretreatment (less than 14 days after diagnosis, n = 1384) (P = .002). These data suggest that PPM1D variants in EOC cases are primarily somatic mosaic mutations caused by treatment and are not associated with germline predisposition to EOC.

  View details for DOI 10.1093/jnci/djv347

  View details for PubMedID 26823519

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

  Abstract

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

  View details for DOI 10.1038/ncomms12675

  View details for PubMedID 27601076

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

  Abstract

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

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

  View details for PubMedID 27459855

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

  Abstract

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

  View details for DOI 10.1038/ncomms11375

  View details for PubMedID 27117709

• Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium. Clinical cancer research Johnatty, S. E., Tyrer, J. P., Kar, S., Beesley, J., Lu, Y., Gao, B., Fasching, P. A., Hein, A., Ekici, A. B., Beckmann, M. W., Lambrechts, D., van Nieuwenhuysen, E., Vergote, I., Lambrechts, S., Rossing, M. A., Doherty, J. A., Chang-Claude, J., Modugno, F., Ness, R. B., Moysich, K. B., Levine, D. A., Kiemeney, L. A., Massuger, L. F., Gronwald, J., Lubinski, J., Jakubowska, A., Cybulski, C., Brinton, L., Lissowska, J., Wentzensen, N., Song, H., Rhenius, V., Campbell, I., Eccles, D., Sieh, W., Whittemore, A. S., McGuire, V., Rothstein, J. H., Sutphen, R., Anton-Culver, H., Ziogas, A., Gayther, S. A., Gentry-Maharaj, A., Menon, U., Ramus, S. J., Pearce, C. L., Pike, M. C., Stram, D. O., Wu, A. H., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Rzepecka, I. K., Spiewankiewicz, B., Goodman, M. T., Wilkens, L. R., Carney, M. E., Thompson, P. J., Heitz, F., du Bois, A., Schwaab, I., Harter, P., Pisterer, J., Hillemanns, P., Karlan, B. Y., Walsh, C., Lester, J., Orsulic, S., Winham, S. J., Earp, M., Larson, M. C., Fogarty, Z. C., Høgdall, E., Jensen, A., Kjaer, S. K., Fridley, B. L., Cunningham, J. M., Vierkant, R. A., Schildkraut, J. M., Iversen, E. S., Terry, K. L., Cramer, D. W., Bandera, E. V., Orlow, I., Pejovic, T., Bean, Y., Høgdall, C., Lundvall, L., McNeish, I., Paul, J., Carty, K., Siddiqui, N., Glasspool, R., Sellers, T., Kennedy, C., Chiew, Y., Berchuck, A., Macgregor, S., Pharoah, P. D., Goode, E. L., deFazio, A., Webb, P. M., Chenevix-Trench, G. 2015; 21 (23): 5264-5276

  Abstract

  Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome.We analyzed ~2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent firstline treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients including patients from The Cancer Genome Atlas. Additionally we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis.Five SNPs were significantly associated (p≤1.0x10(-5)) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23) and rs6674079 (1q22) were located in long non-coding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1 and RP11-284F21.8 respectively (p≤7.1x10(-6)). ENCODE ChIP-seq data at 1q22 for normal ovary shows evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression, and HDL-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA≤6x10(-3)).We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies.

  View details for DOI 10.1158/1078-0432.CCR-15-0632

  View details for PubMedID 26152742

• Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk. Genetic epidemiology Amankwah, E. K., Lin, H., Tyrer, J. P., Lawrenson, K., Dennis, J., Chornokur, G., Aben, K. K., Anton-Culver, H., Antonenkova, N., Bruinsma, F., Bandera, E. V., Bean, Y. T., Beckmann, M. W., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L. A., Brooks-Wilson, A., Bunker, C. H., Butzow, R., Campbell, I. G., Carty, K., Chen, Z., Chen, Y. A., Chang-Claude, J., Cook, L. S., Cramer, D. W., Cunningham, J. M., Cybulski, C., Dansonka-Mieszkowska, A., du Bois, A., Despierre, E., Dicks, E., Doherty, J. A., Dörk, T., Dürst, M., Easton, D. F., Eccles, D. M., Edwards, R. P., Ekici, A. B., Fasching, P. A., Fridley, B. L., Gao, Y., Gentry-Maharaj, A., Giles, G. G., Glasspool, R., Goodman, M. T., Gronwald, J., Harrington, P., Harter, P., Hasmad, H. N., Hein, A., Heitz, F., Hildebrandt, M. A., Hillemanns, P., Hogdall, C. K., Hogdall, E., Hosono, S., Iversen, E. S., Jakubowska, A., Jensen, A., Ji, B., Karlan, B. Y., Jim, H., Kellar, M., Kiemeney, L. A., Krakstad, C., Kjaer, S. K., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N. D., Lee, A. W., Lele, S., Leminen, A., Lester, J., Levine, D. A., Liang, D., Lim, B. K., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L. F., Matsuo, K., McGuire, V., McLaughlin, J. R., McNeish, I., Menon, U., Milne, R. L., Modugno, F., Moysich, K. B., Ness, R. B., Nevanlinna, H., Eilber, U., Odunsi, K., Olson, S. H., Orlow, I., Orsulic, S., Weber, R. P., Paul, J., Pearce, C. L., Pejovic, T., Pelttari, L. M., Permuth-Wey, J., Pike, M. C., Poole, E. M., Risch, H. A., Rosen, B., Rossing, M. A., Rothstein, J. H., Rudolph, A., Runnebaum, I. B., Rzepecka, I. K., Salvesen, H. B., Schernhammer, E., Schwaab, I., Shu, X., Shvetsov, Y. B., Siddiqui, N., Sieh, W., Song, H., Southey, M. C., Spiewankiewicz, B., Sucheston-Campbell, L., Teo, S., Terry, K. L., Thompson, P. J., Thomsen, L., Tangen, I. L., Tworoger, S. S., van Altena, A. M., Vierkant, R. A., Vergote, I., Walsh, C. S., Wang-Gohrke, S., Wentzensen, N., Whittemore, A. S., Wicklund, K. G., Wilkens, L. R., Wu, A. H., Wu, X., Woo, Y., Yang, H., Zheng, W., Ziogas, A., Kelemen, L. E., Berchuck, A., Schildkraut, J. M., Ramus, S. J., Goode, E. L., Monteiro, A. N., Gayther, S. A., Narod, S. A., Pharoah, P. D., Sellers, T. A., Phelan, C. M. 2015; 39 (8): 689-697

  Abstract

  Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07-1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69-0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.

  View details for DOI 10.1002/gepi.21921

  View details for PubMedID 26399219

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

  Abstract

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

  View details for DOI 10.1093/jnci/djv219

  View details for Web of Science ID 000366972300027

  View details for PubMedID 26296642

  View details for PubMedCentralID PMC4643630

• Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. Journal of the National Cancer Institute Ramus, S. J., Song, H., Dicks, E., Tyrer, J. P., Rosenthal, A. N., Intermaggio, M. P., Fraser, L., Gentry-Maharaj, A., Hayward, J., Philpott, S., Anderson, C., Edlund, C. K., Conti, D., Harrington, P., Barrowdale, D., Bowtell, D. D., Alsop, K., Mitchell, G., Cicek, M. S., Cunningham, J. M., Fridley, B. L., Alsop, J., Jimenez-Linan, M., Poblete, S., Lele, S., Sucheston-Campbell, L., Moysich, K. B., Sieh, W., McGuire, V., Lester, J., Bogdanova, N., Dürst, M., Hillemanns, P., Odunsi, K., Whittemore, A. S., Karlan, B. Y., Dörk, T., Goode, E. L., Menon, U., Jacobs, I. J., Antoniou, A. C., Pharoah, P. D., Gayther, S. A. 2015; 107 (11)

  Abstract

  Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13 000 deaths per year in the United States. Risk prediction based on identifying germline mutations in ovarian cancer susceptibility genes could have a clinically significant impact on reducing disease mortality.Next generation sequencing was used to identify germline mutations in the coding regions of four candidate susceptibility genes-BRIP1, BARD1, PALB2 and NBN-in 3236 invasive EOC case patients and 3431 control patients of European origin, and in 2000 unaffected high-risk women from a clinical screening trial of ovarian cancer (UKFOCSS). For each gene, we estimated the prevalence and EOC risks and evaluated associations between germline variant status and clinical and epidemiological risk factor information. All statistical tests were two-sided.We found an increased frequency of deleterious mutations in BRIP1 in case patients (0.9%) and in the UKFOCSS participants (0.6%) compared with control patients (0.09%) (P = 1 x 10(-4) and 8 x 10(-4), respectively), but no differences for BARD1 (P = .39), NBN1 ( P = .61), or PALB2 (P = .08). There was also a difference in the frequency of rare missense variants in BRIP1 between case patients and control patients (P = 5.5 x 10(-4)). The relative risks associated with BRIP1 mutations were 11.22 for invasive EOC (95% confidence interval [CI] = 3.22 to 34.10, P = 1 x 10(-4)) and 14.09 for high-grade serous disease (95% CI = 4.04 to 45.02, P = 2 x 10(-5)). Segregation analysis in families estimated the average relative risks in BRIP1 mutation carriers compared with the general population to be 3.41 (95% CI = 2.12 to 5.54, P = 7×10(-7)).Deleterious germline mutations in BRIP1 are associated with a moderate increase in EOC risk. These data have clinical implications for risk prediction and prevention approaches for ovarian cancer and emphasize the critical need for risk estimates based on very large sample sizes before genes of moderate penetrance have clinical utility in cancer prevention.

  View details for DOI 10.1093/jnci/djv214

  View details for PubMedID 26315354

• Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. Journal of the National Cancer Institute Ramus, S. J., Song, H., Dicks, E., Tyrer, J. P., Rosenthal, A. N., Intermaggio, M. P., Fraser, L., Gentry-Maharaj, A., Hayward, J., Philpott, S., Anderson, C., Edlund, C. K., Conti, D., Harrington, P., Barrowdale, D., Bowtell, D. D., Alsop, K., Mitchell, G., Cicek, M. S., Cunningham, J. M., Fridley, B. L., Alsop, J., Jimenez-Linan, M., Poblete, S., Lele, S., Sucheston-Campbell, L., Moysich, K. B., Sieh, W., McGuire, V., Lester, J., Bogdanova, N., Dürst, M., Hillemanns, P., Odunsi, K., Whittemore, A. S., Karlan, B. Y., Dörk, T., Goode, E. L., Menon, U., Jacobs, I. J., Antoniou, A. C., Pharoah, P. D., Gayther, S. A. 2015; 107 (11)

  Abstract

  Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13 000 deaths per year in the United States. Risk prediction based on identifying germline mutations in ovarian cancer susceptibility genes could have a clinically significant impact on reducing disease mortality.Next generation sequencing was used to identify germline mutations in the coding regions of four candidate susceptibility genes-BRIP1, BARD1, PALB2 and NBN-in 3236 invasive EOC case patients and 3431 control patients of European origin, and in 2000 unaffected high-risk women from a clinical screening trial of ovarian cancer (UKFOCSS). For each gene, we estimated the prevalence and EOC risks and evaluated associations between germline variant status and clinical and epidemiological risk factor information. All statistical tests were two-sided.We found an increased frequency of deleterious mutations in BRIP1 in case patients (0.9%) and in the UKFOCSS participants (0.6%) compared with control patients (0.09%) (P = 1 x 10(-4) and 8 x 10(-4), respectively), but no differences for BARD1 (P = .39), NBN1 ( P = .61), or PALB2 (P = .08). There was also a difference in the frequency of rare missense variants in BRIP1 between case patients and control patients (P = 5.5 x 10(-4)). The relative risks associated with BRIP1 mutations were 11.22 for invasive EOC (95% confidence interval [CI] = 3.22 to 34.10, P = 1 x 10(-4)) and 14.09 for high-grade serous disease (95% CI = 4.04 to 45.02, P = 2 x 10(-5)). Segregation analysis in families estimated the average relative risks in BRIP1 mutation carriers compared with the general population to be 3.41 (95% CI = 2.12 to 5.54, P = 7×10(-7)).Deleterious germline mutations in BRIP1 are associated with a moderate increase in EOC risk. These data have clinical implications for risk prediction and prevention approaches for ovarian cancer and emphasize the critical need for risk estimates based on very large sample sizes before genes of moderate penetrance have clinical utility in cancer prevention.

  View details for DOI 10.1093/jnci/djv214

  View details for PubMedID 26315354

• Shared genetics underlying epidemiological association between endometriosis and ovarian cancer. Human molecular genetics Lu, Y., Cuellar-Partida, G., Painter, J. N., Nyholt, D. R., Morris, A. P., Fasching, P. A., Hein, A., Burghaus, S., Beckmann, M. W., Lambrechts, D., van Nieuwenhuysen, E., Vergote, I., Vanderstichele, A., Doherty, J. A., Rossing, M. A., Wicklund, K. G., Chang-Claude, J., Eilber, U., Rudolph, A., Wang-Gohrke, S., Goodman, M. T., Bogdanova, N., Dörk, T., Dürst, M., Hillemanns, P., Runnebaum, I. B., Antonenkova, N., Butzow, R., Leminen, A., Nevanlinna, H., Pelttari, L. M., Edwards, R. P., Kelley, J. L., Modugno, F., Moysich, K. B., Ness, R. B., Cannioto, R., Høgdall, E., Jensen, A., Giles, G. G., Bruinsma, F., Kjaer, S. K., Hildebrandt, M. A., Liang, D., Lu, K. H., Wu, X., Bisogna, M., Dao, F., Levine, D. A., Cramer, D. W., Terry, K. L., Tworoger, S. S., Missmer, S., Bjorge, L., Salvesen, H. B., Kopperud, R. K., Bischof, K., Aben, K. K., Kiemeney, L. A., Massuger, L. F., Brooks-Wilson, A., Olson, S. H., McGuire, V., Rothstein, J. H., Sieh, W., Whittemore, A. S., Cook, L. S., Le, N. D., Gilks, C. B., Gronwald, J., Jakubowska, A., Lubinski, J., Gawelko, J., Song, H., Tyrer, J. P., Wentzensen, N., Brinton, L., Trabert, B., Lissowska, J., McLaughlin, J. R., Narod, S. A., Phelan, C., Anton-Culver, H., Ziogas, A., Eccles, D., Gayther, S. A., Gentry-Maharaj, A., Menon, U., Ramus, S. J., Wu, A. H., Dansonka-Mieszkowska, A., Kupryjanczyk, J., Timorek, A., Szafron, L., Cunningham, J. M., Fridley, B. L., Winham, S. J., Bandera, E. V., Poole, E. M., Morgan, T. K., Risch, H. A., Goode, E. L., Schildkraut, J. M., Webb, P. M., Pearce, C. L., Berchuck, A., Pharoah, P. D., Montgomery, G. W., Zondervan, K. T., Chenevix-Trench, G., Macgregor, S. 2015; 24 (20): 5955-5964

  Abstract

  Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3,194 cases and 7,060 controls) and a large ovarian cancer dataset genotyped on the customised iCOGS arrays (10,065 cases and 21,663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI=0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI=0.07-0.89 and 0.40, 95% CI=0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI=0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci.

  View details for DOI 10.1093/hmg/ddv306

  View details for PubMedID 26231222

• Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Kar, S. P., Tyrer, J. P., Li, Q., Lawrenson, K., Aben, K. K., Anton-Culver, H., Antonenkova, N., Chenevix-Trench, G., Baker, H., Bandera, E. V., Bean, Y. T., Beckmann, M. W., Berchuck, A., Bisogna, M., Bjørge, L., Bogdanova, N., Brinton, L., Brooks-Wilson, A., Butzow, R., Campbell, I., Carty, K., Chang-Claude, J., Chen, Y. A., Chen, Z., Cook, L. S., Cramer, D., Cunningham, J. M., Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Dicks, E., Doherty, J. A., Dörk, T., du Bois, A., Dürst, M., Eccles, D., Easton, D. F., Edwards, R. P., Ekici, A. B., Fasching, P. A., Fridley, B. L., Gao, Y., Gentry-Maharaj, A., Giles, G. G., Glasspool, R., Goode, E. L., Goodman, M. T., Grownwald, J., Harrington, P., Harter, P., Hein, A., Heitz, F., Hildebrandt, M. A., Hillemanns, P., Hogdall, E., Hogdall, C. K., Hosono, S., Iversen, E. S., Jakubowska, A., Paul, J., Jensen, A., Ji, B., Karlan, B. Y., Kjaer, S. K., Kelemen, L. E., Kellar, M., Kelley, J., Kiemeney, L. A., Krakstad, C., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N. D., Lee, A. W., Lele, S., Leminen, A., Lester, J., Levine, D. A., Liang, D., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L., Matsuo, K., McGuire, V., McLaughlin, J. R., McNeish, I. A., Menon, U., Modugno, F., Moysich, K. B., Narod, S. A., Nedergaard, L., Ness, R. B., Nevanlinna, H., Odunsi, K., Olson, S. H., Orlow, I., Orsulic, S., Weber, R. P., Pearce, C. L., Pejovic, T., Pelttari, L. M., Permuth-Wey, J., Phelan, C. M., Pike, M. C., Poole, E. M., Ramus, S. J., Risch, H. A., Rosen, B., Rossing, M. A., Rothstein, J. H., Rudolph, A., Runnebaum, I. B., Rzepecka, I. K., Salvesen, H. B., Schildkraut, J. M., Schwaab, I., Shu, X., Shvetsov, Y. B., Siddiqui, N., Sieh, W., Song, H., Southey, M. C., Sucheston-Campbell, L. E., Tangen, I. L., Teo, S., Terry, K. L., Thompson, P. J., Timorek, A., Tsai, Y., Tworoger, S. S., van Altena, A. M., van Nieuwenhuysen, E., Vergote, I., Vierkant, R. A., Wang-Gohrke, S., Walsh, C., Wentzensen, N., Whittemore, A. S., Wicklund, K. G., Wilkens, L. R., Woo, Y., Wu, X., Wu, A., Yang, H., Zheng, W., Ziogas, A., Sellers, T. A., Monteiro, A. N., Freedman, M. L., Gayther, S. A., Pharoah, P. D. 2015; 24 (10): 1574-1584

  Abstract

  Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by co-expression may also be enriched for additional EOC risk associations.We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly co-expressed with each selected TF gene in the unified microarray data set of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this data set were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls).Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P<0.05 and FDR<0.05). These results were replicated (P<0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network.We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development.Network analysis integrating large, context-specific data sets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.

  View details for DOI 10.1158/1055-9965.EPI-14-1270

  View details for PubMedID 26209509

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

  Abstract

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

  View details for DOI 10.1093/hmg/ddv252

  View details for Web of Science ID 000361317200024

  View details for PubMedCentralID PMC4550826

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

  Abstract

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

  View details for DOI 10.1093/hmg/ddv252

  View details for PubMedID 26138067

• Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium. British journal of cancer Nagle, C. M., Dixon, S. C., Jensen, A., Kjaer, S. K., Modugno, F., Defazio, A., Fereday, S., Hung, J., Johnatty, S. E., Fasching, P. A., Beckmann, M. W., Lambrechts, D., Vergote, I., Van Nieuwenhuysen, E., Lambrechts, S., Risch, H. A., Rossing, M. A., Doherty, J. A., Wicklund, K. G., Chang-Claude, J., Goodman, M. T., Ness, R. B., Moysich, K., Heitz, F., du Bois, A., Harter, P., Schwaab, I., Matsuo, K., Hosono, S., Goode, E. L., Vierkant, R. A., Larson, M. C., Fridley, B. L., Høgdall, C., Schildkraut, J. M., WEBER, R. P., Cramer, D. W., Terry, K. L., Bandera, E. V., Paddock, L., Rodriguez-Rodriguez, L., Wentzensen, N., Yang, H. P., Brinton, L. A., Lissowska, J., Høgdall, E., Lundvall, L., Whittemore, A., McGuire, V., Sieh, W., Rothstein, J., Sutphen, R., Anton-Culver, H., Ziogas, A., Pearce, C. L., Wu, A. H., Webb, P. M. 2015; 113 (5): 817-826

  Abstract

  Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer.We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype.Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant.Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.British Journal of Cancer advance online publication, 7 July 2015; doi:10.1038/bjc.2015.245 www.bjcancer.com.

  View details for DOI 10.1038/bjc.2015.245

  View details for PubMedID 26151456

• Genome-wide significant risk associations for mucinous ovarian carcinoma NATURE GENETICS Kelemen, L. E., Lawrenson, K., Tyrer, J., Li, Q., Lee, J. M., Seo, J., Phelan, C. M., Beesley, J., Chen, X., Spindler, T. J., Aben, K. K., Anton-Culver, H., Antonenkova, N., Baker, H., Bandera, E. V., Bean, Y., Beckmann, M. W., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L. A., Brooks-Wilson, A., Bruinsma, F., Butzow, R., Campbell, I. G., Carty, K., Chang-Claude, J., Chen, Y. A., Chen, Z., Cook, L. S., Cramer, D. W., Cunningham, J. M., Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Dicks, E., Doherty, J. A., Dicks, E., Doherty, J. A., Doerk, T., du Bois, A., Duerst, M., Eccles, D., Easton, D. T., Edwards, R. P., Eilber, U., Ekici, A. B., Engelholm, S. A., Fasching, P. A., Fridley, B. L., Gao, Y., Gentry-Maharaj, A., Giles, G. G., Glasspool, R., Goode, E. L., Goodman, M. T., Grownwald, J., Harrington, P., Harter, P., Hasmad, H. N., Hein, A., Heitz, F., Hildebrandt, M. A., Hillemanns, P., Hogdall, E., Hogdall, C., Hosono, S., Iversen, E. S., Jakubowska, A., Jensen, A., Ji, B., Karlan, B. Y., Kellar, M., Kelley, J. L., Kiemeney, L. A., Krakstad, C., Kjaer, S. K., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N. D., Lee, A. W., Lele, S., Leminen, A., Lester, J., Levine, D. A., Liang, D., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L. F., Matsuo, K., McGuire, V., McLaughlin, J. R., McNeish, I., Menon, U., Modugno, F., Moes-Sosnowska, J., Moysich, K. B., Narod, S. A., Nedergaard, L., Ness, R. B., Nevanlinna, H., Adenan, N. A., Odunsi, K., Olson, S. H., Orlow, I., Orsulic, S., Weber, R. P., Paul, J., Pearce, C. L., Pejovic, T., Pelttari, L. M., Permuth-Wey, J., Pike, M. C., Poole, E. M., Ramus, S. J., Risch, H. A., Rosen, B., Rossing, M. A., Rothstein, J. H., Rudolph, A., Runnebaum, I. B., Rzepecka, I. K., Salvesen, H. B., Schildkraut, J. M., Schwaab, I., Shu, X., Shvetsov, Y. B., Siddiqui, N., Sieh, W., Song, H., Southey, M. C., Sucheston, L., Tangen, I. L., Teo, S., Terry, K. L., Thompson, P. J., Tworoger, S. S., van Altena, A. M., van Nieuwenhuysen, E., Vergote, I., Vierkant, R. A., Wang-Gohrke, S., Walsh, C., Wentzensen, N., Whittemore, A. S., Wicklund, K. G., Wilkens, L. R., Sawicki, W., Woo, Y., Wu, X., Wu, A. H., Yang, H., Zheng, W., Ziogas, A., Sellers, T. A., Freedman, M. L., Chenevix-Trench, G., Pharoah, P. D., Gayther, S. A., Berchuck, A. 2015; 47 (8): 888-?

  Abstract

  Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10(-8)), rs711830 at 2q31.1 (P = 7.5 × 10(-12)) and rs688187 at 19q13.2 (P = 6.8 × 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.

  View details for DOI 10.1038/ng.3336

  View details for Web of Science ID 000358674100012

• Assessing absolute changes in breast cancer risk due to modifiable risk factors BREAST CANCER RESEARCH AND TREATMENT Quante, A. S., Herz, J., Whittemore, A. S., Fischer, C., Strauch, K., Terry, M. B. 2015; 152 (1): 193-197

  Abstract

  Clinical risk assessment involves absolute risk measures, but information on modifying risk and preventing cancer is often communicated in relative terms. To illustrate the potential impact of risk factor modification in model-based risk assessment, we evaluated the performance of the IBIS Breast Cancer Risk Evaluation Tool, with and without current body mass index (BMI), for predicting future breast cancer occurrence in a prospective cohort of 665 postmenopausal women. Overall, IBIS's accuracy (overall agreement between observed and assigned risks) and discrimination (AUC concordance between assigned risks and outcomes) were similar with and without the BMI information. However, in women with BMI > 25 kg/m(2), adding BMI information improved discrimination (AUC = 63.9 % and 61.4 % with and without BMI, P < 0.001). The model-assigned 10-year risk difference for a woman with high (27 kg/m(2)) versus low (21 kg/m(2)) BMI was only 0.3 % for a woman with neither affected first-degree relatives nor BRCA1 mutation, compared to 4.5 % for a mutation carrier with three such relatives. This contrast illustrates the value of using information on modifiable risk factors in risk assessment and in sharing information with patients of their absolute risks with and without modifiable risk factors.

  View details for DOI 10.1007/s10549-015-3411-6

  View details for Web of Science ID 000356248900020

  View details for PubMedID 26012643

• Practical problems with clinical guidelines for breast cancer prevention based on remaining lifetime risk. Journal of the National Cancer Institute Quante, A. S., Whittemore, A. S., Shriver, T., Hopper, J. L., Strauch, K., Terry, M. B. 2015; 107 (7)

  Abstract

  Clinical guidelines for breast cancer chemoprevention and MRI screening involve estimates of remaining lifetime risk (RLR); in the United States, women with an RLR of 20% or higher meet "high-risk" criteria for MRI screening.We prospectively followed 1764 women without breast cancer to compare the RLRs and 10-year risks assigned by the risk models International Breast Cancer Intervention Study (IBIS) and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) and to compare both sets of model-assigned 10-year risks to subsequent incidence of breast cancer in the cohort. We used chi-square statistics to assess calibration and the area under the receiver operating characteristic curve (AUC) to assess discrimination. All statistical tests are two-sided.The models classified different proportions of women as high-risk (IBIS = 59.3% vs BOADICEA = 20.1%) using the RLR threshold of 20%. The difference was smaller (IBIS = 52.9% vs BOADICEA = 43.2%) using a 10-year risk threshold of 3.34%. IBIS risks (mean = 4.9%) were better calibrated to observed breast cancer incidence (5.2%, 95% confidence interval (CI) = 4.2% to 6.4%) than were those of BOADICEA (mean = 3.7%) overall and within quartiles of model risk (P = .20 by IBIS and P = .07 by BOADICEA). Both models gave similar discrimination, with AUCs of 0.67 (95% CI = 0.61 to 0.73) using IBIS and 0.68 (95% CI = 0.62 to 0.74) using BOADICEA. Model sensitivities at thresholds for a 20% false-positive rate were also similar, with 41.8% using IBIS and 38.0% using BOADICEA.RLR-based guidelines for high-risk women are limited by discordance between commonly used risk models. Guidelines based on short-term risks would be more useful, as models are generally developed and validated under a short fixed time horizon (≤10 years).

  View details for DOI 10.1093/jnci/djv124

  View details for PubMedID 25956172

  View details for PubMedCentralID PMC4554256

• Practical Problems With Clinical Guidelines for Breast Cancer Prevention Based on Remaining Lifetime Risk JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Quante, A. S., Whittemore, A. S., Shriver, T., Hopper, J. L., Strauch, K., Terry, M. B. 2015; 107 (7)

  View details for DOI 10.1093/jnci/djv124

  View details for Web of Science ID 000358782900014

• Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk PLOS ONE Chornokur, G., Lin, H., Tyrer, J. P., Lawrenson, K., Dennis, J., Amankwah, E. K., Qu, X., Tsai, Y., Jim, H. S., Chen, Z., Chen, A. Y., Permuth-Wey, J., Aben, K. K., Anton-Culver, H., Antonenkova, N., Bruinsma, F., Bandera, E. V., Bean, Y. T., Beckmann, M. W., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L. A., Brooks-Wilson, A., Bunker, C. H., Butzow, R., Campbell, I. G., Carty, K., Chang-Claude, J., Cook, L. S., Cramer, D. W., Cunningham, J. M., Cybulski, C., Dansonka-Mieszkowska, A., du Bois, A., Despierre, E., Dicks, E., Doherty, J. A., Dork, T., Durst, M., Easton, D. F., Eccles, D. M., Edwards, R. P., Ekici, A. B., Fasching, P. A., Fridley, B. L., Gao, Y., Gentry-Maharaj, A., Giles, G. G., Glasspool, R., Goodman, M. T., Gronwald, J., Harrington, P., Harter, P., Hein, A., Heitz, F., Hildebrandt, M. A., Hillemanns, P., Hogdall, C. K., Hogdall, E., Hosono, S., Jakubowska, A., Jensen, A., Ji, B., Karlan, B. Y., Kelemen, L. E., Kellar, M., Kiemeney, L. A., Krakstad, C., Kjaer, S. K., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N. D., Lee, A. W., Lele, S., Leminen, A., Lester, J., Levine, D. A., Liang, D., Lim, B. K., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L. F., Matsuo, K., McGuire, V., McLaughlin, J. R., McNeish, I., Menon, U., Milne, R. L., Modugno, F., Moysich, K. B., Ness, R. B., Nevanlinna, H., Eilber, U., Odunsi, K., Olson, S. H., Orlow, I., Orsulic, S., Weber, R. P., Paul, J., Pearce, C. L., Pejovic, T., Pelttari, L. M., Pike, M. C., Poole, E. M., Risch, H. A., Rosen, B., Rossing, M. A., Rothstein, J. H., Rudolph, A., Runnebaum, I. B., Rzepecka, I. K., Salvesen, H. B., Schernhammer, E., Schwaab, I., Shu, X., Shvetsov, Y. B., Siddiqui, N., Sieh, W., Song, H., Southey, M. C., Spiewankiewicz, B., Sucheston, L., Teo, S., Terry, K. L., Thompson, P. J., Thomsen, L., Tangen, I. L., Tworoger, S. S., van Altena, A. M., Vierkant, R. A., Vergote, I., Walsh, C. S., Wang-Gohrke, S., Wentzensen, N., Whittemore, A. S., Wicklund, K. G., Wilkens, L. R., Wu, A. H., Wu, X., Woo, Y., Yang, H., Zheng, W., Ziogas, A., Hasmad, H. N., Berchuck, A., Iversen, E. S., Schildkraut, J. M., Ramus, S. J., Goode, E. L., Monteiro, A. N., Gayther, S. A., Narod, S. A., Pharoah, P. P., Sellers, T. A., Phelan, C. M. 2015; 10 (6)

  Abstract

  Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4).These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.

  View details for DOI 10.1371/journal.pone.0128106

  View details for Web of Science ID 000356835000013

  View details for PubMedID 26091520

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

  View details for DOI 10.1093/jnci/djv036

  View details for Web of Science ID 000355088600009

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

  Abstract

  Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking.We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates.There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer.The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.

  View details for DOI 10.1093/jnci/djv036

  View details for PubMedID 25855707

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

  Abstract

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

  View details for DOI 10.1001/jama.2014.5985

  View details for PubMedID 25849179

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

  Abstract

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

  View details for DOI 10.1038/ng.3242

  View details for Web of Science ID 000351922900013

  View details for PubMedCentralID PMC4549775

• Family History of Skin Cancer Is Associated With Increased Risk of Cutaneous Squamous Cell Carcinoma DERMATOLOGIC SURGERY Asgari, M. M., Warton, E. M., Whittemore, A. S. 2015; 41 (4): 481-486

  Abstract

  The contribution of family history to cutaneous squamous cell carcinoma (SCC) risk has not been systematically quantified.To examine the association between self-reported family history of skin cancer and SCC risk.Cases (n = 415) with a pathology-verified SCC and 415 age-, gender-, and race-matched controls were identified within a large integrated health care delivery system. Family history and skin cancer risk factors were ascertained by survey. Odds ratios (ORs) for associations of SCC with family history of skin cancer were estimated using conditional logistic regression adjusted for environmental and innate SCC risk factors.Any known family history of skin cancer was associated with a four-fold higher risk of SCC, adjusting for known environmental and innate SCC risk factors (OR, 4.0; confidence interval [CI]: 2.5-6.5). An unknown family history of skin cancer showed similar risk for SCC (OR, 3.9; CI: 2.4-6.5). In models including skin cancer type, the strongest association was for family history of basal cell carcinoma (OR, 9.8; CI: 2.6-36.8) and for multiple skin cancer types (OR, 10.5; CI: 3.7-29.6).Family history of skin cancer is an important independent risk factor for cutaneous SCCs.

  View details for DOI 10.1097/DSS.0000000000000292

  View details for Web of Science ID 000354114500007

  View details for PubMedID 25760557

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

  Abstract

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

  View details for DOI 10.1038/ng.3242

  View details for PubMedID 25751625

• Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study. Gynecologic oncology Lee, A. W., Tyrer, J. P., Doherty, J. A., Stram, D. A., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Plisiecka-Halasa, J., Spiewankiewicz, B., Myers, E. J., Chenevix-Trench, G., Fasching, P. A., Beckmann, M. W., Ekici, A. B., Hein, A., Vergote, I., van Nieuwenhuysen, E., Lambrechts, D., Wicklund, K. G., Eilber, U., Wang-Gohrke, S., Chang-Claude, J., Rudolph, A., Sucheston-Campbell, L., Odunsi, K., Moysich, K. B., Shvetsov, Y. B., Thompson, P. J., Goodman, M. T., Wilkens, L. R., Dörk, T., Hillemanns, P., Dürst, M., Runnebaum, I. B., Bogdanova, N., Pelttari, L. M., Nevanlinna, H., Leminen, A., Edwards, R. P., Kelley, J. L., Harter, P., Schwaab, I., Heitz, F., du Bois, A., Orsulic, S., Lester, J., Walsh, C., Karlan, B. Y., Hogdall, E., Kjaer, S. K., Jensen, A., Vierkant, R. A., Cunningham, J. M., Goode, E. L., Fridley, B. L., Southey, M. C., Giles, G. G., Bruinsma, F., Wu, X., Hildebrandt, M. A., Lu, K., Liang, D., Bisogna, M., Levine, D. A., Weber, R. P., Schildkraut, J. M., Iversen, E. S., Berchuck, A., Terry, K. L., Cramer, D. W., Tworoger, S. S., Poole, E. M., Olson, S. H., Orlow, I., Bandera, E. V., Bjorge, L., Tangen, I. L., Salvesen, H. B., Krakstad, C., Massuger, L. F., Kiemeney, L. A., Aben, K. K., van Altena, A. M., Bean, Y., Pejovic, T., Kellar, M., Le, N. D., Cook, L. S., Kelemen, L. E., Brooks-Wilson, A., Lubinski, J., Gronwald, J., Cybulski, C., Jakubowska, A., Wentzensen, N., Brinton, L. A., Lissowska, J., Yang, H., Nedergaard, L., Lundvall, L., Hogdall, C., Song, H., Campbell, I. G., Eccles, D., Glasspool, R., Siddiqui, N., Carty, K., Paul, J., McNeish, I. A., Sieh, W., McGuire, V., Rothstein, J. H., Whittemore, A. S., McLaughlin, J. R., Risch, H. A., Phelan, C. M., Anton-Culver, H., Ziogas, A., Menon, U., Ramus, S. J., Gentry-Maharaj, A., Harrington, P., Pike, M. C., Modugno, F., Rossing, M. A., Ness, R. B., Pharoah, P. D., Stram, D. O., Wu, A. H., Pearce, C. L. 2015; 136 (3): 542-548

  Abstract

  Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted.Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations.We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive).Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.

  View details for DOI 10.1016/j.ygyno.2014.12.017

  View details for PubMedID 25528498

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

  Abstract

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

  View details for DOI 10.1038/ng.3185

  View details for PubMedID 25581431

• Germline Mutation in BRCA1 or BRCA2 and Ten-Year Survival for Women Diagnosed with Epithelial Ovarian Cancer. Clinical cancer research Candido-dos-Reis, F. J., Song, H., Goode, E. L., Cunningham, J. M., Fridley, B. L., Larson, M. C., Alsop, K., Dicks, E., Harrington, P., Ramus, S. J., de Fazio, A., Mitchell, G., Fereday, S., Bolton, K. L., Gourley, C., Michie, C., Karlan, B., Lester, J., Walsh, C., Cass, I., Olsson, H., Gore, M., Benitez, J. J., Garcia, M. J., Andrulis, I., Mulligan, A. M., Glendon, G., Blanco, I., Lazaro, C., Whittemore, A. S., McGuire, V., Sieh, W., Montagna, M., Alducci, E., Sadetzki, S., Chetrit, A., Kwong, A., Kjaer, S. K., Jensen, A., Høgdall, E., Neuhausen, S., Nussbaum, R., Daly, M., Greene, M. H., Mai, P. L., Loud, J. T., Moysich, K., Toland, A. E., Lambrechts, D., Ellis, S., Frost, D., Brenton, J. D., Tischkowitz, M., Easton, D. F., Antoniou, A., Chenevix-Trench, G., Gayther, S. A., Bowtell, D., Pharoah, P. D. 2015; 21 (3): 652-657

  Abstract

  Purpose:To analyse the effect of germline mutations in BRCA1 and BRCA2 on mortality in ovarian cancer patients up to ten years after diagnosis. Experimental Design:We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival-time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analysed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analysed using Fine and Gray model. Results: The combined 10-year overall survival was 30% (95% CI, 28%-31%) for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The hazard ratio for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the hazard ratio was 0.42 at time zero and increased over time (predicted to become greater than one at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors, and to ovarian cancer specific mortality. Conclusions: BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and, in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers.

  View details for DOI 10.1158/1078-0432.CCR-14-2497

  View details for PubMedID 25398451

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

  View details for DOI 10.1038/ng.3185

  View details for PubMedID 25581431

• Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk. PloS one Chornokur, G., Lin, H., Tyrer, J. P., Lawrenson, K., Dennis, J., Amankwah, E. K., Qu, X., Tsai, Y., Jim, H. S., Chen, Z., Chen, A. Y., Permuth-Wey, J., Aben, K. K., Anton-Culver, H., Antonenkova, N., Bruinsma, F., Bandera, E. V., Bean, Y. T., Beckmann, M. W., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L. A., Brooks-Wilson, A., Bunker, C. H., Butzow, R., Campbell, I. G., Carty, K., Chang-Claude, J., Cook, L. S., Cramer, D. W., Cunningham, J. M., Cybulski, C., Dansonka-Mieszkowska, A., du Bois, A., Despierre, E., Dicks, E., Doherty, J. A., Dörk, T., Dürst, M., Easton, D. F., Eccles, D. M., Edwards, R. P., Ekici, A. B., Fasching, P. A., Fridley, B. L., Gao, Y., Gentry-Maharaj, A., Giles, G. G., Glasspool, R., Goodman, M. T., Gronwald, J., Harrington, P., Harter, P., Hein, A., Heitz, F., Hildebrandt, M. A., Hillemanns, P., Hogdall, C. K., Hogdall, E., Hosono, S., Jakubowska, A., Jensen, A., Ji, B., Karlan, B. Y., Kelemen, L. E., Kellar, M., Kiemeney, L. A., Krakstad, C., Kjaer, S. K., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N. D., Lee, A. W., Lele, S., Leminen, A., Lester, J., Levine, D. A., Liang, D., Lim, B. K., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L. F., Matsuo, K., McGuire, V., McLaughlin, J. R., McNeish, I., Menon, U., Milne, R. L., Modugno, F., Moysich, K. B., Ness, R. B., Nevanlinna, H., Eilber, U., Odunsi, K., Olson, S. H., Orlow, I., Orsulic, S., Weber, R. P., Paul, J., Pearce, C. L., Pejovic, T., Pelttari, L. M., Pike, M. C., Poole, E. M., Risch, H. A., Rosen, B., Rossing, M. A., Rothstein, J. H., Rudolph, A., Runnebaum, I. B., Rzepecka, I. K., Salvesen, H. B., Schernhammer, E., Schwaab, I., Shu, X., Shvetsov, Y. B., Siddiqui, N., Sieh, W., Song, H., Southey, M. C., Spiewankiewicz, B., Sucheston, L., Teo, S., Terry, K. L., Thompson, P. J., Thomsen, L., Tangen, I. L., Tworoger, S. S., van Altena, A. M., Vierkant, R. A., Vergote, I., Walsh, C. S., Wang-Gohrke, S., Wentzensen, N., Whittemore, A. S., Wicklund, K. G., Wilkens, L. R., Wu, A. H., Wu, X., Woo, Y., Yang, H., Zheng, W., Ziogas, A., Hasmad, H. N., Berchuck, A., Iversen, E. S., Schildkraut, J. M., Ramus, S. J., Goode, E. L., Monteiro, A. N., Gayther, S. A., Narod, S. A., Pharoah, P. D., Sellers, T. A., Phelan, C. M. 2015; 10 (6)

  Abstract

  Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4).These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.

  View details for DOI 10.1371/journal.pone.0128106

  View details for PubMedID 26091520

• Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC). Journal of genetics and genome research Jim, H. S., Lin, H., Tyrer, J. P., Lawrenson, K., Dennis, J., Chornokur, G., Chen, Z., Chen, A. Y., Permuth-Wey, J., Aben, K. K., Anton-Culver, H., Antonenkova, N., Bruinsma, F., Bandera, E. V., Bean, Y. T., Beckmann, M. W., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L. A., Brooks-Wilson, A., Bunker, C. H., Butzow, R., Campbell, I. G., Carty, K., Chang-Claude, J., Cook, L. S., Cramer, D. W., Cunningham, J. M., Cybulski, C., Dansonka-Mieszkowska, A., du Bois, A., Despierre, E., Sieh, W., Doherty, J. A., Dörk, T., Dürst, M., Easton, D. F., Eccles, D. M., Edwards, R. P., Ekici, A. B., Fasching, P. A., Fridley, B. L., Gao, Y., Gentry-Maharaj, A., Giles, G. G., Glasspool, R., Goodman, M. T., Gronwald, J., Harter, P., Hasmad, H. N., Hein, A., Heitz, F., Hildebrandt, M. A., Hillemanns, P., Hogdall, C. K., Hogdall, E., Hosono, S., Iversen, E. S., Jakubowska, A., Jensen, A., Ji, B., Karlan, B. Y., Kellar, M., Kiemeney, L. A., Krakstad, C., Kjaer, S. K., Kupryjanczyk, J., Vierkant, R. A., Lambrechts, D., Lambrechts, S., Le, N. D., Lee, A. W., Lele, S., Leminen, A., Lester, J., Levine, D. A., Liang, D., Lim, B. K., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L. F., Matsuo, K., McGuire, V., McLaughlin, J. R., McNeish, I., Menon, U., Milne, R. L., Modugno, F., Thomsen, L., Moysich, K. B., Ness, R. B., Nevanlinna, H., Eilber, U., Odunsi, K., Olson, S. H., Orlow, I., Orsulic, S., Palmieri Weber, R., Paul, J., Pearce, C. L., Pejovic, T., Pelttari, L. M., Pike, M. C., Poole, E. M., Schernhammer, E., Risch, H. A., Rosen, B., Rossing, M. A., Rothstein, J. H., Rudolph, A., Runnebaum, I. B., Rzepecka, I. K., Salvesen, H. B., Schwaab, I., Shu, X., Shvetsov, Y. B., Siddiqui, N., Song, H., Southey, M. C., Spiewankiewicz, B., Sucheston-Campbell, L., Teo, S., Terry, K. L., Thompson, P. J., Tangen, I. L., Tworoger, S. S., van Altena, A. M., Vergote, I., Walsh, C. S., Wang-Gohrke, S., Wentzensen, N., Whittemore, A. S., Wicklund, K. G., Wilkens, L. R., Wu, A. H., Wu, X., Woo, Y., Yang, H., Zheng, W., Ziogas, A., Amankwah, E., Berchuck, A., Schildkraut, J. M., Kelemen, L. E., Ramus, S. J., Monteiro, A. N., Goode, E. L., Narod, S. A., Gayther, S. A., Pharoah, P. D., Sellers, T. A., Phelan, C. M. 2015; 2 (2)

  Abstract

  Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10(-4)]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.

  View details for PubMedID 26807442

• The Role of Genome Sequencing in Personalized Breast Cancer Prevention CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Sieh, W., Rothstein, J. H., McGuire, V., Whittemore, A. S. 2014; 23 (11): 2322-2327

  View details for DOI 10.1158/1055-9965.EPI-14-0559

  View details for Web of Science ID 000345279600014

• The role of genome sequencing in personalized breast cancer prevention. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Sieh, W., Rothstein, J. H., McGuire, V., Whittemore, A. S. 2014; 23 (11): 2322-2327

  Abstract

  There is uncertainty about the benefits of using genome-wide sequencing to implement personalized preventive strategies at the population level, with some projections suggesting little benefit. We used data for all currently known breast cancer susceptibility variants to assess the benefits and harms of targeting preventive efforts to a population subgroup at highest genomic risk of breast cancer.We used the allele frequencies and effect sizes of 86 known breast cancer variants to estimate the population distribution of breast cancer risks and evaluate the strategy of targeting preventive efforts to those at highest risk. We compared the efficacy of this strategy with that of a "best-case" strategy based on a risk distribution estimated from breast cancer concordance in monozygous twins, and with strategies based on previously estimated risk distributions.Targeting those in the top 25% of the risk distribution would include approximately half of all future breast cancer cases, compared with 70% captured by the best-case strategy and 35% based on previously known variants. In addition, current evidence suggests that reducing exposure to modifiable nongenetic risk factors will have greatest benefit for those at highest genetic risk.These estimates suggest that personalized breast cancer preventive strategies based on genome sequencing will bring greater gains in disease prevention than previously projected. Moreover, these gains will increase with increased understanding of the genetic etiology of breast cancer.These results support the feasibility of using genome-wide sequencing to target the women who would benefit from mammography screening. Cancer Epidemiol Biomarkers Prev; 1-6. ©2014 AACR.

  View details for DOI 10.1158/1055-9965.EPI-14-0559

  View details for PubMedID 25342391

• Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk MOLECULAR NUTRITION & FOOD RESEARCH Kelemen, L. E., Terry, K. L., Goodman, M. T., Webb, P. M., Bandera, E. V., McGuire, V., Rossing, M. A., Wang, Q., Dicks, E., Tyrer, J. P., Song, H., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Plisiecka-Halasa, J., Timorek, A., Menon, U., Gentry-Maharaj, A., Gayther, S. A., Ramus, S. J., Narod, S. A., Risch, H. A., McLaughlin, J. R., Siddiqui, N., Glasspool, R., Paul, J., Carty, K., Gronwald, J., Lubinski, J., Jakubowska, A., Cybulski, C., Kiemeney, L. A., Massuger, L. F., van Altena, A. M., Aben, K. K., Olson, S. H., Orlow, I., Cramer, D. W., Levine, D. A., Bisogna, M., Giles, G. G., Southey, M. C., Bruinsma, F., Kjaer, S. K., Hogdall, E., Jensen, A., Hogdall, C. K., Lundvall, L., Engelholm, S., Heitz, F., du Bois, A., Harter, P., Schwaab, I., Butzow, R., Nevanlinna, H., Pelttari, L. M., Leminen, A., Thompson, P. J., Lurie, G., Wilkens, L. R., Lambrechts, D., van Nieuwenhuysen, E., Lambrechts, S., Vergote, I., Beesley, J., Investigators, A. S., Fasching, P. A., Beckmann, M. W., Hein, A., Ekici, A. B., Doherty, J. A., Wu, A. H., Pearce, C. L., Pike, M. C., Stram, D., Chang-Claude, J., Rudolph, A., Doerk, T., Duerst, M., Hillemanns, P., Runnebaum, I. B., Bogdanova, N., Antonenkova, N., Odunsi, K., Edwards, R. P., Kelley, J. L., Modugno, F., Ness, R. B., Karlan, B. Y., Walsh, C., Lester, J., Orsulic, S., Fridley, B. L., Vierkant, R. A., Cunningham, J. M., Wu, X., Lu, K., Liang, D., Hildebrandt, M. A., Weber, R. P., Iversen, E. S., Tworoger, S. S., Poole, E. M., Salvesen, H. B., Krakstad, C., Bjorge, L., Tangen, I. L., Pejovic, T., Bean, Y., Kellar, M., Wentzensen, N., Brinton, L. A., Lissowska, J., Garcia-Closas, M., Campbell, I. G., Eccles, D., Whittemore, A. S., Sieh, W., Rothstein, J. H., Anton-Culver, H., Ziogas, A., Phelan, C. M., Moysich, K. B., Goode, E. L., Schildkraut, J. M., Berchuck, A., Pharoah, P. D., Sellers, T. A., Brooks-Wilson, A., Cook, L. S., Le, N. D. 2014; 58 (10): 2023-2035

  Abstract

  We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.Odds ratios (OR) for 446 genetic variants were estimated among 13 410 OC cases and 22 635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10(-5) ) and rs828054 (OR = 1.06; p = 1 × 10(-4) ). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10(-6) ) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (pinteraction = 0.03-0.006).Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

  View details for DOI 10.1002/mnfr.201400068

  View details for Web of Science ID 000342898900010

• Assessing the goodness of fit of personal risk models STATISTICS IN MEDICINE Gong, G., Quante, A. S., Terry, M. B., Whittemore, A. S. 2014; 33 (18): 3179-3190

  Abstract

  We describe a flexible family of tests for evaluating the goodness of fit (calibration) of a pre-specified personal risk model to the outcomes observed in a longitudinal cohort. Such evaluation involves using the risk model to assign each subject an absolute risk of developing the outcome within a given time from cohort entry and comparing subjects' assigned risks with their observed outcomes. This comparison involves several issues. For example, subjects followed only for part of the risk period have unknown outcomes. Moreover, existing tests do not reveal the reasons for poor model fit when it occurs, which can reflect misspecification of the model's hazards for the competing risks of outcome development and death. To address these issues, we extend the model-specified hazards for outcome and death, and use score statistics to test the null hypothesis that the extensions are unnecessary. Simulated cohort data applied to risk models whose outcome and mortality hazards agreed and disagreed with those generating the data show that the tests are sensitive to poor model fit, provide insight into the reasons for poor fit, and accommodate a wide range of model misspecification. We illustrate the methods by examining the calibration of two breast cancer risk models as applied to a cohort of participants in the Breast Cancer Family Registry. The methods can be implemented using the Risk Model Assessment Program, an R package freely available at http://stanford.edu/~ggong/rmap/.

  View details for DOI 10.1002/sim.6176

  View details for Web of Science ID 000339113400009

  View details for PubMedID 24753038

  View details for PubMedCentralID PMC4362710

• Clinical Evaluation of a Multiple-Gene Sequencing Panel for Hereditary Cancer Risk Assessment JOURNAL OF CLINICAL ONCOLOGY Kurian, A. W., Hare, E. E., Mills, M. A., Kingham, K. E., McPherson, L., Whittemore, A. S., McGuire, V., Ladabaum, U., Kobayashi, Y., Lincoln, S. E., Cargill, M., Ford, J. M. 2014; 32 (19): 2001-2009

  Abstract

  Multiple-gene sequencing is entering practice, but its clinical value is unknown. We evaluated the performance of a customized germline-DNA sequencing panel for cancer-risk assessment in a representative clinical sample.Patients referred for clinical BRCA1/2 testing from 2002 to 2012 were invited to donate a research blood sample. Samples were frozen at -80° C, and DNA was extracted from them after 1 to 10 years. The entire coding region, exon-intron boundaries, and all known pathogenic variants in other regions were sequenced for 42 genes that had cancer risk associations. Potentially actionable results were disclosed to participants.In total, 198 women participated in the study: 174 had breast cancer and 57 carried germline BRCA1/2 mutations. BRCA1/2 analysis was fully concordant with prior testing. Sixteen pathogenic variants were identified in ATM, BLM, CDH1, CDKN2A, MUTYH, MLH1, NBN, PRSS1, and SLX4 among 141 women without BRCA1/2 mutations. Fourteen participants carried 15 pathogenic variants, warranting a possible change in care; they were invited for targeted screening recommendations, enabling early detection and removal of a tubular adenoma by colonoscopy. Participants carried an average of 2.1 variants of uncertain significance among 42 genes.Among women testing negative for BRCA1/2 mutations, multiple-gene sequencing identified 16 potentially pathogenic mutations in other genes (11.4%; 95% CI, 7.0% to 17.7%), of which 15 (10.6%; 95% CI, 6.5% to 16.9%) prompted consideration of a change in care, enabling early detection of a precancerous colon polyp. Additional studies are required to quantify the penetrance of identified mutations and determine clinical utility. However, these results suggest that multiple-gene sequencing may benefit appropriately selected patients.

  View details for DOI 10.1200/JCO.2013.53.6607

  View details for Web of Science ID 000337925500007

• Variation in NF-?B Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Block, M. S., Charbonneau, B., Vierkant, R. A., Fogarty, Z., Bamlet, W. R., Pharoah, P. D., Rossing, M. A., Cramer, D., Pearce, C. L., Schildkraut, J., Menon, U., Kjaer, S. K., Levine, D. A., Gronwald, J., Culver, H. A., Whittemore, A. S., Karlan, B. Y., Lambrechts, D., Wentzensen, N., Kupryjanczyk, J., Chang-Claude, J., Bandera, E. V., Hogdall, E., Heitz, F., Kaye, S. B., Fasching, P. A., Campbell, I., Goodman, M. T., Pejovic, T., Bean, Y. T., Hays, L. E., Lurie, G., Eccles, D., Hein, A., Beckmann, M. W., Ekici, A. B., Paul, J., Brown, R., Flanagan, J. M., Harter, P., du Bois, A., Schwaab, I., Hogdall, C. K., Lundvall, L., Olson, S. H., Orlow, I., Paddock, L. E., Rudolph, A., Eilber, U., Dansonka-Mieszkowska, A., Rzepecka, I. K., Ziolkowska-Seta, I., Brinton, L. A., Yang, H., Garcia-Closas, M., Despierre, E., Lambrechts, S., Vergote, I., Walsh, C. S., Lester, J., Sieh, W., McGuire, V., Rothstein, J. H., Ziogas, A., Lubinski, J., Cybulski, C., Menkiszak, J., Jensen, A., Gayther, S. A., Ramus, S. J., Gentry-Maharaj, A., Berchuck, A., Wu, A. H., Pike, M. C., Van Den Berg, D., Terry, K. L., Vitonis, A. F., Ramirez, S. M., Rider, D. N., Knutson, K. L., Sellers, T. A., Phelan, C. M., Doherty, J. A., Johnatty, S. E., deFazio, A., Song, H., Tyrer, J., Kalli, K. R., Fridley, B. L., Cunningham, J. M., Goode, E. L. 2014; 23 (7): 1421-1427

  Abstract

  Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that impact prognosis are not known. The nuclear factor-kappa B (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance-p < 2.5x10-5). Results were statistically significant when assessed for patients of a single histology. Key associations were with CARD11 (caspase recruitment domain family, member 11) rs41324349 in patients with mucinous EOC (HR 1.82, 95% CI 1.41-2.35, p=4.13x10-6) and TNFRSF13B (tumor necrosis factor receptor superfamily, member 13B) rs7501462 in patients with endometrioid EOC (HR 0.68, 95% CI 0.56-0.82, p=2.33x10-5). Other associations of note included TRAF2 (TNF receptor-associated factor 2) rs17250239 in patients with high-grade serous EOC (HR 0.84, 95% CI 0.77-0.92, p=6.49x10-5) and PLCG1 (phospholipase C, gamma 1) rs11696662 in patients with clear cell EOC (HR 0.43, 95% CI 0.26-0.73, p=4.56x10-4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.

  View details for DOI 10.1158/1055-9965.EPI-13-0962

  View details for PubMedID 24740199

• Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA HUMAN GENETICS Earp, M. A., Kelemen, L. E., Magliocco, A. M., Swenerton, K. D., Chenevix-Trench, G., Lu, Y., Hein, A., Ekici, A. B., Beckmann, M. W., Fasching, P. A., Lambrechts, D., Despierre, E., Vergote, I., Lambrechts, S., Doherty, J. A., Rossing, M. A., Chang-Claude, J., Rudolph, A., Friel, G., Moysich, K. B., Odunsi, K., Sucheston-Campbell, L., Lurie, G., Goodman, M. T., Carney, M. E., Thompson, P. J., Runnebaum, I. B., Duerst, M., Hillemanns, P., Doerk, T., Antonenkova, N., Bogdanova, N., Leminen, A., Nevanlinna, H., Pelttari, L. M., Butzow, R., Bunker, C. H., Modugno, F., Edwards, R. P., Ness, R. B., du Bois, A., Heitz, F., Schwaab, I., Harter, P., Karlan, B. Y., Walsh, C., Lester, J., Jensen, A., Kjaer, S. K., Hogdall, C. K., Hogdall, E., Lundvall, L., Sellers, T. A., Fridley, B. L., Goode, E. L., Cunningham, J. M., Vierkant, R. A., Giles, G. G., Baglietto, L., Severi, G., Southey, M. C., Liang, D., Wu, X., Lu, K., Hildebrandt, M. A., Levine, D. A., Bisogna, M., Schildkraut, J. M., Iversen, E. S., Weber, R. P., Berchuck, A., Cramer, D. W., Terry, K. L., Poole, E. M., Tworoger, S. S., Bandera, E. V., Chandran, U., Orlow, I., Olson, S. H., Wik, E., Salvesen, H. B., Bjorge, L., Halle, M. K., van Altena, A. M., Aben, K. K., Kiemeney, L. A., Massuger, L. F., Pejovic, T., Bean, Y. T., Cybulski, C., Gronwald, J., Lubinski, J., Wentzensen, N., Brinton, L. A., Lissowska, J., Garcia-Closas, M., Dicks, E., Dennis, J., Easton, D. F., Song, H., Tyrer, J. P., Pharoah, P. D., Eccles, D., Campbell, I. G., Whittemore, A. S., McGuire, V., Sieh, W., Rothstein, J. H., Flanagan, J. M., Paul, J., Brown, R., Phelan, C. M., Risch, H. A., McLaughlin, J. R., Narod, S. A., Ziogas, A., Anton-Culver, H., Gentry-Maharaj, A., Menon, U., Gayther, S. A., Ramus, S. J., Wu, A. H., Pearce, C. L., Pike, M. C., Dansonka-Mieszkowska, A., Rzepecka, I. K., Szafron, L. M., Kupryjanczyk, J., Cook, L. S., Le, N. D., Brooks-Wilson, A. 2014; 133 (5): 481-497

  Abstract

  Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.

  View details for DOI 10.1007/s00439-013-1383-3

  View details for Web of Science ID 000334519900002

  View details for PubMedID 24190013

• Clinical Evaluation of a Multiple-Gene Sequencing Panel for Hereditary Cancer Risk Assessment. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Kurian, A. W., Hare, E. E., Mills, M. A., Kingham, K. E., McPherson, L., Whittemore, A. S., McGuire, V., Ladabaum, U., Kobayashi, Y., Lincoln, S. E., Cargill, M., Ford, J. M. 2014

  Abstract

  Multiple-gene sequencing is entering practice, but its clinical value is unknown. We evaluated the performance of a customized germline-DNA sequencing panel for cancer-risk assessment in a representative clinical sample.Patients referred for clinical BRCA1/2 testing from 2002 to 2012 were invited to donate a research blood sample. Samples were frozen at -80° C, and DNA was extracted from them after 1 to 10 years. The entire coding region, exon-intron boundaries, and all known pathogenic variants in other regions were sequenced for 42 genes that had cancer risk associations. Potentially actionable results were disclosed to participants.In total, 198 women participated in the study: 174 had breast cancer and 57 carried germline BRCA1/2 mutations. BRCA1/2 analysis was fully concordant with prior testing. Sixteen pathogenic variants were identified in ATM, BLM, CDH1, CDKN2A, MUTYH, MLH1, NBN, PRSS1, and SLX4 among 141 women without BRCA1/2 mutations. Fourteen participants carried 15 pathogenic variants, warranting a possible change in care; they were invited for targeted screening recommendations, enabling early detection and removal of a tubular adenoma by colonoscopy. Participants carried an average of 2.1 variants of uncertain significance among 42 genes.Among women testing negative for BRCA1/2 mutations, multiple-gene sequencing identified 16 potentially pathogenic mutations in other genes (11.4%; 95% CI, 7.0% to 17.7%), of which 15 (10.6%; 95% CI, 6.5% to 16.9%) prompted consideration of a change in care, enabling early detection of a precancerous colon polyp. Additional studies are required to quantify the penetrance of identified mutations and determine clinical utility. However, these results suggest that multiple-gene sequencing may benefit appropriately selected patients.

  View details for DOI 10.1200/JCO.2013.53.6607

  View details for PubMedID 24733792

• Predictors of bronchopulmonary dysplasia or death in premature infants with a patent ductus arteriosus. Pediatric research Chock, V. Y., Punn, R., Oza, A., Benitz, W. E., Van Meurs, K. P., Whittemore, A. S., Behzadian, F., Silverman, N. H. 2014; 75 (4): 570-575

  Abstract

  Background:Preterm infants with a PDA are at risk for death or development of BPD. However, PDA treatment remains controversial. We investigated if PDA treatment and other clinical or echocardiographic (ECHO) factors were associated with the development of death or BPD.Methods:We retrospectively studied clinical and ECHO characteristics of preterm infants with birth weight <1500 g and ECHO diagnosis of a PDA. Logistic regression and classification and regression tree (CART) analyses were performed to assess variables associated with the combined outcome of death or BPD.Results:Of 187 preterm infants with a PDA, 75% were treated with indomethacin or surgery and 25% were managed conservatively. Death or BPD occurred in 80 (43%). Logistic regression found lower gestational age (OR 0.5), earlier year of birth during the study period (OR 0.9), and larger ductal diameter (OR 4.3) were associated with the decision to treat the PDA, while gestational age was the only variable associated with death or BPD (OR 0.6, 95% CI 0.5-0.8).Conclusion:Only lower gestational age and not PDA treatment or ECHO score was associated with the adverse outcome of death or BPD. Further investigation of PDA management strategies and effects on adverse outcomes of prematurity is needed.Pediatric Research (2013); doi:10.1038/pr.2013.253.

  View details for DOI 10.1038/pr.2013.253

  View details for PubMedID 24378897

• DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers. PLoS genetics Osorio, A., Milne, R. L., Kuchenbaecker, K., Vaclová, T., Pita, G., Alonso, R., Peterlongo, P., Blanco, I., de la Hoya, M., Duran, M., Díez, O., Ramón y Cajal, T., Konstantopoulou, I., Martínez-Bouzas, C., Andrés Conejero, R., Soucy, P., McGuffog, L., Barrowdale, D., Lee, A., Swe-Brca, Arver, B., Rantala, J., Loman, N., Ehrencrona, H., Olopade, O. I., Beattie, M. S., Domchek, S. M., Nathanson, K., Rebbeck, T. R., Arun, B. K., Karlan, B. Y., Walsh, C., Lester, J., John, E. M., Whittemore, A. S., Daly, M. B., Southey, M., Hopper, J., Terry, M. B., Buys, S. S., Janavicius, R., Dorfling, C. M., Van Rensburg, E. J., Steele, L., Neuhausen, S. L., Ding, Y. C., Hansen, T. v., Jønson, L., Ejlertsen, B., Gerdes, A., Infante, M., Herráez, B., Moreno, L. T., Weitzel, J. N., Herzog, J., Weeman, K., Manoukian, S., Peissel, B., Zaffaroni, D., Scuvera, G., Bonanni, B., Mariette, F., Volorio, S., Viel, A., Varesco, L., Papi, L., Ottini, L., Tibiletti, M. G., Radice, P., Yannoukakos, D., Garber, J., Ellis, S., Frost, D., Platte, R., Fineberg, E., Evans, G., Lalloo, F., Izatt, L., Eeles, R., Adlard, J., Davidson, R., Cole, T., Eccles, D., Cook, J., Hodgson, S., Brewer, C., Tischkowitz, M., Douglas, F., Porteous, M., Side, L., Walker, L., Morrison, P., Donaldson, A., Kennedy, J., Foo, C., Godwin, A. K., Schmutzler, R. K., Wappenschmidt, B., Rhiem, K., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Plendl, H. J., Niederacher, D., Sutter, C., Wang-Gohrke, S., Steinemann, D., Preisler-Adams, S., Kast, K., Varon-Mateeva, R., Gehrig, A., Stoppa-Lyonnet, D., Sinilnikova, O. M., Mazoyer, S., Damiola, F., Poppe, B., Claes, K., Piedmonte, M., Tucker, K., Backes, F., Rodríguez, G., Brewster, W., Wakeley, K., Rutherford, T., Caldés, T., Nevanlinna, H., Aittomäki, K., Rookus, M. A., van Os, T. A., van der Kolk, L., de Lange, J. L., Meijers-Heijboer, H. E., van der Hout, A. H., van Asperen, C. J., Gómez Garcia, E. B., Hoogerbrugge, N., Collée, J. M., van Deurzen, C. H., van der Luijt, R. B., Devilee, P., Hebon, Olah, E., Lázaro, C., Teulé, A., Menéndez, M., Jakubowska, A., Cybulski, C., Gronwald, J., Lubinski, J., Durda, K., Jaworska-Bieniek, K., Johannsson, O. T., Maugard, C., Montagna, M., Tognazzo, S., Teixeira, M. R., Healey, S., Investigators, K., Olswold, C., Guidugli, L., Lindor, N., Slager, S., Szabo, C. I., Vijai, J., Robson, M., Kauff, N., Zhang, L., Rau-Murthy, R., Fink-Retter, A., Singer, C. F., Rappaport, C., Geschwantler Kaulich, D., Pfeiler, G., Tea, M., Berger, A., Phelan, C. M., Greene, M. H., Mai, P. L., Lejbkowicz, F., Andrulis, I., Mulligan, A. M., Glendon, G., Toland, A. E., Bojesen, A., Pedersen, I. S., Sunde, L., Thomassen, M., Kruse, T. A., Jensen, U. B., friedman, e., Laitman, Y., Shimon, S. P., Simard, J., Easton, D. F., Offit, K., Couch, F. J., Chenevix-Trench, G., Antoniou, A. C., Benitez, J. 2014; 10 (4)

  Abstract

  Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.

  View details for DOI 10.1371/journal.pgen.1004256

  View details for PubMedID 24698998

• DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. PLoS genetics Osorio, A., Milne, R. L., Kuchenbaecker, K., Vaclová, T., Pita, G., Alonso, R., Peterlongo, P., Blanco, I., de la Hoya, M., Duran, M., Díez, O., Ramón y Cajal, T., Konstantopoulou, I., Martínez-Bouzas, C., Andrés Conejero, R., Soucy, P., McGuffog, L., Barrowdale, D., Lee, A., Swe-Brca, Arver, B., Rantala, J., Loman, N., Ehrencrona, H., Olopade, O. I., Beattie, M. S., Domchek, S. M., Nathanson, K., Rebbeck, T. R., Arun, B. K., Karlan, B. Y., Walsh, C., Lester, J., John, E. M., Whittemore, A. S., Daly, M. B., Southey, M., Hopper, J., Terry, M. B., Buys, S. S., Janavicius, R., Dorfling, C. M., Van Rensburg, E. J., Steele, L., Neuhausen, S. L., Ding, Y. C., Hansen, T. v., Jønson, L., Ejlertsen, B., Gerdes, A., Infante, M., Herráez, B., Moreno, L. T., Weitzel, J. N., Herzog, J., Weeman, K., Manoukian, S., Peissel, B., Zaffaroni, D., Scuvera, G., Bonanni, B., Mariette, F., Volorio, S., Viel, A., Varesco, L., Papi, L., Ottini, L., Tibiletti, M. G., Radice, P., Yannoukakos, D., Garber, J., Ellis, S., Frost, D., Platte, R., Fineberg, E., Evans, G., Lalloo, F., Izatt, L., Eeles, R., Adlard, J., Davidson, R., Cole, T., Eccles, D., Cook, J., Hodgson, S., Brewer, C., Tischkowitz, M., Douglas, F., Porteous, M., Side, L., Walker, L., Morrison, P., Donaldson, A., Kennedy, J., Foo, C., Godwin, A. K., Schmutzler, R. K., Wappenschmidt, B., Rhiem, K., Engel, C., Meindl, A., Ditsch, N., Arnold, N., Plendl, H. J., Niederacher, D., Sutter, C., Wang-Gohrke, S., Steinemann, D., Preisler-Adams, S., Kast, K., Varon-Mateeva, R., Gehrig, A., Stoppa-Lyonnet, D., Sinilnikova, O. M., Mazoyer, S., Damiola, F., Poppe, B., Claes, K., Piedmonte, M., Tucker, K., Backes, F., Rodríguez, G., Brewster, W., Wakeley, K., Rutherford, T., Caldés, T., Nevanlinna, H., Aittomäki, K., Rookus, M. A., van Os, T. A., van der Kolk, L., de Lange, J. L., Meijers-Heijboer, H. E., van der Hout, A. H., van Asperen, C. J., Gómez Garcia, E. B., Hoogerbrugge, N., Collée, J. M., van Deurzen, C. H., van der Luijt, R. B., Devilee, P., Hebon, Olah, E., Lázaro, C., Teulé, A., Menéndez, M., Jakubowska, A., Cybulski, C., Gronwald, J., Lubinski, J., Durda, K., Jaworska-Bieniek, K., Johannsson, O. T., Maugard, C., Montagna, M., Tognazzo, S., Teixeira, M. R., Healey, S., Investigators, K., Olswold, C., Guidugli, L., Lindor, N., Slager, S., Szabo, C. I., Vijai, J., Robson, M., Kauff, N., Zhang, L., Rau-Murthy, R., Fink-Retter, A., Singer, C. F., Rappaport, C., Geschwantler Kaulich, D., Pfeiler, G., Tea, M., Berger, A., Phelan, C. M., Greene, M. H., Mai, P. L., Lejbkowicz, F., Andrulis, I., Mulligan, A. M., Glendon, G., Toland, A. E., Bojesen, A., Pedersen, I. S., Sunde, L., Thomassen, M., Kruse, T. A., Jensen, U. B., friedman, e., Laitman, Y., Shimon, S. P., Simard, J., Easton, D. F., Offit, K., Couch, F. J., Chenevix-Trench, G., Antoniou, A. C., Benitez, J. 2014; 10 (4)

  View details for DOI 10.1371/journal.pgen.1004256

  View details for PubMedID 24698998

• A Genome-wide Association Study of Early-Onset Breast Cancer Identifies PFKM as a Novel Breast Cancer Gene and Supports a Common Genetic Spectrum for Breast Cancer at Any Age. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Ahsan, H., Halpern, J., Kibriya, M. G., Pierce, B. L., Tong, L., Gamazon, E., McGuire, V., Felberg, A., Shi, J., Jasmine, F., Roy, S., Brutus, R., Argos, M., Melkonian, S., Chang-Claude, J., Andrulis, I., Hopper, J. L., John, E. M., Malone, K., Ursin, G., Gammon, M. D., Thomas, D. C., Seminara, D., Casey, G., Knight, J. A., Southey, M. C., Giles, G. G., Santella, R. M., Lee, E., Conti, D., Duggan, D., Gallinger, S., Haile, R., Jenkins, M., Lindor, N. M., Newcomb, P., Michailidou, K., Apicella, C., Park, D. J., Peto, J., Fletcher, O., dos Santos Silva, I., Lathrop, M., Hunter, D. J., Chanock, S. J., Meindl, A., Schmutzler, R. K., Müller-Myhsok, B., Lochmann, M., Beckmann, L., Hein, R., Makalic, E., Schmidt, D. F., Bui, Q. M., Stone, J., Flesch-Janys, D., Dahmen, N., Nevanlinna, H., Aittomäki, K., Blomqvist, C., Hall, P., Czene, K., Irwanto, A., Liu, J., Rahman, N., Turnbull, C., Dunning, A. M., Pharoah, P., Waisfisz, Q., Meijers-Heijboer, H., Uitterlinden, A. G., Rivadeneira, F., Nicolae, D., Easton, D. F., Cox, N. J., Whittemore, A. S. 2014; 23 (4): 658-669

  Abstract

  Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ≤ 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10(-8)) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10(-4)) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10(-6). In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer. Cancer Epidemiol Biomarkers Prev; 23(4); 658-69. ©2014 AACR.

  View details for DOI 10.1158/1055-9965.EPI-13-0340

  View details for PubMedID 24493630

• Large-Scale Evaluation of Common Variation in Regulatory T Cell-Related Genes and Ovarian Cancer Outcome CANCER IMMUNOLOGY RESEARCH Charbonneau, B., Moysich, K. B., Kalli, K. R., Oberg, A. L., Vierkant, R. A., Fogarty, Z. C., Block, M. S., Maurer, M. J., Goergen, K. M., Fridley, B. L., Cunningham, J. M., Rider, D. N., Preston, C., Hartmann, L. C., Lawrenson, K., Wang, C., Tyrer, J., Song, H., deFazio, A., Johnatty, S. E., Doherty, J. A., Phelan, C. M., Sellers, T. A., Ramirez, S. M., Vitonis, A. F., Terry, K. L., Van Den Berg, D., Pike, M. C., Wu, A. H., Berchuck, A., Gentry-Maharaj, A., Ramus, S. J., Diergaarde, B., Shen, H., Jensen, A., Menkiszak, J., Cybulski, C., Lubinski, J., Ziogas, A., Rothstein, J. H., McGuire, V., Sieh, W., Lester, J., Walsh, C., Vergote, I., Lambrechts, S., Despierre, E., Garcia-Closas, M., Yang, H., Brinton, L. A., Spiewankiewicz, B., Rzepecka, I. K., Dansonka-Mieszkowska, A., Seibold, P., Rudolph, A., Paddock, L. E., Orlow, I., Lundvall, L., Olson, S. H., Hogdall, C. K., Schwaab, I., du Bois, A., Harter, P., Flanagan, J. M., Brown, R., Paul, J., Ekici, A. B., Beckmann, M., Hein, A., Eccles, D., Lurie, G., Hays, L. E., Bean, Y. T., Pejovic, T., Goodman, M. T., Campbell, I., Fasching, P. A., Konecny, G., Kaye, S. B., Heitz, F., Hogdall, E., Bandera, E. V., Chang-Claude, J., Kupryjanczyk, J., Wentzensen, N., Lambrechts, D., Karlan, B. Y., Whittemore, A. S., Culver, H. A., Gronwald, J., Levine, D. A., Kjaer, S. K., Menon, U., Schildkraut, J. M., Pearce, C. L., Cramer, D. W., Rossing, M. A., Chenevix-Trench, G., Pharoah, P. D., Gayther, S. A., Ness, R. B., Odunsi, K., Sucheston, L. E., Knutson, K. L., Goode, E. L. 2014; 2 (4): 332-340

  Abstract

  The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 × 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 × 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19-1.64; P = 5.6 × 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 × 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 × 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. Cancer Immunol Res; 2(4); 332-40. ©2014 AACR.

  View details for DOI 10.1158/2326-6066.CIR-13-0136

  View details for Web of Science ID 000340033600008

  View details for PubMedID 24764580

• Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome. Cancer immunology research Charbonneau, B., Moysich, K. B., Kalli, K. R., Oberg, A. L., Vierkant, R. A., Fogarty, Z. C., Block, M. S., Maurer, M. J., Goergen, K. M., Fridley, B. L., Cunningham, J. M., Rider, D. N., Preston, C., Hartmann, L. C., Lawrenson, K., Wang, C., Tyrer, J., Song, H., deFazio, A., Johnatty, S. E., Doherty, J. A., Phelan, C. M., Sellers, T. A., Ramirez, S. M., Vitonis, A. F., Terry, K. L., Van Den Berg, D., Pike, M. C., Wu, A. H., Berchuck, A., Gentry-Maharaj, A., Ramus, S. J., Diergaarde, B., Shen, H., Jensen, A., Menkiszak, J., Cybulski, C., Lubilski, J., Ziogas, A., Rothstein, J. H., McGuire, V., Sieh, W., Lester, J., Walsh, C., Vergote, I., Lambrechts, S., Despierre, E., Garcia-Closas, M., Yang, H., Brinton, L. A., Spiewankiewicz, B., Rzepecka, I. K., Dansonka-Mieszkowska, A., Seibold, P., Rudolph, A., Paddock, L. E., Orlow, I., Lundvall, L., Olson, S. H., Hogdall, C. K., Schwaab, I., du Bois, A., Harter, P., Flanagan, J. M., Brown, R., Paul, J., Ekici, A. B., Beckmann, M. W., Hein, A., Eccles, D., Lurie, G., Hays, L. E., Bean, Y. T., Pejovic, T., Goodman, M. T., Campbell, I., Fasching, P. A., Konecny, G., Kaye, S. B., Heitz, F., Hogdall, E., Bandera, E. V., Chang-Claude, J., Kupryjanczyk, J., Wentzensen, N., Lambrechts, D., Karlan, B. Y., Whittemore, A. S., Culver, H. A., Gronwald, J., Levine, D. A., Kjaer, S. K., Menon, U., Schildkraut, J. M., Pearce, C. L., Cramer, D. W., Rossing, M. A., Chenevix-Trench, G., Pharoah, P. D., Gayther, S. A., Ness, R. B., Odunsi, K., Sucheston, L. E., Knutson, K. L., Goode, E. L. 2014; 2 (4): 332-340

  Abstract

  The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 × 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 × 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19-1.64; P = 5.6 × 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 × 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 × 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. Cancer Immunol Res; 2(4); 332-40. ©2014 AACR.

  View details for DOI 10.1158/2326-6066.CIR-13-0136

  View details for PubMedID 24764580

• Association analysis of 9,560 prostate cancer cases from the International Consortium of Prostate Cancer Genetics confirms the role of reported prostate cancer associated SNPs for familial disease HUMAN GENETICS Teerlink, C. C., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., Rinckleb, A., Maier, C., Vogel, W., Cancel-Tassin, G., Egrot, C., Cussenot, O., Foulkes, W. D., Giles, G. G., Hopper, J. L., Severi, G., Eeles, R., Easton, D., Kote-Jarai, Z., Guy, M., Cooney, K. A., Ray, A. M., Zuhlke, K. A., Lange, E. M., FitzGerald, L. M., Stanford, J. L., Ostrander, E. A., Wiley, K. E., Isaacs, S. D., Walsh, P. C., Isaacs, W. B., Wahlfors, T., Tammela, T., Schleutker, J., Wiklund, F., Gronberg, H., Emanuelsson, M., Carpten, J., Bailey-Wilson, J., Whittemore, A. S., Oakley-Girvan, I., Hsieh, C., Catalona, W. J., Zheng, S. L., Jin, G., Lu, L., Xu, J., Camp, N. J., Cannon-Albright, L. A. 2014; 133 (3): 347-356

  Abstract

  Previous GWAS studies have reported significant associations between various common SNPs and prostate cancer risk using cases unselected for family history. How these variants influence risk in familial prostate cancer is not well studied. Here, we analyzed 25 previously reported SNPs across 14 loci from prior prostate cancer GWAS. The International Consortium for Prostate Cancer Genetics (ICPCG) previously validated some of these using a family-based association method (FBAT). However, this approach suffered reduced power due to the conditional statistics implemented in FBAT. Here, we use a case-control design with an empirical analysis strategy to analyze the ICPCG resource for association between these 25 SNPs and familial prostate cancer risk. Fourteen sites contributed 12,506 samples (9,560 prostate cancer cases, 3,368 with aggressive disease, and 2,946 controls from 2,283 pedigrees). We performed association analysis with Genie software which accounts for relationships. We analyzed all familial prostate cancer cases and the subset of aggressive cases. For the familial prostate cancer phenotype, 20 of the 25 SNPs were at least nominally associated with prostate cancer and 16 remained significant after multiple testing correction (p ≤ 1E (-3)) occurring on chromosomal bands 6q25, 7p15, 8q24, 10q11, 11q13, 17q12, 17q24, and Xp11. For aggressive disease, 16 of the SNPs had at least nominal evidence and 8 were statistically significant including 2p15. The results indicate that the majority of common, low-risk alleles identified in GWAS studies for all prostate cancer also contribute risk for familial prostate cancer, and that some may contribute risk to aggressive disease.

  View details for DOI 10.1007/s00439-013-1384-2

  View details for Web of Science ID 000331622700009

  View details for PubMedID 24162621

  View details for PubMedCentralID PMC3945961

• Risk of Ovarian Cancer and the NF-?B Pathway: Genetic Association with IL1A and TNFSF10. Cancer research Charbonneau, B., Block, M. S., Bamlet, W. R., Vierkant, R. A., Kalli, K. R., Fogarty, Z., Rider, D. N., Sellers, T. A., Tworoger, S. S., Poole, E., Risch, H. A., Salvesen, H. B., Kiemeney, L. A., Baglietto, L., Giles, G. G., Severi, G., Trabert, B., Wentzensen, N., Chenevix-Trench, G., Whittemore, A. S., Sieh, W., Chang-Claude, J., Bandera, E. V., Orlow, I., Terry, K., Goodman, M. T., Thompson, P. J., Cook, L. S., Rossing, M. A., Ness, R. B., Narod, S. A., Kupryjanczyk, J., Lu, K., Butzow, R., Dörk, T., Pejovic, T., Campbell, I., Le, N. D., Bunker, C. H., Bogdanova, N., Runnebaum, I. B., Eccles, D., Paul, J., Wu, A. H., Gayther, S. A., Hogdall, E., Heitz, F., Kaye, S. B., Karlan, B. Y., Anton-Culver, H., Gronwald, J., Hogdall, C. K., Lambrechts, D., Fasching, P. A., Menon, U., Schildkraut, J., Pearce, C. L., Levine, D. A., Kjaer, S. K., Cramer, D., Flanagan, J. M., Phelan, C. M., Brown, R., Massuger, L. F., Song, H., Doherty, J. A., Krakstad, C., Liang, D., Odunsi, K., Berchuck, A., Jensen, A., Lubinski, J., Nevanlinna, H., Bean, Y. T., Lurie, G., Ziogas, A., Walsh, C., Despierre, E., Brinton, L., Hein, A., Rudolph, A., Dansonka-Mieszkowska, A., Olson, S. H., Harter, P., Tyrer, J., Vitonis, A. F., Brooks-Wilson, A., Aben, K. K., Pike, M. C., Ramus, S. J., Wik, E., Cybulski, C., Lin, J., Sucheston, L., Edwards, R., McGuire, V., Lester, J., du Bois, A., Lundvall, L., Wang-Gohrke, S., Szafron, L. M., Lambrechts, S., Yang, H., Beckmann, M. W., Pelttari, L. M., van Altena, A. M., Van Den Berg, D., Halle, M. K., Gentry-Maharaj, A., Schwaab, I., Chandran, U., Menkiszak, J., Ekici, A. B., Wilkens, L. R., Leminen, A., Modugno, F., Friel, G., Rothstein, J. H., Vergote, I., Garcia-Closas, M., Hildebrandt, M. A., Sobiczewski, P., Kelemen, L. E., Pharoah, P. D., Moysich, K., Knutson, K. L., Cunningham, J. M., Fridley, B. L., Goode, E. L. 2014; 74 (3): 852-861

  Abstract

  A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 × 10(-5), only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted. Cancer Res; 74(3); 852-61. ©2013 AACR.

  View details for DOI 10.1158/0008-5472.CAN-13-1051

  View details for PubMedID 24272484

• Ovarian Cancer Rates After Hysterectomy With and Without Salpingo-Oophorectomy OBSTETRICS AND GYNECOLOGY Chan, J. K., Md, R. U., Capra, A. M., Jacoby, V., Osann, K., Whittemore, A., Habel, L. A. 2014; 123 (1): 65-72

  Abstract

  To estimate ovarian and peritoneal cancer rates after hysterectomy with and without salpingo-oophorectomy for benign conditions.All patients after hysterectomy for benign disease from 1988 to 2006 in Kaiser Permanente Northern California, an integrated health organization. Incidence rates per 100,000 person-years were calculated.Of 56,692 patients, the majority (54%) underwent hysterectomy with bilateral salpingo-oophorectomy; 7% had hysterectomy with unilateral salpingo-oophorectomy, and 39% had hysterectomy alone. There were 40 ovarian and eight peritoneal cancers diagnosed during follow-up. Median age at ovarian and peritoneal cancer diagnosis was 50 and 64 years, respectively. Age-standardized rates (per 100,000 person-years) of ovarian or peritoneal cancer were 26.7 (95% confidence interval [CI] 16-37.5) for those with hysterectomy alone, 22.8 (95% CI 0.0-46.8) for hysterectomy and unilateral salpingo-oophorectomy, and 3.9 (95% CI 1.5-6.4) for hysterectomy and bilateral salpingo-oophorectomy. Rates of ovarian cancer were 26.2 (95% CI 15.5-37) for those with hysterectomy alone, 17.5 (95% CI 0.0-39.1) for hysterectomy and unilateral salpingo-oophorectomy, and 1.7 (95% CI 0.4-3) for those with hysterectomy and bilateral salpingo-oophorectomy. Compared with women undergoing hysterectomy alone, those receiving an unilateral salpingo-oophorectomy had a hazard ratio (HR) for ovarian cancer of 0.58 (95% CI 0.18-1.9) and those undergoing bilateral salpingo-oophorectomy had an HR of 0.12 (95% CI 0.05-0.28).The removal of both ovaries decreases the incidence of ovarian and peritoneal cancers. Removal of one ovary might also decrease the incidence of ovarian cancer but warrants further investigation.II.

  View details for DOI 10.1097/AOG.0000000000000061

  View details for Web of Science ID 000336808500011

  View details for PubMedID 24463665

• Diagnostic Chest X-Rays and Breast Cancer Risk before Age 50 Years for BRCA1 and BRCA2 Mutation Carriers CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION John, E. M., McGuire, V., Thomas, D., Haile, R., Ozcelik, H., Milne, R. L., Felberg, A., West, D. W., Miron, A., Knight, J. A., Terry, M. B., Daly, M., Buys, S. S., Andrulis, I. L., Hopper, J. L., Southey, M. C., Giles, G. G., Apicella, C., Thorne, H., Whittemore, A. S. 2013; 22 (9): 1547-1556

  Abstract

  Background: The effects of low-dose medical radiation on breast cancer risk are uncertain, and few studies have included genetically susceptible women, such as those who carry germline BRCA1 and BRCA2 mutations. Methods: We studied 454 BRCA1 and 273 BRCA2 mutation carriers aged <50 years from three breast cancer family registries in the USA, Canada, and Australia/New Zealand. We estimated breast cancer risk associated with diagnostic chest x-rays by comparing mutation carriers with breast cancer (cases) with those without breast cancer (controls). Exposure to chest x-rays was self-reported. Mammograms were not considered in the analysis. Results: After adjusting for known risk factors for breast cancer, the odds ratio (OR) for a history of diagnostic chest x-rays, excluding those for tuberculosis or pneumonia, was 1.16 (95% confidence interval (CI) = 0.64-2.11) for BRCA1 mutations carriers and 1.22 (95% CI=0.62-2.42) for BRCA2 mutations carriers. The OR was statistically elevated for BRCA2 mutation carriers with 3-5 diagnostic chest x-rays (p = 0.01), but not for those with 6 or more chest x-rays. Few women reported chest fluoroscopy for tuberculosis or chest x-rays for pneumonia; the OR estimates were elevated, but not statistically significant, for BRCA1 mutation carriers. Conclusions: Our findings do not support a positive association between diagnostic chest x-rays and breast cancer risk before age 50 years for BRCA1 or BRCA2 mutation carriers. Impact: Given the increasing use of diagnostic imaging involving higher ionizing radiation doses, further studies of genetically predisposed women are warranted.

  View details for DOI 10.1158/1055-9965.EPI-13-0189

  View details for Web of Science ID 000324674500008

  View details for PubMedID 23853209

• Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study. lancet oncology Sieh, W., Köbel, M., Longacre, T. A., Bowtell, D. D., deFazio, A., Goodman, M. T., Høgdall, E., Deen, S., Wentzensen, N., Moysich, K. B., Brenton, J. D., Clarke, B. A., Menon, U., Gilks, C. B., Kim, A., Madore, J., Fereday, S., George, J., Galletta, L., Lurie, G., Wilkens, L. R., Carney, M. E., Thompson, P. J., Matsuno, R. K., Kjær, S. K., Jensen, A., Høgdall, C., Kalli, K. R., Fridley, B. L., Keeney, G. L., Vierkant, R. A., Cunningham, J. M., Brinton, L. A., Yang, H. P., Sherman, M. E., García-Closas, M., Lissowska, J., Odunsi, K., Morrison, C., Lele, S., Bshara, W., Sucheston, L., Jimenez-Linan, M., Driver, K., Alsop, J., Mack, M., McGuire, V., Rothstein, J. H., Rosen, B. P., Bernardini, M. Q., Mackay, H., Oza, A., Wozniak, E. L., Benjamin, E., Gentry-Maharaj, A., Gayther, S. A., Tinker, A. V., Prentice, L. M., Chow, C., Anglesio, M. S., Johnatty, S. E., Chenevix-Trench, G., Whittemore, A. S., Pharoah, P. D., Goode, E. L., Huntsman, D. G., Ramus, S. J. 2013; 14 (9): 853-862

  Abstract

  Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival.12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (≥50%). Associations with disease-specific survival were assessed.2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21-0·51; p<0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55-0·91; p=0·0080), but weak PR expression was not (1·02, 0·89-1·18; p=0·74).PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer.Carraresi Foundation and others.

  View details for DOI 10.1016/S1470-2045(13)70253-5

  View details for PubMedID 23845225

• Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study. lancet oncology Sieh, W., Köbel, M., Longacre, T. A., Bowtell, D. D., deFazio, A., Goodman, M. T., Høgdall, E., Deen, S., Wentzensen, N., Moysich, K. B., Brenton, J. D., Clarke, B. A., Menon, U., Gilks, C. B., Kim, A., Madore, J., Fereday, S., George, J., Galletta, L., Lurie, G., Wilkens, L. R., Carney, M. E., Thompson, P. J., Matsuno, R. K., Kjær, S. K., Jensen, A., Høgdall, C., Kalli, K. R., Fridley, B. L., Keeney, G. L., Vierkant, R. A., Cunningham, J. M., Brinton, L. A., Yang, H. P., Sherman, M. E., García-Closas, M., Lissowska, J., Odunsi, K., Morrison, C., Lele, S., Bshara, W., Sucheston, L., Jimenez-Linan, M., Driver, K., Alsop, J., Mack, M., McGuire, V., Rothstein, J. H., Rosen, B. P., Bernardini, M. Q., Mackay, H., Oza, A., Wozniak, E. L., Benjamin, E., Gentry-Maharaj, A., Gayther, S. A., Tinker, A. V., Prentice, L. M., Chow, C., Anglesio, M. S., Johnatty, S. E., Chenevix-Trench, G., Whittemore, A. S., Pharoah, P. D., Goode, E. L., Huntsman, D. G., Ramus, S. J. 2013; 14 (9): 853-862

  Abstract

  Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival.12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (≥50%). Associations with disease-specific survival were assessed.2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21-0·51; p<0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55-0·91; p=0·0080), but weak PR expression was not (1·02, 0·89-1·18; p=0·74).PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer.Carraresi Foundation and others.

  View details for DOI 10.1016/S1470-2045(13)70253-5

  View details for PubMedID 23845225

• Analysis of Over 10,000 Cases Finds No Association between Previously Reported Candidate Polymorphisms and Ovarian Cancer Outcome. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology White, K. L., Vierkant, R. A., Fogarty, Z. C., Charbonneau, B., Block, M. S., Pharoah, P. D., Chenevix-Trench, G., Rossing, M. A., Cramer, D. W., Pearce, C. L., Schildkraut, J. M., Menon, U., Kjaer, S. K., Levine, D. A., Gronwald, J., Culver, H. A., Whittemore, A. S., Karlan, B. Y., Lambrechts, D., Wentzensen, N., Kupryjanczyk, J., Chang-Claude, J., Bandera, E. V., Hogdall, E., Heitz, F., Kaye, S. B., Fasching, P. A., Campbell, I., Goodman, M. T., Pejovic, T., Bean, Y., Lurie, G., Eccles, D., Hein, A., Beckmann, M. W., Ekici, A. B., Paul, J., Brown, R., Flanagan, J. M., Harter, P., du Bois, A., Schwaab, I., Hogdall, C. K., Lundvall, L., Olson, S. H., Orlow, I., Paddock, L. E., Rudolph, A., Eilber, U., Dansonka-Mieszkowska, A., Rzepecka, I. K., Ziolkowska-Seta, I., Brinton, L., Yang, H., Garcia-Closas, M., Despierre, E., Lambrechts, S., Vergote, I., Walsh, C., Lester, J., Sieh, W., McGuire, V., Rothstein, J. H., Ziogas, A., Lubinski, J., Cybulski, C., Menkiszak, J., Jensen, A., Gayther, S. A., Ramus, S. J., Gentry-Maharaj, A., Berchuck, A., Wu, A. H., Pike, M. C., Van Denberg, D., Terry, K. L., Vitonis, A. F., Doherty, J. A., Johnatty, S. E., deFazio, A., Song, H., Tyrer, J., Sellers, T. A., Phelan, C. M., Kalli, K. R., Cunningham, J. M., Fridley, B. L., Goode, E. L. 2013; 22 (5): 987-992

  Abstract

  Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes.Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates.We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined.These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed. Cancer Epidemiol Biomarkers Prev; 22(5); 987-. ©2013 AACR.

  View details for DOI 10.1158/1055-9965.EPI-13-0028

  View details for PubMedID 23513043

  View details for PubMedCentralID PMC3650102

• Combined and Interactive Effects of Environmental and GWAS-Identified Risk Factors in Ovarian Cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Pearce, C. L., Rossing, M. A., Lee, A. W., Ness, R. B., Webb, P. M., Chenevix-Trench, G., Jordan, S. M., Stram, D. A., Chang-Claude, J., Hein, R., Nickels, S., Lurie, G., Thompson, P. J., Carney, M. E., Goodman, M. T., Moysich, K., Hogdall, E., Jensen, A., Goode, E. L., Fridley, B. L., Cunningham, J. M., Vierkant, R. A., Weber, R. P., Ziogas, A., Anton-Culver, H., Gayther, S. A., Gentry-Maharaj, A., Menon, U., Ramus, S. J., Brinton, L., Wentzensen, N., Lissowska, J., Garcia-Closas, M., Massuger, L. F., Kiemeney, L. A., van Altena, A. M., Aben, K. K., Berchuck, A., Doherty, J. A., Iversen, E., McGuire, V., Moorman, P. G., Pharoah, P., Pike, M. C., Risch, H., Sieh, W., Stram, D. O., Terry, K. L., Whittemore, A., Wu, A. H., Schildkraut, J. M., Kjaer, S. K. 2013; 22 (5): 880-890

  Abstract

  There are several well-established environmental risk factors for ovarian cancer, and recent genome-wide association studies have also identified six variants that influence disease risk. However, the interplay between such risk factors and susceptibility loci has not been studied.Data from 14 ovarian cancer case-control studies were pooled, and stratified analyses by each environmental risk factor with tests for heterogeneity were conducted to determine the presence of interactions for all histologic subtypes. A genetic "risk score" was created to consider the effects of all six variants simultaneously. A multivariate model was fit to examine the association between all environmental risk factors and genetic risk score on ovarian cancer risk.Among 7,374 controls and 5,566 cases, there was no statistical evidence of interaction between the six SNPs or genetic risk score and the environmental risk factors on ovarian cancer risk. In a main effects model, women in the highest genetic risk score quartile had a 65% increased risk of ovarian cancer compared with women in the lowest [95% confidence interval (CI), 1.48-1.84]. Analyses by histologic subtype yielded risk differences across subtype for endometriosis (Phet < 0.001), parity (Phet < 0.01), and tubal ligation (Phet = 0.041).The lack of interactions suggests that a multiplicative model is the best fit for these data. Under such a model, we provide a robust estimate of the effect of each risk factor that sets the stage for absolute risk prediction modeling that considers both environmental and genetic risk factors. Further research into the observed differences in risk across histologic subtype is warranted. Cancer Epidemiol Biomarkers Prev; 22(5); 880-90. ©2013 AACR.

  View details for DOI 10.1158/1055-9965.EPI-12-1030-T

  View details for PubMedID 23462924

• Cigarette smoking and risk of ovarian cancer: a pooled analysis of 21 case-control studies. Cancer causes & control Faber, M. T., Kjær, S. K., Dehlendorff, C., Chang-Claude, J., Andersen, K. K., Høgdall, E., Webb, P. M., Jordan, S. J., Rossing, M. A., Doherty, J. A., Lurie, G., Thompson, P. J., Carney, M. E., Goodman, M. T., Ness, R. B., Modugno, F., Edwards, R. P., Bunker, C. H., Goode, E. L., Fridley, B. L., Vierkant, R. A., Larson, M. C., Schildkraut, J., Cramer, D. W., Terry, K. L., Vitonis, A. F., Bandera, E. V., Olson, S. H., King, M., Chandran, U., Kiemeney, L. A., Massuger, L. F., van Altena, A. M., Vermeulen, S. H., Brinton, L., Wentzensen, N., Lissowska, J., Yang, H. P., Moysich, K. B., Odunsi, K., Kasza, K., Odunsi-Akanji, O., Song, H., Pharaoh, P., Shah, M., Whittemore, A. S., McGuire, V., Sieh, W., Sutphen, R., Menon, U., Gayther, S. A., Ramus, S. J., Gentry-Maharaj, A., Pearce, C. L., Wu, A. H., Pike, M. C., Risch, H. A., Jensen, A. 2013; 24 (5): 989-1004

  Abstract

  The majority of previous studies have observed an increased risk of mucinous ovarian tumors associated with cigarette smoking, but the association with other histological types is unclear. In a large pooled analysis, we examined the risk of epithelial ovarian cancer associated with multiple measures of cigarette smoking with a focus on characterizing risks according to tumor behavior and histology.We used data from 21 case-control studies of ovarian cancer (19,066 controls, 11,972 invasive and 2,752 borderline cases). Study-specific odds ratios (OR) and 95 % confidence intervals (CI) were obtained from logistic regression models and combined into a pooled odds ratio using a random effects model.Current cigarette smoking increased the risk of invasive mucinous (OR = 1.31; 95 % CI: 1.03-1.65) and borderline mucinous ovarian tumors (OR = 1.83; 95 % CI: 1.39-2.41), while former smoking increased the risk of borderline serous ovarian tumors (OR = 1.30; 95 % CI: 1.12-1.50). For these histological types, consistent dose-response associations were observed. No convincing associations between smoking and risk of invasive serous and endometrioid ovarian cancer were observed, while our results provided some evidence of a decreased risk of invasive clear cell ovarian cancer.Our results revealed marked differences in the risk profiles of histological types of ovarian cancer with regard to cigarette smoking, although the magnitude of the observed associations was modest. Our findings, which may reflect different etiologies of the histological types, add to the fact that ovarian cancer is a heterogeneous disease.

  View details for DOI 10.1007/s10552-013-0174-4

  View details for PubMedID 23456270

• Tubal ligation and risk of ovarian cancer subtypes: a pooled analysis of case-control studies INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Sieh, W., Salvador, S., McGuire, V., Weber, R. P., Terry, K. L., Rossing, M. A., Risch, H., Wu, A. H., Webb, P. M., Moysich, K., Doherty, J. A., Felberg, A., Miller, D., Jordan, S. J., Goodman, M. T., Lurie, G., Chang-Claude, J., Rudolph, A., Kjaer, S. K., Jensen, A., Hogdall, E., Bandera, E. V., Olson, S. H., King, M. G., Rodriguez-Rodriguez, L., Kiemeney, L. A., Marees, T., Massuger, L. F., van Altena, A. M., Ness, R. B., Cramer, D. W., Pike, M. C., Pearce, C. L., Berchuck, A., Schildkraut, J. M., Whittemore, A. S. 2013; 42 (2): 579-589

  Abstract

  Tubal ligation is a protective factor for ovarian cancer, but it is unknown whether this protection extends to all invasive histological subtypes or borderline tumors. We undertook an international collaborative study to examine the association between tubal ligation and ovarian cancer subtypes.We pooled primary data from 13 population-based case-control studies, including 10,157 patients with ovarian cancer (7942 invasive; 2215 borderline) and 13,904 control women. Invasive cases were analysed by histological type, grade and stage, and borderline cases were analysed by histological type. Pooled odds ratios were estimated using conditional logistic regression to match on site, race/ethnicity and age categories, and to adjust for age, oral contraceptive use duration and number of full-term births.Tubal ligation was associated with significantly reduced risks of invasive serous (OR, 0.81; 95% CI, 0.74-0.89; P < 0.001), endometrioid (OR, 0.48; 95% CI, 0.40-0.59; P < 0.001), clear cell (OR, 0.52; 95% CI, 0.40-0.67; P < 0.001) and mucinous (OR, 0.68; 95% CI, 0.52-0.89; P = 0.005) cancers. The magnitude of risk reduction was significantly greater for invasive endometrioid (P < 0.0001) and clear cell (P = 0.0018) than for serous cancer. No significant associations were found with borderline serous or mucinous tumours.We found that the protective effects of tubal ligation on ovarian cancer risk were subtype-specific. These findings provide insights into distinct aetiologies of ovarian cancer subtypes and mechanisms underlying the protective effects of tubal ligation.

  View details for DOI 10.1093/ije/dyt042

  View details for PubMedID 23569193

• Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer NATURE GENETICS Bojesen, S. E., Pooley, K. A., Johnatty, S. E., Beesley, J., Michailidou, K., Tyrer, J. P., Edwards, S. L., Pickett, H. A., Shen, H. C., Smart, C. E., Hillman, K. M., Mai, P. L., Lawrenson, K., Stutz, M. D., Lu, Y., Karevan, R., Woods, N., Johnstonw, R. L., French, J. D., Chen, X., Weischer, M., Nielsen, S. F., Maranian, M. J., Ghoussaini, M., Ahmed, S., Baynes, C., Bolla, M. K., Wang, Q., Dennis, J., McGuffog, L., Barrowdale, D., Lee, A., Healey, S., Lush, M., Tessier, D. C., Vincent, D., Bacot, F., Vergote, I., Lambrechts, S., Despierre, E., Risch, H. A., Gonzalez-Neira, A., Rossing, M. A., Pita, G., Doherty, J. A., Alvarez, N., Larson, M. C., Fridley, B. L., Schoof, N., Chang-Claude, J., Cicek, M. S., Peto, J., Kalli, K. R., Broeks, A., Armasu, S. M., Schmidt, M. K., Braaf, L. M., Winterhoff, B., Nevanlinna, H., Konecny, G. E., Lambrechts, D., Rogmann, L., Guenel, P., Teoman, A., Milne, R. L., Garcia, J. J., Cox, A., Shridhar, V., Burwinkel, B., Marme, F., Hein, R., Sawyer, E. J., Haiman, C. A., Wang-Gohrke, S., Andrulis, I. L., Moysich, K. B., Hopper, J. L., Odunsi, K., Lindblom, A., Giles, G. G., Brenner, H., Simard, J., Lurie, G., Fasching, P. A., Carney, M. E., Radice, P., Wilkens, L. R., Swerdlow, A., Goodman, M. T., Brauch, H., Garcia-Closas, M., Hillemanns, P., Winqvist, R., Durst, M., Devilee, P., Runnebaum, I., Jakubowska, A., Lubinski, J., Mannermaa, A., Butzow, R., Bogdanova, N. V., Doerk, T., Pelttari, L. M., Zheng, W., Leminen, A., Anton-Culver, H., Bunker, C. H., Kristensen, V., Ness, R. B., Muir, K., Edwards, R., Meindl, A., Heitz, F., Matsuo, K., du Bois, A., Wu, A. H., Harter, P., Teo, S., Schwaab, I., Shu, X., Blot, W., Hosono, S., Kang, D., Nakanishi, T., Hartman, M., Yatabe, Y., Hamann, U., Karlan, B. Y., Sangrajrang, S., Kjaer, S. K., Gaborieau, V., Jensen, A., Eccles, D., Hogdall, E., Shen, C., Brown, J., Woo, Y. L., Shah, M., Azmi, M. A., Luben, R., Omar, S. Z., Czene, K., Vierkant, R. A., Nordestgaard, B. G., Flyger, H., Vachon, C., Olson, J. E., Wang, X., Levine, D. A., Rudolph, A., Weber, R. P., Flesch-Janys, D., Iversen, E., Nickels, S., Schildkraut, J. M., Silva, I. d., Cramer, D. W., Gibson, L., Terry, K. L., Fletcher, O., Vitonis, A. F., van der Schoot, C. E., Poole, E. M., Hogervorst, F. B., Tworoger, S. S., Liu, J., Bandera, E. V., Li, J., Olson, S. H., Humphreys, K., Row, I., Blomqvist, C., Rodriguez-Rodriguez, L., Aittomaki, K., Salvesen, H. B., Muranen, T. A., Wik, E., Brouwers, B., Krakstad, C., Wauters, E., Halle, M. K., Wildiers, H., Kiemeney, L. A., Mulot, C., Aben, K. K., Laurent-Puig, P., Altena, A. M., Therese Truong, T., Massuger, L. F., Benitez, J., Pejovic, T., Arias Perez, J. I., Hoatlin, M., Zamora, M. P., Cook, L. S., Balasubramanian, S. P., Kelemen, L. E., Schneeweiss, A., Le, N. D., Sohn, C., Brooks-Wilson, A., Tomlinson, I., Kerin, M. J., Miller, N., Cybulski, C., Henderson, B. E., Menkiszak, J., Schumacher, F., Wentzensen, N., Marchand, L. L., Yang, H. P., Mulligan, A. M., Glendon, G., Engelholm, S. A., Knight, J. A., Hogdall, C. K., Apicella, C., Gore, M., Tsimiklis, H., Song, H., Southey, M. C., Jager, A., den Ouweland, A. M., Brown, R., Martens, J. W., Flanagan, J. M., Kriege, M., Paul, J., Margolin, S., Siddiqui, N., Severi, G., Whittemore, A. S., Baglietto, L., McGuire, V., Stegmaier, C., Sieh, W., Mueller, H., Arndt, V., Labreche, F., Gao, Y., Goldberg, M. S., Yang, G., Dumont, M., McLaughlin, J. R., Hartmann, A., Ekici, A. B., Beckmann, M. W., Phelan, C. M., Lux, M. P., Permuth-Wey, J., Peissel, B., Sellers, T. A., Ficarazzi, F., Barile, M., Ziogas, A., Ashworth, A., Gentry-Maharaj, A., Jones, M., Ramus, S. J., Orr, N., Menon, U., Pearce, C. L., Bruening, T., Pike, M. C., Ko, Y., Lissowska, J., Figueroa, J., Kupryjanczyk, J., Chanock, S. J., Dansonka-Mieszkowska, A., Jukkola-Vuorinen, A., Rzepecka, I. K., Pylkas, K., Bidzinski, M., Kauppila, S., Hollestelle, A., Seynaeve, C., Tollenaar, R. A., Durda, K., Jaworska, K., Hartikainen, J. M., Kosma, V., Kataja, V., Antonenkova, N. N., Long, J., Shrubsole, M., Deming-Halverson, S., Lophatananon, A., Siriwanarangsan, P., Stewart-Brown, S., Ditsch, N., Lichtner, P., Schmutzler, R. K., Ito, H., Iwata, H., Tajima, K., Tseng, C., Stram, D. O., Van Den Berg, D., Yip, C. H., Ikrarn, M. K., Teh, Y., Cai, H., Lu, W., Signorello, L. B., Cai, Q., Noh, D., Yoo, K., Miao, H., Iau, P. T., Teo, Y. Y., McKay, J., Shapiro, C., Ademuyiwa, F., Fountzilas, G., Hsiung, C., Yu, J., Hou, M., Healey, C. S., Luccarini, C., Peock, S., Stoppa-Lyonnet, D., Peterlongo, P., Rebbeck, T. R., Piedmonte, M., Singer, C. F., friedman, e., Thomassen, M., Offit, K., Hansen, T. v., Neuhausen, S. L., Szabo, C. I., Blanco, I., Garber, J., Narod, S. A., Weitzel, J. N., Montagna, M., Olah, E., Godwin, A. K., Yannoukakos, D., Goldgar, D. E., Caldes, T., Imyanitov, E. N., Tihomirova, L., Arun, B. K., Campbell, I., Mensenkamp, A. R., van Asperen, C. J., van Roozendaa, K. E., Meijers-Heijboer, H., Collee, J. M., Oosterwijk, J. C., Hooning, M. J., Rookus, M. A., van der Luijt, R. B., Os, T. A., Evans, D. G., Frost, D., Fineberg, E., Barwell, J., Walker, L., Kennedy, M. J., Platte, R., Davidson, R., Ellis, S. D., Cole, T., Bressac-de Paillerets, B., Buecher, B., Damiola, F., Faivre, L., Frenay, M., Sinilnikova, O. M., Caron, O., Giraud, S., Mazoyer, S., Bonadona, V., Caux-Moncoutier, V., Toloczko-Grabarek, A., Gronwald, J., Byrski, T., Spurdle, A. B., Bonanni, B., Zaffaroni, D., Giannini, G., Bernard, L., Dolcetti, R., Manoukian, S., Arnold, N., Engel, C., Deissler, H., Rhiem, K., Niederacher, D., Pendl, H., Sutter, C., Wappenschmidt, B., Borg, A., Mein, B., Rantala, J., Soller, M., Nathanson, K. L., Domchek, S. M., Rodriguez, G. C., Salani, R., Kaulich, D. G., Tea, M., Paluch, S. S., Laitman, Y., Skytte, A., Kruse, T. A., Jensen, U. B., Robson, M., Gerdes, A., Ejlertsen, B., Foretova, L., Savage, S. A., Lesterm, J., Soucy, P., Kuchenbaecker, K. B., Olswold, C., Cunningham, J. M., Slager, S., Pankratz, V. S., Dicks, E., Lakhani, S. R., Couch, F. J., Hall, P., Monteiro, A. N., Gayther, S. A., Pharoah, P. D., Reddel, R. R., Goode, E. L., Greene, M. H., Easton, D. F., Berchuck, A., Antoniou, A. C., Chenevix-Trench, G., Dunning, A. M. 2013; 45 (4): 371-384

  Abstract

  TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.

  View details for DOI 10.1038/ng.2566

  View details for Web of Science ID 000316840600007

  View details for PubMedID 23535731

  View details for PubMedCentralID PMC3670748

• GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer NATURE GENETICS Pharoah, P. D., Tsai, Y., Ramus, S. J., Phelan, C. M., Goode, E. L., Lawrenson, K., Buckley, M., Fridley, B. L., Tyrer, J. P., Shen, H., Weber, R., Karevan, R., Larson, M. C., Song, H., Tessier, D. C., Bacot, F., Vincent, D., Cunningham, J. M., Dennis, J., Dicks, E., Aben, K. K., Anton-Culver, H., Antonenkova, N., Armasu, S. M., Baglietto, L., Bandera, E. V., Beckmann, M. W., Birrer, M. J., Bloom, G., Bogdanova, N., Brenton, J. D., Brinton, L. A., Brooks-Wilson, A., Brown, R., Butzow, R., Campbell, I., Carney, M. E., Carvalho, R. S., Chang-Claude, J., Chen, Y. A., Chen, Z., Chow, W., Cicek, M. S., Coetzee, G., Cook, L. S., Cramer, D. W., Cybulski, C., Dansonka-Mieszkowska, A., Despierre, E., Doherty, J. A., Doerk, T., du Bois, A., Duerst, M., Eccles, D., Edwards, R., Ekici, A. B., Fasching, P. A., Fenstermacher, D., Flanagan, J., Gao, Y., Garcia-Closas, M., Gentry-Maharaj, A., Giles, G., Gjyshi, A., Gore, M., Gronwald, J., Guo, Q., Halle, M. K., Harter, P., Hein, A., Heitz, F., Hillemanns, P., Hoatlin, M., Hogdall, E., Hogdall, C. K., Hosono, S., Jakubowska, A., Jensen, A., Kalli, K. R., Karlan, B. Y., Kelemen, L. E., Kiemeney, L. A., Kjaer, S. K., Konecny, G. E., Krakstad, C., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N. D., Lee, N., Lee, J., Leminen, A., Lim, B. K., Lissowska, J., Lubinski, J., Lundvall, L., Lurie, G., Massuger, L. F., Matsuo, K., McGuire, V., McLaughlin, J. R., Menon, U., Modugno, F., Moysich, K. B., Nakanishi, T., Narod, S. A., Ness, R. B., Nevanlinna, H., Nickels, S., Noushmehr, H., Odunsi, K., Olson, S., Orlow, I., Paul, J., Pejovic, T., Pelttari, L. M., Permuth-Wey, J., Pike, M. C., Poole, E. M., Qu, X., Risch, H. A., Rodriguez-Rodriguez, L., Rossing, M. A., Rudolph, A., Runnebaum, I., Rzepecka, I. K., Salvesen, H. B., Schwaab, I., Severi, G., Shen, H., Shridhar, V., Shu, X., Sieh, W., Southey, M. C., Spellman, P., Tajima, K., Teo, S., Terry, K. L., Thompson, P. J., Timorek, A., Tworoger, S. S., van Altena, A. M., Van Den Berg, D., Vergote, I., Vierkant, R. A., Vitonis, A. F., Wang-Gohrke, S., Wentzensen, N., Whittemore, A. S., Wik, E., Winterhoff, B., Woo, Y. L., Wu, A. H., Yang, H. P., Zheng, W., Ziogas, A., Zulkifli, F., Goodman, M. T., Hall, P., Easton, D. F., Pearce, C. L., Berchuck, A., Chenevix-Trench, G., Iversen, E., Monteiro, A. N., Gayther, S. A., Schildkraut, J. M., Sellers, T. A. 2013; 45 (4): 362-370

  Abstract

  Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10(-9)) and 10p12 (rs1243180, P = 1.8 × 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.

  View details for DOI 10.1038/ng.2564

  View details for Web of Science ID 000316840600006

  View details for PubMedID 23535730

• Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31. Nature communications Permuth-Wey, J., Lawrenson, K., Shen, H. C., Velkova, A., Tyrer, J. P., Chen, Z., Lin, H., Chen, Y. A., Tsai, Y., Qu, X., Ramus, S. J., Karevan, R., Lee, J., Lee, N., Larson, M. C., Aben, K. K., Anton-Culver, H., Antonenkova, N., Antoniou, A. C., Armasu, S. M., Bacot, F., Baglietto, L., Bandera, E. V., Barnholtz-Sloan, J., Beckmann, M. W., Birrer, M. J., Bloom, G., Bogdanova, N., Brinton, L. A., Brooks-Wilson, A., Brown, R., Butzow, R., Cai, Q., Campbell, I., Chang-Claude, J., Chanock, S., Chenevix-Trench, G., Cheng, J. Q., Cicek, M. S., Coetzee, G. A., Cook, L. S., Couch, F. J., Cramer, D. W., Cunningham, J. M., Dansonka-Mieszkowska, A., Despierre, E., Doherty, J. A., Dörk, T., du Bois, A., Dürst, M., Easton, D. F., Eccles, D., Edwards, R., Ekici, A. B., Fasching, P. A., Fenstermacher, D. A., Flanagan, J. M., Garcia-Closas, M., Gentry-Maharaj, A., Giles, G. G., Glasspool, R. M., Gonzalez-Bosquet, J., Goodman, M. T., Gore, M., Górski, B., Gronwald, J., Hall, P., Halle, M. K., Harter, P., Heitz, F., Hillemanns, P., Hoatlin, M., Høgdall, C. K., Høgdall, E., Hosono, S., Jakubowska, A., Jensen, A., Jim, H., Kalli, K. R., Karlan, B. Y., Kaye, S. B., Kelemen, L. E., Kiemeney, L. A., Kikkawa, F., Konecny, G. E., Krakstad, C., Kjaer, S. K., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Lancaster, J. M., Le, N. D., Leminen, A., Levine, D. A., Liang, D., Lim, B. K., Lin, J., Lissowska, J., Lu, K. H., Lubinski, J., Lurie, G., Massuger, L. F., Matsuo, K., McGuire, V., McLaughlin, J. R., Menon, U., Modugno, F., Moysich, K. B., Nakanishi, T., Narod, S. A., Nedergaard, L., Ness, R. B., Nevanlinna, H., Nickels, S., Noushmehr, H., Odunsi, K., Olson, S. H., Orlow, I., Paul, J., Pearce, C. L., Pejovic, T., Pelttari, L. M., Pike, M. C., Poole, E. M., Raska, P., Renner, S. P., Risch, H. A., Rodriguez-Rodriguez, L., Rossing, M. A., Rudolph, A., Runnebaum, I. B., Rzepecka, I. K., Salvesen, H. B., Schwaab, I., Severi, G., Shridhar, V., Shu, X., Shvetsov, Y. B., Sieh, W., Song, H., Southey, M. C., Spiewankiewicz, B., Stram, D., Sutphen, R., Teo, S., Terry, K. L., Tessier, D. C., Thompson, P. J., Tworoger, S. S., van Altena, A. M., Vergote, I., Vierkant, R. A., Vincent, D., Vitonis, A. F., Wang-Gohrke, S., Palmieri Weber, R., Wentzensen, N., Whittemore, A. S., Wik, E., Wilkens, L. R., Winterhoff, B., Woo, Y. L., Wu, A. H., Xiang, Y., Yang, H. P., Zheng, W., Ziogas, A., Zulkifli, F., Phelan, C. M., Iversen, E., Schildkraut, J. M., Berchuck, A., Fridley, B. L., Goode, E. L., Pharoah, P. D., Monteiro, A. N., Sellers, T. A., Gayther, S. A. 2013; 4: 1627-?

  Abstract

  Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.

  View details for DOI 10.1038/ncomms2613

  View details for PubMedID 23535648

• HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG) HUMAN GENETICS Xu, J., Lange, E. M., Lu, L., Zheng, S. L., Wang, Z., Thibodeau, S. N., Cannon-Albright, L. A., Teerlink, C. C., Camp, N. J., Johnson, A. M., Zuhlke, K. A., Stanford, J. L., Ostrander, E. A., Wiley, K. E., Isaacs, S. D., Walsh, P. C., Maier, C., Luedeke, M., Vogel, W., Schleutker, J., Wahlfors, T., Tammela, T., Schaid, D., McDonnell, S. K., DeRycke, M. S., Cancel-Tassin, G., Cussenot, O., Wiklund, F., Gronberg, H., Eeles, R., Easton, D., Kote-Jarai, Z., Whittemore, A. S., Hsieh, C., Giles, G. G., Hopper, J. L., Severi, G., Catalona, W. J., Mandal, D., Ledet, E., Foulkes, W. D., Hamel, N., Mahle, L., Moller, P., Powell, I., Bailey-Wilson, J. E., Carpten, J. D., Seminara, D., Cooney, K. A., Isaacs, W. B. 2013; 132 (1): 5-14

  Abstract

  Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10(-8) [odds ratio 4.42 (95 % confidence interval 2.56-7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10(-6)). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.

  View details for DOI 10.1007/s00439-012-1229-4

  View details for Web of Science ID 000313005800002

  View details for PubMedID 23064873

  View details for PubMedCentralID PMC3535370

• Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer. Nature communications Shen, H., Fridley, B. L., Song, H., Lawrenson, K., Cunningham, J. M., Ramus, S. J., Cicek, M. S., Tyrer, J., Stram, D., Larson, M. C., Köbel, M., Ziogas, A., Zheng, W., Yang, H. P., Wu, A. H., Wozniak, E. L., Woo, Y. L., Winterhoff, B., Wik, E., Whittemore, A. S., Wentzensen, N., Weber, R. P., Vitonis, A. F., Vincent, D., Vierkant, R. A., Vergote, I., Van Den Berg, D., van Altena, A. M., Tworoger, S. S., Thompson, P. J., Tessier, D. C., Terry, K. L., Teo, S., Templeman, C., Stram, D. O., Southey, M. C., Sieh, W., Siddiqui, N., Shvetsov, Y. B., Shu, X., Shridhar, V., Wang-Gohrke, S., Severi, G., Schwaab, I., Salvesen, H. B., Rzepecka, I. K., Runnebaum, I. B., Rossing, M. A., Rodriguez-Rodriguez, L., Risch, H. A., Renner, S. P., Poole, E. M., Pike, M. C., Phelan, C. M., Pelttari, L. M., Pejovic, T., Paul, J., Orlow, I., Omar, S. Z., Olson, S. H., Odunsi, K., Nickels, S., Nevanlinna, H., Ness, R. B., Narod, S. A., Nakanishi, T., Moysich, K. B., Monteiro, A. N., Moes-Sosnowska, J., Modugno, F., Menon, U., McLaughlin, J. R., McGuire, V., Matsuo, K., Adenan, N. A., Massuger, L. F., Lurie, G., Lundvall, L., Lubinski, J., Lissowska, J., Levine, D. A., Leminen, A., Lee, A. W., Le, N. D., Lambrechts, S., Lambrechts, D., Kupryjanczyk, J., Krakstad, C., Konecny, G. E., Kjaer, S. K., Kiemeney, L. A., Kelemen, L. E., Keeney, G. L., Karlan, B. Y., Karevan, R., Kalli, K. R., Kajiyama, H., Ji, B., Jensen, A., Jakubowska, A., Iversen, E., Hosono, S., Høgdall, C. K., Høgdall, E., Hoatlin, M., Hillemanns, P., Heitz, F., Hein, R., Harter, P., Halle, M. K., Hall, P., Gronwald, J., Gore, M., Goodman, M. T., Giles, G. G., Gentry-Maharaj, A., Garcia-Closas, M., Flanagan, J. M., Fasching, P. A., Ekici, A. B., Edwards, R., Eccles, D., Easton, D. F., Dürst, M., du Bois, A., Dörk, T., Doherty, J. A., Despierre, E., Dansonka-Mieszkowska, A., Cybulski, C., Cramer, D. W., Cook, L. S., Chen, X., Charbonneau, B., Chang-Claude, J., Campbell, I., Butzow, R., Bunker, C. H., Brueggmann, D., Brown, R., Brooks-Wilson, A., Brinton, L. A., Bogdanova, N., Block, M. S., Benjamin, E., Beesley, J., Beckmann, M. W., Bandera, E. V., Baglietto, L., Bacot, F., Armasu, S. M., Antonenkova, N., Anton-Culver, H., Aben, K. K., Liang, D., Wu, X., Lu, K., Hildebrandt, M. A., Schildkraut, J. M., Sellers, T. A., Huntsman, D., Berchuck, A., Chenevix-Trench, G., Gayther, S. A., Pharoah, P. D., Laird, P. W., Goode, E. L., Pearce, C. L. 2013; 4: 1628-?

  Abstract

  HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.

  View details for DOI 10.1038/ncomms2629

  View details for PubMedID 23535649

• Prediction of BRCA1 Germline Mutation Status in Women With Ovarian Cancer Using Morphology-based Criteria Identification of a BRCA1 Ovarian Cancer Phenotype AMERICAN JOURNAL OF SURGICAL PATHOLOGY Fujiwara, M., McGuire, V. A., Felberg, A., Sieh, W., Whittemore, A. S., Longacre, T. A. 2012; 36 (8): 1170-1177

  Abstract

  Specific morphologic features that may predict BRCA1 germline mutation in ovarian cancer have neither been well described nor independently tested. We identified 5 morphologic features associated with BRCA1 mutation status in a series of 20 ovarian cancers from BRCA1 mutation carriers: (1) modified Nottingham grade 3; (2) serous/undifferentiated histology; (3) prominent intraepithelial lymphocytes; (4) marked nuclear atypia with giant/bizarre forms; and (5) abundant mitotic figures. These morphologic features were then tested on 325 ovarian tumors drawn from a population-based Greater Bay Area Cancer Registry and classified into 3 categories independent of the BRCA1 status: "Compatible with BRCA1," "Possibly compatible with BRCA1," and "Not compatible with BRCA1." All "Compatible with BRCA1" tumors were additionally investigated for presence of dominant adnexal mass, fallopian tube mucosal involvement, and uterine cornu involvement. The positive and negative predictive values for "Compatible with BRCA1" were 11/42 (26.2%) and 267/283 (94.3%), respectively, whereas combining the "Compatible with BRCA1" and "Possibly compatible with BRCA1" had positive and negative predictive values of 18/85 (21.2%) and 231/240 (96.3%), respectively. Although dominant adnexal mass and uterine cornu involvement did not add further predictive value, the likelihood of BRCA1 positivity increased to 42.9% when a tumor with "Compatible with BRCA1" histology was also associated with fallopian tube mucosal involvement. The combination of modified Nottingham grade 3 serous or undifferentiated histology, prominent intraepithelial lymphocytes, marked nuclear atypia with giant/bizarre nuclei, and high mitotic index should help to identify women for BRCA1 mutational analysis in the appropriate clinical setting. Ovarian tumors lacking this specific phenotype are unlikely to be associated with BRCA1 and should not undergo mutational analysis in the absence of other indications.

  View details for DOI 10.1097/PAS.0b013e31825d9b8d

  View details for Web of Science ID 000306656500008

  View details for PubMedID 22790858

  View details for PubMedCentralID PMC3422129

• Validation of prostate cancer risk-related loci identified from genome-wide association studies using family-based association analysis: evidence from the International Consortium for Prostate Cancer Genetics (ICPCG) HUMAN GENETICS Jin, G., Lu, L., Cooney, K. A., Ray, A. M., Zuhlke, K. A., Lange, E. M., Cannon-Albright, L. A., Camp, N. J., Teerlink, C. C., FitzGerald, L. M., Stanford, J. L., Wiley, K. E., Isaacs, S. D., Walsh, P. C., Foulkes, W. D., Giles, G. G., Hopper, J. L., Severi, G., Eeles, R., Easton, D., Kote-Jarai, Z., Guy, M., Rinckleb, A., Maier, C., Vogel, W., Cancel-Tassin, G., Egrot, C., Cussenot, O., Thibodeau, S. N., McDonnell, S. K., Schaid, D. J., Wiklund, F., Gronberg, H., Emanuelsson, M., Whittemore, A. S., Oakley-Girvan, I., Hsieh, C., Wahlfors, T., Tammela, T., Schleutker, J., Catalona, W. J., Zheng, S. L., Ostrander, E. A., Isaacs, W. B., Xu, J. 2012; 131 (7): 1095-1103

  Abstract

  Multiple prostate cancer (PCa) risk-related loci have been discovered by genome-wide association studies (GWAS) based on case-control designs. However, GWAS findings may be confounded by population stratification if cases and controls are inadvertently drawn from different genetic backgrounds. In addition, since these loci were identified in cases with predominantly sporadic disease, little is known about their relationships with hereditary prostate cancer (HPC). The association between seventeen reported PCa susceptibility loci was evaluated with a family-based association test using 1,979 hereditary PCa families of European descent collected by members of the International Consortium for Prostate Cancer Genetics, with a total of 5,730 affected men. The risk alleles for 8 of the 17 loci were significantly over-transmitted from parents to affected offspring, including SNPs residing in 8q24 (regions 1, 2 and 3), 10q11, 11q13, 17q12 (region 1), 17q24 and Xp11. In subgroup analyses, three loci, at 8q24 (regions 1 and 2) plus 17q12, were significantly over-transmitted in hereditary PCa families with five or more affected members, while loci at 3p12, 8q24 (region 2), 11q13, 17q12 (region 1), 17q24 and Xp11 were significantly over-transmitted in HPC families with an average age of diagnosis at 65 years or less. Our results indicate that at least a subset of PCa risk-related loci identified by case-control GWAS are also associated with disease risk in HPC families.

  View details for DOI 10.1007/s00439-011-1136-0

  View details for Web of Science ID 000305195400008

  View details for PubMedID 22198737

  View details for PubMedCentralID PMC3535428

• Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families BMC MEDICAL GENETICS Bailey-Wilson, J. E., Childs, E. J., Cropp, C. D., Schaid, D. J., Xu, J., Camp, N. J., Cannon-Albright, L. A., Farnham, J. M., George, A., Powell, I., Carpten, J. D., Giles, G. G., Hopper, J. L., Severi, G., English, D. R., Foulkes, W. D., Maehle, L., Moller, P., Eeles, R., Easton, D., Guy, M., Edwards, S., Badzioch, M. D., Whittemore, A. S., Oakley-Girvan, I., Hsieh, C., Dimitrov, L., Stanford, J. L., Karyadi, D. M., Deutsch, K., McIntosh, L., Ostrander, E. A., Wiley, K. E., Isaacs, S. D., Walsh, P. C., Thibodeau, S. N., McDonnell, S. K., Hebbring, S., Lange, E. M., Cooney, K. A., Tammela, T. L., Schleutker, J., Maier, C., Bochum, S., Hoegel, J., Gronberg, H., Wiklund, F., Emanuelsson, M., Cancel-Tassin, G., Valeri, A., Cussenot, O., Isaacs, W. B. 2012; 13

  Abstract

  Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive.Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed.Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded.Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.

  View details for DOI 10.1186/1471-2350-13-46

  View details for Web of Science ID 000311143100001

  View details for PubMedID 22712434

  View details for PubMedCentralID PMC3495053

• IMPROVING SEQUENCE-BASED GENOTYPE CALLS WITH LINKAGE DISEQUILIBRIUM AND PEDIGREE INFORMATION ANNALS OF APPLIED STATISTICS Zhou, B., Whittemore, A. S. 2012; 6 (2): 457-475

  View details for DOI 10.1214/11-AOAS527

  View details for Web of Science ID 000307716400003

• Chromosomes 4 and 8 implicated in a genome wide SNP linkage scan of 762 prostate cancer families collected by the ICPCG PROSTATE Lu, L., Cancel-Tassin, G., Valeri, A., Cussenot, O., Lange, E. M., Cooney, K. A., Farnham, J. M., Camp, N. J., Cannon-Albright, L. A., Tammela, T. L., Schleutker, J., Hoegel, J., Herkommer, K., Maier, C., Vogel, W., Wiklund, F., Emanuelsson, M., Groenberg, H., Wiley, K. E., Isaacs, S. D., Walsh, P. C., Helfand, B. T., Kan, D., Catalona, W. J., Stanford, J. L., FitzGerald, L. M., Johanneson, B., Deutsch, K., McIntosh, L., Ostrander, E. A., Thibodeau, S. N., McDonnell, S. K., Hebbring, S., Schaid, D. J., Whittemore, A. S., Oakley-Girvan, I., Hsieh, C., Powell, I., Bailey-Wilson, J. E., Cropp, C. D., Simpson, C., Carpten, J. D., Seminara, D., Zheng, S. L., Xu, J., Giles, G. G., Severi, G., Hopper, J. L., English, D. R., Foulkes, W. D., Maehle, L., Moller, P., Badzioch, M. D., Edwards, S., Guy, M., Eeles, R., Easton, D., Isaacs, W. B. 2012; 72 (4): 410-426

  Abstract

  In spite of intensive efforts, understanding of the genetic aspects of familial prostate cancer (PC) remains largely incomplete. In a previous microsatellite-based linkage scan of 1,233 PC families, we identified suggestive evidence for linkage (i.e., LOD ≥ 1.86) at 5q12, 15q11, 17q21, 22q12, and two loci on 8p, with additional regions implicated in subsets of families defined by age at diagnosis, disease aggressiveness, or number of affected members.In an attempt to replicate these findings and increase linkage resolution, we used the Illumina 6000 SNP linkage panel to perform a genome-wide linkage scan of an independent set of 762 multiplex PC families, collected by 11 International Consortium for Prostate Cancer Genetics (ICPCG) groups.Of the regions identified previously, modest evidence of replication was observed only on the short arm of chromosome 8, where HLOD scores of 1.63 and 3.60 were observed in the complete set of families and families with young average age at diagnosis, respectively. The most significant linkage signals found in the complete set of families were observed across a broad, 37 cM interval on 4q13-25, with LOD scores ranging from 2.02 to 2.62, increasing to 4.50 in families with older average age at diagnosis. In families with multiple cases presenting with more aggressive disease, LOD scores over 3.0 were observed at 8q24 in the vicinity of previously identified common PC risk variants, as well as MYC, an important gene in PC biology.These results will be useful in prioritizing future susceptibility gene discovery efforts in this common cancer.

  View details for DOI 10.1002/pros.21443

  View details for Web of Science ID 000299159000007

  View details for PubMedID 21748754

  View details for PubMedCentralID PMC3568777

• Association Between BRCA1 and BRCA2 Mutations and Survival in Women With Invasive Epithelial Ovarian Cancer JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Bolton, K. L., Chenevix-Trench, G., Goh, C., Sadetzki, S., Ramus, S. J., Karlan, B. Y., Lambrechts, D., Despierre, E., Barrowdale, D., McGuffog, L., Healey, S., Easton, D. F., Sinilnikova, O., Benitez, J., Garcia, M. J., Neuhausen, S., Gail, M. H., Hartge, P., Peock, S., Frost, D., Evans, G., Eeles, R., Godwin, A. K., Daly, M. B., Kwong, A., Ma, E. S., Lazaro, C., Blanco, I., Montagna, M., D'Andrea, E., Nicoletto, M. O., Johnatty, S. E., Krueger, S., Jensen, A., Hogdall, E., Goode, E. L., Fridley, B. L., Loud, J. T., Greene, M. H., Mai, P. L., Chetrit, A., Lubin, F., Hirsh-Yechezkel, G., Glendon, G., Andrulis, I. L., Toland, A. E., Senter, L., Gore, M. E., Gourley, C., Michie, C. O., Song, H., Tyrer, J., Whittemore, A. S., McGuire, V., Sieh, W., Kristoffersson, U., Olsson, H., Borg, A., Levine, D. A., Steele, L., Beattie, M. S., Chan, S., Nussbaum, R. L., Moysich, K. B., Gross, J., Cass, I., Walsh, C., Li, A. J., Leuchter, R., Gordon, O., Garcia-Closas, M., Gayther, S. A., Chanock, S. J., Antoniou, A. C., Pharoah, P. D. 2012; 307 (4): 382-390

  Abstract

  Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear.To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns.A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n = 909) or BRCA2 (n = 304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998).Five-year overall mortality.The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P < .001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P < .001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P < .001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P < .001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity = .003).Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis.

  View details for Web of Science ID 000299464000024

  View details for PubMedID 22274685

• Breast cancer risk assessment across the risk continuum: genetic and nongenetic risk factors contributing to differential model performance BREAST CANCER RESEARCH Quante, A. S., Whittemore, A. S., Shriver, T., Strauch, K., Terry, M. B. 2012; 14 (6)

  Abstract

  Clinicians use different breast cancer risk models for patients considered at average and above-average risk, based largely on their family histories and genetic factors. We used longitudinal cohort data from women whose breast cancer risks span the full spectrum to determine the genetic and nongenetic covariates that differentiate the performance of two commonly used models that include nongenetic factors - BCRAT, also called Gail model, generally used for patients with average risk and IBIS, also called Tyrer Cuzick model, generally used for patients with above-average risk.We evaluated the performance of the BCRAT and IBIS models as currently applied in clinical settings for 10-year absolute risk of breast cancer, using prospective data from 1,857 women over a mean follow-up length of 8.1 years, of whom 83 developed cancer. This cohort spans the continuum of breast cancer risk, with some subjects at lower than average population risk. Therefore, the wide variation in individual risk makes it an interesting population to examine model performance across subgroups of women. For model calibration, we divided the cohort into quartiles of model-assigned risk and compared differences between assigned and observed risks using the Hosmer-Lemeshow (HL) chi-squared statistic. For model discrimination, we computed the area under the receiver operator curve (AUC) and the case risk percentiles (CRPs).The 10-year risks assigned by BCRAT and IBIS differed (range of difference 0.001 to 79.5). The mean BCRAT- and IBIS-assigned risks of 3.18% and 5.49%, respectively, were lower than the cohort's 10-year cumulative probability of developing breast cancer (6.25%; 95% confidence interval (CI) = 5.0 to 7.8%). Agreement between assigned and observed risks was better for IBIS (HL X4(2) = 7.2, P value 0.13) than BCRAT (HL X4(2) = 22.0, P value <0.001). The IBIS model also showed better discrimination (AUC = 69.5%, CI = 63.8% to 75.2%) than did the BCRAT model (AUC = 63.2%, CI = 57.6% to 68.9%). In almost all covariate-specific subgroups, BCRAT mean risks were significantly lower than the observed risks, while IBIS risks showed generally good agreement with observed risks, even in the subgroups of women considered at average risk (for example, no family history of breast cancer, BRCA1/2 mutation negative).Models developed using extended family history and genetic data, such as the IBIS model, also perform well in women considered at average risk (for example, no family history of breast cancer, BRCA1/2 mutation negative). Extending such models to include additional nongenetic information may improve performance in women across the breast cancer risk continuum.

  View details for DOI 10.1186/bcr3352

  View details for Web of Science ID 000320156600015

  View details for PubMedID 23127309

• Breast Cancer Risk for Noncarriers of Family-Specific BRCA1 and BRCA2 Mutations: Findings From the Breast Cancer Family Registry JOURNAL OF CLINICAL ONCOLOGY Kurian, A. W., Gong, G. D., John, E. M., Johnston, D. A., Felberg, A., West, D. W., Miron, A., Andrulis, I. L., Hopper, J. L., Knight, J. A., Ozcelik, H., Dite, G. S., Apicella, C., Southey, M. C., Whittemore, A. S. 2011; 29 (34): 4505-4509

  Abstract

  Women with germline BRCA1 and BRCA2 mutations have five- to 20-fold increased risks of developing breast and ovarian cancer. A recent study claimed that women testing negative for their family-specific BRCA1 or BRCA2 mutation (noncarriers) have a five-fold increased risk of breast cancer. We estimated breast cancer risks for noncarriers by using a population-based sample of patients with breast cancer and their female first-degree relatives (FDRs).Patients were women with breast cancer and their FDRs enrolled in the population-based component of the Breast Cancer Family Registry; patients with breast cancer were tested for BRCA1 and BRCA2 mutations, as were FDRs of identified mutation carriers. We used segregation analysis to fit a model that accommodates familial correlation in breast cancer risk due to unobserved shared risk factors.We studied 3,047 families; 160 had BRCA1 and 132 had BRCA2 mutations. There was no evidence of increased breast cancer risk for noncarriers of identified mutations compared with FDRs from families without BRCA1 or BRCA2 mutations: relative risk was 0.39 (95% CI, 0.04 to 3.81). Residual breast cancer correlation within families was strong, suggesting substantial risk heterogeneity in women without BRCA1 or BRCA2 mutations, with some 3.4% of them accounting for roughly one third of breast cancer cases.These results support the practice of advising noncarriers that they do not have any increase in breast cancer risk attributable to the family-specific BRCA1 or BRCA2 mutation.

  View details for DOI 10.1200/JCO.2010.34.4440

  View details for PubMedID 22042950

  View details for PubMedCentralID PMC3236651

• Optimal Methods for Meta-Analysis of Genome-Wide Association Studies GENETIC EPIDEMIOLOGY Zhou, B., Shi, J., Whittemore, A. S. 2011; 35 (7): 581-591

  Abstract

  Meta-analysis of genome-wide association studies involves testing single nucleotide polymorphisms (SNPs) using summary statistics that are weighted sums of site-specific score or Wald statistics. This approach avoids having to pool individual-level data. We describe the weights that maximize the power of the summary statistics. For small effect-sizes, any choice of weights yields summary Wald and score statistics with the same power, and the optimal weights are proportional to the square roots of the sites' Fisher information for the SNP's regression coefficient. When SNP effect size is constant across sites, the optimal summary Wald statistic is the well-known inverse-variance-weighted combination of estimated regression coefficients, divided by its standard deviation. We give simple approximations to the optimal weights for various phenotypes, and show that weights proportional to the square roots of study sizes are suboptimal for data from case-control studies with varying case-control ratios, for quantitative trait data when the trait variance differs across sites, for count data when the site-specific mean counts differ, and for survival data with different proportions of failing subjects. Simulations suggest that weights that accommodate intersite variation in imputation error give little power gain compared to those obtained ignoring imputation uncertainties. We note advantages to combining site-specific score statistics, and we show how they can be used to assess effect-size heterogeneity across sites. The utility of the summary score statistic is illustrated by application to a meta-analysis of schizophrenia data in which only site-specific P-values and directions of association are available.

  View details for DOI 10.1002/gepi.20603

  View details for Web of Science ID 000296846900001

  View details for PubMedID 21922536

  View details for PubMedCentralID PMC3197760

• The potential value of sibling controls compared with population controls for association studies of lifestyle-related risk factors: an example from the Breast Cancer Family Registry INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Milne, R. L., John, E. M., Knight, J. A., Dite, G. S., Southey, M. C., Giles, G. G., Apicella, C., West, D. W., Andrulis, I. L., Whittemore, A. S., Hopper, J. L. 2011; 40 (5): 1342-1354

  Abstract

  A previous Australian population-based breast cancer case-control study found indirect evidence that control participation, although high, was not random. We hypothesized that unaffected sisters may provide a more appropriate comparison group than unrelated population controls.Three population-based case-control-family studies of breast cancer in women of white European origin were carried out by the Australian, Ontario and Northern California sites of the Breast Cancer Family Registry. We compared risk factors between 3643 cases, 2444 of their unaffected sisters and 2877 population controls and conducted separate case-control analyses based on population and sister controls using unconditional multivariable logistic regression.Compared with sister controls, population controls were more highly educated, had an earlier age at menarche, fewer births, their first birth at a later age and their last birth more recently. The established breast cancer associations detected using sister controls, but not detected using population controls, were decreasing risk with each of later age at menarche, more births, younger age at first birth and greater time since last birth.Since participation of population controls might be unintentionally related to some risk factors, we hypothesize that sister controls could provide more valid relative risk estimates and be recruited at lower cost. Given declining study participation by population controls, this contention is highly relevant to epidemiologic research.

  View details for DOI 10.1093/ije/dyr110

  View details for Web of Science ID 000296634900025

  View details for PubMedID 21771852

  View details for PubMedCentralID PMC3204209

• Estrogen Receptor Beta rs1271572 Polymorphism and Invasive Ovarian Carcinoma Risk: Pooled Analysis within the Ovarian Cancer Association Consortium PLOS ONE Lurie, G., Wilkens, L. R., Thompson, P. J., Shvetsov, Y. B., Matsuno, R. K., Carney, M. E., Palmieri, R. T., Wu, A. H., Pike, M. C., Pearce, C. L., Menon, U., Gentry-Maharaj, A., Gayther, S. A., Ramus, S. J., Whittemore, A. S., McGuire, V., Sieh, W., Pharoah, P. D., Song, H., Gronwald, J., Jakubowska, A., Cybulski, C., Lubinski, J., Schildkraut, J. M., Berchuck, A., Kjaer, S. K., Hogdall, E., Fasching, P. A., Beckmann, M. W., Ekici, A. B., Hein, A., Chenevix-Trench, G., Webb, P. M., Beesley, J., Goodman, M. T. 2011; 6 (6)

  Abstract

  The association of ovarian carcinoma risk with the polymorphism rs1271572 in the estrogen receptor beta (ESR2) gene was examined in 4946 women with primary invasive ovarian carcinoma and 6582 controls in a pooled analysis of ten case-control studies within the Ovarian Cancer Association Consortium (OCAC). All participants were non-Hispanic white women. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression adjusted for site and age. Women with the TT genotype were at increased risk of ovarian carcinoma compared to carriers of the G allele (OR = 1.10; 95%; CI: 1.01-1.21; p = 0.04); the OR was 1.09 (CI: 0.99-1.20; p = 0.07) after excluding data from the center (Hawaii) that nominated this SNP for OCAC genotyping A stronger association of rs1271572 TT versus GT/GG with risk was observed among women aged ≤50 years versus older women (OR = 1.35; CI: 1.12-1.62; p = 0.002; p for interaction = 0.02) that remained statistically significant after excluding Hawaii data (OR = 1.34; CI: 1.11-1.61; p = 0.009). No heterogeneity of the association was observed by study, menopausal status, gravidity, parity, use of contraceptive or menopausal hormones, tumor histological type, or stage at diagnosis. This pooled analysis suggests that rs1271572 might influence the risk of ovarian cancer, in particular among younger women.

  View details for DOI 10.1371/journal.pone.0020703

  View details for Web of Science ID 000291356400020

  View details for PubMedID 21673961

  View details for PubMedCentralID PMC3108970

• Genetic variation in insulin-like growth factor 2 may play a role in ovarian cancer risk HUMAN MOLECULAR GENETICS Pearce, C. L., Doherty, J. A., Van den Berg, D. J., Moysich, K., Hsu, C., Cushing-Haugen, K. L., Conti, D. V., Ramus, S. J., Gentry-Maharaj, A., Menon, U., Gayther, S. A., Pharoah, P. D., Song, H., Kjaer, S. K., Hogdall, E., Hogdall, C., Whittemore, A. S., McGuire, V., Sieh, W., Gronwald, J., Medrek, K., Jakubowska, A., Lubinski, J., Chenevix-Trench, G., Beesley, J., Webb, P. M., Berchuck, A., Schildkraut, J. M., Iversen, E. S., Moorman, P. G., Edlund, C. K., Stram, D. O., Pike, M. C., Ness, R. B., Rossing, M. A., Wu, A. H. 2011; 20 (11): 2263-2272

  Abstract

  The insulin-like growth factor (IGF) signaling axis plays an important role in cancer biology. We hypothesized that genetic variation in this pathway may influence risk of ovarian cancer. A three-center study of non-Hispanic whites including 1880 control women, 1135 women with invasive epithelial ovarian cancer and 321 women with borderline epithelial ovarian tumors was carried out to test the association between tag single-nucleotide polymorphisms (tSNPs) (n=58) in this pathway and risk of ovarian cancer. We found no association between variation in IGF1, IGFBP1 or IGFBP3 and risk of invasive disease, whereas five tSNPs in IGF2 were associated with risk of invasive epithelial ovarian cancer at P<0.05 and followed-up one of the associated SNPs. We conducted genotyping in 3216 additional non-Hispanic white cases and 5382 additional controls and were able to independently replicate our initial findings. In the combined set of studies, rs4320932 was associated with a 13% decreased risk of ovarian cancer per copy of the minor allele carried (95% confidence interval 0.81-0.93, P-trend=7.4 × 10(-5)). No heterogeneity of effect across study centers was observed (p(het)=0.25). IGF2 is emerging as an important gene for ovarian cancer; additional genotyping is warranted to further confirm these associations with IGF2 and to narrow down the region harboring the causal SNP.

  View details for DOI 10.1093/hmg/ddr087

  View details for Web of Science ID 000290589800016

  View details for PubMedID 21422097

  View details for PubMedCentralID PMC3090188

• Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer INTERNATIONAL JOURNAL OF CANCER Notaridou, M., Quaye, L., Dafou, D., Jones, C., Song, H., Hogdall, E., Kjaer, S. K., Christensen, L., Hogdall, C., Blaakaer, J., McGuire, V., Wu, A. H., Van den Berg, D. J., Pike, M. C., Gentry-Maharaj, A., Wozniak, E., Sher, T., Jacobs, I. J., Tyrer, J., Schildkraut, J. M., Moorman, P. G., Iversen, E. S., Jakubowska, A., Medrek, K., Lubinski, J., Ness, R. B., Moysich, K. B., Lurie, G., Wilkens, L. R., Carney, M. E., Wang-Gohrke, S., Doherty, J. A., Rossing, M. A., Beckmann, M. W., Thiel, F. C., Ekici, A. B., Chen, X., Beesley, J., Gronwald, J., Fasching, P. A., Chang-Claude, J., Goodman, M. T., Chenevix-Trench, G., Berchuck, A., Pearce, C. L., Whittemore, A. S., Menon, U., Pharoah, P. D., Gayther, S. A., Ramus, S. J. 2011; 128 (9): 2063-2074

  Abstract

  Common germline genetic variation in the population is associated with susceptibility to epithelial ovarian cancer. Microcell-mediated chromosome transfer and expression microarray analysis identified nine genes associated with functional suppression of tumorogenicity in ovarian cancer cell lines; AIFM2, AKTIP, AXIN2, CASP5, FILIP1L, RBBP8, RGC32, RUVBL1 and STAG3. Sixty-three tagging single nucleotide polymorphisms (tSNPs) in these genes were genotyped in 1,799 invasive ovarian cancer cases and 3,045 controls to look for associations with disease risk. Two SNPs in RUVBL1, rs13063604 and rs7650365, were associated with increased risk of serous ovarian cancer [HetOR = 1.42 (1.15-1.74) and the HomOR = 1.63 (1.10-1.42), p-trend = 0.0002] and [HetOR = 0.97 (0.80-1.17), HomOR = 0.74 (0.58-0.93), p-trend = 0.009], respectively. We genotyped rs13063604 and rs7650365 in an additional 4,590 cases and 6,031 controls from ten sites from the United States, Europe and Australia; however, neither SNP was significant in Stage 2. We also evaluated the potential role of tSNPs in these nine genes in ovarian cancer development by testing for allele-specific loss of heterozygosity (LOH) in 286 primary ovarian tumours. We found frequent LOH for tSNPs in AXIN2, AKTIP and RGC32 (64, 46 and 34%, respectively) and one SNP, rs1637001, in STAG3 showed significant allele-specific LOH with loss of the common allele in 94% of informative tumours (p = 0.015). Array comparative genomic hybridisation indicated that this nonrandom allelic imbalance was due to amplification of the rare allele. In conclusion, we show evidence for the involvement of a common allele of STAG3 in the development of epithelial ovarian cancer.

  View details for DOI 10.1002/ijc.25554

  View details for Web of Science ID 000288176600007

  View details for PubMedID 20635389

  View details for PubMedCentralID PMC3098608

• Prostate Cancer Susceptibility Polymorphism rs2660753 Is Not Associated with Invasive Ovarian Cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Amankwah, E. K., Kelemen, L. E., Wang, Q., Song, H., Chenevix-Trench, G., Beesley, J., Webb, P. M., Pearce, C. L., Wu, A. H., Pike, M. C., Stram, D. O., Chang-Claude, J., Wang-Gohrke, S., Ness, R. B., Goode, E. L., Cunningham, J. M., Fridley, B. L., Vierkant, R. A., Tworoger, S. S., Whittemore, A. S., McGuire, V., Sieh, W., Gayther, S. A., Gentry-Maharaj, A., Menon, U., Ramus, S. J., Rossing, M. A., Doherty, J. A., Goodman, M. T., Carney, M. E., Lurie, G., Wilkens, L. R., Kjaer, S. K., Hogdall, E., Cramer, D. W., Terry, K. L., Garcia-Closas, M., Yang, H., Lissowska, J., Anton-Culver, H., Ziogas, A., Schildkraut, J. M., Berchuck, A., Pharoah, P. D. 2011; 20 (5): 1028-1031

  Abstract

  We previously reported an association between rs2660753, a prostate cancer susceptibility polymorphism, and invasive epithelial ovarian cancer (EOC; OR = 1.2, 95% CI=1.0-1.4, P(trend) = 0.01) that showed a stronger association with the serous histological subtype (OR = 1.3, 95% CI = 1.1-1.5, P(trend) = 0.003).We sought to replicate this association in 12 other studies comprising 4,482 cases and 6,894 controls of white non-Hispanic ancestry in the Ovarian Cancer Association Consortium.No evidence for an association with all cancers or serous cancers was observed in a combined analysis of data from the replication studies (all: OR = 1.0, 95% CI = 0.9-1.1, P(trend) = 0.61; serous: OR = 1.0, 95% CI = 0.9-1.1, P(trend) = 0.85) or from the combined analysis of discovery and replication studies (all: OR = 1.0, 95% CI = 1.0-1.1, P(trend) = 0.28; serous: OR = 1.1, 95% CI = 1.0-1.2, P(trend) = 0.11). There was no evidence for statistical heterogeneity in ORs across the studies.Although rs2660753 is a strong prostate cancer susceptibility polymorphism, the association with another hormonally related cancer, invasive EOC, is not supported by this replication study.Our findings, based on a larger sample size, emphasize the importance of replicating potentially promising genetic risk associations.

  View details for DOI 10.1158/1055-9965.EPI-11-0053

  View details for Web of Science ID 000290251000036

  View details for PubMedID 21415361

  View details for PubMedCentralID PMC3176661

• Vitamin D receptor rs2228570 polymorphism and invasive ovarian carcinoma risk: pooled analysis in five studies within the Ovarian Cancer Association Consortium INTERNATIONAL JOURNAL OF CANCER Lurie, G., Wilkens, L. R., Thompson, P. J., Carney, M. E., Palmieri, R. T., Pharoah, P. D., Song, H., Hogdalls, E., Kjaer, S. K., DiCioccio, R. A., McGuire, V., Whittemore, A. S., Gayther, S. A., Gentry-Maharaj, A., Menon, U., Ramus, S. J., Goodman, M. T. 2011; 128 (4): 936-943

  Abstract

  The association of invasive ovarian carcinoma risk with the functional polymorphism rs2228570 (aka rs10735810; FokI polymorphism) in the vitamin D receptor (VDR) gene was examined in 1820 white non-Hispanic cases and 3479 controls in a pooled analysis of five population-based case-control studies within the Ovarian Cancer Association Consortium. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. Carriers of the rare T allele were at increased risk of ovarian carcinoma compared to women with the CC genotype in all studies combined; each copy of the T allele was associated with a modest 9% increased risk (OR = 1.09; 95% CI: 1.01-1.19; p = 0.04). No significant heterogeneity among studies was observed (p = 0.37) and, after excluding the dataset from the Hawaii study, the risk association for rs2228570 among replication studies was unchanged (OR = 1.09; 95% CI: 1.00-1.19; p = 0.06). A stronger association of rs2228570 with risk was observed among younger women (aged < 50 years versus 50 years or older) (p = 0.04). In all studies combined, the increased risk per copy of the T allele among younger women was 24% (OR = 1.24; 95% CI: 1.04-1.47; p = 0.02). This association remained statistically significant after excluding the Hawaii data (OR = 1.20; 95% CI: 1.01-1.43; p = 0.04). No heterogeneity of the association was observed by stage (p = 0.46), tumor histology (p = 0.98), or time between diagnosis and interview (p = 0.94). This pooled analysis provides further evidence that the VDR rs2228570 polymorphism might influence ovarian cancer susceptibility.

  View details for DOI 10.1002/ijc.25403

  View details for Web of Science ID 000286555700021

  View details for PubMedID 20473893

• Evaluating health risk models STATISTICS IN MEDICINE Whittemore, A. S. 2010; 29 (23): 2438-2452

  Abstract

  Interest in targeted disease prevention has stimulated development of models that assign risks to individuals, using their personal covariates. We need to evaluate these models and quantify the gains achieved by expanding a model to include additional covariates. This paper reviews several performance measures and shows how they are related. Examples are used to show that appropriate performance criteria for a risk model depend upon how the model is used. Application of the performance measures to risk models for hypothetical populations and for US women at risk of breast cancer illustrate two additional points. First, model performance is constrained by the distribution of risk-determining covariates in the population. This complicates the comparison of two models when applied to populations with different covariate distributions. Second, all summary performance measures obscure model features of relevance to its utility for the application at hand, such as performance in specific subgroups of the population. In particular, the precision gained by adding covariates to a model can be small overall, but large in certain subgroups. We propose new ways to identify these subgroups and to quantify how much they gain by measuring the additional covariates. Those with largest gains could be targeted for cost-efficient covariate assessment.

  View details for DOI 10.1002/sim.3991

  View details for Web of Science ID 000282622200006

  View details for PubMedID 20623821

  View details for PubMedCentralID PMC2990501

• Common variants at 19p13 are associated with susceptibility to ovarian cancer NATURE GENETICS Bolton, K. L., Tyrer, J., Song, H., Ramus, S. J., Notaridou, M., Jones, C., Sher, T. 3., Gentry-Maharaj, A., Wozniak, E., Tsai, Y., Weidhaas, J., Paik, D., Van den Berg, D. J., Stram, D. O., Pearce, C. L., Wu, A. H., Brewster, W., Anton-Culver, H., Ziogas, A., Narod, S. A., Levine, D. A., Kaye, S. B., Brown, R., Paul, J., Flanagan, J., Sieh, W., McGuire, V., Whittemore, A. S., Campbell, I., Gore, M. E., Lissowska, J., Yang, H. P., Medrek, K., Gronwald, J., Lubinski, J., Jakubowska, A., Le, N. D., Cook, L. S., Kelemen, L. E., Brook-Wilson, A., Massuger, L. F., Kiemeney, L. A., Aben, K. K., van Altena, A. M., Houlston, R., Tomlinson, I., Palmieri, R. T., Moorman, P. G., Schildkraut, J., Iversen, E. S., Phelan, C., Vierkant, R. A., Cunningham, J. M., Goode, E. L., Fridley, B. L., Kruger-Kjaer, S., Blaeker, J., Hogdall, E., Hogdall, C., Gross, J., Karlan, B. Y., Ness, R. B., Edwards, R. P., Odunsi, K., Moyisch, K. B., Baker, J. A., Modugno, F., Heikkinenen, T., Butzow, R., Nevanlinna, H., Leminen, A., Bogdanova, N., Antonenkova, N., Doerk, T., Hillemanns, P., Duerst, M., Runnebaum, I., Thompson, P. J., Carney, M. E., Goodman, M. T., Lurie, G., Wang-Gohrke, S., Hein, R., Chang-Claude, J., Rossing, M. A., Cushing-Haugen, K. L., Doherty, J., Chen, C., Rafnar, T., Besenbacher, S., Sulem, P., Stefansson, K., Birrer, M. J., Terry, K. L., Hernandez, D., Cramer, D. W., Vergote, I., Amant, F., Lambrechts, D., Despierre, E., Fasching, P. A., Beckmann, M. W., Thiel, F. C., Ekici, A. B., Chen, X., Johnatty, S. E., Webb, P. M., Beesley, J., Chanock, S., Garcia-Closas, M., Sellers, T., Easton, D. F., Berchuck, A., Chenevix-Trench, G., Pharoah, P. D., Gayther, S. A. 2010; 42 (10): 880-?

  Abstract

  Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 × 10⁻⁴ and P = 6 × 10⁻⁴, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 × 10⁻⁹ and P = 4 × 10⁻¹¹, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.

  View details for DOI 10.1038/ng.666

  View details for Web of Science ID 000282276600019

  View details for PubMedID 20852633

  View details for PubMedCentralID PMC3125495

• A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24 NATURE GENETICS Goode, L. L., Chenevix-Trench, G., Song, H., Ramus, S. J., Notaridou, M., Lawrenson, K., Widschwendter, M., Vierkant, R. A., Larson, M. C., Kjaer, S. K., Birrer, M. J., Berchuck, A., Schildkraut, J., Tomlinson, I., Kiemeney, L. A., Cook, L. S., Gronwald, J., Garcia-Closas, M., Gore, M. E., Campbell, I., Whittemore, A. S., Sutphen, R., Phelan, C., Anton-Culver, H., Pearce, C. L., Lambrechts, D., Rossing, M. A., Chang-Claude, J., Moysich, K. B., Goodman, M. T., Doerk, T., Nevanlinna, H., Ness, R. B., Rafnar, T., Hogdall, C., Hogdall, E., Fridley, B. L., Cunningham, J. M., Sieh, W., McGuire, V., Godwin, A. K., Cramer, D. W., Hernandez, D., Levine, D., Lu, K., Iversen, E. S., Palmieri, R. T., Houlston, R., van Altena, A. M., Aben, K. K., Massuger, L. F., Brooks-Wilson, A., Kelemen, L. E., Le, N. D., Jakubowska, A., Lubinski, J., Medrek, K., Stafford, A., Easton, D. F., Tyrer, J., Bolton, K. L., Harrington, P., Eccles, D., Chen, A., Molina, A. N., Davila, B. N., Arango, H., Tsai, Y., Chen, Z., Risch, H. A., McLaughlin, J., Narod, S. A., Ziogas, A., Brewster, W., Gentry-Maharaj, A., Menon, U., Wu, A. H., Stram, D. O., Pike, M. C., Beesley, J., Webb, P. M., Chen, X., Ekici, A. B., Thiel, F. C., Beckmann, M. W., Yang, H., Wentzensen, N., Lissowska, J., Fasching, P. A., Despierre, E., Amant, F., Vergote, I., Doherty, J., Hein, R., Wang-Gohrke, S., Lurie, G., Carney, M. E., Thompson, P. J., Runnebaum, I., Hillemanns, P., Duerst, M., Antonenkova, N., Bogdanova, N., Leminen, A., Butzow, R., Heikkinen, T., Stefansson, K., Sulem, P., Besenbacher, S., Sellers, T. A., Gayther, S. A., Pharoah, P. D. 2010; 42 (10): 874-?

  Abstract

  Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with follow up of 21,955 SNPs in 4,162 cases and 4,810 controls, leading to the identification of a confirmed susceptibility locus at 9p22 (in BNC2). Here, we report on nine additional candidate loci (defined as having P ≤ 10⁻⁴) identified after stratifying cases by histology, which we genotyped in an additional 4,353 cases and 6,021 controls. We confirmed two new susceptibility loci with P ≤ 5 × 10⁻⁸ (8q24, P = 8.0 × 10⁻¹⁵ and 2q31, P = 3.8 × 10⁻¹⁴) and identified two additional loci that approached genome-wide significance (3q25, P = 7.1 × 10⁻⁸ and 17q21, P = 1.4 × 10⁻⁷). The associations of these loci with serous ovarian cancer were generally stronger than with other cancer subtypes. Analysis of HOXD1, MYC, TIPARP and SKAP1 at these loci and of BNC2 at 9p22 supports a functional role for these genes in ovarian cancer development.

  View details for DOI 10.1038/ng.668

  View details for Web of Science ID 000282276600018

  View details for PubMedID 20852632

  View details for PubMedCentralID PMC3020231

• Increased cancer risks for relatives of very early-onset breast cancer cases with and without BRCA1 and BRCA2 mutations BRITISH JOURNAL OF CANCER Dite, G. S., Whittemore, A. S., Knight, J. A., John, E. M., Milne, R. L., Andrulis, I. L., Southey, M. C., McCredie, M. R., Giles, G. G., Miron, A., Phipps, A. I., West, D. W., Hopper, J. L. 2010; 103 (7): 1103-1108

  Abstract

  Little is known regarding cancer risks for relatives of women with very early-onset breast cancer.We studied 2208 parents and siblings of 504 unselected population-based Caucasian women with breast cancer diagnosed before age 35 years (103 from USA, 124 from Canada and 277 from Australia), 41 known to carry a mutation (24 in BRCA1, 16 in BRCA2 and one in both genes). Cancer-specific standardised incidence ratios (SIRs) were estimated by comparing the number of affected relatives (50% verified overall) with that expected based on incidences specific for country, sex, age and year of birth.For relatives of carriers, the female breast cancer SIRs were 13.13 (95% CI 6.57-26.26) and 12.52 (5.21-30.07) for BRCA1 and BRCA2, respectively. The ovarian cancer SIR was 12.38 (3.1-49.51) for BRCA1 and the prostate cancer SIR was 18.55 (4.64-74.17) for BRCA2. For relatives of non-carriers, the SIRs for female breast, prostate, lung, brain and urinary cancers were 4.03 (2.91-5.93), 5.25 (2.50-11.01), 7.73 (4.74-12.62), 5.19 (2.33-11.54) and 4.35 (1.81-10.46), respectively. For non-carriers, the SIRs remained elevated and were statistically significant for breast and prostate cancer when based on verified cancers.First-degree relatives of women with very early-onset breast cancer are at increased risk of cancers not explained by BRCA1 and BRCA2 mutations.

  View details for DOI 10.1038/sj.bjc.6605876

  View details for Web of Science ID 000282222000025

  View details for PubMedID 20877337

  View details for PubMedCentralID PMC2965877

• Past recreational physical activity, body size, and all-cause mortality following breast cancer diagnosis: results from the breast cancer family registry BREAST CANCER RESEARCH AND TREATMENT Keegan, T. H., Milne, R. L., Andrulis, I. L., Chang, E. T., Sangaramoorthy, M., Phillips, K., Giles, G. G., Goodwin, P. J., Apicella, C., Hopper, J. L., Whittemore, A. S., John, E. M. 2010; 123 (2): 531-542

  Abstract

  Few studies have considered the joint association of body mass index (BMI) and physical activity, two modifiable factors, with all-cause mortality after breast cancer diagnosis. Women diagnosed with invasive breast cancer (n = 4,153) between 1991 and 2000 were enrolled in the Breast Cancer Family Registry through population-based sampling in Northern California, USA; Ontario, Canada; and Melbourne and Sydney, Australia. During a median follow-up of 7.8 years, 725 deaths occurred. Baseline questionnaires assessed moderate and vigorous recreational physical activity and BMI prior to diagnosis. Associations with all-cause mortality were assessed using Cox proportional hazards regression, adjusting for established prognostic factors. Compared with no physical activity, any recreational activity during the 3 years prior to diagnosis was associated with a 34% lower risk of death [hazard ratio (HR) = 0.66, 95% confidence interval (CI): 0.51-0.85] for women with estrogen receptor (ER)-positive tumors, but not those with ER-negative tumors; this association did not appear to differ by race/ethnicity or BMI. Lifetime physical activity was not associated with all-cause mortality. BMI was positively associated with all-cause mortality for women diagnosed at age > or =50 years with ER-positive tumors (compared with normal-weight women, HR for overweight = 1.39, 95% CI: 0.90-2.15; HR for obese = 1.77, 95% CI: 1.11-2.82). BMI associations did not appear to differ by race/ethnicity. Our findings suggest that physical activity and BMI exert independent effects on overall mortality after breast cancer.

  View details for DOI 10.1007/s10549-010-0774-6

  View details for Web of Science ID 000280807900023

  View details for PubMedID 20140702

  View details for PubMedCentralID PMC2920352

• Genetic Variation in TYMS in the One-Carbon Transfer Pathway Is Associated with Ovarian Carcinoma Types in the Ovarian Cancer Association Consortium CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Kelemen, L. E., Goodman, M. T., McGuire, V., Rossing, M. A., Webb, P. M., Koebel, M., Anton-Culver, H., Beesley, J., Berchuck, A., Brar, S., Carney, M. E., Chang-Claude, J., Chenevix-Trench, G., Cramer, D. W., Cunningham, J. M., DiCioccio, R. A., Doherty, J. A., Easton, D. F., Fredericksen, Z. S., Fridley, B. L., Gates, M. A., Gayther, S. A., Gentry-Maharaj, A., Hogdall, E., Kjaer, S. K., Lurie, G., Menon, U., Moorman, P. G., Moysich, K., Ness, R. B., Palmieri, R. T., Pearce, C. L., Pharoah, P. D., Ramus, S. J., Song, H., Stram, D. O., Tworoger, S. S., Van Den Berg, D., Vierkant, R. A., Wang-Gohrke, S., Whittemore, A. S., Wilkens, L. R., Wu, A. H., Schildkraut, J. M., Sellers, T. A., Goode, E. L. 2010; 19 (7): 1822-1830

  Abstract

  We previously reported the risks of ovarian carcinoma for common polymorphisms in one-carbon transfer genes. We sought to replicate associations for DPYD rs1801265, DNMT3A rs13420827, MTHFD1 rs1950902, MTHFS rs17284990, and TYMS rs495139 with risk of ovarian carcinoma overall and to use the large sample of assembled cases to investigate associations by histologic type.Associations were evaluated in the Ovarian Cancer Association Consortium, including 16 studies of 5,593 epithelial ovarian carcinoma cases and 9,962 controls of white non-Hispanic origin. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for age and study site.The five polymorphisms were not associated with ovarian carcinoma overall (P(trend) > 0.13); however, associations for the minor allele at TYMS rs495139 were observed for carcinomas of mucinous type (OR, 1.19; 95% CI, 1.03-1.39; P = 0.02), clear cell type (OR, 0.86; 95% CI, 0.75-0.99; P = 0.04), and endometrioid type (OR, 0.90; 95% CI, 0.81-0.99; P = 0.04; P(heterogeneity) = 0.001). Restriction to low-grade mucinous carcinomas further strengthened the association for the mucinous type (OR, 1.32; 95% CI, 1.07-1.62; P = 0.01). TYMS rs495139 was not associated with serous type (OR, 1.06; 95% CI, 1.00-1.13; P = 0.05).TYMS rs495139 may be associated with a differential risk of ovarian carcinoma types, indicating the importance of accurate histopathologic classification.Biomarkers that distinguish ovarian carcinoma types are few, and TYMS rs495139 may provide a novel clue to type etiology.

  View details for DOI 10.1158/1055-9965.EPI-09-1317

  View details for Web of Science ID 000279590100018

  View details for PubMedID 20570913

  View details for PubMedCentralID PMC3013232

• Evaluation of Candidate Stromal Epithelial Cross-Talk Genes Identifies Association between Risk of Serous Ovarian Cancer and TERT, a Cancer Susceptibility "Hot-Spot'' PLOS GENETICS Johnatty, S. E., Beesley, J., Chen, X., Macgregor, S., Duffy, D. L., Spurdle, A. B., deFazio, A., Gava, N., Webb, P. M., Rossing, M. A., Doherty, J. A., Goodman, M. T., Lurie, G., Thompson, P. J., Wilkens, L. R., Ness, R. B., Moysich, K. B., Chang-Claude, J., Wang-Gohrke, S., Cramer, D. W., Terry, K. L., Hankinson, S. E., Tworoger, S. S., Garcia-Closas, M., Yang, H., Lissowska, J., Chanock, S. J., Pharoah, P. D., Song, H., Whitemore, A. S., Pearce, C. L., Stram, D. O., Wu, A. H., Pike, M. C., Gayther, S. A., Ramus, S. J., Menon, U., Gentry-Maharaj, A., Anton-Culver, H., Ziogas, A., Hogdall, E., Kjaer, S. K., Hogdall, C., Berchuck, A., Schildkraut, J. M., Iversen, E. S., Moorman, P. G., Phelan, C. M., Sellers, T. A., Cunningham, J. M., Vierkant, R. A., Rider, D. N., Goode, E. L., Haviv, I., Chenevix-Trench, G. 2010; 6 (7)

  Abstract

  We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n=675) and controls (n=1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-allele<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n=1,233 serous invasive cases; n=3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. Pper-allele>or=0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele=0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24) p=0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.

  View details for DOI 10.1371/journal.pgen.1001016

  View details for Web of Science ID 000280512700012

  View details for PubMedID 20628624

  View details for PubMedCentralID PMC2900295

• Genome-Wide Linkage Analysis of 1,233 Prostate Cancer Pedigrees From the International Consortium for Prostate Cancer Genetics Using Novel sum LINK and sum LOD Analyses PROSTATE Christensen, G. B., Baffoe-Bonnie, A. B., George, A., Powell, I., Bailey-Wilson, J. E., Carpten, J. D., Giles, G. G., Hopper, J. L., Seven, G., English, D. R., Foulkes, W. D., Maehle, L., Moller, P., Eeles, R., Easton, D., Badzioch, M. D., Whittemore, A. S., Oakley-Girvan, I., Hsieh, C., Dimitrov, L., Xu, J., Stanford, J. L., Johanneson, B., Deutsch, K., McIntosh, L., Ostrander, E. A., Wiley, K. E., Isaacs, S. D., Walsh, P. C., Isaacs, W. B., Thibodeau, S. N., McDonnell, S. K., Hebbring, S., Schaid, D. J., Lange, E. M., Cooney, K. A., Tammela, T. L., Schleutker, J., Paiss, T., Maier, C., Gronberg, H., Wiklund, F., Emanuelsson, M., Farnham, J. M., Cannon-Albright, L. A., Camp, N. J. 2010; 70 (7): 735-744

  Abstract

  Prostate cancer (PC) is generally believed to have a strong inherited component, but the search for susceptibility genes has been hindered by the effects of genetic heterogeneity. The recently developed sumLINK and sumLOD statistics are powerful tools for linkage analysis in the presence of heterogeneity.We performed a secondary analysis of 1,233 PC pedigrees from the International Consortium for Prostate Cancer Genetics (ICPCG) using two novel statistics, the sumLINK and sumLOD. For both statistics, dominant and recessive genetic models were considered. False discovery rate (FDR) analysis was conducted to assess the effects of multiple testing.Our analysis identified significant linkage evidence at chromosome 22q12, confirming previous findings by the initial conventional analyses of the same ICPCG data. Twelve other regions were identified with genome-wide suggestive evidence for linkage. Seven regions (1q23, 5q11, 5q35, 6p21, 8q12, 11q13, 20p11-q11) are near loci previously identified in the initial ICPCG pooled data analysis or the subset of aggressive PC pedigrees. Three other regions (1p12, 8p23, 19q13) confirm loci reported by others, and two (2p24, 6q27) are novel susceptibility loci. FDR testing indicates that over 70% of these results are likely true positive findings. Statistical recombinant mapping narrowed regions to an average of 9 cM.Our results represent genomic regions with the greatest consistency of positive linkage evidence across a very large collection of high-risk PC pedigrees using new statistical tests that deal powerfully with heterogeneity. These regions are excellent candidates for further study to identify PC predisposition genes.

  View details for DOI 10.1002/pros.21106

  View details for Web of Science ID 000277338800006

  View details for PubMedID 20333727

  View details for PubMedCentralID PMC3428045

• Estimating Gene Penetrance From Family Data GENETIC EPIDEMIOLOGY Gong, G., Hannon, N., Whittemore, A. S. 2010; 34 (4): 373-381

  Abstract

  Family data are useful for estimating disease risk in carriers of specific genotypes of a given gene (penetrance). Penetrance is frequently estimated assuming that relatives' phenotypes are independent, given their genotypes for the gene of interest. This assumption is unrealistic when multiple shared risk factors contribute to disease risk. In this setting, the phenotypes of relatives are correlated even after adjustment for the genotypes of any one gene (residual correlation). Many methods have been proposed to address this problem, but their performance has not been evaluated systematically. In simulations we generated genotypes for a rare (frequency 0.35%) allele of moderate penetrance, and a common (frequency 15%) allele of low penetrance, and then generated correlated disease survival times using the Clayton-Oakes copula model. We ascertained families using both population and clinic designs. We then compared the estimates of several methods to the optimal ones obtained from the model used to generate the data. We found that penetrance estimates for common low-risk genotypes were more robust to model misspecification than those for rare, moderate-risk genotypes. For the latter, penetrance estimates obtained ignoring residual disease correlation had large biases. Also biased were estimates based only on families that segregate the risk allele. In contrast, a method for accommodating phenotype correlation by assuming the presence of genetic heterogeneity performed nearly optimally, even when the survival data were coded as binary outcomes. We conclude that penetrance estimates that accommodate residual phenotype correlation (even only approximately) outperform those that ignore it, and that coding censored survival outcomes as binary does not substantially increase the mean-square error of the estimates, provided the censoring is not extensive.

  View details for DOI 10.1002/gepi.20493

  View details for Web of Science ID 000277642800010

  View details for PubMedID 20397150

  View details for PubMedCentralID PMC3003663

• Second Malignant Neoplasms in Survivors of Pediatric Hodgkin's Lymphoma Treated With Low-Dose Radiation and Chemotherapy JOURNAL OF CLINICAL ONCOLOGY O'Brien, M. M., Donaldson, S. S., Balise, R. R., Whittemore, A. S., Link, M. P. 2010; 28 (7): 1232-1239

  Abstract

  Survivors of childhood Hodgkin's lymphoma (HL) are at risk for second malignant neoplasms (SMNs). It is theorized that this risk may be attenuated in patients treated with lower doses of radiation. We report the first long-term outcomes of a cohort of pediatric survivors of HL treated with chemotherapy and low-dose radiation.Pediatric patients with HL (n = 112) treated at Stanford from 1970 to 1990 on two combined modality treatment protocols were identified. Treatment included six cycles of chemotherapy with 15 to 25.5 Gy involved-field radiation with optional 10 Gy boosts to bulky sites. Follow-up through September 1, 2007, was obtained from retrospective chart review and patient questionnaires.One hundred ten children completed HL therapy; median follow-up was 20.6 years. Eighteen patients developed one or more SMNs, including four leukemias, five thyroid carcinomas, six breast carcinomas, and four sarcomas. Cumulative incidence of first SMN was 17% (95% CI, 10.5 to 26.7) at 20 years after HL diagnosis. The standard incidence ratio for any SMN was 22.9 (95% CI, 14.2 to 35) with an absolute excess risk of 93.7 cases per 10,000 person-years. All four secondary leukemias were fatal. For those with second solid tumors, the mean (+/- SE) 5-year disease-free and overall survival were 76% +/- 12% and 85% +/- 10% with median follow-up 5 years from SMN diagnosis.Despite treatment with low-dose radiation, children treated for HL remain at significant risk for SMN. Sarcomas, breast and thyroid carcinomas occurred with similar frequency and latency as found in studies of children with HL who received high-dose radiation.

  View details for DOI 10.1200/JCO.2009.24.8062

  View details for Web of Science ID 000274892500025

  View details for PubMedID 20124178

• Polymorphism in the GALNT1 Gene and Epithelial Ovarian Cancer in Non-Hispanic White Women: The Ovarian Cancer Association Consortium CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Phelan, C. M., Tsai, Y., Goode, E. L., Vierkant, R. A., Fridley, B. L., Beesley, J., Chen, X. Q., Webb, P. M., Chanock, S., Cramer, D. W., Moysich, K., Edwards, R. P., Chang-Claude, J., Garcia-Closas, M., Yang, H., Wang-Gohrke, S., Hein, R., Green, A. C., Lissowska, J., Carney, M. E., Lurie, G., Wilkens, L. R., Ness, R. B., Pearce, C. L., Wu, A. H., Van den Berg, D. J., Stram, D. O., Terry, K. L., Whiteman, D. C., Whittemore, A. S., DiCioccio, R. A., McGuire, V., Doherty, J. A., Rossing, M. A., Anton-Culver, H., Ziogas, A., Hogdall, C., Hogdall, E., Kjaer, S. K., Blaakaer, J., Quaye, L., Ramus, S. J., Jacobs, I., Song, H., Pharoah, P. D., Iversen, E. S., Marks, J. R., Pike, M. C., Gayther, S. A., Cunningham, J. M., Goodman, M. T., Schildkraut, J. M., Chenevix-Trench, G., Berchuck, A., Sellers, T. A. 2010; 19 (2): 600-604

  Abstract

  Aberrant glycosylation is a well-described hallmark of cancer. In a previous ovarian cancer case control study that examined polymorphisms in 26 glycosylation-associated genes, we found strong statistical evidence (P = 0.00017) that women who inherited two copies of a single-nucleotide polymorphism in the UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase, GALNT1, had decreased ovarian cancer risk. The current study attempted to replicate this observation. The GALNT1 single-nucleotide polymorphism rs17647532 was genotyped in 6,965 cases and 8,377 controls from 14 studies forming the Ovarian Cancer Association Consortium. The fixed effects estimate per rs17647532 allele was null (odds ratio, 0.99; 95% confidence interval, 0.92-1.07). When a recessive model was fit, the results were unchanged. Test for heterogeneity of the odds ratios revealed consistency across the 14 replication sites but significant differences compared with the original study population (P = 0.03). This study underscores the need for replication of putative findings in genetic association studies.

  View details for DOI 10.1158/1055-9965.EPI-09-0861

  View details for Web of Science ID 000278403900034

  View details for PubMedID 20142253

  View details for PubMedCentralID PMC2880167

• ESR1/SYNE1 Polymorphism and Invasive Epithelial Ovarian Cancer Risk: An Ovarian Cancer Association Consortium Study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Doherty, J. A., Rossing, M. A., Cushing-Haugen, K. L., Chen, C., Van den Berg, D. J., Wu, A. H., Pike, M. C., Ness, R. B., Moysich, K., Chenevix-Trench, G., Beesley, J., Webb, P. M., Chang-Claude, J., Wang-Gohrke, S., Goodman, M. T., Lurie, G., Thompson, P. J., Carney, M. E., Hogdall, E., Kjaer, S. K., Hogdall, C., Goode, E. L., Cunningham, J. M., Fridley, B. L., Vierkant, R. A., Berchuck, A., Moorman, P. G., Schildkraut, J. M., Palmieri, R. T., Cramer, D. W., Terry, K. L., Yang, H. P., Garcia-Closas, M., Chanock, S., Lissowska, J., Song, H., Pharoah, P. D., Shah, M., Perkins, B., McGuire, V., Whittemore, A. S., Di Cioccio, R. A., Gentry-Maharaj, A., Menon, U., Gayther, S. A., Ramus, S. J., Ziogas, A., Brewster, W., Anton-Culver, H., Pearce, C. L. 2010; 19 (1): 245-250

  Abstract

  We genotyped 13 single nucleotide polymorphisms (SNPs) in the estrogen receptor alpha gene (ESR1) region in three population-based case-control studies of epithelial ovarian cancer conducted in the United States, comprising a total of 1,128 and 1,866 non-Hispanic white invasive cases and controls, respectively. A SNP 19 kb downstream of ESR1 (rs2295190, G-to-T change) was associated with invasive ovarian cancer risk, with a per-T-allele odds ratio (OR) of 1.24 [95% confidence interval (CI), 1.06-1.44, P = 0.006]. rs2295190 is a nonsynonymous coding SNP in a neighboring gene called spectrin repeat containing, nuclear envelope 1 (SYNE1), which is involved in nuclear organization and structural integrity, function of the Golgi apparatus, and cytokinesis. An isoform encoded by SYNE1 has been reported to be downregulated in ovarian and other cancers. rs2295190 was genotyped in an additional 12 studies through the Ovarian Cancer Association Consortium, with 5,279 invasive epithelial cases and 7,450 controls. The per-T-allele OR for this 12-study set was 1.09 (95% CI, 1.02-1.17; P = 0.017). Results for the serous subtype in the 15 combined studies were similar to those overall (n = 3,545; OR, 1.09; 95% CI, 1.01-1.18; P = 0.025), and our findings were strongest for the mucinous subtype (n = 447; OR, 1.32; 95% CI, 1.11-1.58; P = 0.002). No association was observed for the endometrioid subtype. In an additional analysis of 1,459 borderline ovarian cancer cases and 7,370 controls, rs2295190 was not associated with risk. These data provide suggestive evidence that the rs2295190 T allele, or another allele in linkage disequilibrium with it, may be associated with increased risk of invasive ovarian cancer.

  View details for DOI 10.1158/1055-9965.EPI-09-0729

  View details for Web of Science ID 000273586700028

  View details for PubMedID 20056644

  View details for PubMedCentralID PMC2863004

• Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study BREAST CANCER RESEARCH Milne, R. L., Gaudet, M. M., Spurdle, A. B., Fasching, P. A., Couch, F. J., Benitez, J., Arias Perez, J. I., Pilar Zamora, M., Malats, N., dos Santos Silva, I., Gibson, L. J., Fletcher, O., Johnson, N., Anton-Culver, H., Ziogas, A., Figueroa, J., Brinton, L., Sherman, M. E., Lissowska, J., Hopper, J. L., Dite, G. S., Apicella, C., Southey, M. C., Sigurdson, A. J., Linet, M. S., Schonfeld, S. J., Freedman, D. M., Mannermaa, A., Kosma, V., Kataja, V., Auvinen, P., Andrulis, I. L., Glendon, G., Knight, J. A., Weerasooriya, N., Cox, A., Reed, M. W., Cross, S. S., Dunning, A. M., Ahmed, S., Shah, M., Brauch, H., Ko, Y., Bruening, T., Lambrechts, D., Reumers, J., Smeets, A., Wang-Gohrke, S., Hall, P., Czene, K., Liu, J., Irwanto, A. K., Chenevix-Trench, G., Holland, H., Giles, G. G., Baglietto, L., Severi, G., Bojensen, S. E., Nordestgaard, B. G., Flyger, H., John, E. M., West, D. W., Whittemore, A. S., Vachon, C., Olson, J. E., Fredericksen, Z., Kosel, M., Hein, R., Vrieling, A., Flesch-Janys, D., Heinz, J., Beckmann, M. W., Heusinger, K., Ekici, A. B., Haeberle, L., Humphreys, M. K., Morrison, J., Easton, D. F., Pharoah, P. D., Garcia-Closas, M., Goode, E. L., Chang-Claude, J. 2010; 12 (6)

  Abstract

  Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium.We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects.These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar.The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified.

  View details for DOI 10.1186/bcr2797

  View details for Web of Science ID 000288751500021

  View details for PubMedID 21194473

  View details for PubMedCentralID PMC3046455

• No evidence of familial correlation in breast cancer metastasis BREAST CANCER RESEARCH AND TREATMENT Whittemore, A. S., Stearman, B., Venne, V., Halpern, J., Felberg, A., McGuire, V., Daly, M., Buys, S. S. 2009; 118 (3): 575-581

  Abstract

  Animal experiments support the hypothesis that the metastatic potential of breast cancer is a heritable trait of the host. Our objective was to evaluate correlations in metastasis occurrence in large families with multiple cases of breast cancer. We evaluated correlation among pairs of relatives in the occurrence and timing of distant metastasis using retrospective cohort data from 743 female breast cancer patients in 242 families. We adjusted for correlation in their age at diagnosis, year of diagnosis, educational level, lymph node involvement, and estrogen receptor status. Distant metastasis occurred in 255 patients (34.3%) during mean followup of 11.7 years. None of the correlation coefficients for metastasis in blood relatives differed significantly from zero. The estimated correlation coefficient in first-degree relatives was -0.03 (95% confidence interval -0.11 to 0.06). These findings suggest that a family history of metastatic breast cancer does not contribute substantially to risk of metastasis for breast cancer patients.

  View details for DOI 10.1007/s10549-009-0368-3

  View details for Web of Science ID 000271640900015

  View details for PubMedID 19296215

  View details for PubMedCentralID PMC2783315

• An Admixture Scan in 1,484 African American Women with Breast Cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Fejerman, L., Haiman, C. A., Reich, D., Tandon, A., Deo, R. C., John, E. M., Ingles, S. A., Ambrosone, C. B., Bovbjerg, D. H., Jandorf, L. H., Davis, W., Ciupak, G., Whittemore, A. S., Press, M. F., Ursin, G., Bernstein, L., Huntsman, S., Henderson, B. E., Ziv, E., Freedman, M. L. 2009; 18 (11): 3110-3117

  Abstract

  African American women with breast cancer present more commonly with aggressive tumors that do not express the estrogen receptor (ER) and progesterone receptor (PR) compared with European American women. Whether this disparity is the result of inherited factors has not been established. We did an admixture-based genome-wide scan to search for risk alleles for breast cancer that are highly differentiated in frequency between African American and European American women, and may contribute to specific breast cancer phenotypes, such as ER-negative (ER-) disease. African American women with invasive breast cancer (n = 1,484) were pooled from six population-based studies and typed at approximately 1,500 ancestry-informative markers. We investigated global genetic ancestry and did a whole genome admixture scan searching for breast cancer-predisposing loci in association with disease phenotypes. We found a significant difference in ancestry between ER+PR+ and ER-PR- women, with higher European ancestry among ER+PR+ individuals, after controlling for possible confounders (odds ratios for a 0 to 1 change in European ancestry proportion, 2.84; 95% confidence interval, 1.13-7.14; P = 0.026). Women with localized tumors had higher European ancestry than women with non-localized tumors (odds ratios, 2.65; 95% confidence interval, 1.11-6.35; P = 0.029). No genome-wide statistically significant associations were observed between European or African ancestry at any specific locus and breast cancer, or in analyses stratified by ER/PR status, stage, or grade. In summary, in African American women, genetic ancestry is associated with ER/PR status and disease stage. However, we found little evidence that genetic ancestry at any one region contributes significantly to breast cancer risk or hormone receptor status.

  View details for DOI 10.1158/1055-9965.EPI-09-0464

  View details for Web of Science ID 000271562600045

  View details for PubMedID 19843668

  View details for PubMedCentralID PMC2783219

• Cell cycle genes and ovarian cancer susceptibility: a tagSNP analysis BRITISH JOURNAL OF CANCER Cunningham, J. M., Vierkant, R. A., Sellers, T. A., Phelan, C., Rider, D. N., Liebow, M., Schildkraut, J., Berchuck, A., Couch, F. J., Wang, X., Fridley, B. L., Gentry-Maharaj, A., Menon, U., Hogdall, E., Kjaer, S., Whittemore, A., DiCioccio, R., Song, H., Gayther, S. A., Ramus, S. J., Pharaoh, P. D., Goode, E. L. 2009; 101 (8): 1461-1468

  Abstract

  Dysregulation of the cell cycle is a hallmark of many cancers including ovarian cancer, a leading cause of gynaecologic cancer mortality worldwide.We examined single nucleotide polymorphisms (SNPs) (n=288) from 39 cell cycle regulation genes, including cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors, in a two-stage study. White, non-Hispanic cases (n=829) and ovarian cancer-free controls (n=941) were genotyped using an Illumina assay.Eleven variants in nine genes (ABL1, CCNB2, CDKN1A, CCND3, E2F2, CDK2, E2F3, CDC2, and CDK7) were associated with risk of ovarian cancer in at least one genetic model. Seven SNPs were then assessed in four additional studies with 1689 cases and 3398 controls. Association between risk of ovarian cancer and ABL1 rs2855192 found in the original population [odds ratio, OR(BB vs AA) 2.81 (1.29-6.09), P=0.01] was also observed in a replication population, and the association remained suggestive in the combined analysis [OR(BB vs AA) 1.59 (1.08-2.34), P=0.02]. No other SNP associations remained suggestive in the replication populations.ABL1 has been implicated in multiple processes including cell division, cell adhesion and cellular stress response. These results suggest that characterization of the function of genetic variation in this gene in other ovarian cancer populations is warranted.

  View details for DOI 10.1038/sj.bjc.6605284

  View details for Web of Science ID 000270767200032

  View details for PubMedID 19738611

• Finding the missing heritability of complex diseases NATURE Manolio, T. A., Collins, F. S., Cox, N. J., Goldstein, D. B., Hindorff, L. A., Hunter, D. J., McCarthy, M. I., Ramos, E. M., Cardon, L. R., Chakravarti, A., Cho, J. H., Guttmacher, A. E., Kong, A., Kruglyak, L., Mardis, E., Rotimi, C. N., Slatkin, M., Valle, D., Whittemore, A. S., Boehnke, M., Clark, A. G., Eichler, E. E., Gibson, G., Haines, J. L., Mackay, T. F., McCarroll, S. A., Visscher, P. M. 2009; 461 (7265): 747-753

  Abstract

  Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

  View details for DOI 10.1038/nature08494

  View details for Web of Science ID 000270547500027

  View details for PubMedID 19812666

  View details for PubMedCentralID PMC2831613

• Family history of breast cancer and all-cause mortality after breast cancer diagnosis in the Breast Cancer Family Registry BREAST CANCER RESEARCH AND TREATMENT Chang, E. T., Milne, R. L., Phillips, K., Figueiredo, J. C., Sangaramoorthy, M., Keegan, T. H., Andrulis, I. L., Hopper, J. L., Goodwin, P. J., O'Malley, F. P., Weerasooriya, N., Apicella, C., Southey, M. C., Friedlander, M. L., Giles, G. G., Whittemore, A. S., West, D. W., John, E. M. 2009; 117 (1): 167-176

  Abstract

  Although having a family history of breast cancer is a well established breast cancer risk factor, it is not known whether it influences mortality after breast cancer diagnosis. We studied 4,153 women with first primary incident invasive breast cancer diagnosed between 1991 and 2000, and enrolled in the Breast Cancer Family Registry through population-based sampling in Northern California, USA; Ontario, Canada; and Melbourne and Sydney, Australia. Cases were oversampled for younger age at diagnosis and/or family history of breast cancer. Carriers of germline mutations in BRCA1 or BRCA2 were excluded. Cases and their relatives completed structured questionnaires assessing breast cancer risk factors and family history of cancer. Cases were followed for a median of 6.5 years, during which 725 deaths occurred. Cox proportional hazards regression was used to evaluate associations between family history of breast cancer at the time of diagnosis and risk of all-cause mortality after breast cancer diagnosis, adjusting for established prognostic factors. The hazard ratios for all-cause mortality were 0.98 (95% confidence interval [CI] = 0.84-1.15) for having at least one first- or second-degree relative with breast cancer, and 0.85 (95% CI = 0.70-1.02) for having at least one first-degree relative with breast cancer, compared with having no such family history. Estimates did not vary appreciably when stratified by case or tumor characteristics. In conclusion, family history of breast cancer is not associated with all-cause mortality after breast cancer diagnosis for women without a known germline mutation in BRCA1 or BRCA2. Therefore, clinical management should not depend on family history of breast cancer.

  View details for DOI 10.1007/s10549-008-0255-3

  View details for Web of Science ID 000269005400020

  View details for PubMedID 19034644

  View details for PubMedCentralID PMC2728159

• A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2 NATURE GENETICS Song, H., Ramus, S. J., Tyrer, J., Bolton, K. L., Gentry-Maharaj, A., Wozniak, E., Anton-Culver, H., Chang-Claude, J., Cramer, D. W., DiCioccio, R., Doerk, T., Goode, E. L., Goodman, M. T., Schildkraut, J. M., Sellers, T., Baglietto, L., Beckmann, M. W., Beesley, J., Blaakaer, J., Carney, M. E., Chanock, S., Chen, Z., Cunningham, J. M., Dicks, E., Doherty, J. A., Duerst, M., Ekici, A. B., Fenstermacher, D., Fridley, B. L., Giles, G., Gore, M. E., De Vivo, I., Hillemanns, P., Hogdall, C., Hogdall, E., Iversen, E. S., Jacobs, I. J., Jakubowska, A., Li, D., Lissowska, J., Lubinski, J., Lurie, G., McGuire, V., McLaughlin, J., Medrek, K., Moorman, P. G., Moysich, K., Narod, S., Phelan, C., Pye, C., Risch, H., Runnebaum, I. B., Severi, G., Southey, M., Stram, D. O., Thiel, F. C., Terry, K. L., Tsai, Y., Tworoger, S. S., Van den Berg, D. J., Vierkant, R. A., Wang-Gohrke, S., Webb, P. M., Wilkens, L. R., Wu, A. H., Yang, H., Brewster, W., Ziogas, A., Houlston, R., Tomlinson, I., Whittemore, A. S., Rossing, M. A., Ponder, B. A., Pearce, C. L., Ness, R. B., Menon, U., Kjaer, S. K., Gronwald, J., Garcia-Closas, M., Fasching, P. A., Easton, D. F., Chenevix-Trench, G., Berchuck, A., Pharoah, P. D., Gayther, S. A. 2009; 41 (9): 996-U60

  Abstract

  Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes explain less than half the excess familial risk. We performed a genome-wide association study (GWAS) to identify common ovarian cancer susceptibility alleles. We evaluated 507,094 SNPs genotyped in 1,817 cases and 2,353 controls from the UK and approximately 2 million imputed SNPs. We genotyped the 22,790 top ranked SNPs in 4,274 cases and 4,809 controls of European ancestry from Europe, USA and Australia. We identified 12 SNPs at 9p22 associated with disease risk (P < 10(-8)). The most significant SNP (rs3814113; P = 2.5 x 10(-17)) was genotyped in a further 2,670 ovarian cancer cases and 4,668 controls, confirming its association (combined data odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.79-0.86, P(trend) = 5.1 x 10(-19)). The association differs by histological subtype, being strongest for serous ovarian cancers (OR 0.77, 95% CI 0.73-0.81, P(trend) = 4.1 x 10(-21)).

  View details for DOI 10.1038/ng.424

  View details for Web of Science ID 000269382100011

  View details for PubMedID 19648919

  View details for PubMedCentralID PMC2844110

• Common variants on chromosome 6p22.1 are associated with schizophrenia NATURE Shi, J., Levinson, D. F., Duan, J., Sanders, A. R., Zheng, Y., Pe'er, I., Dudbridge, F., Holmans, P. A., Whittemore, A. S., Mowry, B. J., Olincy, A., Amin, F., Cloninger, C. R., Silverman, J. M., Buccola, N. G., Byerley, W. F., Black, D. W., Crowe, R. R., Oksenberg, J. R., Mirel, D. B., Kendler, K. S., Freedman, R., Gejman, P. V. 2009; 460 (7256): 753-757

  Abstract

  Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5-1%, with high heritability (80-85%) and complex transmission. Recent studies implicate rare, large, high-penetrance copy number variants in some cases, but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 x 10(-9)). This region includes a histone gene cluster and several immunity-related genes--possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms.

  View details for DOI 10.1038/nature08192

  View details for PubMedID 19571809

• BRCA1 and BRCA2 mutation carriers in the Breast Cancer Family Registry: an open resource for collaborative research BREAST CANCER RESEARCH AND TREATMENT Neuhausen, S. L., Ozcelik, H., Southey, M. C., John, E. M., Godwin, A. K., Chung, W., Iriondo-Perez, J., Miron, A., Santella, R. M., Whittemore, A., Andrulis, I. L., Buys, S. S., Daly, M. B., Hopper, J. L., Seminara, D., Senie, R. T., Terry, M. B. 2009; 116 (2): 379-386

  Abstract

  The Breast Cancer Family Registry is a resource for interdisciplinary and translational studies of the genetic epidemiology of breast cancer. This resource is available to researchers worldwide for collaborative studies. Herein, we report the results of testing for germline mutations in BRCA1 and BRCA2. We have tested 4,531 probands for mutations in BRCA1 and 4,084 in BRCA2. Deleterious mutations in BRCA1 and BRCA2 were identified for 9.8% of probands tested [233/4,531 (5.1%) for BRCA1 and 193/4,084 (4.7%) for BRCA2]. Of 1,385 Ashkenazi Jewish women tested for only the three founder mutations, 17.4% carried a deleterious mutation. In total, from the proband and subsequent family testing, 1,360 female mutation carriers (788 in BRCA1, 566 in BRCA2, 6 in both BRCA1 and BRCA2) have been identified. The value of the resource has been greatly enhanced by determining the germline BRCA1 and BRCA2 mutation statuses of nearly 6,000 probands.

  View details for DOI 10.1007/s10549-008-0153-8

  View details for Web of Science ID 000266988000018

  View details for PubMedID 18704680

  View details for PubMedCentralID PMC2775077

• Association between Common Germline Genetic Variation in 94 Candidate Genes or Regions and Risks of Invasive Epithelial Ovarian Cancer PLOS ONE Quaye, L., Tyrer, J., Ramus, S. J., Song, H., Wozniak, E., DiCioccio, R. A., McGuire, V., Hogdall, E., Hogdall, C., Blaakaer, J., Goode, E. L., Schildkraut, J. M., Easton, D. F., Krueger-Kjaer, S., Whittemore, A. S., Gayther, S. A., Pharoah, P. D. 2009; 4 (6)

  Abstract

  Recent studies have identified several single nucleotide polymorphisms (SNPs) in the population that are associated with variations in the risks of many different diseases including cancers such as breast, prostate and colorectal. For ovarian cancer, the known highly penetrant susceptibility genes (BRCA1 and BRCA2) are probably responsible for only 40% of the excess familial ovarian cancer risks, suggesting that other susceptibility genes of lower penetrance exist.We have taken a candidate approach to identifying moderate risk susceptibility alleles for ovarian cancer. To date, we have genotyped 340 SNPs from 94 candidate genes or regions, in up to 1,491 invasive epithelial ovarian cancer cases and 3,145 unaffected controls from three different population based studies from the UK, Denmark and USA.After adjusting for population stratification by genomic control, 18 SNPs (5.3%) were significant at the 5% level, and 5 SNPs (1.5%) were significant at the 1% level. The most significant association was for the SNP rs2107425, located on chromosome 11p15.5, which has previously been identified as a susceptibility allele for breast cancer from a genome wide association study (P-trend = 0.0012). When SNPs/genes were stratified into 7 different pathways or groups of validation SNPs, the breast cancer associated SNPs were the only group of SNPs that were significantly associated with ovarian cancer risk (P-heterogeneity = 0.0003; P-trend = 0.0028; adjusted (for population stratification) P-trend = 0.006). We did not find statistically significant associations when the combined data for all SNPs were analysed using an admixture maximum likelihood (AML) experiment-wise test for association (P-heterogeneity = 0.051; P-trend = 0.068).These data suggest that a proportion of the SNPs we evaluated were associated with ovarian cancer risk, but that the effect sizes were too small to detect associations with individual SNPs.

  View details for DOI 10.1371/journal.pone.0005983

  View details for Web of Science ID 000267237400009

  View details for PubMedID 19543528

• Association between invasive ovarian cancer susceptibility and 11 best candidate SNPs from breast cancer genome-wide association study HUMAN MOLECULAR GENETICS Song, H., Ramus, S. J., Kjaer, S. K., DiCioccio, R. A., Chenevix-Trench, G., Pearce, C. L., Hogdall, E., Whittemore, A. S., McGuire, V., Hogdall, C., Blaakaer, J., Wu, A. H., Van den Berg, D. J., Stram, D. O., Menon, U., Gentry-Maharaj, A., Jacobs, I. J., Webb, P. M., Beesley, J., Chen, X., Rossing, M. A., Doherty, J. A., Chang-Claude, J., Wang-Gohrke, S., Goodman, M. T., Lurie, G., Thompson, P. J., Carney, M. E., Ness, R. B., Moysich, K., Goode, E. L., Vierkant, R. A., Cunningham, J. M., Anderson, S., Schildkraut, J. M., Berchuck, A., Iversen, E. S., Moorman, P. G., Garcia-Closas, M., Chanock, S., Lissowska, J., Brinton, L., Anton-Culver, H., Ziogas, A., Brewster, W. R., Ponder, B. A., Easton, D. F., Gayther, S. A., Pharoah, P. D. 2009; 18 (12): 2297-2304

  Abstract

  Because both ovarian and breast cancer are hormone-related and are known to have some predisposition genes in common, we evaluated 11 of the most significant hits (six with confirmed associations with breast cancer) from the breast cancer genome-wide association study for association with invasive ovarian cancer. Eleven SNPs were initially genotyped in 2927 invasive ovarian cancer cases and 4143 controls from six ovarian cancer case-control studies. Genotype frequencies in cases and controls were compared using a likelihood ratio test in a logistic regression model stratified by study. Initially, three SNPs (rs2107425 in MRPL23, rs7313833 in PTHLH, rs3803662 in TNRC9) were weakly associated with ovarian cancer risk and one SNP (rs4954956 in NXPH2) was associated with serous ovarian cancer in non-Hispanic white subjects (P-trend < 0.1). These four SNPs were then genotyped in an additional 4060 cases and 6308 controls from eight independent studies. Only rs4954956 was significantly associated with ovarian cancer risk both in the replication study and in combined analyses. This association was stronger for the serous histological subtype [per minor allele odds ratio (OR) 1.07 95% CI 1.01-1.13, P-trend = 0.02 for all types of ovarian cancer and OR 1.14 95% CI 1.07-1.22, P-trend = 0.00017 for serous ovarian cancer]. In conclusion, we found that rs4954956 was associated with increased ovarian cancer risk, particularly for serous ovarian cancer. However, none of the six confirmed breast cancer susceptibility variants we tested was associated with ovarian cancer risk. Further work will be needed to identify the causal variant associated with rs4954956 or elucidate its function.

  View details for DOI 10.1093/hmg/ddp138

  View details for Web of Science ID 000266349400017

  View details for PubMedID 19304784

  View details for PubMedCentralID PMC2685754

• Performance of Prediction Models for BRCA Mutation Carriage in Three Racial/Ethnic Groups: Findings from the Northern California Breast Cancer Family Registry CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Kurian, A. W., Gong, G. D., John, E. M., Miron, A., Felberg, A., Phipps, A. I., West, D. W., Whittemore, A. S. 2009; 18 (4): 1084-1091

  Abstract

  Patients with early-onset breast and/or ovarian cancer frequently wish to know if they inherited a mutation in one of the cancer susceptibility genes, BRCA1 or BRCA2. Accurate carrier prediction models are needed to target costly testing. Two widely used models, BRCAPRO and BOADICEA, were developed using data from non-Hispanic Whites (NHW), but their accuracies have not been evaluated in other racial/ethnic populations.We evaluated the BRCAPRO and BOADICEA models in a population-based series of African American, Hispanic, and NHW breast cancer patients tested for BRCA1 and BRCA2 mutations. We assessed model calibration by evaluating observed versus predicted mutations and attribute diagrams, and model discrimination using areas under the receiver operating characteristic curves.Both models were well-calibrated within each racial/ethnic group, with some exceptions. BOADICEA overpredicted mutations in African Americans and older NHWs, and BRCAPRO underpredicted in Hispanics. In all racial/ethnic groups, the models overpredicted in cases whose personal and family histories indicated >80% probability of carriage. The two models showed similar discrimination in each racial/ethnic group, discriminating least well in Hispanics. For example, BRCAPRO's areas under the receiver operating characteristic curves were 83% (95% confidence interval, 63-93%) for NHWs, compared with 74% (59-85%) for African Americans and 58% (45-70%) for Hispanics.The poor performance of the model for Hispanics may be due to model misspecification in this racial/ethnic group. However, it may also reflect racial/ethnic differences in the distributions of personal and family histories among breast cancer cases in the Northern California population.

  View details for DOI 10.1158/1055-9965.EPI-08-1090

  View details for PubMedID 19336551

• Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer BRITISH JOURNAL OF CANCER Quaye, L., Song, H., Ramus, S. J., Gentry-Maharaj, A., Hogdall, E., DiCioccio, R. A., McGuire, V., Wu, A. H., Van den Berg, D. J., Pike, M. C., Wozniak, E., Doherty, J. A., Rossing, M. A., Ness, R. B., Moysich, K. B., Hogdall, C., Blaakaer, J., Easton, D. F., Ponder, B. A., Jacobs, I. J., Menon, U., Whittemore, A. S., Kruger-Kjaer, S., Pearce, C. L., Pharoah, P. D., Gayther, S. A. 2009; 100 (6): 993-1001

  Abstract

  Low-moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in approximately 1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P(dominant)=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case-control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80-0.99) and remained statistically significant (P(dominant)=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P(global)=0.034) and a haplotype in BRAF that had a protective effect (P(global)=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC.

  View details for DOI 10.1038/sj.bjc.6604947

  View details for Web of Science ID 000264306400019

  View details for PubMedID 19240718

• Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer CANCER RESEARCH Schildkraut, J. M., Goode, E. L., Clyde, M. A., Iversen, E. S., Moorman, P. G., Berchuck, A., Marks, J. R., Lissowska, J., Brinton, L., Peplonska, B., Cunningham, J. M., Vierkant, R. A., Rider, D. N., Chenevix-Trench, G., Webb, P. M., Beesley, J., Chen, X., Phelan, C., Sutphen, R., Sellers, T. A., Pearce, L., Wu, A. H., Van Den Berg, D., Conti, D., Elund, C. K., Anderson, R., Goodman, M. T., Lurie, G., Carney, M. E., Thompson, P. J., Gayther, S. A., Ramus, S. J., Jacobs, I., Kjaer, S. K., Hogdall, E., Blaakaer, J., Hogdall, C., Easton, D. F., Song, H., Pharoah, P. D., Whittemore, A. S., McGuire, V., Quaye, L., Anton-Culver, H., Ziogas, A., Terry, K. L., Cramer, D. W., Hankinson, S. E., Tworoger, S. S., Calingaert, B., Chanock, S., Sherman, M., Garcia-Closas, M. 2009; 69 (6): 2349-2357

  Abstract

  The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP) in the TP53 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (OR), 95% probability intervals (PI), and Bayes factors (BF) for genotype associations. Five SNPs showed significant associations with risk in one or more of the discovery investigations and were followed up by OCAC. Mixed effects analysis confirmed associations with serous invasive cancers for two correlated (r(2) = 0.62) SNPs: rs2287498 (median per allele OR, 1.30; 95% PI, 1.07-1.57) and rs12951053 (median per allele OR, 1.19; 95% PI, 1.01-1.38). Analyses of other histologic subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated with common variants in the TP53 region.

  View details for DOI 10.1158/0008-5472.CAN-08-2902

  View details for Web of Science ID 000264541300027

  View details for PubMedID 19276375

  View details for PubMedCentralID PMC2666150

• Candidate Gene Analysis Using Imputed Genotypes: Cell Cycle Single-Nucleotide Polymorphisms and Ovarian Cancer Risk CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Goode, E. L., Fridley, B. L., Vierkant, R. A., Cunningham, J. M., Phelan, C. M., Anderson, S., Rider, D. N., White, K. L., Pankratz, V. S., Song, H., Hogdall, E., Kjaer, S. K., Whittemore, A. S., DiCioccio, R., Ramus, S. J., Gayther, S. A., Schildkraut, J. M., Pharaoh, P. P., Sellers, T. A. 2009; 18 (3): 935-944

  Abstract

  Polymorphisms in genes critical to cell cycle control are outstanding candidates for association with ovarian cancer risk; numerous genes have been interrogated by multiple research groups using differing tagging single-nucleotide polymorphism (SNP) sets. To maximize information gleaned from existing genotype data, we conducted a combined analysis of five independent studies of invasive epithelial ovarian cancer. Up to 2,120 cases and 3,382 controls were genotyped in the course of two collaborations at a variety of SNPs in 11 cell cycle genes (CDKN2C, CDKN1A, CCND3, CCND1, CCND2, CDKN1B, CDK2, CDK4, RB1, CDKN2D, and CCNE1) and one gene region (CDKN2A-CDKN2B). Because of the semi-overlapping nature of the 123 assayed tagging SNPs, we performed multiple imputation based on fastPHASE using data from White non-Hispanic study participants and participants in the international HapMap Consortium and National Institute of Environmental Health Sciences SNPs Program. Logistic regression assuming a log-additive model was done on combined and imputed data. We observed strengthened signals in imputation-based analyses at several SNPs, particularly CDKN2A-CDKN2B rs3731239; CCND1 rs602652, rs3212879, rs649392, and rs3212891; CDK2 rs2069391, rs2069414, and rs17528736; and CCNE1 rs3218036. These results exemplify the utility of imputation in candidate gene studies and lend evidence to a role of cell cycle genes in ovarian cancer etiology, suggest a reduced set of SNPs to target in additional cases and controls.

  View details for DOI 10.1158/1055-9965.EPI-08-0860

  View details for Web of Science ID 000264226100034

  View details for PubMedID 19258477

• Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium BRITISH JOURNAL OF CANCER Pearce, C. L., Near, A. M., Van den Berg, D. J., Ramus, S. J., Gentry-Maharaj, A., Menon, U., Gayther, S. A., Anderson, A. R., Edlund, C. K., Wu, A. H., Chen, X., Beesley, J., Webb, P. M., Holt, S. K., Chen, C., Doherty, J. A., Rossing, M. A., Whittemore, A. S., McGuire, V., DiCioccio, R. A., Goodman, M. T., Lurie, G., Carney, M. E., Wilkens, L. R., Ness, R. B., Moysich, K. B., Edwards, R., JENNISON, E., Kjaer, S. K., Hogdall, E., Hogdall, C. K., Goode, E. L., Sellers, T. A., Vierkant, R. A., Cunningham, J. C., Schildkraut, J. M., Berchuck, A., Moorman, P. G., Iversen, E. S., Cramer, D. W., Terry, K. L., Vitonis, A. F., Titus-Ernstoff, L., Song, H., Pharoah, P. D., Spurdle, A. B., Anton-Culver, H., Ziogas, A., Brewster, W., Galitovskiy, V., Chenevix-Trench, G. 2009; 100 (2): 412-420

  Abstract

  The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

  View details for DOI 10.1038/sj.bjc.6604820

  View details for Web of Science ID 000262637800028

  View details for PubMedID 19127255

  View details for PubMedCentralID PMC2634713

• Polymorphism in the IL18 Gene and Epithelial Ovarian Cancer in Non-Hispanic White Women CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Palmieri, R. T., Wilson, M. A., Iversen, E. S., Clyde, M. A., Calingaert, B., Moorman, P. G., Poole, C., Anderson, A. R., Anderson, S., Anton-Culver, H., Beesley, J., Hogdall, E., Brewster, W., Carney, M. E., Chen, X., Chenevix-Trench, G., Chang-Claude, J., Cunningham, J. M., DiCioccio, R. A., Doherty, J. A., Easton, D. F., Edlund, C. K., Gayther, S. A., Gentry-Maharaj, A., Goode, E. L., Goodman, M. T., Kjaer, S. K., Hogdall, C. K., Hopkins, M. P., Jenison, E. L., Blaakaer, J., Lurie, G., McGuire, V., Menon, U., Moysich, K. B., Ness, R. B., Pearce, C. L., Pharoah, P. D., Pike, M. C., Ramus, S. J., Rossing, M. A., Song, H., Terada, K. Y., VanDenBerg, D., Vierkant, R. A., Wang-Gohrke, S., Webb, P. M., Whittemore, A. S., Wu, A. H., Ziogas, A., Berchuck, A., Schildkraut, J. M. 2008; 17 (12): 3567-3572

  Abstract

  Over 22,000 cases of ovarian cancer were diagnosed in 2007 in the United States, but only a fraction of them can be attributed to mutations in highly penetrant genes such as BRCA1. To determine whether low-penetrance genetic variants contribute to ovarian cancer risk, we genotyped 1,536 single nucleotide polymorphisms (SNP) in several candidate gene pathways in 848 epithelial ovarian cancer cases and 798 controls in the North Carolina Ovarian Cancer Study (NCO) using a customized Illumina array. The inflammation gene interleukin-18 (IL18) showed the strongest evidence for association with epithelial ovarian cancer in a gene-by-gene analysis (P = 0.002) with a <25% chance of being a false-positive finding (q value = 0.240). Using a multivariate model search algorithm over 11 IL18 tagging SNPs, we found that the association was best modeled by rs1834481. Further, this SNP uniquely tagged a significantly associated IL18 haplotype and there was an increased risk of epithelial ovarian cancer per rs1834481 allele (odds ratio, 1.24; 95% confidence interval, 1.06-1.45). In a replication stage, 12 independent studies from the Ovarian Cancer Association Consortium (OCAC) genotyped rs1834481 in an additional 5,877 cases and 7,791 controls. The fixed effects estimate per rs1834481 allele was null (odds ratio, 0.99; 95% confidence interval, 0.94-1.05) when data from the 12 OCAC studies were combined. The effect estimate remained unchanged with the addition of the initial North Carolina Ovarian Cancer Study data. This analysis shows the importance of consortia, like the OCAC, in either confirming or refuting the validity of putative findings in studies with smaller sample sizes. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3567-72).

  View details for DOI 10.1158/1055-9965.EPI-08-0548

  View details for Web of Science ID 000261724000038

  View details for PubMedID 19064572

  View details for PubMedCentralID PMC2664299

• Association Study of Prostate Cancer Susceptibility Variants with Risks of Invasive Ovarian, Breast, and Colorectal Cancer CANCER RESEARCH Song, H., Koessler, T., Ahmed, S., Ramus, S. J., Kjaer, S. K., DiCioccio, R. A., Wozniak, E., Hogdall, E., Whittemore, A. S., McGuire, V., Ponder, B. A., Turnbull, C., Hines, S., Rahman, N., Eeles, R. A., Easton, D. F., Gayther, S. A., Dunning, A. M., Pharoah, P. D. 2008; 68 (21): 8837-8842

  Abstract

  Several prostate cancer susceptibility loci have recently been identified by genome-wide association studies. These loci are candidates for susceptibility to other epithelial cancers. The aim of this study was to test these tag single nucleotide polymorphisms (SNP) for association with invasive ovarian, colorectal, and breast cancer. Twelve prostate cancer-associated tag SNPs were genotyped in ovarian (2,087 cases/3,491 controls), colorectal (2,148 cases/2,265 controls) and breast (first set, 4,339 cases/4,552 controls; second set, 3,800 cases/3,995 controls) case-control studies. The primary test of association was a comparison of genotype frequencies between cases and controls, and a test for trend stratified by study where appropriate. Genotype-specific odds ratios (OR) were estimated by logistic regression. SNP rs2660753 (chromosome 3p12) showed evidence of association with ovarian cancer [per minor allele OR, 1.19; 95% confidence interval (95% CI), 1.04-1.37; P(trend) = 0.012]. This association was stronger for the serous histologic subtype (OR, 1.29; 95% CI, 1.09-1.53; P = 0.003). SNP rs7931342 (chromosome 11q13) showed some evidence of association with breast cancer (per minor allele OR, 0.95; 95% CI, 0.91-0.99; P(trend) = 0.028). This association was somewhat stronger for estrogen receptor-positive tumors (OR, 0.92; 95% CI, 0.87-0.98; P = 0.011). None of these tag SNPs were associated with risk of colorectal cancer. In conclusion, loci associated with risk of prostate cancer may also be associated with ovarian and breast cancer susceptibility. However, the effects are modest and warrant replication in larger studies.

  View details for DOI 10.1158/0008-5472.CAN-08-2363

  View details for Web of Science ID 000260698900025

  View details for PubMedID 18974127

  View details for PubMedCentralID PMC2666188

• Performance of BRCA1/2 mutation prediction models in Asian Americans 43rd Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Kurian, A. W., Gong, G. D., Chun, N. M., Mills, M. A., Staton, A. D., Kingham, K. E., Crawford, B. B., Lee, R., Chan, S., Donlon, S. S., Ridge, Y., Panabaker, K., West, D. W., Whittemore, A. S., Ford, J. M. AMER SOC CLINICAL ONCOLOGY. 2008: 4752–58

  Abstract

  There are established differences in breast cancer epidemiology between Asian and white individuals, but little is known about hereditary breast cancer in Asian populations. Although increasing numbers of Asian individuals are clinically tested for BRCA1/2 mutations, it is not known whether computer models that predict mutations work accurately in Asian individuals. We compared the performance in Asian and white individuals of two widely used BRCA1/2 mutation prediction models, BRCAPRO and Myriad II.We evaluated BRCAPRO and Myriad II in 200 Asian individuals and a matched control group of 200 white individuals who were tested for BRCA1/2 mutations at four cancer genetics clinics, by comparing numbers of observed versus predicted mutation carriers and by evaluating area under the receiver operating characteristic curve (AUC) for each model.BRCAPRO and Myriad II accurately predicted the number of white BRCA1/2 mutation carriers (25 observed v 24 predicted by BRCAPRO; 25 predicted by Myriad II, P > or = .69), but underpredicted Asian carriers by two-fold (49 observed v 25 predicted by BRCAPRO; 26 predicted by Myriad II; P < or = 3 x 10(-7)). For BRCAPRO, this racial difference reflects substantial underprediction of Asian BRCA2 mutation carriers (26 observed v 4 predicted; P = 1 x 10(-30)); for Myriad II, separate mutation predictions were not available. For both models, AUCs were nonsignificantly lower in Asian than white individuals, suggesting less accurate discrimination between Asian carriers and noncarriers.Both BRCAPRO and Myriad II underestimated the proportion of BRCA1/2 mutation carriers, and discriminated carriers from noncarriers less well, in Asian compared with white individuals.

  View details for DOI 10.1200/JCO.2008.16.8310

  View details for PubMedID 18779604

• Mismatch repair gene polymorphisms and survival in invasive ovarian cancer patients EUROPEAN JOURNAL OF CANCER Mann, A., Hogdall, E., Ramus, S. J., DiCioccio, R. A., Hogdall, C., Quaye, L., McGuire, V., Whittemore, A. S., Shah, M., Greenberg, D., Easton, D. F., Ponder, B. A., Kjaer, S. K., Gayther, S. A., Thompson, D. J., Pharoah, P. D., Song, H. 2008; 44 (15): 2259-2265

  Abstract

  Inherited genetic factors may help partially explain variability of survival length amongst ovarian cancer patients. Of particular interest are genes involved in DNA repair, specifically those involved in mismatch repair (MMR). The aim of this study was to investigate the possible association between the common variants in MMR genes and invasive ovarian cancer overall survival.We examined associations between 44 variants that tag the known common variants (minor allele frequency 0.05) in seven MMR genes (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2) and survival of invasive ovarian cancer patients in three case-control studies from United Kingdom (UK), Denmark and California of United States of America (USA). DNA from up to 1495 women were genotyped. The genotypes of each polymorphism were tested for association with survival using Cox regression analysis stratified by study. A nominally significant association (P=0.04) between genotype and ovarian cancer survival was observed for rs2228006 in PMS2. The per-rare allele hazard ratio (HR 95%CI) was 0.84 (0.71-0.99), however, it was not significant after adjusting for multiple covariants (P=0.47). When the analyses were restricted to serous type ovarian cancer, two SNPs showed marginal significant associations; the per-rare allele HR was 1.3 (1.05-1.6) (P=0.02) for rs1799977 in MLH1 and 1.4 (1.03-1.9) (P=0.04) for rs6151662 in MSH3. Neither was significant after adjusting for multiple covariants.It is unlikely that common variants in the MMR pathways examined have moderate effects on survival after diagnosis with ovarian cancer. Much larger studies would be needed to exclude common variants with small effects.

  View details for DOI 10.1016/j.ejca.2008.07.010

  View details for Web of Science ID 000261020800025

  View details for PubMedID 18723338

• The effects of common genetic variants in oncogenes on ovarian cancer survival CLINICAL CANCER RESEARCH Quaye, L., Gayther, S. A., Ramus, S. J., Di Cioccio, R. A., McGuire, V., Hogdall, E., Hogdall, C., Blaakr, J., Easton, D. F., Ponder, B. A., Jacobs, I., Kjaer, S. K., Whittemore, A. S., Pearce, C. L., Pharoah, P. D., Song, H. 2008; 14 (18): 5833-5839

  Abstract

  The 5-year survival rate for invasive epithelial ovarian cancer is <35%. It has been suggested that common, germline genetic variation may influence survival after cancer diagnoses, which might enable the prediction of response to treatment and survival in the clinical setting. The aim of this study was to evaluate associations between common germline genetic variants in the oncogenes BRAF, ERBB2, KRAS, NMI, and PIK3CA, and survival after a diagnosis of epithelial ovarian cancer.We evaluated the association between 34 tagging single nucleotide polymorphisms and survival in 1,480 cases of invasive epithelial ovarian cancer cases from three different studies. Cox regression analysis, stratified by study, was used to estimate per rare allele hazard ratios (HR).The minor allele rs6944385 in BRAF was significantly associated with poor survival [HR, 1.19; 95% confidence intervals (95% CI), 1.02-1.39; P = 0.024]. The association remained after adjusting for prognostic factors (adjusted HR, 1.20; 95 CI, 1.03-1.40; P = 0.018). A haplotype of BRAF was also associated with poor survival (HR, 1.24; 95% CI, 1.02-1.51; P = 0.029) and was more significant after adjustment (HR, 1.44; 95% CI, 1.15-1.81; P = 0.001). We also found evidence of an association between a KRAS haplotype and poor survival in serous subtype (HR, 1.69; 95% CI, 1.21-2.38; P = 0.002), but this was no longer significant after adjustment. Finally, when analyses were restricted to the serous histologic subtype, the rare allele rs10842513 in KRAS, was associated with poor survival (HR, 1.40; 95% CI, 1.10-1.78; P = 0.007).Common genetic variants in the BRAF and KRAS oncogenes may be important in the prediction of survival in patients with invasive epithelial ovarian cancer.

  View details for DOI 10.1158/1078-0432.CCR-08-0819

  View details for Web of Science ID 000259347600027

  View details for PubMedID 18794094

• Facility factors dominate the ability to achieve target haemoglobin levels in haemodialysis patients NEPHROLOGY DIALYSIS TRANSPLANTATION Chan, K. E., Lafayette, R. A., Whittemore, A. S., Hlatky, M. A., Moran, J. 2008; 23 (9): 2948-2956

  Abstract

  Our objective was to determine whether patient factors, processes of care and measures of erythropoietin (EPO) responsiveness were associated with successful anemia management at the individual patient level.We retrospectively reviewed laboratory and demographic data from 1499 patients receiving hemodialysis in 15 units operated by the same dialysis provider. We performed univariate and multivariate logistic regression analysis to determine predictors of an average 3-month hemoglobin level below or above the target interval of 11.0-12.5 g/dL. To explain the effect of facility on anemia performance, we calculated correlations between measures of EPO responsiveness and the probability of achieving the target interval by facility.Patients above the target hemoglobin range demonstrated an association with parathyroid hormone (PTH) (OR = 0.96 per 100 pg/mL increase), female gender (OR = 0.68), EPO protocol use (OR = 0.94 per 10% increase in use) and facility (range of OR = 0.26-2.59 for 15 participating sites). Patients below the target hemoglobin range demonstrated an association with CRP (OR = 1.10 per mg/L increase), PTH (OR = 1.07 per 100 pg/mL increase), iron deficiency (OR = 1.07 per 10% increase), EPO protocol use (OR = 0.89 per 10% increase in use), iron protocol use (OR = 0.93 per 10% increase in use) and facility (range of OR = 0.58-3.41 over 15 units). EPO index (r = 0.71), EPO dose (r = 0.73), hemoglobin (r = -0.60) and EPO per unit weight (r = 0.76) were significantly correlated with the probability of achieving the target hemoglobin by facility.The facility significantly influences the outcome of anemia management in patients with ESRD. In part, this is due to the patients' EPO responsiveness, which may be influenced by facility care patterns.

  View details for DOI 10.1093/ndt/gfn172

  View details for Web of Science ID 000259372400039

  View details for PubMedID 18469314

• Veterans affairs cooperative studies program study 553: Chemotherapy after prostatectomy, a phase III randomized study of prostatectomy versus prostatectomy with adjuvant docetaxel for patients with high-risk, localized prostate cancer UROLOGY Montgomery, B., Lavori, P., Garzotto, M., Lee, K., Brophy, M., Thaneemit-Chen, S., Kelly, W., Basler, J., Ringer, R., Yu, W., Whittemore, A., Lin, D. W. 2008; 72 (3): 474-480

  View details for DOI 10.1016/j.urology.2008.02.050

  View details for Web of Science ID 000259853800003

  View details for PubMedID 18407333

• Consortium analysis of 7 candidate SNPs for ovarian cancer INTERNATIONAL JOURNAL OF CANCER Ramus, S. J., Vierkant, R. A., Johnatty, S. E., Pike, M. C., Van den Berg, D. J., Wu, A. H., Pearce, C. L., Menon, U., Gentry-Maharaj, A., Gayther, S. A., DiCioccio, R. A., McGuire, V., Whittemore, A. S., Song, H., Easton, D. F., Pharoah, P. D., Garcia-Closas, M., Chanock, S., Lissowska, J., Brinton, L., Terry, K. L., Cramer, D. W., Tworoger, S. S., Hankinson, S. E., Berchuck, A., Moorman, P. G., Schildkraut, J. M., Cunningham, J. M., Liebow, M., Kjaer, S. K., Hogdall, E., Hogdall, C., Blaakaer, J., Ness, R. B., Moysich, K. B., Edwards, R. P., Carney, M. E., Lurie, G., Goodman, M. T., Wang-Gohrke, S., Kropp, S., Chang-Claude, J., Webb, P. M., Chen, X., Beesley, J., Chenevix-Trench, G., Goode, E. L. 2008; 123 (2): 380-388

  Abstract

  The Ovarian Cancer Association Consortium selected 7 candidate single nucleotide polymorphisms (SNPs), for which there is evidence from previous studies of an association with variation in ovarian cancer or breast cancer risks. The SNPs selected for analysis were F31I (rs2273535) in AURKA, N372H (rs144848) in BRCA2, rs2854344 in intron 17 of RB1, rs2811712 5' flanking CDKN2A, rs523349 in the 3' UTR of SRD5A2, D302H (rs1045485) in CASP8 and L10P (rs1982073) in TGFB1. Fourteen studies genotyped 4,624 invasive epithelial ovarian cancer cases and 8,113 controls of white non-Hispanic origin. A marginally significant association was found for RB1 when all studies were included [ordinal odds ratio (OR) 0.88 (95% confidence interval (CI) 0.79-1.00) p = 0.041 and dominant OR 0.87 (95% CI 0.76-0.98) p = 0.025]; when the studies that originally suggested an association were excluded, the result was suggestive although no longer statistically significant (ordinal OR 0.92, 95% CI 0.79-1.06). This SNP has also been shown to have an association with decreased risk in breast cancer. There was a suggestion of an association for AURKA, when one study that caused significant study heterogeneity was excluded [ordinal OR 1.10 (95% CI 1.01-1.20) p = 0.027; dominant OR 1.12 (95% CI 1.01-1.24) p = 0.03]. The other 5 SNPs in BRCA2, CDKN2A, SRD5A2, CASP8 and TGFB1 showed no association with ovarian cancer risk; given the large sample size, these results can also be considered to be informative. These null results for SNPs identified from relatively large initial studies shows the importance of replicating associations by a consortium approach.

  View details for DOI 10.1002/ijc.23448

  View details for Web of Science ID 000256760300018

  View details for PubMedID 18431743

  View details for PubMedCentralID PMC2667795

• Multiple loci with different cancer specificities within the 8q24 gene desert JOURNAL OF THE NATIONAL CANCER INSTITUTE Ghoussaini, M., Song, H., Koessler, T., Al Olama, A. A., Kote-Jarai, Z., Driver, K. E., Pooley, K. A., Ramus, S. J., Kjaer, S. K., Hogdall, E., DiCioccio, R. A., Whittemore, A. S., Gayther, S. A., Giles, G. G., Guy, M., Edwards, S. M., Morrison, J., Donovan, J. L., Hamdy, F. C., Dearnaley, D. P., Ardern-Jones, A. T., Hall, A. L., O'Brien, L. T., Gehr-Swain, B. N., Wilkinson, R. A., Brown, P. M., Hopper, J. L., Neal, D. E., Pharoah, P. D., Ponder, B. A., Eeles, R. A., Easton, D. F., Dunning, A. M. 2008; 100 (13): 962-966

  Abstract

  Recent studies based on genome-wide association, linkage, and admixture scan analysis have reported associations of various genetic variants in 8q24 with susceptibility to breast, prostate, and colorectal cancer. This locus lies within a 1.18-Mb region that contains no known genes but is bounded at its centromeric end by FAM84B and at its telomeric end by c-MYC, two candidate cancer susceptibility genes. To investigate the associations of specific loci within 8q24 with specific cancers, we genotyped the nine previously reported cancer-associated single-nucleotide polymorphisms across the region in four case-control sets of prostate (1854 case subjects and 1894 control subjects), breast (2270 case subjects and 2280 control subjects), colorectal (2299 case subjects and 2284 control subjects), and ovarian (1975 case subjects and 3411 control subjects) cancer. Five different haplotype blocks within this gene desert were specifically associated with risks of different cancers. One block was solely associated with risk of breast cancer, three others were associated solely with the risk of prostate cancer, and a fifth was associated with the risk of prostate, colorectal, and ovarian cancer, but not breast cancer. We conclude that there are at least five separate functional variants in this region.

  View details for DOI 10.1093/jnci/djn190

  View details for Web of Science ID 000257403100010

  View details for PubMedID 18577746

• Significance levels for studies with correlated test statistics BIOSTATISTICS Shi, J., Levinson, D. F., Whittemore, A. S. 2008; 9 (3): 458-466

  Abstract

  When testing large numbers of null hypotheses, one needs to assess the evidence against the global null hypothesis that none of the hypotheses is false. Such evidence typically is based on the test statistic of the largest magnitude, whose statistical significance is evaluated by permuting the sample units to simulate its null distribution. Efron (2007) has noted that correlation among the test statistics can induce substantial interstudy variation in the shapes of their histograms, which may cause misleading tail counts. Here, we show that permutation-based estimates of the overall significance level also can be misleading when the test statistics are correlated. We propose that such estimates be conditioned on a simple measure of the spread of the observed histogram, and we provide a method for obtaining conditional significance levels. We justify this conditioning using the conditionality principle described by Cox and Hinkley (1974). Application of the method to gene expression data illustrates the circumstances when conditional significance levels are needed.

  View details for DOI 10.1093/biostatistics/kxm047

  View details for PubMedID 18089626

• Ovarian cysts and breast cancer: results from the Women's Contraceptive and Reproductive Experiences Study BREAST CANCER RESEARCH AND TREATMENT Knight, J. A., Lesosky, M., Blackmore, K. M., Voigt, L. F., Holt, V. L., Bernstein, L., Marchbanks, P. A., Burkman, R. T., Daling, J. R., Whittemore, A. S. 2008; 109 (1): 157-164

  Abstract

  A diagnosis of ovarian cysts is likely an indicator of hormonal milieu and thus may be related to breast cancer risk. Recent studies have reported an inverse relationship between prior ovarian cyst diagnosis and breast cancer risk. We evaluated this relationship in the Women's Contraceptive and Reproductive Experiences (CARE) Study, a population-based case-control study conducted in Atlanta, Detroit, Philadelphia, Los Angeles, and Seattle. Cases had first primary invasive breast cancer diagnosed between 1994 and 1998 at ages 35-64 years. African American women were over-sampled. Controls were identified through random digit dialling and were frequency matched to cases on centre, race, and five-year age group. A total of 4575 cases and 4682 controls were interviewed. We used unconditional logistic regression adjusted for age and study centre within racial groups to estimate the odds ratio (OR) and 95% confidence interval (CI) for the relationship between prior ovarian cysts and breast cancer. Ovarian cyst diagnosis was associated with a significantly reduced risk among Caucasians (OR=0.85, 95% CI 0.76-0.96) and among African Americans (OR=0.68, 95% CI 0.57-0.81). The association in Caucasians was not significant within subgroups defined by menopausal status, hormone use, or gynecological surgery while the OR estimates in African Americans were consistently lower and frequently significant. These data are consistent with the previously reported inverse association between ovarian cysts and breast cancer, but the evidence for a relationship was stronger in African Americans than Caucasians. Additional studies are required to determine the specific cyst type(s) responsible for the observed relationship.

  View details for DOI 10.1007/s10549-007-9634-4

  View details for Web of Science ID 000255031000016

  View details for PubMedID 17616808

• Effects of common germ-line genetic variation in cell cycle genes on ovarian cancer survival CLINICAL CANCER RESEARCH Song, H., Hogdall, E., Ramus, S. J., DiCioccio, R. A., Hogdall, C., Quaye, L., McGuire, V., Whittemore, A. S., Shah, M., Greenberg, D., Easton, D., Kjaer, S. K., Pharoah, P. D., Gayther, S. A. 2008; 14 (4): 1090-1095

  Abstract

  Somatic alterations have been shown to correlate with ovarian cancer prognosis and survival, but less is known about the effects on survival of common inherited genetic variation. Of particular interest are genes involved in cell cycle pathways, which regulate cell division and could plausibly influence clinical characteristics of multiple tumors types.We examined associations between common germ-line genetic variation in 14 genes involved in cell cycle pathway (CCND1, CCND2, CCND3, CCNE1, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, CDKN2D, CDK2, CDK4, CDK6, and RB1) and survival among women with invasive ovarian cancer participating in a multicenter case-control study from United Kingdom, Denmark, and United States. DNAs from up to 1,499 women were genotyped for 97 single-nucleotide polymorphisms that tagged the known common variants (minor allele frequency > or = 0.05) in these genes. The genotypes of each polymorphism were tested for association with survival by Cox regression analysis.A nominally statistically significant association between genotype and ovarian cancer survival was observed for polymorphisms in CCND2 and CCNE1. The per-allele hazard ratios (95% confidence intervals) were 1.16 (1.03-1.31; P = 0.02) for rs3217933, 1.14 (1.02-1.27; P = 0.024) for rs3217901, and 0.85 (0.73-1.00; P = 0.043) for rs3217862 in CCND2 and 1.39 (1.04-1.85; P = 0.033) for rs3218038 in CCNE1. However, these were not significant after adjusting for multiple hypothesis tests.It is unlikely that common variants in cell cycle pathways examined above associated with moderate effect in survival after diagnosis of ovarian cancer. Much larger studies will be needed to exclude common variants with small effects.

  View details for DOI 10.1158/1078-0432.CCR-07-1195

  View details for Web of Science ID 000253449700018

  View details for PubMedID 18281541

• Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the ovarian cancer association consortium pooled analysis BRITISH JOURNAL OF CANCER Pearce, C. L., Wu, A. H., Gayther, S. A., Bale, A. E., Beck, P. A., Beesley, J., Chanock, S., Cramer, D. W., DiCioccio, R., Edwards, R., Fredericksen, Z. S., Garcia-Closas, M., Goode, E. L., Green, A. C., Hartmann, L. C., Hogdall, E., Kjaer, S. K., Lissowska, J., McGuire, V., Modugno, F., Moysich, K., Ness, R. B., Ramus, S. J., Risch, H. A., Sellers, T. A., Song, H., Stram, D. O., Terry, K. L., Webb, P. M., Whiteman, D. C., Whittemore, A. S., Zheng, W., Pharoah, P. D., Chenevix-Trench, G., Pike, M. C., Schildkraut, J., Berchuck, A. 2008; 98 (2): 282-288

  Abstract

  There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case-control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3' variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case-control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and two-sided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01-1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases; OR=0.80, 95% CI 0.62-1.04, P=0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer.

  View details for DOI 10.1038/sj.bjc.6604170

  View details for Web of Science ID 000252933400007

  View details for PubMedID 18219286

• Prostate cancer risk in relation to insulin-like growth factor (IGF)-I and IGF-binding protein-3: A prospective multiethnic study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Borugian, M. J., Spinelli, J. J., Sun, Z., Kolonel, L. N., Oakley-Girvan, I., Pollak, M. D., Whittemore, A. S., Wu, A. H., Gallagher, R. P. 2008; 17 (1): 252-254

  View details for DOI 10.1158/1055-9965.EPI-07-2694

  View details for Web of Science ID 000252503900034

  View details for PubMedID 18199733

• Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION John, E. M., Miron, A., Gong, G., Phipps, A. I., Felberg, A., Li, F. P., West, D. W., Whittemore, A. S. 2007; 298 (24): 2869-2876

  Abstract

  Information on the prevalence of pathogenic BRCA1 mutation carriers in racial/ethnic minority populations is limited.To estimate BRCA1 carrier prevalence in Hispanic, African American, and Asian American female breast cancer patients compared with non-Hispanic white patients with and without Ashkenazi Jewish ancestry.We estimated race/ethnicity-specific prevalence of BRCA1 in a population-based, multiethnic series of female breast cancer patients younger than 65 years at diagnosis who were enrolled at the Northern California site of the Breast Cancer Family Registry during the period 1996-2005. Race/ethnicity and religious ancestry were based on self-report. Weighted estimates of prevalence and 95% confidence intervals (CIs) were based on Horvitz-Thompson estimating equations.Estimates of BRCA1 prevalence.Estimates of BRCA1 prevalence were 3.5% (95% CI, 2.1%-5.8%) in Hispanic patients (n = 393), 1.3% (95% CI, 0.6%-2.6%) in African American patients (n = 341), and 0.5% (95% CI, 0.1%-2.0%) in Asian American patients (n = 444), compared with 8.3% (95% CI, 3.1%-20.1%) in Ashkenazi Jewish patients (n = 41) and 2.2% (95% CI, 0.7%-6.9%) in other non-Hispanic white patients (n = 508). Prevalence was particularly high in young (<35 years) African American patients (5/30 patients [16.7%]; 95% CI, 7.1%-34.3%). 185delAG was the most common mutation in Hispanics, found in 5 of 21 carriers (24%).Among African American, Asian American, and Hispanic patients in the Northern California Breast Cancer Family Registry, the prevalence of BRCA1 mutation carriers was highest in Hispanics and lowest in Asian Americans. The higher carrier prevalence in Hispanics may reflect the presence of unrecognized Jewish ancestry in this population.

  View details for Web of Science ID 000251816000019

  View details for PubMedID 18159056

• Association between single-nucleotide polymorphisms in hormone metabolism and DNA repair genes and epithelial ovarian cancer: Results from two Australian studies and an additional validation set CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Beesley, J., Jordan, S. J., Spurdle, A. B., Song, H., Ramus, S. J., Kjaer, S. K., Hogdall, E., DiCioccio, R. A., McGuire, V., Whittemore, A. S., Gayther, S. A., Pharoah, P. D., Webb, P. M., Chenevix-Trench, G. 2007; 16 (12): 2557-2565

  Abstract

  Although some high-risk ovarian cancer genes have been identified, it is likely that common low penetrance alleles exist that confer some increase in ovarian cancer risk. We have genotyped nine putative functional single-nucleotide polymorphisms (SNP) in genes involved in steroid hormone synthesis (SRD5A2, CYP19A1, HSB17B1, and HSD17B4) and DNA repair (XRCC2, XRCC3, BRCA2, and RAD52) using two Australian ovarian cancer case-control studies, comprising a total of 1,466 cases and 1,821 controls of Caucasian origin. Genotype frequencies in cases and controls were compared using logistic regression. The only SNP we found to be associated with ovarian cancer risk in both of these two studies was SRD5A2 V89L (rs523349), which showed a significant trend of increasing risk per rare allele (P = 0.00002). We then genotyped another SNP in this gene (rs632148; r(2) = 0.945 with V89L) in an attempt to validate this finding in an independent set of 1,479 cases and 2,452 controls from United Kingdom, United States, and Denmark. There was no association between rs632148 and ovarian cancer risk in the validation samples, and overall, there was no significant heterogeneity between the results of the five studies. Further analyses of SNPs in this gene are therefore warranted to determine whether SRD5A2 plays a role in ovarian cancer predisposition.

  View details for DOI 10.1158/1055-9965.EPI-07-0542

  View details for Web of Science ID 000251856100006

  View details for PubMedID 18086758

• Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer HUMAN MUTATION Ramus, S. J., Harrington, P. A., Pye, C., DiCioccio, R. A., Cox, M. J., Garlinghouse-Jones, K., Oakley-Girvan, I., Jacobs, I. J., Hardy, R. M., Whittemore, A. S., Ponder, B. A., Piver, M. S., Pharoah, P. D., Gayther, S. A. 2007; 28 (12): 1207-1215

  Abstract

  A total of 283 epithelial ovarian cancer families from the United Kingdom (UK) and the United States (US) were screened for coding sequence changes and large genomic alterations (rearrangements and deletions) in the BRCA1 and BRCA2 genes. Deleterious BRCA1 mutations were identified in 104 families (37%) and BRCA2 mutations in 25 families (9%). Of the 104 BRCA1 mutations, 12 were large genomic alterations; thus this type of change represented 12% of all BRCA1 mutations. Six families carried a previously described exon 13 duplication, known to be a UK founder mutation. The remaining six BRCA1 genomic alterations were previously unreported and comprised five deletions and an amplification of exon 15. One of the 25 BRCA2 mutations identified was a large genomic deletion of exons 19-20. The prevalence of BRCA1/2 mutations correlated with the extent of ovarian and breast cancer in families. Of 37 families containing more than two ovarian cancer cases and at least one breast cancer case with diagnosis at less than 60 years of age, 30 (81%) had a BRCA1/2 mutation. The mutation prevalence was appreciably less in families without breast cancer; mutations were found in only 38 out of 141 families (27%) containing two ovarian cancer cases only, and in 37 out of 59 families (63%) containing three or more ovarian cancer cases. These data indicate that BRCA1 and BRCA2 are the major susceptibility genes for ovarian cancer but that other susceptibility genes may exist. Finally, it is likely that these data will be of clinical importance for individuals in families with a history of epithelial ovarian cancer, in providing accurate estimates of their disease risks.

  View details for DOI 10.1002/humu.20599

  View details for Web of Science ID 000251534700008

  View details for PubMedID 17688236

• Comparison of admixture and association mapping in admixed families GENETIC EPIDEMIOLOGY Clarke, G., Whittemore, A. S. 2007; 31 (7): 763-775

  Abstract

  The family-based admixture mapping test (AMT) identifies disease-related genes using family data from admixed individuals with the disease of interest (cases). The cases' genotypes at a set of markers are used to infer their DNA ancestry as it varies in blocks along the chromosomes. The test compares the cases' inferred ancestries to those expected from their family histories. Deviation between observed and expected ancestries in a region suggests the presence of a disease gene. We use a likelihood-based development of the AMT to compare it with the transmission disequilibrium test (TDT) as applied to admixed populations. The two tests have a common framework but differ significantly when the disease locus is untyped. The TDT infers disease-locus genotypes using the markers with which it is in linkage disequilibrium (LD). In contrast, the AMT infers disease locus ancestries using those of its linked markers. Thus, TDT power depends on LD between disease and marker loci, while AMT power depends on the lengths of the ancestry blocks containing the disease locus. We compare the power of the two tests when applied to cases with descent from two ancestral populations. The AMT outperforms the TDT when case marker ancestries are correctly specified and LD between disease and marker loci is less than one-third its maximal value (Delta' < 1/3). However, the TDT performs better in the presence of uncertain marker ancestries, even for weak LD between disease and marker loci (Delta' = 0.1). These findings have implications for the design of studies using admixed populations.

  View details for DOI 10.1002/gepi.20239

  View details for Web of Science ID 000250904800009

  View details for PubMedID 17508341

• Prediagnostic C-peptide and risk of prostate cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Borugian, M. J., Spinelli, J. J., Sun, Z., Kolonel, L. N., Oakley-Girvan, I., Pollak, M. D., Whittemore, A. S., Wu, A. H., Gallagher, R. P. 2007; 16 (10): 2164-2165

  View details for DOI 10.1158/1055-9965.EPI-07-0495

  View details for Web of Science ID 000250285900036

  View details for PubMedID 17932367

• UDP-glucuronosyltransferase 1A1 gene polymorphisms and total bilirubin levels in an ethnically diverse cohort of women DRUG METABOLISM AND DISPOSITION Hong, A. L., Huo, D., Kim, H., Niu, Q., Fackenthal, D. L., Cummings, S. A., John, E. M., West, D. W., Whittemore, A. S., Das, S., Olopade, O. I. 2007; 35 (8): 1254-1261

  Abstract

  The objective of this study was to investigate variations in UGT1A1 polymorphisms and haplotypes among African-American and Caucasian women and to assess whether variants other than UGT1A1*28 are associated with total serum bilirubin levels. The (TA)(n) repeats and 14 single nucleotide polymorphisms (SNPs) in the UGT1A1 gene were genotyped in 335 African Americans and 181 Caucasians. Total serum bilirubin levels were available in a subset of 125 women. Allele frequencies of all SNPs and (TA)(n) repeats were significantly different between African Americans and Caucasians. In Caucasians, three common haplotypes accounted for 71.8% of chromosomes, whereas five common haplotypes accounted for only 46.6% of chromosomes in African Americans. Mean total serum bilirubin levels were significantly lower (p = 0.005) in African Americans (0.36 mg/dl) than in Caucasians (0.44 mg/dl). The (TA)(n) repeats explained a significant amount of variation in total bilirubin levels (R(2) = 0.27, p < 0.0001), whereas other SNPs were less correlative. Thus, significant variations in UGT1A1 haplotype structure exist between African Americans and Caucasians in this relatively large cohort of women. The correlation of UGT1A1 with total bilirubin levels was mainly due to (TA)(n) repeats in Caucasians but a clear correlation was not observed in African Americans because of the high diversity of haplotypes and the small sample size. These data have implications for the design of epidemiologic studies of cancer susceptibility and pharmacogenetic studies for adverse drug reactions in populations of African ancestry.

  View details for DOI 10.1124/dmd.106.014183

  View details for Web of Science ID 000248200000003

  View details for PubMedID 17478602

• Medical radiation exposure and breast cancer risk: Findings from the Breast Cancer Family Registry INTERNATIONAL JOURNAL OF CANCER John, E. M., Phipps, A. I., Knight, J. A., Milne, R. L., Dite, G. S., Hopper, J. L., Andrulis, I. L., Southey, M., Giles, G. G., West, D. W., Whittemore, A. S. 2007; 121 (2): 386-394

  Abstract

  Moderate to high-dose radiotherapy is known to increase the risk of breast cancer. Uncertainties remain about the effects of low-dose chest X-rays, particularly in individuals at increased genetic risk. We analyzed case-control data from the Breast Cancer Family Registry. Self-reported data on therapeutic and diagnostic radiation exposures to the chest were available for 2,254 breast cancer cases and 3,431 controls (1,556 unaffected sisters and 1,875 unrelated population controls). We used unconditional logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with radiation exposure, after adjusting for age, study center, country of birth, and education. Increased risks for breast cancer were found for women who had radiotherapy for a previous cancer (OR=3.55, CI=1.47-8.54) and diagnostic chest X-rays for tuberculosis (OR=2.49, CI=1.82-3.40) or pneumonia (OR=2.19, CI=1.38-3.47). Risks were highest for women with a large number of exposures at a young age or exposed in earlier calendar years. There was no evidence of increased risk associated with other diagnostic chest X-rays (not including tuberculosis or pneumonia), both in women with and without indicators of increased genetic risk (i.e., diagnosed at age <40 years or family history of breast cancer). Given the widespread and increasing use of medical diagnostic radiation, continued surveillance of breast cancer risk is warranted, particularly in women at specific genetic risk, such as those carrying mutations in BRCA1 or BRCA2.

  View details for DOI 10.1002/ijc.22668

  View details for Web of Science ID 000247155000021

  View details for PubMedID 17372900

• Compelling evidence for a prostate cancer gene at 22q12.3 by the International Consortium for Prostate Cancer Genetics HUMAN MOLECULAR GENETICS Camp, N. J., Cannon-Albright, L. A., Farnham, J. M., Baffoe-Bonnie, A. B., George, A., Powell, I., Bailey-Wilson, J. E., Carpten, J. D., Giles, G. G., Hopper, J. L., Severi, G., English, D. R., Foulkes, W. D., Maehle, L., Moller, P., Eeles, R., Easton, D., Badzioch, M. D., Whittemore, A. S., Oakley-Girvan, I., Hsieh, C., Dimitrov, L., Xu, J., Stanford, J. L., Johanneson, B., Deutsch, K., McIntosh, L., Ostrander, E. A., Wiley, K. E., Isaacs, S. D., Walsh, P. C., Thibodeau, S. N., McDonnell, S. K., Hebbring, S., Schaid, D. J., Lange, E. M., Cooney, K. A., Tammela, T. L., Schleutker, J., Paiss, T., Maier, C., Gronberg, H., Wiklund, F., Emanuelsson, M., Isaacs, W. B. 2007; 16 (11): 1271-1278

  Abstract

  Previously, an analysis of 14 extended, high-risk Utah pedigrees localized in the chromosome 22q linkage region to 3.2 Mb at 22q12.3-13.1 (flanked on each side by three recombinants) contained 31 annotated genes. In this large, multi-centered, collaborative study, we performed statistical recombinant mapping in 54 pedigrees selected to be informative for recombinant mapping from nine member groups of the International Consortium for Prostate Cancer Genetics (ICPCG). These 54 pedigrees included the 14 extended pedigrees from Utah and 40 pedigrees from eight other ICPCG member groups. The additional 40 pedigrees were selected from a total pool of 1213 such that each pedigree was required to contain both at least four prostate cancer (PRCA) cases and exhibit evidence for linkage to the chromosome 22q region. The recombinant events in these 40 independent pedigrees confirmed the previously proposed region. Further, when all 54 pedigrees were considered, the three-recombinant consensus region was narrowed down by more than a megabase to 2.2 Mb at chromosome 22q12.3 flanked by D22S281 and D22S683. This narrower region eliminated 20 annotated genes from that previously proposed, leaving only 11 genes. This region at 22q12.3 is the most consistently identified and smallest linkage region for PRCA. This collaborative study by the ICPCG illustrates the value of consortium efforts and the continued utility of linkage analysis using informative pedigrees to localize genes for complex diseases.

  View details for DOI 10.1093/hmg/ddm075

  View details for Web of Science ID 000248053300001

  View details for PubMedID 17478474

  View details for PubMedCentralID PMC2653215

• Multiple regions within 8q24 independently affect risk for prostate cancer NATURE GENETICS Haiman, C. A., Patterson, N., Freedman, M. L., Myers, S. R., Pike, M. C., Waliszewska, A., Neubauer, J., Tandon, A., Schirmer, C., McDonald, G. J., Greenway, S. C., Stram, D. O., Le Marchand, L., Kolonel, L. N., Frasco, M., Wong, D., Pooler, L. C., Ardlie, K., Oakley-Girvan, I., Whittemore, A. S., Cooney, K. A., John, E. M., Ingles, S. A., Altshuler, D., Henderson, B. E., Reich, D. 2007; 39 (5): 638-644

  Abstract

  After the recent discovery that common genetic variation in 8q24 influences inherited risk of prostate cancer, we genotyped 2,973 SNPs in up to 7,518 men with and without prostate cancer from five populations. We identified seven risk variants, five of them previously undescribed, spanning 430 kb and each independently predicting risk for prostate cancer (P = 7.9 x 10(-19) for the strongest association, and P < 1.5 x 10(-4) for five of the variants, after controlling for each of the others). The variants define common genotypes that span a more than fivefold range of susceptibility to cancer in some populations. None of the prostate cancer risk variants aligns to a known gene or alters the coding sequence of an encoded protein.

  View details for DOI 10.1038/ng2015

  View details for Web of Science ID 000245971300019

  View details for PubMedID 17401364

  View details for PubMedCentralID PMC2638766

• Screening for the BRCA1-ins6kbEx13 mutation: potential for misdiagnosis. Mutation in brief #964. Online. Human mutation Ramus, S. J., Harrington, P. A., Pye, C., Peock, S., Cook, M. R., Cox, M. J., Jacobs, I. J., DiCioccio, R. A., Whittemore, A. S., Piver, M. S., EMBRACE, Easton, D. F., Ponder, B. A., Pharoah, P. D., Gayther, S. A. 2007; 28 (5): 525-526

  Abstract

  Misdiagnosis of a germline mutation associated with an inherited disease syndrome can have serious implications for the clinical management of patients. A false negative diagnosis (mutation missed by genetic screening) limits decision making about intervention strategies within families. More serious is the consequence of a false positive diagnosis (genetic test suggesting a mutation is present when it is not). This could lead to an individual, falsely diagnosed as a mutation carrier, undergoing unnecessary clinical intervention, possibly involving risk-reducing surgery. As part of screening 283 ovarian cancer families for BRCA1 mutations, we used two different methods (mutation specific PCR and multiplex ligation-dependent probe amplification) to screen for a known rearrangement mutation L78833.1:g.44369_50449dup (ins6kbEx13). We found false positive and false negative results in several families. We then tested 61 known carriers or non-carriers from an epidemiological study of BRCA1 and BRCA2 mutation carriers (the EMBRACE study). These data highlight the need for caution when interpreting analyses of the ins6kbEx13 mutation and similar mutations, where characterising the exact sequence alteration for a deleterious mutation is not a part of the routine genetic test.

  View details for PubMedID 17397054

• Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer CANCER RESEARCH Gayther, S. A., Song, H., Ramus, S. J., Kjaer, S. K., Whittemore, A. S., Quaye, L., Tyrer, J., Shadforth, D., Hogdall, E., Hogdall, C., Blaeker, J., DiCioccio, R., McGuire, V., Webb, P. M., Beesley, J., Green, A. C., Whiteman, D. C., Goodman, M. T., Lurie, G., Carney, M. E., Modugno, F., Ness, R. B., Edwards, R. P., Moysich, K. B., Goode, E. L., Couch, F. J., Cunningham, J. M., Sellers, T. A., Wu, A. H., Pike, M. C., Iversen, E. S., Marks, J. R., Garcia-Closas, M., Brinton, L., Lissowska, J., Peplonska, B., Easton, D. F., Jacobs, I., Ponder, B. A., Schildkraut, J., Pearce, C. L., Chenevix-Trench, G., Berchuck, A., Pharoah, P. D. 2007; 67 (7): 3027-3035

  Abstract

  High-risk susceptibility genes explain <40% of the excess risk of familial ovarian cancer. Therefore, other ovarian cancer susceptibility genes are likely to exist. We have used a single nucleotide polymorphism (SNP)-tagging approach to evaluate common variants in 13 genes involved in cell cycle control-CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, and CDKN2D-and risk of invasive epithelial ovarian cancer. We used a two-stage, multicenter, case-control study. In stage 1, 88 SNPs that tag common variation in these genes were genotyped in three studies from the United Kingdom, United States, and Denmark ( approximately 1,500 cases and 2,500 controls). Genotype frequencies in cases and controls were compared using logistic regression. In stage 2, eight other studies from Australia, Poland, and the United States ( approximately 2,000 cases and approximately 3,200 controls) were genotyped for the five most significant SNPs from stage 1. No SNP was significant in the stage 2 data alone. Using the combined stages 1 and 2 data set, CDKN2A rs3731257 and CDKN1B rs2066827 were associated with disease risk (unadjusted P trend = 0.008 and 0.036, respectively), but these were not significant after adjusting for multiple testing. Carrying the minor allele of these SNPs was found to be associated with reduced risk [OR, 0.91 (0.85-0.98) for rs3731257; and OR, 0.93 (0.87-0.995) for rs2066827]. In conclusion, we have found evidence that a single tagged SNP in both the CDKN2A and CDKN1B genes may be associated with reduced ovarian cancer risk. This study highlights the need for multicenter collaborations for genetic association studies.

  View details for DOI 10.1158/0008-5472.CAN-06-3261

  View details for Web of Science ID 000245622900019

  View details for PubMedID 17409409

• Tagging Single Nucleotide Polymorphisms in the BRIP1 Gene and Susceptibility to Breast and Ovarian Cancer PLOS ONE Song, H., Ramus, S. J., Kjaer, S. K., Hogdall, E., DiCioccio, R. A., Whittemore, A. S., McGuire, V., Hogdall, C., Jacobs, I. J., Easton, D. F., Ponder, B. A., Dunning, A. M., Gayther, S. A., Pharoah, P. D. 2007; 2 (3)

  Abstract

  BRIP1 interacts with BRCA1 and functions in regulating DNA double strand break repair pathways. Germline BRIP1 mutations are associated with breast cancer and Fanconi anemia. Thus, common variants in the BRIP1 are candidates for breast and ovarian cancer susceptibility.We used a SNP tagging approach to evaluate the association between common variants (minor allele frequency>or=0.05) in BRIP1 and the risks of breast cancer and invasive ovarian cancer. 12 tagging SNPs (tSNPs) in the gene were identified and genotyped in up to 2,270 breast cancer cases and 2,280 controls from the UK and up to 1,513 invasive ovarian cancer cases and 2,515 controls from the UK, Denmark and USA. Genotype frequencies in cases and controls were compared using logistic regression.Two tSNPs showed a marginal significant association with ovarian cancer: Carriers of the minor allele of rs2191249 were at reduced risk compared with the common homozygotes (Odds Ratio (OR) = 0.90 (95% CI, 0.82-1.0), P-trend = 0.045) and the minor allele of rs4988344 was associated with increased risk (OR = 1.15 (95%CI, 1.02-1.30), P-trend = 0.02). When the analyses were restricted to serous ovarian cancers, these effects became slightly stronger. These results were not significant at the 5% level after adjusting for multiple testing. None of the tSNPs was associated with breast cancer.It is unlikely that common variants in BRIP1 contribute significantly to breast cancer susceptibility. The possible association of rs2191249 and rs4988344 with ovarian cancer risks warrant confirmation in independent case-control studies.

  View details for DOI 10.1371/journal.pone.0000268

  View details for Web of Science ID 000207444700003

  View details for PubMedID 17342202

• BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays AMERICAN JOURNAL OF SURGICAL PATHOLOGY Bane, A. L., Beck, J. C., Bleiweiss, I., Buys, S. S., Catalano, E., Daly, M. B., Giles, G., Godwin, A. K., Hibshoosh, H., Hopper, J. L., John, E. M., Layfield, L., Longacre, T., Miron, A., Senie, R., Southey, M. C., West, D. W., Whittemore, A. S., Wu, H., Andrulis, I. L., O'Malley, F. P. 2007; 31 (1): 121-128

  Abstract

  A distinct morphologic and molecular phenotype has been reported for BRCA1-associated breast cancers; however, the phenotype of BRCA2-associated breast cancers is less certain. To comprehensively characterize BRCA2-associated breast cancers we performed a retrospective case control study using tumors accrued through the Breast Cancer Family Registry. We examined the tumor morphology and hormone receptor status in 157 hereditary breast cancers with germline mutations in BRCA2 and 314 control tumors negative for BRCA1 and BRCA2 mutations that were matched for age and ethnicity. Tissue microarrays were constructed from 64 BRCA2-associated and 185 control tumors. Tissue microarray sections were examined for HER2/neu protein overexpression, p53 status and the expression of basal markers, luminal markers, cyclin D1, bcl2, and MIB1 by immunohistochemistry. The majority of BRCA2-associated tumors and control tumors were invasive ductal, no special-type tumors. In contrast to control tumors, BRCA2-associated cancers were more likely to be high grade (P<0.0001) and to have pushing tumor margins (P=0.0005). Adjusting for grade, BRCA2-associated tumors were more often estrogen receptor positive (P=0.008) and exhibited a luminal phenotype (P=0.003). They were less likely than controls to express the basal cytokeratin CK5 (P=0.03) or to overexpress HER2/neu protein (P=0.06). There was no difference in p53, bcl2, MIB1, or cyclin D1 expression between BRCA2-associated and control tumors. We have demonstrated, in the largest series of BRCA2-associated breast cancers studied to date, that these tumors are predominantly high-grade invasive ductal carcinomas of no special type and they demonstrate a luminal phenotype despite their high histologic grade.

  View details for Web of Science ID 000243236000015

  View details for PubMedID 17197928

• A Bayesian false discovery rate for multiple testing JOURNAL OF APPLIED STATISTICS Whittemore, A. S. 2007; 34 (1): 1-9

  View details for DOI 10.1080/02664760600994745

  View details for Web of Science ID 000243126900001

• Assessing environmental modifiers of disease risk associated with rare mutations HUMAN HEREDITY Whittemore, A. S. 2007; 63 (2): 134-143

  Abstract

  As disease-predisposing mutations are increasingly identified, there is growing need to assess the effects of lifestyle and environmental factors on disease risks in mutation carriers. Such assessment is difficult when the mutations are rare and evaluating them in large population samples is costly.This paper describes four study designs for evaluating the effects of environmental exposures in carriers of rare disease-predisposing mutations.The strengths and weaknesses of the designs are assessed, and strategies for analyzing the data obtained from such designs are considered.When exposure effects in noncarriers are well-established and exposure is independent of carrier status in the population of disease-free controls, the case-only design provides a feasible and efficient method for inferring effects in carriers. When exposure effects in noncarriers are not well established, the most feasible design options are those that compare exposures in carrier cases to either untyped controls or to carrier controls. These two designs have complementary strengths and weaknesses; thus inferences are stronger when measures of association estimated using the two designs are consistent.

  View details for DOI 10.1159/000099185

  View details for Web of Science ID 000244256500008

  View details for PubMedID 17283442

• Imputation of missing ages in pedigree data HUMAN HEREDITY Balise, R. R., Chen, Y., Dite, G., Felberg, A., Sun, L., Ziogas, A., Whittemore, A. S. 2007; 63 (3-4): 168-174

  Abstract

  In human pedigree data age at disease occurrence frequently is missing and is imputed using various methods. However, little is known about the performance of these methods when applied to families. In particular, there is little information about the level of agreement between imputed and actual values of temporal data and their effects on inferences.We performed two evaluations of five imputation methods used to generate complete data for repositories to be shared by many investigators. Two of the methods are mean substitution methods, two are regression methods and one is a multiple imputation method based on one of the regression methods. To evaluate the methods, we randomly deleted the years of disease diagnosis of some men in a sample of pedigrees ascertained as part of a prostate cancer study. In the first evaluation, we used the five methods to impute the missing diagnosis years and evaluated agreement between imputed and actual values. In the second evaluation, we compared agreement between regression coefficients estimated using imputed diagnosis years with those estimated using the actual years.For both evaluations, we found optimal or near-optimal performance from a regression method that imputes a man's diagnosis year based on the year of birth and year of last observation of all affected men with complete data. The multiple imputation analogue of this method also performed well.

  View details for DOI 10.1159/000099829

  View details for Web of Science ID 000244952500003

  View details for PubMedID 17310126

• Sex steroid hormones in young manhood and the risk of subsequent prostate cancer: a longitudinal study in African-Americans and Caucasians (United States) CANCER CAUSES & CONTROL Tsai, C. J., Cohn, B. A., Cirillo, P. M., Feldman, D., Stanczyk, F. Z., Whittemore, A. S. 2006; 17 (10): 1237-1244

  Abstract

  To investigate the relation of sex hormone levels in young adults to subsequent prostate cancer risk.From 1959 to 1967, the Child Health and Development Studies collected sera from 10,442 men (median age: 34 years) and followed them for a median of 32 years. In this analysis, we selected 119 African-Americans and 206 Caucasians diagnosed with prostate cancer during the follow-up period. Two prostate cancer-free men were chosen to match each prostate cancer case on race and birth year. We compared the levels of testosterone, estradiol, and sex hormone-binding globulin in cases to those of their matched controls using conditional logistic regression.There was no significant association between absolute levels of sex hormones in youth and prostate cancer risk in either race. However, among Caucasians, but not African-Americans, prostate cancer risk was positively associated with the ratio of total testosterone to total estradiol (odds ratio relating the fourth to the first quartile: 3.01; 95% confidence interval: 1.42-6.39).The association between testosterone to estradiol ratio and prostate cancer risk in young Caucasians is consistent with similar findings in older Caucasians. The absence of this association in African-Americans needs confirmation in other data involving larger numbers of African-Americans.

  View details for DOI 10.1007/s10552-006-0052-4

  View details for Web of Science ID 000242145700003

  View details for PubMedID 17111254

• Pooled genome linkage scan of aggressive prostate cancer: results from the International Consortium for Prostate Cancer Genetics HUMAN GENETICS Schaid, D. J. 2006; 120 (4): 471-485

  Abstract

  While it is widely appreciated that prostate cancers vary substantially in their propensity to progress to a life-threatening stage, the molecular events responsible for this progression have not been identified. Understanding these molecular mechanisms could provide important prognostic information relevant to more effective clinical management of this heterogeneous cancer. Hence, through genetic linkage analyses, we examined the hypothesis that the tendency to develop aggressive prostate cancer may have an important genetic component. Starting with 1,233 familial prostate cancer families with genome scan data available from the International Consortium for Prostate Cancer Genetics, we selected those that had at least three members with the phenotype of clinically aggressive prostate cancer, as defined by either high tumor grade and/or stage, resulting in 166 pedigrees (13%). Genome-wide linkage data were then pooled to perform a combined linkage analysis for these families. Linkage signals reaching a suggestive level of significance were found on chromosomes 6p22.3 (LOD = 3.0), 11q14.1-14.3 (LOD = 2.4), and 20p11.21-q11.21 (LOD = 2.5). For chromosome 11, stronger evidence of linkage (LOD = 3.3) was observed among pedigrees with an average at diagnosis of 65 years or younger. Other chromosomes that showed evidence for heterogeneity in linkage across strata were chromosome 7, with the strongest linkage signal among pedigrees without male-to-male disease transmission (7q21.11, LOD = 4.1), and chromosome 21, with the strongest linkage signal among pedigrees that had African American ancestry (21q22.13-22.3; LOD = 3.2). Our findings suggest several regions that may contain genes which, when mutated, predispose men to develop a more aggressive prostate cancer phenotype. This provides a basis for attempts to identify these genes, with potential clinical utility for men with aggressive prostate cancer and their relatives.

  View details for DOI 10.1007/s00439-006-0219-9

  View details for Web of Science ID 000241791900003

  View details for PubMedID 16932970

• Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T > G and c.1066-6T > G (IVS10-6T > G) from the breast cancer family registry HUMAN MUTATION Bernstein, J. L., Teraoka, S., Southey, M. C., Jenkins, M. A., Andrulis, I. L., Knight, J. A., John, E. M., Lapinski, R., Wolitzer, A. L., Whittemore, A. S., West, D., Seminara, D., Olson, E. R., Spurdle, A. B., Chenevix-Trench, G., Giles, G. G., Hopper, J. L., Concannon, P. 2006; 27 (11): 1122-1128

  Abstract

  The ATM gene variants segregating in ataxia-telangiectasia families are associated with increased breast cancer risk, but the contribution of specific variants has been difficult to estimate. Previous small studies suggested two functional variants, c.7271T>G and c.1066-6T>G (IVS10-6T>G), are associated with increased risk. Using population-based blood samples we found that 7 out of 3,743 breast cancer cases (0.2%) and 0 out of 1,268 controls were heterozygous for the c.7271T>G allele (P=0.1). In cases, this allele was more prevalent in women with an affected mother (odds ratio [OR]=5.5, 95% confidence interval [CI]=1.2-25.5; P=0.04) and delayed child-bearing (OR=5.1; 95% CI=1.0-25.6; P=0.05). The estimated cumulative breast cancer risk to age 70 years (penetrance) was 52% (95% CI=28-80%; hazard ratio [HR]=8.6; 95% CI=3.9-18.9; P<0.0001). In contrast, 13 of 3,757 breast cancer cases (0.3%) and 10 of 1,268 controls (0.8%) were heterozygous for the c.1066-6T>G allele (OR=0.4; 95% CI=0.2-1.0; P=0.05), and the penetrance was not increased (P=0.5). These findings suggest that although the more common c.1066-6T>G variant is not associated with breast cancer, the rare ATM c.7271T>G variant is associated with a substantially elevated risk. Since c.7271T>G is only one of many rare ATM variants predicted to have deleterious consequences on protein function, an effective means of identifying and grouping these variants is essential to assess the contribution of ATM variants to individual risk and to the incidence of breast cancer in the population.

  View details for DOI 10.1002/humu.20415

  View details for Web of Science ID 000241529500007

  View details for PubMedID 16958054

• Common variants in mismatch repair genes and risk of invasive ovarian cancer CARCINOGENESIS Song, H., Ramus, S. J., Quaye, L., DiCioccio, R. A., Tyrer, J., Lomas, E., Shadforth, D., Hogdall, E., Hogdall, C., McGuire, V., Whittemore, A. S., Easton, D. F., Ponder, B. A., Kjaer, S. K., Pharoah, P. D., Gayther, S. A. 2006; 27 (11): 2235-2242

  Abstract

  Mismatch repair (MMR) is important for repairing of nucleotide mismatches during DNA replication. Germline mutations in MMR genes are associated with hereditary non-polyposis colorectal cancer (HNPCC). Ovarian cancer occurs as part of the HNPCC phenotype, and so common variants in MMR genes are candidates for ovarian cancer susceptibility. We performed a large multicentre case-control study to investigate associations of common variations in MMR genes and ovarian cancer using a single nucleotide polymorphism (SNP) tagging approach. A total of 2570 controls and 1531 cases from three separate studies were genotyped for 44 tagging SNPs (stSNP) in seven MMR genes (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2). Genotype frequencies were marginally different between cases and controls for PMS2 rs7797466 (P(2df) = 0.046) with a 1.17-fold (95% CI 1.03-1.33) increase in risk for each 'a' allele carried (P-trend = 0.013). Haplotype analysis of PMS2 also showed significant differences in frequencies between cases and controls (P(7df) = 0.005), with one haplotype accounting for most of the effect. There was also marginal evidence for a recessive protective effect with common homozygote as the baseline comparator for two SNPs--MSH6 rs3136245 (OR 0.67; 95% CI 0.46-0.98) and MSH3 rs6151662 (OR 0.28; 95% CI 0.08-0.91)--but the comparisons of genotype frequencies for these variants were not significant (P = 0.10 and 0.054). In conclusion, it is unlikely that common variants in MLH1, MLH3, PMS1, MSH2, MSH3 and MSH6 contribute significantly to ovarian cancer susceptibility. The observed association of PMS2 rs7797466 with ovarian cancer warrants confirmation in an independent study.

  View details for DOI 10.1093/carcin/bg1089

  View details for Web of Science ID 000241629700011

  View details for PubMedID 16774946

• Common variants in RB1 gene and risk of invasive ovarian cancer CANCER RESEARCH Song, H., Ramus, S. J., Shadforth, D., Quaye, L., Kjaer, S. K., DiCioccio, R. A., Dunning, A. M., Hogdall, E., Hogdall, C., Whittemore, A. S., McGuire, V., Lesueur, F., Easton, D. F., Jacobs, I. J., Ponder, B. A., Gayther, S. A., Pharoah, P. D. 2006; 66 (20): 10220-10226

  Abstract

  Somatic alteration of the RB1 gene is common in several types of cancer, and germ-line variants are implicated in others. We have used a single nucleotide polymorphism (SNP) tagging approach to evaluate the association between common variants (SNP) in RB1 and risks of invasive ovarian cancer. We genotyped 11 tagging SNPs in three ovarian case-control studies from the United Kingdom, United States, and Denmark, comprising >1500 cases and 4,800 controls. Two SNPs showed significant association with ovarian cancer risk: carriers of the minor allele of rs2854344 were at reduced risk compared with the common homozygotes [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.61-0.89; P = 0.0009 dominant model]. Similarly, the minor allele of rs4151620 was found to be associated with reduced risk (rare versus common homozygote; OR, 0.19; 95% CI, 0.07-0.53; P = 0.00005 recessive model). After adjusting for multiple testing, the most significant association (rs4151620) was P = 0.001. A global test comparing common haplotype frequencies in cases and controls was of borderline significance (P(8df) = 0.04). There are no common coding SNPs in the RB1 gene. However, intron 17 of RB1 contains the open reading frame for the P2RY5 gene, and rs4151620 is perfectly correlated with rs2227311, which is located in the 5'-untranslated region of P2RY5 and is predicted to affect P2RY5 transcription. rs2854344 has been reported previously to be associated with breast cancer risk. The possible associations of rs2854344 and rs4151620 with ovarian cancer risk warrant confirmation in independent case-control studies before studies on their biological mode of action.

  View details for DOI 10.1158/0008-5472.CAN-06-2222

  View details for Web of Science ID 000241392700053

  View details for PubMedID 17047088

• BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50 CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Haile, R. W., Thomas, D. C., McGuire, V., Felberg, A., John, E. M., Milne, R. L., Hopper, J. L., Jenkins, M. A., Levine, A. J., Daly, M. M., Buys, S. S., Senie, R. T., Andrulis, I. L., Knight, J. A., Godwin, A. K., Southey, M., McCredie, M. R., Giles, G. G., Andrews, L., Tucker, K., Miron, A., Apicella, C., Tesoriero, A., Bane, A., Pike, M. C., Whittemore, A. S. 2006; 15 (10): 1863-1870

  Abstract

  Understanding the effect of oral contraceptives on risk of breast cancer in BRCA1 or BRCA2 mutation carriers is important because oral contraceptive use is a common, modifiable practice.We studied 497 BRCA1 and 307 BRCA2 mutation carriers, of whom 195 and 128, respectively, had been diagnosed with breast cancer. Case-control analyses were conducted using unconditional logistic regression with adjustments for family history and familial relationships and were restricted to subjects with a reference age under 50 years.For BRCA1 mutation carriers, there was no significant association between risk of breast cancer and use of oral contraceptives for at least 1 year [odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.53-1.12] or duration of oral contraceptive use (P(trend) = 0.62). For BRCA2 mutation carriers, there was no association with use of oral contraceptives for at least 1 year (OR, 1.62; 95% CI, 0.90-2.92); however, there was an association of elevated risk with oral contraceptive use for at least 5 years (OR, 2.06; 95% CI, 1.08-3.94) and with duration of use (OR(trend) per year of use, 1.08; P = 0.008). Similar results were obtained when we considered only use of oral contraceptives that first started in 1975 or later.We found no evidence overall that use of oral contraceptives for at least 1 year is associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers before age 50. For BRCA2 mutation carriers, use of oral contraceptives may be associated with an increased risk of breast cancer among women who use them for at least 5 years. Further studies reporting results separately for BRCA1 and BRCA2 mutation carriers are needed to resolve this important issue.

  View details for DOI 10.1158/1055-9965.EPI-06-0258

  View details for Web of Science ID 000241616800019

  View details for PubMedID 17021353

• Getting more from digital SNP data STATISTICS IN MEDICINE El Karoui, N., Zhou, W., Whittemore, A. S. 2006; 25 (18): 3124-3133

  Abstract

  The digital SNP method has been proposed for identifying loss of heterozygosity (LOH) in tumour tissue and correlating it with patients' clinical characteristics. The method evaluates a tumour's allelic count at a single nucleotide polymorphism (SNP) for which the patient's normal tissue is heterozygous. The count is used to classify the tumour as positive or negative for LOH, using the sequential probability ratio test (SPRT). However, the SPRT was not developed for analysing digital SNP experiments. When applied to digital SNP data, the SPRT has several anomalies that can result in both loss of data and tumour misclassification. The anomalies are caused by discrepancies between the design of digital SNP experiments and the setting for which SPRT was developed. We propose an alternative classification scheme based on the false discovery rate, and show that it outperforms the SPRT when applied to Digital SNP data.

  View details for DOI 10.1002/sim.2379

  View details for Web of Science ID 000240568100005

  View details for PubMedID 16397858

• Predicting and preventing hereditary colorectal cancer JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ford, J. M., Whittemore, A. S. 2006; 296 (12): 1521-1523

  View details for Web of Science ID 000240770000029

  View details for PubMedID 17003401

• Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Freedman, M. L., Haiman, C. A., Patterson, N., McDonald, G. J., Tandon, A., Waliszewska, A., Penney, K., Steen, R. G., Ardlie, K., John, E. M., Clakley-Girvan, I., Whitternore, A. S., Cooney, K. A., Ingles, S. A., Altshuler, D., Henderson, B. E., Reich, D. 2006; 103 (38): 14068-14073

  Abstract

  A whole-genome admixture scan in 1,597 African Americans identified a 3.8 Mb interval on chromosome 8q24 as significantly associated with susceptibility to prostate cancer [logarithm of odds (LOD) = 7.1]. The increased risk because of inheriting African ancestry is greater in men diagnosed before 72 years of age (P < 0.00032) and may contribute to the epidemiological observation that the higher risk for prostate cancer in African Americans is greatest in younger men (and attenuates with older age). The same region was recently identified through linkage analysis of prostate cancer, followed by fine-mapping. We strongly replicated this association (P < 4.2 x 10(-9)) but find that the previously described alleles do not explain more than a fraction of the admixture signal. Thus, admixture mapping indicates a major, still-unidentified risk gene for prostate cancer at 8q24, motivating intense work to find it.

  View details for DOI 10.1073/pnas.0605832103

  View details for Web of Science ID 000240746600031

  View details for PubMedID 16945910

  View details for PubMedCentralID PMC1599913

• Patterns and progress in ovarian cancer over 14 years OBSTETRICS AND GYNECOLOGY Chan, J. K., Cheung, M. K., Husain, A., Teng, N. N., West, D., Whittemore, A. S., Berek, J. S., Osann, K. 2006; 108 (3): 521-528

  Abstract

  To estimate the change in survival rates of women with ovarian cancer during the past 14 years.Women diagnosed with epithelial, germ cell, sarcomas, and sex-cord stromal ovarian tumors were identified from the Surveillance Epidemiology and End Results Database. Demographic and clinicopathologic factors, and survival information were extracted and tested using chi 2 and Kaplan-Meier and Cox regression analyses.A total of 30,246 women were diagnosed with ovarian cancer, including 26,753 non-clear cell epithelial, 1,411 clear cell, 818 sarcoma, 778 germ cell, and 486 sex-cord stromal tumors. The 5-year disease-specific survival rate across 1988-1992 and 1993-1997 improved from 45.4% to 48.6% (P < .001). The corresponding estimates show increases for non-clear cell epithelial carcinoma from 42.5% to 45.8% (P < .001), and for sarcomas from 33.5% to 38.8% (P = .07). However, improvements were not observed in those with clear cell, 64.3% to 63.9% (P = .82), and sex-cord stromal, 89.7% to 85.7% (P = .18), tumors of the ovary. In multivariable analyses, younger age, early stage, favorable histologic cell types, low-grade tumors, standard surgery, and recent time interval from 1993-1997 were independent prognostic factors for improved survival.In this large population-based study, there has been some improvement in the overall survival of women with ovarian cancers during a 14-year period. However, new treatment strategies are warranted for those with epithelial cancer and sarcomas of the ovary, given their overall poor prognosis. These results from our updated analyses might help to counsel women diagnosed with ovarian cancers.

  View details for Web of Science ID 000246769000008

  View details for PubMedID 16946210

• Breast cancer followed by corpus cancer: Is there a higher risk for aggressive histologic subtypes? GYNECOLOGIC ONCOLOGY Chan, J. K., Manuel, M. R., Cheung, M. K., Osann, K., Husain, A., Teng, N. N., Rao, A., Carlson, R. W., Whittemore, A. S. 2006; 102 (3): 508-512

  Abstract

  To analyze corpus cancer patients with a breast cancer history for risk of developing aggressive uterine histologic types.Corpus cancer patients with a history of breast cancer were identified from the Surveillance Epidemiology and End Results database from 1988 to 2001. Demographics, clinico-pathologic, and survival data were analyzed using Kaplan-Meier and logistic regression analyses.Of 52,109 women diagnosed with corpus cancer, 1922 had a history of breast cancer. Women with a history of breast cancer had a significantly higher proportion of uterine papillary serous carcinomas (UPSC) and sarcomas compared to those without a breast cancer history (9.4% vs. 6.3% for UPSC and 10.3% vs. 8.4% for sarcoma; P < 0.001). Patients with endometrioid or sarcoma of the uterus after breast cancer had significantly worse 5-year survivals than patients without a breast cancer history (84.4% vs. 90.5%; P < 0.001 and 49.0% vs. 63.6%, P < 0.001, respectively). Older age, advanced stage, lack of surgery and radiation treatment, poor histologic types, and history of breast cancer were independent prognostic factors for poorer survival.In this study, the proportional incidence of UPSC and sarcoma was significantly higher in women with a breast cancer history. These findings highlight the association of breast cancer and high-risk corpus cancer subtypes.

  View details for DOI 10.1016/j.ygyno.2006.01.014

  View details for Web of Science ID 000240871000017

  View details for PubMedID 16483640

• No increased risk of breast cancer associated with alcohol consumption among carriers of BRCA1 and BRCA2 mutations ages < 50 years CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION McGuire, V., John, E. M., Felberg, A., Haile, R. W., Boyd, N. F., Thomas, D. C., Jenkins, M. A., Milne, R. L., Daly, M. B., Ward, J., Terry, M. B., Andrulis, I. L., Knight, J. A., Godwin, A. K., Giles, G. G., Southey, M., West, D. W., Hopper, J. L., Whittemore, A. S. 2006; 15 (8): 1565-1567

  View details for DOI 10.1158/1055-9965.EPI-06-0323

  View details for PubMedID 16896052

• Nonparametric linkage analysis using person-specific covariates GENETIC EPIDEMIOLOGY Whittemore, A. S., Halpern, J. 2006; 30 (5): 369-379

  Abstract

  Linkage analysis provides an important tool for mapping genes for complex disease. However its usefulness has been limited by inadequate marker density, inadequate sample sizes and the possibility that different genes account for different subtypes of the disease (phenotypic heterogeneity). The first two limitations can be addressed by high-density single nucleotide polymorphism (SNP) genotyping and the pooling of large sets of multiple-case families. Phenotypic heterogeneity can be addressed by analyses that weigh the contributions of affected family members according to characteristics of their disease phenotypes. Here we introduce a method for including such person-specific weights in nonparametric linkage analysis. We show with simulations that such weighting can provide stronger linkage signals when a causal polymorphism affects some manifestations of the disease more than others. We applied the method to prostate cancer linkage data in a region on chromosome 19p, and obtained higher lod scores by assigning weights of one to men with early-onset aggressive cancers, weights of zero to those with late-onset nonaggressive cancers, and intermediate weights to all other affected men. We have developed a modified version of GENEHUNTER that allows inclusion of person-specific weights in the nonparametric analyses. This program is freely available at http://med.stanford.edu/epidemiology/statisticalSoftware/weightedKAC.

  View details for DOI 10.1002/gepi.20153

  View details for Web of Science ID 000238690600001

  View details for PubMedID 16671107

• Breast and ovarian cancer in relatives of cancer patients, with and without BRCA mutations CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Lee, J. S., John, E. M., McGuire, V., Felberg, A., Ostrow, K. L., DiCioccio, R. A., Li, F. P., Miron, A., West, D. W., Whittemore, A. S. 2006; 15 (2): 359-363

  Abstract

  First-degree relatives of patients with breast or ovarian cancer have increased risks for these cancers. Little is known about how their risks vary with the patient's cancer site, carrier status for predisposing genetic mutations, or age at cancer diagnosis.We evaluated breast and ovarian cancer incidence in 2,935 female first-degree relatives of non-Hispanic White female patients with incident invasive cancers of the breast (n = 669) or ovary (n = 339) who were recruited from a population-based cancer registry in northern California. Breast cancer patients were tested for BRCA1 and BRCA2 mutations. Ovarian cancer patients were tested for BRCA1 mutations. We estimated standardized incidence ratios (SIR) and 95% confidence intervals (95% CI) for breast and ovarian cancer among the relatives according to the patient's mutation status, cancer site, and age at cancer diagnosis.In families of patients who were negative or untested for BRCA1 or BRCA2 mutations, risks were elevated only for the patient's cancer site. The breast cancer SIR was 1.5 (95% CI, 1.2-1.8) for relatives of breast cancer patients, compared with 1.1 (95% CI, 0.8-1.6) for relatives of ovarian cancer patients (P = 0.12 for difference by patient's cancer site). The ovarian cancer SIR was 0.9 (95% CI, 0.5-1.4) for relatives of breast cancer patients, compared with 1.9 (95% CI, 1.0-4.0) for relatives of ovarian cancer patients (P = 0.04 for difference by site). In families of BRCA1-positive patients, relatives' risks also correlated with the patient's cancer site. The breast cancer SIR was 10.6 (95% CI, 5.2-21.6) for relatives of breast cancer patients, compared with 3.3 (95% CI, 1.4-7.3) for relatives of ovarian cancer patients (two-sided P = 0.02 for difference by site). The ovarian cancer SIR was 7.9 (95% CI, 1.2-53.0) for relatives of breast cancer patients, compared with 11.3 (3.6-35.9) for relatives of ovarian cancer patients (two-sided P = 0.37 for difference by site). Relatives' risks were independent of patients' ages at diagnosis, with one exception: In families ascertained through a breast cancer patient without BRCA mutations, breast cancer risks were higher if the patient had been diagnosed before age 40 years.In families of patients with and without BRCA1 mutations, breast and ovarian cancer risks correlate with the patient's cancer site. Moreover, in families of breast cancer patients without BRCA mutations, breast cancer risk depends on the patient's age at diagnosis. These patterns support the presence of genes that modify risk specific to cancer site, in both carriers and noncarriers of BRCA1 and BRCA2 mutations.

  View details for DOI 10.1158/1055-9965.EPI-05-0687

  View details for PubMedID 16492929

• The CHEK2*1100de/C allelic variant and risk of breast cancer: Screening results from the breast cancer family registry CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Bernstein, J. L., Teraoka, S. N., John, E. M., Andrulis, I. L., Knight, J. A., Lapinski, R., Olson, E. R., Wolitzer, A. L., Seminara, D., Whittemore, A. S., Concannon, P. 2006; 15 (2): 348-352

  Abstract

  CHEK2, a serine-threonine kinase, is activated in response to agents, such as ionizing radiation, which induce DNA double-strand breaks. Activation of CHEK2 can result in cell cycle checkpoint arrest or apoptosis. One specific variant, CHEK2*1100delC, has been associated with an increased risk of breast cancer. In this population-based study, we screened 2,311 female breast cancer cases and 496 general population controls enrolled in the Ontario and Northern California Breast Cancer Family Registries for this variant (all controls were Canadian). Overall, 30 cases and one control carried the 1100delC allele. In Ontario, the weighted mutation carrier frequency among cases and controls was 1.34% and 0.20%, respectively [odds ratio (OR), 6.65; 95% confidence interval (95% CI), 2.37-18.68]. In California, the weighted population mutation carrier frequency in cases was 0.40%. Across all cases, 1 of 524 non-Caucasians (0.19%) and 29 of 1,775 Caucasians (1.63%) were mutation carriers (OR, 0.12; 95% CI, 0.02-0.89). Among Caucasian cases >45 years age at diagnosis, carrier status was associated with history of benign breast disease (OR, 3.18; 95% CI, 1.30-7.80) and exposure to diagnostic ionizing radiation (excluding mammography; OR, 3.21; 95% CI, 1.13-9.14); compared with women without exposure to ionizing radiation, the association was strongest among women exposed >15 years before diagnosis (OR, 4.28; 95% CI, 1.50-12.20) and among those who received two or more chest X-rays (OR, 3.63; 95% CI, 1.25-10.52). These data supporting the biological relevance of CHEK2 in breast carcinogenesis suggest that further studies examining the joint roles of CHEK2*1100delC carrier status and radiation exposure may be warranted.

  View details for DOI 10.1158/1055-9965.EPI-05-0557

  View details for Web of Science ID 000235587200024

  View details for PubMedID 16492927

• Improved survival of Asians with corpus cancer compared with whites - An analysis of underlying factors OBSTETRICS AND GYNECOLOGY Zhang, M. M., Cheung, M. K., Osann, K., Lee, M. M., Gomez, S. S., Whittemore, A. S., Husain, A., Teng, N. N., Chan, J. K. 2006; 107 (2): 329-335

  Abstract

  To compare the clinicopathologic prognosticators and survival of Asians and whites with corpus cancer.Demographic, clinicopathologic, and survival data were obtained from the 1992-2001 Surveillance, Epidemiology, and End Results Program. Statistical analyses were performed by Kaplan-Meier methods and Cox proportional hazards model.A total of 2,144 Asians and 32,999 whites with corpus cancer were identified. The age-adjusted incidence of uterine cancer in Asians compared with whites was 16.8 compared with 26.1 per 100,000. Asians presented at a younger age (mean 58.4 years compared with 65.1; P < .01) and with more advanced stage disease than whites (21.5% compared with 15.4%; P < .01). The 5-year survival rate for Asians was 79.4% compared with 75.2% for whites (P < .01). Asians with stage I-II and III-IV cancers had 5-year survival rates of 89.3% and 41.2% compared with 82.3% and 34.0% for the whites, respectively (P < .01, early stage; P < .01, advanced stage). The survival advantage of Asians persists in endometrioid (P < .01) and uterine papillary serous carcinomas (P < .01), but not in clear cell carcinoma (P = .62) or sarcomas (P = .78). In multivariate analysis, younger age (P < .01), earlier stage (P < .01), favorable histology (P < .01), and lower grade (P < .01) remained as significant independent prognosticators for improved survival. However, race was not an important prognosticator.The overall survival advantage experienced by Asians with uterine cancer is attributable to their younger age at diagnosis. Because Asian women present at a younger age with more advanced disease, physicians should have an increased index of suspicion for malignancy in young Asian women with suspicious symptoms and consider a lower age threshold for biopsy in this group.II-2.

  View details for Web of Science ID 000241295400019

  View details for PubMedID 16449120

• Disengagement and social support moderate distress among women with a family history of breast cancer BREAST JOURNAL Turner-Cobb, J. M., Bloor, L. E., Whittemore, A. S., West, D., Spiegel, D. 2006; 12 (1): 7-15

  Abstract

  Using a cross-sectional, exploratory design, this pilot study analyzed the relationships between familial history of breast cancer and psychological distress in order to evaluate who is more distressed and to assess the possible need for intervention. Coping style, social support, and family relations were investigated as potential moderators of these relationships. Participants were 45 women with a familial history of breast cancer recruited from the Family Registry for Breast Cancer (FRBC) at the Northern California Cancer Center (NCCC). Contrary to previous reports of similar cohorts, the overall level of psychological distress in this cohort was comparable to normative samples. The number of relatives with breast cancer was related to distress as measured by the State-Trait Anxiety Inventory (STAI) scale, but there was no significant differentiation in distress associated with the number of first-degree as compared to second- and third-degree relatives with breast cancer. Having more relatives that had died from breast cancer was associated with greater distress on a number of measures. The number of first-degree relative deaths, including maternal death, was also associated with distress. Positive and network support, disengagement coping responses, and family cohesion were each significant moderators of the impact of family history on distress. This association between distress and disengagement is similar to that found in metastatic breast cancer patients themselves, and the findings suggest a subgroup that merits and might respond to more intensive intervention to provide support and facilitate emotional expression.

  View details for Web of Science ID 000235532900003

  View details for PubMedID 16409581

• An inverse association between ovarian cysts and breast cancer in the Breast Cancer Family Registry INTERNATIONAL JOURNAL OF CANCER Knight, J. A., John, E. M., Milne, R. L., Dite, G. S., Balbuena, R., Shi, E. J., Giles, G. G., Ziogas, A., Andrulis, I. L., Whittemore, A. S., Hopper, J. L. 2006; 118 (1): 197-202

  Abstract

  Ovarian cysts of several types are common in women of reproductive age. Their etiology is not well understood but is likely related to perturbations in the hypothalamic-pituitary-gonadal axis. The relationship of ovarian cysts to breast cancer risk is not known, although a negative association with polycystic ovarian syndrome has been reported. Incident, invasive female breast cancer cases, population-based controls and unaffected sisters of cases were studied from 3 countries participating in the Breast Cancer Family Registry: Melbourne and Sydney, Australia; the San Francisco Bay Area, USA; and Ontario, Canada. Using the same questionnaire, information was collected on self-reported history of ovarian cysts and other risk factors. Analyses were based on 3,049 cases, 2,344 population controls and 1,934 sister controls from all sites combined. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using both unconditional and conditional logistic regression using an offset term to account for sampling fractions at 2 of the sites. A significantly reduced risk of breast cancer was observed for women reporting a history of ovarian cysts (OR = 0.70, 95% CI 0.59-0.82, among all cases and all controls). This risk estimate was similar regardless of control group used, within all 3 sites and in both premenopausal and postmenopausal women (ORs ranging from 0.68-0.75, all 95% CI excluded 1.00). A self-reported history of ovarian cysts was strongly and consistently associated with a reduced risk of breast cancer. Further study of ovarian cysts may increase our understanding of hormonal and other mechanisms of breast cancer etiology.

  View details for DOI 10.1002/ijc.21298

  View details for Web of Science ID 000233376000027

  View details for PubMedID 16032703

• Short-term chloral hydrate administration and cancer in humans DRUG SAFETY Haselkorn, T., Whittemore, A. S., Udaltsova, N., Friedman, G. D. 2006; 29 (1): 67-77

  Abstract

  Chloral hydrate, used as a hypnosedative in adults and children, has been shown to be genotoxic and carcinogenic in animal studies. We investigated the potential causal association between chloral hydrate exposure and cancer risk in humans.Cancer incidence was previously determined via biennial screening analyses of the 215 most commonly used drugs between 1976 and 1998 for a cohort of 143,574 outpatients at Kaiser Permanente who had prescriptions filled between 1969 and 1973. Among users of chloral hydrate, statistically significant elevations in standardised morbidity ratios were observed during various years for cancer at five anatomical sites, including the lung, stomach, prostate, skin melanoma and mouth floor. In this analysis, these associations were investigated using: (i) a dose-response analysis among exposed subjects; and (ii) a two-stage design with exposed and non-exposed persons.There was evidence of an increasing risk of prostate cancer with increasing number of dispensings of chloral hydrate, which persisted after controlling for benign prostatic hypertrophy, vasectomy and obesity; however, the trend was not statistically significant. There was no evidence of a dose-response relationship between chloral hydrate and risk of any of the other four cancers. In the two-stage design, analyses comparing exposed and unexposed subjects showed no increased risk of cancer after controlling for confounding variables; however, the data were suggestive for prostate cancer, where the increased risk associated with chloral hydrate exposure after adjustment for confounding variables persisted. No dose-response relationship was seen for any of the other four cancer sites.To our knowledge, this is the first study to examine the relationship between chloral hydrate exposure and cancer risk in humans. There was no persuasive evidence to support a causal relationship between chloral hydrate exposure in humans and the development of cancer. However, statistical power was low for weak associations, particularly for some of the individual cancer sites. Although animal data using much higher doses of chloral hydrate have demonstrated its genotoxicity and carcinogenicity, the effects of chloral hydrate in humans are still uncertain.

  View details for Web of Science ID 000235639000005

  View details for PubMedID 16454535

• Polymorphisms in DNA repair genes and epithelial ovarian cancer risk INTERNATIONAL JOURNAL OF CANCER Auranen, A., Song, H. L., Waterfall, C., DiCioccio, R. A., Kuschel, B., Kjaer, S. K., Hogdall, E., Hogdall, C., Stratton, J., Whittemore, A. S., Easton, D. F., Ponder, B. A., Novik, K. L., Dunning, A. M., Gayther, S., Pharoah, P. D. 2005; 117 (4): 611-618

  Abstract

  DNA repair gene polymorphisms and mutations are known to influence cancer risk. We studied whether polymorphisms in DNA double strand break (DSB) repair genes are associated with epithelial ovarian cancer (EOC) risk. Up to 1,600 cases and 4,241 controls from 4 separate genetic association studies from 3 countries were genotyped for 13 single nucleotide polymorphisms (SNP) in 6 genes (BRCA1, NBS1, RAD51, RAD52, XRCC2 and XRCC3) involved in homologous recombination of DNA double strand breaks. Genotype specific risks were estimated as odds ratios (OR) by unconditional logistic regression. No association was detected between EOC risk and BRCA1 Q356R, BRCA1 P871L, RAD51 g135c, RAD51 g172t, RAD52 c2259t, NBS1 L34L, NBS1 E185Q, NBS1 A399A, NBS1 P672P, XRCC2 g4324c, XRCC2 c41657t and XRCC3 T241M. The XRCC2 R188H polymorphism was associated with a modest reduction in EOC risk: OR for heterozygotes was 0.8 (95% confidence interval [CI] = 0.7-1.0) and for rare homozygotes 0.3 (0.1-0.9). The XRCC3 a4541g polymorphism, situated in the 5'UTR, and the intronic XRCC3 a17893g polymorphism were not associated with EOC risk in general, but when the serous EOC subset only was analysed, the OR for heterozygotes for a4541g was 1.0 (0.9-1.2) and for the rare homozygotes 0.5 (0.3-0.9). For the XRCC3 a17893g polymorphism, the OR for the heterozygotes and the rare homozygotes were 0.8 (0.7-0.9) and 0.9 (0.7-1.2), respectively. In our study, some polymorphisms in XRCC2 and XRCC3 genes were associated with EOC risk. Further research on the role of these genes on epithelial ovarian cancer is warranted.

  View details for DOI 10.1002/ijc.21047

  View details for Web of Science ID 000232666500012

  View details for PubMedID 15924337

• Prostate specific antigen levels in young adulthood predict prostate cancer risk: Results from a cohort of black and white Americans JOURNAL OF UROLOGY Whittemore, A. S., Cirillo, P. M., Feldman, D., Cohn, B. A. 2005; 174 (3): 872-876

  Abstract

  Prostate specific antigen (PSA) is a serine protease produced by normal and malignant prostate epithelial cells. Serum PSA increases with age, due largely to age related increases in the prevalence of benign prostatic disease. Little is known about PSA distribution in young adulthood, when benign and malignant prostatic diseases are rare, or about how PSA within the normal range in youth relates to subsequent prostate cancer risk.We evaluated serum PSA and subsequent prostate cancer occurrence in a cohort of young black and white American men with a median age at blood draw of 34 years, who in 1959 to 1966 participated as the fathers of newborns enrolled in the Child Health and Development Study, and who were followed for several decades for prostate cancer. We examined associations between PSA in young adulthood and subsequent prostate cancer risk using a nested case-control design based on 119 black and 206 white cases with 2 control men matched to each case on race and year of birth.Prostate cancer risk increased with increasing PSA in black and white men. The OR comparing risk in the highest to lowest quartiles of PSA was 4.4 (95% CI 2.0 to 9.6) in black men and 3.5 (95% CI 2.0 to 6.1) in white men. ORs relating risk to PSA were higher when analysis was restricted to cases diagnosed before age 65 years.These findings suggest that PSA levels in young adulthood indicate increased risk of prostate cancer and, thus, they may be useful for targeting men for screening and early diagnosis.

  View details for DOI 10.1097/01.ju.0000169262.18000.8a

  View details for Web of Science ID 000231274700019

  View details for PubMedID 16093978

• Incidence of small bowel cancer in the United States and worldwide: geographic, temporal, and racial differences CANCER CAUSES & CONTROL Haselkorn, T., Whittemore, A. S., Lilienfeld, D. E. 2005; 16 (7): 781-787

  Abstract

  To examine the demographic and geographic patterns of small bowel cancer incidence in the United States and worldwide.Incidence data from the Surveillance, Epidemiology, and End Results (SEER) program between 1973 to 2000 were used to analyze the four histologic types of small bowel cancer, adenocarcinomas, carcinoid tumors, lymphomas, and sarcomas. International comparisons were made using data from Cancer Incidence in Five Continents (CIVIII). Geographic correlations between small bowel and both large bowel and stomach cancer incidence, were performed.Men had higher rates than women for all types of small bowel cancer. Blacks had almost double the incidence of carcinomas and carcinoid tumors compared to whites (10.6 vs. 5.6 per million people; 9.2 vs. 5.4 per million people, respectively). Small bowel cancer incidence has risen, with the greatest increase for carcinoid tumors (21%) and black men (120%). A geographic correlation between small and large bowel cancer incidence, but not small bowel and stomach cancer, were observed.Small bowel cancer incidence in the U.S. is higher in blacks compared to whites, particularly for carcinomas and carcinoid tumors. Small bowel cancer incidence is rising, particularly in black men. The geographic correlation between large and small bowel cancer suggests shared etiologies.

  View details for DOI 10.1007/s10552-005-3635-6

  View details for Web of Science ID 000231220800002

  View details for PubMedID 16132788

• A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics AMERICAN JOURNAL OF HUMAN GENETICS Xu, J. F., Dimitrov, L., Chang, B. L., Adams, T. S., Turner, A. R., Meyers, D. A., Eeles, R. A., Easton, D. F., Foulkes, W. D., Simard, J., Giles, G. G., Hopper, J. L., Mahle, L., Moller, P., Bishop, T., Evans, C., Edwards, S., Meitz, J., Bullock, S., Hope, Q., Hsieh, C. L., Halpern, J., Balise, R. N., Oakley-Girvan, I., Whittemore, A. S., Ewing, C. M., Gielzak, M., Isaacs, S. D., Walsh, P. C., Wiley, K. E., Isaacs, W. B., Thibodeau, S. N., McDonnell, S. K., Cunningham, J. M., Zarfas, K. E., Hebbring, S., Schaid, D. J., Friedrichsen, D. M., Deutsch, K., Kolb, S., Badzioch, M., Jarvik, G. P., Janer, M., Hood, L., Ostrander, E. A., Stanford, J. L., Lange, E. M., Beebe-Dimmer, J. L., Mohai, C. E., Cooney, K. A., Ikonen, T., Baffoe-Bonnie, A., Fredriksson, H., Matikainen, M. P., Tammela, T. L., Bailey-Wilson, J., Schleutker, J., Maier, C., Herkommer, K., Hoegel, J. J., Vogel, W., Paiss, T., Wiklund, F., Emanuelsson, M., Stenman, E., Jonsson, B. A., Gronberg, H., Camp, N. J., Farnham, J., Cannon-Albright, L. A., Seminara, D. 2005; 77 (2): 219-229

  Abstract

  Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric (dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score >1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of < or = 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study.

  View details for Web of Science ID 000230387200004

  View details for PubMedID 15988677

• Genetic association studies: Time for a new paradigm? CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Whittemore, A. S. 2005; 14 (6): 1359-1360

  View details for Web of Science ID 000229766600003

  View details for PubMedID 15941936

• Serum steroid hormones in young manhood and the risk of subsequent prostate cancer Joint Meeting of the Society-for-Epidemiologic-Research/Canadian-Society-for-Epidemiology-and-Biostatistics Tsai, C. J., Cohn, B. A., Cirillo, P. M., Feldman, D., Whittemore, A. S. OXFORD UNIV PRESS INC. 2005: S16–S16

  View details for Web of Science ID 000229594100064

• Covariate adjustment in family-based association studies GENETIC EPIDEMIOLOGY Whittemore, A. S., Halpern, J., Ahsan, H. 2005; 28 (3): 244-255

  Abstract

  Family-based tests of association between a candidate locus and a disease evaluate how often a variant allele at the locus is transmitted from parents to offspring. These tests assume that in the absence of association, an affected offspring is equally likely to have inherited either one of the two homologous alleles carried by a parent. However, transmission distortion was documented in families in which the offspring are unselected for phenotype. Moreover, if offspring genotypes are associated with a risk factor for the disease, transmission distortion to affected offspring can occur in the absence of a causal relation between gene and disease risk. We discuss the appropriateness of adjusting for established risk factors when evaluating association in family-based studies. We present methods for adjusting the transmission/disequilibrium test for risk factors when warranted, and we apply them to data on CYP19 (aromatase) genotypes in nuclear families with multiple cases of breast cancer. Simulations show that when genotypes are correlated with risk factors, the unadjusted test statistics have inflated size, while the adjusted ones do not. The covariate-adjusted tests are less powerful than the unadjusted ones, suggesting the need to check the relationship between genotypes and known risk factors to verify that adjustment is needed. The adjusted tests are most useful for data containing a large proportion of families that lack disease-discordant sibships, i.e., data for which multiple logistic regression of matched sibships would have little power. Software for performing the covariate-adjusted tests is available at http://www.stanford.edu/dept/HRP/epidemiology/COVTDT.

  View details for DOI 10.1002/gepi.20055

  View details for Web of Science ID 000227898400005

  View details for PubMedID 15593089

• Re: Reason for late-stage breast cancer: Absence of screening or detection, or breakdown in follow-up? JOURNAL OF THE NATIONAL CANCER INSTITUTE Whittemore, A. S. 2005; 97 (5): 400-400

  View details for DOI 10.1093/jnci/dji062

  View details for Web of Science ID 000227352800016

  View details for PubMedID 15741577

• Oral contraceptive use and risk of early-onset breast cancer in carriers and noncarriers of BRCA1 and BRCA2 mutations CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Milne, R. L., Knight, J. A., John, E. M., Dite, G. S., Balbuena, R., Ziogas, A., Andrulis, I. L., West, D. W., Li, F. P., Southey, M. C., Giles, G. G., McCredie, M. R., Hopper, J. L., Whittemore, A. S. 2005; 14 (2): 350-356

  Abstract

  Recent oral contraceptive use has been associated with a small increase in breast cancer risk and a substantial decrease in ovarian cancer risk. The effects on risks for women with germ line mutations in BRCA1 or BRCA2 are unclear.Subjects were population-based samples of Caucasian women that comprised 1,156 incident cases of invasive breast cancer diagnosed before age 40 (including 47 BRCA1 and 36 BRCA2 mutation carriers) and 815 controls from the San Francisco Bay area, California, Ontario, Canada, and Melbourne and Sydney, Australia. Relative risks by carrier status were estimated using unconditional logistic regression, comparing oral contraceptive use in case groups defined by mutation status with that in controls.After adjustment for potential confounders, oral contraceptive use for at least 12 months was associated with decreased breast cancer risk for BRCA1 mutation carriers [odds ratio (OR), 0.22; 95% confidence interval (CI), 0.10-0.49; P < 0.001], but not for BRCA2 mutation carriers (OR, 1.02; 95% CI, 0.34-3.09) or noncarriers (OR, 0.93; 95% CI, 0.69-1.24). First use during or before 1975 was associated with increased risk for noncarriers (OR, 1.52 per year of use before 1976; 95% CI, 1.22-1.91; P < 0.001).There was no evidence that use of current low-dose oral contraceptive formulations increases risk of early-onset breast cancer for mutation carriers, and there may be a reduced risk for BRCA1 mutation carriers. Because current formulations of oral contraceptives may reduce, or at least not exacerbate, ovarian cancer risk for mutation carriers, they should not be contraindicated for a woman with a germ line mutation in BRCA1 or BRCA2.

  View details for Web of Science ID 000227113800010

  View details for PubMedID 15734957

• Histologic types of epithelial ovarian cancer: have they different risk factors? GYNECOLOGIC ONCOLOGY Kurian, A. W., Balise, R. R., McGuire, V., Whittemore, A. S. 2005; 96 (2): 520-530

  Abstract

  The histologic types of epithelial ovarian cancer differ in clinical behavior, descriptive epidemiology, and genetic origins. The goals of the current study were to characterize further the relation of histologic-specific ovarian cancer risks to reproductive and lifestyle attributes.The authors conducted a pooled analysis of 10 case-control studies of ovarian cancer in US White women, involving 1834 patients with invasive epithelial ovarian cancer (1067 serous, 254 mucinous, 373 endometrioid, and 140 clear cell) and 7484 control women.Risks of all four histological types were inversely associated with parity and oral contraceptive use, but the histologic types showed different associations with nonreproductive factors. Unique associations include an inverse relation of serous cancer risk to body mass index, a positive relation of mucinous cancer risk to cigarette smoking, and a weakly positive relation of endometrioid cancer risk to body mass index. Risk of all histologic types was unassociated with age at menarche, age at menopause, a history of infertility, noncontraceptive estrogen use, and alcohol consumption.The most important modifiers of ovarian cancer risk (parity and oral contraceptive use) showed similar associations across the histologies. Nevertheless, the unique associations seen for other modifiers support the conjecture that the histologic types of epithelial ovarian cancer have different etiologies, which should be addressed in future investigations of the molecular basis of ovarian cancers and their responses to therapies.

  View details for DOI 10.1016/j.gygno.2004.10.037

  View details for Web of Science ID 000226636600041

  View details for PubMedID 15661246

• Response to C. Bosetti et al. (Trends in colorectal cancer mortality in Japan, 1970-2000) INTERNATIONAL JOURNAL OF CANCER Yin, H. Y., Whittemore, A. S., Shibata, A. 2005; 113 (2): 342-342

  View details for DOI 10.1002/ijc.20554

  View details for Web of Science ID 000225717500025

  View details for PubMedID 15476198

• Variants in estrogen-biosynthesis genes CYP17 and CYP19 and breast cancer risk: a family-based genetic association study BREAST CANCER RESEARCH Ahsan, H., Whittemore, A. S., Chen, Y., Senie, R. T., Hamilton, S. P., Wang, Q., Gurvich, I., Santella, R. M. 2005; 7 (1): R71-R81

  Abstract

  Case-control studies have reported inconsistent results concerning breast cancer risk and polymorphisms in genes that control endogenous estrogen biosynthesis. We report findings from the first family-based association study examining associations between female breast cancer risk and polymorphisms in two key estrogen-biosynthesis genes CYP17 (T-->C promoter polymorphism) and CYP19 (TTTA repeat polymorphism).We conducted the study among 278 nuclear families containing one or more daughters with breast cancer, with a total of 1123 family members (702 with available constitutional DNA and questionnaire data and 421 without them). These nuclear families were selected from breast cancer families participating in the Metropolitan New York Registry, one of the six centers of the National Cancer Institute's Breast Cancer Family Registry. We used likelihood-based statistical methods to examine allelic associations.We found the CYP19 allele with 11 TTTA repeats to be associated with breast cancer risk in these families. We also found that maternal (but not paternal) carrier status of CYP19 alleles with 11 repeats tended to be associated with breast cancer risk in daughters (independently of the daughters' own genotype), suggesting a possible in utero effect of CYP19. We found no association of a woman's breast cancer risk either with her own or with her mother's CYP17 genotype.This family-based study indicates that a woman's personal and maternal carrier status of CYP19 11 TTTA repeat allele might be related to increased breast cancer risk. However, because this is the first study to report an association between CYP19 11 TTTA repeat allele and breast cancer, and because multiple comparisons have been made, the associations should be interpreted with caution and need confirmation in future family-based studies.

  View details for DOI 10.1186/bcr951

  View details for Web of Science ID 000226247000019

  View details for PubMedID 15642171

  View details for PubMedCentralID PMC1064100

• Breast cancer risks for BRCA1/2 carriers SCIENCE Easton, D. F., Hopper, J. L., Thomas, D. C., Antoniou, A., Pharoah, P. D., Whittemore, A. S., Haile, R. W. 2004; 306 (5705): 2187-2188

  View details for Web of Science ID 000225950000015

  View details for PubMedID 15622557

• Prevalence of BRCA1 mutation carriers among US non-Hispanic Whites CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Whittemore, A. S., Gong, G., John, E. M., McGuire, V., Li, F. P., Ostrow, K. L., DiCioccio, R., Felberg, A., West, D. W. 2004; 13 (12): 2078-2083

  Abstract

  Data from several countries indicate that 1% to 2% of Ashkenazi Jews carry a pathogenic ancestral mutation of the tumor suppressor gene BRCA1. However, the prevalence of BRCA1 mutations among non-Ashkenazi Whites is uncertain. We estimated mutation carrier prevalence in U.S. non-Hispanic Whites, specific for Ashkenazi status, using data from two population-based series of San Francisco Bay Area patients with invasive cancers of the breast or ovary, and data on breast and ovarian cancer risks in Ashkenazi and non-Ashkenazi carriers. Assuming that 90% of the BRCA1 mutations were detected, we estimate a carrier prevalence of 0.24% (95% confidence interval, 0.15-0.39%) in non-Ashkenazi Whites, and 1.2% (95% confidence interval, 0.5-2.6%) in Ashkenazim. When combined with U.S. White census counts, these prevalence estimates suggest that approximately 550,513 U.S. Whites (506,206 non-Ashkenazim and 44,307 Ashkenazim) carry germ line BRCA1 mutations. These estimates may be useful in guiding resource allocation for genetic testing and genetic counseling and in planning preventive interventions.

  View details for PubMedID 15598764

• Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations BRITISH JOURNAL OF CANCER Whittemore, A. S., Balise, R. R., Pharoah, P. D., DiCioccio, R. A., Oakley-Girvan, I., Ramus, S. J., Daly, M., Usinowicz, M. B., Garlinghouse-Jones, K., Ponder, B. A., Buys, S., Senie, R., Andrulis, I., John, E., Hopper, J. L., Piver, M. S. 2004; 91 (11): 1911-1915

  Abstract

  Women with mutations of the genes BRCA1 or BRCA2 are at increased risk of ovarian cancer. Oral contraceptives protect against ovarian cancer in general, but it is not known whether they protect against the disease in carriers of these mutations. We obtained self-reported lifetime histories of oral contraceptive use from 451 women who carried mutations of BRCA1 or BRCA2. We used conditional logistic regression to estimate the odds ratios associated with oral contraceptive use, comparing the histories of 147 women with ovarian cancer (cases) to those of 304 women without ovarian cancer (controls) who were matched to cases on year of birth, country of residence and gene (BRCA1 vs BRCA2). Reference ages for controls had to exceed the ages at diagnosis of their matched cases. After adjusting for parity, the odds-ratio for ovarian cancer associated with use of oral contraceptives for at least 1 year was 0.85 (95 percent confidence interval, 0.53-1.36). The risk decreased by 5% (1-9%) with each year of use (P for trend=0.01). Use for 6 or more years was associated with an odds-ratio of 0.62 (0.35-1.09). These data support the hypothesis that long-term oral contraceptive use reduces the risk of ovarian cancer among women who carry mutations of BRCA1 or BRCA2.

  View details for DOI 10.1038/sj.bjc.6602239

  View details for PubMedID 15545966

• Classifying disease chromosomes arising from multiple founders, with application to fine-scale haplotype mapping GENETIC EPIDEMIOLOGY Yu, K., MARTIN, R. B., Whittemore, A. S. 2004; 27 (3): 173-181

  Abstract

  The availability of high-density haplotype data has motivated several fine-scale linkage disequilibrium mapping methods for locating disease-causing mutations. These methods identify loci around which haplotypes of case chromosomes exhibit greater similarity than do those of control chromosomes. A difficulty arising in such mapping is the possibility that case chromosomes have inherited disease-causing mutations from different ancestral chromosomes (founder heterogeneity). Such heterogeneity dilutes measures of case haplotype similarity. This dilution can be mitigated by separating case chromosomes into subsets according to their putative mutation origin, and searching for an area with excessive haplotype similarity within each subset. We propose a nonparametric method for identifying subsets of case chromosomes likely to share a common ancestral progenitor. By simulation studies and application to published data, we show that the method accurately identifies relatively large subsets of chromosomes that share a common founder. We also show that the method allows more precise estimates of the disease mutation loci than obtained by other fine-scale mapping methods.

  View details for DOI 10.1002/gepi.20016

  View details for Web of Science ID 000224813200001

  View details for PubMedID 15389930

• Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations AMERICAN JOURNAL OF EPIDEMIOLOGY McGuire, V., Felberg, A., Mills, M., Ostrow, K. L., DiCioccio, R., John, E. M., West, D. W., Whittemore, A. S. 2004; 160 (7): 613-618

  Abstract

  In the general population, ovarian cancer risk is inversely associated with oral contraceptive use, tubal ligation, and childbearing. Among carriers of BRCA1 gene mutations, the data are conflicting. The authors identified women diagnosed with incident invasive epithelial ovarian cancer in the San Francisco Bay Area of California from March 1997 through July 2001. They compared the contraceptive and reproductive histories of 36 carrier cases and 381 noncarrier cases with those of 568 controls identified by random digit dialing who were frequency matched to cases on age and race/ethnicity. In both carriers and noncarriers, reduced risk was associated with ever use of oral contraceptives (odds ratio = 0.54 (95% confidence interval (CI): 0.26, 1.13) for carriers and 0.55 (95% CI: 0.41, 0.73) for noncarriers), duration of oral contraceptive use (risk reduction per year = 13% (p = 0.01) for carriers and 6% (p < 0.001) for noncarriers), history of tubal ligation (odds ratio = 0.68 (95% CI: 0.25, 1.90) for carriers and 0.65 (95% CI: 0.45, 0.95) for noncarriers), and increasing parity (risk reduction per childbirth = 16% (p = 0.26) for carriers and 24% (p < 0.001) for noncarriers). These data suggest that BRCA1 mutation carriers and noncarriers have similar risk reductions associated with oral contraceptive use, tubal ligation, and parity.

  View details for PubMedID 15383404

• STK15 polymorphisms and association with risk of invasive ovarian cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION DiCioccio, R. A., Song, H. L., Waterfall, C., Kimura, M. T., Nagase, H., McGuire, V., Hogdall, E., Shah, M. N., Luben, R. N., Easton, D. F., Jacobs, I. J., Ponder, B. A., Whittemore, A. S., Gayther, S. A., Pharoah, P. D., Kruger-Kjaer, S. 2004; 13 (10): 1589-1594

  Abstract

  STK15 is a putative oncogene that codes for a centrosome-associated, serine/threonine kinase, the normal function of which is to ensure accurate segregation of chromosomes during mitosis. Amplification of STK15 has been reported in ovarian tumors, suggesting a role in ovarian cancer pathology. STK15 is polymorphic with two single nucleotide substitutions (449t/a and 527g/a) in evolutionarily conserved regions causing amino acid changes (F31I and V57I). Two other nucleotide substitutions (287c/g and 1891g/c) of unknown significance are in 5' and 3' untranslated regions (UTR), respectively. To learn more about the involvement of STK15 in ovarian cancer, we genotyped and haplotyped these polymorphisms in three population-based ovarian cancer case-control studies from the United Kingdom, United States, and Denmark with 1,821 combined cases and 2,467 combined controls and calculated risks for developing ovarian cancer. Genotypes of individual polymorphisms in control groups of the United Kingdom, United States, and Denmark conformed to Hardy-Weinberg equilibrium. In combined cases and combined controls, rare allele frequencies were 0.23 and 0.21 for I31, 0.16 and 0.17 for I57, 0.08 and 0.07 for 5' UTR g, and 0.25 and 0.24 for 3' UTR c, respectively. Using FF common homozygotes of F31I as comparator, there was increased ovarian cancer risk to FI heterozygotes (odds ratio, 1.18; 95% confidence interval, 1.01-1.36), II homozygotes (odds ratio, 1.25; 95% confidence interval, 0.89-1.75), and I31 allele carriers (odds ratio, 1.17; 95% confidence interval, 1.02-1.35) in the combined group data. For either V57I, 5' UTR C/G, or 3' UTR G/C, all genotypic ovarian cancer risks were essentially in unity relative to their respective common homozygotes, VV, cc, or gg. Haplotype analysis of combined group data revealed seven haplotypes with frequencies between 0.02 and 0.5, with c-F-V-g the most common. None of the haplotype-specific risks significantly differed from unity relative to c-F-V-g. These results suggest a model of dominant inheritance of ovarian cancer risk by the I31 allele of F31I and that the I31 allele may be a common ovarian cancer susceptibility allele of low penetrance.

  View details for Web of Science ID 000224453700008

  View details for PubMedID 15466974

• The effects of BRCA1 missense variants V1804D and M1628T on transcriptional activity CANCER GENETICS AND CYTOGENETICS Ostrow, K. L., McGuire, V., Whittemore, A. S., DiCioccio, R. A. 2004; 153 (2): 177-180

  Abstract

  Many families with multiple cases of ovarian cancer, breast cancer, or both segregate inherited mutations in one allele of the tumor suppressor gene BRCA1. Genetic testing is used to assess cancer risk; however, testing can detect missense DNA alterations, called unclassified variants, of unknown functional and biological significance with uncertain risk implications. Some missense variants at the transcriptional activation domain of BRCA1 of cancer patients inactivate transcriptional activity of BRCA1, providing evidence that they are deleterious. We identified the variants V1804D and M1628T at the transcriptional activation domain of BRCA1 of two ovarian cancer patients without a family history of ovarian or breast cancer. To test if these residues are critical for transcriptional activation, we created V1804D and M1628T independently in BRCA1 cDNA via site-directed mutagenesis in a mammalian expression vector, pcDNA3.1. Wild-type, mutant, and empty vector constructs were tested in human kidney 293 cells using a p53-responsive luciferase reporter. M1628T had the same transcriptional activity as wild-type BRCA1 but V1804D and the empty vector control showed a 60% reduction. This indicates that V1804D is deleterious but M1628T is not.

  View details for DOI 10.1016/j.cancergencyto.2004.01.020

  View details for Web of Science ID 000224115800014

  View details for PubMedID 15350310

• Role of Ethnicity in Risk for Hepatocellular Carcinoma in Patients With Chronic Hepatitis C and Cirrhosis CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Nguyen, M. H., Whittemore, A. S., Garcia, R. T., Tawfeek, S. A., Ning, J., Lam, S., Wright, T. L., Keeffe, E. B. 2004; 2 (9): 820-824

  Abstract

  In the United States, hepatocellular carcinoma (HCC) is more common among Asians and African Americans than Caucasians, with chronic hepatitis C virus (HCV) infection accounting for up to half of the patients. Our study examined ethnicity as a potential risk factor for HCC among patients with chronic hepatitis C.We conducted a case-control study of 464 patients with chronic hepatitis C and cirrhosis (207 cancer patients and 257 controls) using medical records and pathology records at 4 medical centers. We estimated odds ratios with 95% confidence intervals by using conditional logistic regression on case-control sets, matched within study centers and study period on sex and age groups (< or =45, 46-55, 56-65, >65 yr). To control for potential confounding caused by severity of cirrhosis and residual confounding caused by age, we also included Child-Turcotte-Pugh (CTP) scores and age (continuous variable) in all regression analyses.Compared with Caucasians, the cancer risk was increased significantly among Asians (adjusted odds ratio, 4.3; 95% confidence interval, 2.1-9.0 for men, and 4.6; 1.2-18.5 for women) and somewhat increased among African-American men (adjusted odds ratio, 2.4; 95% confidence interval, 0.9-6.3).This study suggests that, among patients with chronic hepatitis C and cirrhosis, liver cancer risk is increased 4-fold in Asians and may be doubled in African-American men, compared with Caucasians. These results need confirmation in larger studies from racially diverse populations, but, if confirmed, these results point to high-risk populations that should be targeted for screening and preventive efforts.

  View details for DOI 10.1053/S1542-3565(04)00353-2

  View details for Web of Science ID 000208072100013

  View details for PubMedID 15354283

• Risk of early-onset prostate cancer in relation to germ line polymorphisms of the vitamin D receptor CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Oakley-Girvan, I., Feldman, D., Eccleshall, T. R., Gallagher, R. P., Wu, A. H., Kolonel, L. N., Halpern, J., Balise, R. R., West, D. W., Paffenbarger, R. S., Whittemore, A. S. 2004; 13 (8): 1325-1330

  Abstract

  Vitamin D inhibits prostate cancer cell growth, angiogenesis, and metastasis. These actions are mediated by the vitamin D receptor. We examined associations between prostate cancer risk and five polymorphisms in the VDR gene: four single nucleotide polymorphisms (FokI, BsmI, ApaI, and TaqI restriction sites) and the polyadenylic acid microsatellite. Specifically, we genotyped population-based samples of young African Americans (113 cases and 121 controls) and Whites (232 cases and 171 controls) and members of 98 predominantly White families with multiple cases of prostate cancer. Among Whites, there was no evidence for association between prostate cancer risk and alleles at any of the five polymorphic sites regardless of how the men were ascertained. Moreover, estimated five-locus haplotype frequencies were similar in White cases and controls. Among African Americans, prostate cancer risk was associated with homozygosity for the F allele at the FokI site (odds ratio 1.9, 95% confidence interval 1.0-3.3). In addition, estimated haplotype frequencies differed significantly (P < 0.01) between African American cases and controls. These findings need replication in other studies of African Americans. Homozygosity for the F allele at the FokI site is more prevalent in the African American population than in U.S. Whites. If the FokI association noted here were causal, this difference could account for some of the disease burden among African Americans and some of the excess risk in African Americans compared with Whites.

  View details for Web of Science ID 000223155500010

  View details for PubMedID 15298953

• A family-based genetic association study of variants in estrogen-metabolism genes COMT and CYP1B1 and breast cancer risk BREAST CANCER RESEARCH AND TREATMENT Ahsan, H., Chen, Y., Whittemore, A. S., Kibriya, M. G., Gurvich, I., Senie, R. T., Santella, R. M. 2004; 85 (2): 121-131

  Abstract

  In this paper, we report findings from a family-based association study examining the association between polymorphisms in two key estrogen-metabolism genes CYP1B1 (codon 432 G --> C and codon 453 A --> G variants) and COMT (codon 158 G --> A variant) and female breast cancer. We conducted the study among 280 nuclear families containing one or more daughters with breast cancer with a total of 1124 family members (702 with available constitutional DNA and questionnaire data and 421 without). These nuclear families were selected from breast cancer families participating in the Metropolitan New York Registry (MNYR) - one of the six centers of NCI's Breast Cooperative Family Registry. We used likelihood-based statistical methods to examine the allelic associations. We found none of the variant alleles of the CYP1B1 and COMT genes to be associated with breast cancer in these families. This was consistent with results from matched case-control analyses using all available sib-ships in these families. However, we found that parental carrier status of the CYP1B1 codon 453 variant G allele and the COMT codon 158 variant A allele was associated with breast cancer risk in daughters (independent of the daughters' own genotype). In conclusion, findings from this family-based study indicate that a woman's own CYP1B1 or COMT genotypes are not associated with her breast cancer risk. Although the study found that parental carrier status of certain CYP1B1 or COMT genotypes might be associated with daughter's breast cancer risk, the biological basis as well as independent confirmation of this finding need to be investigated in future larger family-based studies before making meaningful inferences.

  View details for Web of Science ID 000221057400003

  View details for PubMedID 15111770

• Increasing colorectal cancer incidence rates in Japan INTERNATIONAL JOURNAL OF CANCER Yiu, H. Y., Whittemore, A. S., Shibata, A. 2004; 109 (5): 777-781

  Abstract

  We examined trends of colorectal cancer incidence rates among Japanese (Miyagi Prefecture) and United States (US) whites (State of Connecticut) between 1959 and 1992. Age-standardized rates in Japan have increased dramatically and are now similar to US white rates. For both colon and rectum, age-specific rates in Japanese men born after 1930 exceed those in US whites, and the Japanese excess increases with year of birth. Similar patterns are evident for women. The current trends suggest that colorectal cancer will become a major source of morbidity and mortality in Japan, as these young Japanese age and their risks increase.

  View details for DOI 10.1002/ijc.20030

  View details for Web of Science ID 000220524000022

  View details for PubMedID 14999789

• Estimating genetic association parameters from family data BIOMETRIKA Whittemore, A. S. 2004; 91 (1): 219-225

  View details for Web of Science ID 000220652500016

• The Breast Cancer Family Registry: an infrastructure for cooperative multinational, interdisciplinary and translational studies of the genetic epidemiology of breast cancer BREAST CANCER RESEARCH John, E. M., Hopper, J. L., Beck, J. C., Knight, J. A., Neuhausen, S. L., Senie, R. T., Ziogas, A., Andrulis, I. L., Anton-Culver, H., Boyd, N., Buys, S. S., Daly, M. B., O'Malley, F. P., Santella, R. M., Southey, M. C., Venne, V. L., Venter, D. J., West, D. W., Whittemore, A. S., Seminara, D. 2004; 6 (4): R375-R389

  Abstract

  The etiology of familial breast cancer is complex and involves genetic and environmental factors such as hormonal and lifestyle factors. Understanding familial aggregation is a key to understanding the causes of breast cancer and to facilitating the development of effective prevention and therapy. To address urgent research questions and to expedite the translation of research results to the clinical setting, the National Cancer Institute (USA) supported in 1995 the establishment of a novel research infrastructure, the Breast Cancer Family Registry, a collaboration of six academic and research institutions and their medical affiliates in the USA, Canada, and Australia.The sites have developed core family history and epidemiology questionnaires, data dictionaries, and common protocols for biospecimen collection and processing and pathology review. An Informatics Center has been established to collate, manage, and distribute core data.As of September 2003, 9116 population-based and 2834 clinic-based families have been enrolled, including 2346 families from minority populations. Epidemiology questionnaire data are available for 6779 affected probands (with a personal history of breast cancer), 4116 unaffected probands, and 16,526 relatives with or without a personal history of breast or ovarian cancer. The biospecimen repository contains blood or mouthwash samples for 6316 affected probands, 2966 unaffected probands, and 10,763 relatives, and tumor tissue samples for 4293 individuals.This resource is available to internal and external researchers for collaborative, interdisciplinary, and translational studies of the genetic epidemiology of breast cancer. Detailed information can be found at the URL http://www.cfr.epi.uci.edu/.

  View details for DOI 10.1186/bcr801

  View details for Web of Science ID 000222828200022

  View details for PubMedID 15217505

  View details for PubMedCentralID PMC468645

• Histopathology, FIGO stage, and BRCA mutation status of ovarian cancers from the Gilda Radner Familial Ovarian Cancer Registry INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY Werness, B. A., Ramus, S. J., DiCioccio, R. A., Whittemore, A. S., Garlinghouse-Jones, K., Oakley-Girvan, I., Tsukada, Y., Harrington, P., Gayther, S. A., Ponder, B. A., Piver, M. S. 2004; 23 (1): 29-34

  Abstract

  Studies of the histopathology of ovarian cancer arising in patients with germline mutations in BRCA1 or BRCA2 have shown inconsistent findings. We analyzed the large number of tumors from women enrolled in the Gilda Radner Familial Ovarian Cancer Registry for correlations between histopathology and BRCA mutation status. Histopathology slides and reports were reviewed for histology, grade, and stage for cancers of the ovary or peritoneum in 220 women from 126 Gilda Radner Familial Ovarian Cancer Registry families. At least one affected member of each family was analyzed for mutations in the BRCA1 and BRCA2 genes, and tumors from mutation-positive families were compared with those from mutation-negative families. Of 70 patients from 38 BRCA1-positive families, 69 had epithelial ovarian carcinoma and one had a dysgerminoma. Fifteen of 16 patients from nine BRCA2-positive families had epithelial ovarian cancer, and one had a primary peritoneal cancer. Of 134 patients from 79 BRCA-negative families, 118 had epithelial ovarian carcinoma, 11 had ovarian borderline tumors, three had nonepithelial tumors, and two had primary peritoneal carcinoma. There were fewer grade 1 (p < 0.001) and stage I (p = 0.005) cancers in patients from BRCA-positive families than in patients from BRCA-negative families. Neither mucinous nor borderline tumors were found in the BRCA-positive families. In conclusion, ovarian cancers arising in women from BRCA-positive families are more likely to be high-grade and have extraovarian spread than tumors arising in women from BRCA-negative families. Borderline and mucinous tumors do not appear to be part of the phenotype of families with germline mutations in the BRCA genes.

  View details for DOI 10.1097/01.pgp.0000101083.35393.cd

  View details for Web of Science ID 000187434700006

  View details for PubMedID 14668547

• Where are the prostate cancer genes? A summary of eight genome wide searches PROSTATE Easton, D. F., Schaid, D. J., Whittemore, A. S., Isaacs, W. J. 2003; 57 (4): 261-269

  Abstract

  There is strong evidence for genetic susceptibility to prostate cancer, but most of the genes underlying this susceptibility remain to be identified.We reviewed the results of eight genome-wide linkage searches based on 1,293 families with multiple cases of prostate cancer.Across these studies, 11 linkage peaks with LOD scores in excess of 2 were identified. However, no chromosomal region was reported as significant at this level by more than one study and only one corresponded to a peak previously suggested by another group.These results indicate that prostate cancer is genetically complex, and that combined analyses of large family sets will be required to evaluate reliably the linkage evidence.

  View details for DOI 10.1002/pros.10300

  View details for Web of Science ID 000186871700002

  View details for PubMedID 14601022

• Logistic regression of family data from retrospective study designs GENETIC EPIDEMIOLOGY Whittemore, A. S., Halpern, J. 2003; 25 (3): 177-189

  Abstract

  We wish to study the effects of genetic and environmental factors on disease risk, using data from families ascertained because they contain multiple cases of the disease. To do so, we must account for the way participants were ascertained, and for within-family correlations in both disease occurrences and covariates. We model the joint probability distribution of the covariates of ascertained family members, given family disease occurrence and pedigree structure. We describe two such covariate models: the random effects model and the marginal model. Both models assume a logistic form for the distribution of one person's covariates that involves a vector beta of regression parameters. The components of beta in the two models have different interpretations, and they differ in magnitude when the covariates are correlated within families. We describe ascertainment assumptions needed to estimate consistently the parameters beta(RE) in the random effects model and the parameters beta(M) in the marginal model. Under the ascertainment assumptions for the random effects model, we show that conditional logistic regression (CLR) of matched family data gives a consistent estimate beta(RE) for beta(RE) and a consistent estimate for the covariance matrix of beta(RE). Under the ascertainment assumptions for the marginal model, we show that unconditional logistic regression (ULR) gives a consistent estimate for beta(M), and we give a consistent estimator for its covariance matrix. The random effects/CLR approach is simple to use and to interpret, but it can use data only from families containing both affected and unaffected members. The marginal/ULR approach uses data from all individuals, but its variance estimates require special computations. A C program to compute these variance estimates is available at http://www.stanford.edu/dept/HRP/epidemiology. We illustrate these pros and cons by application to data on the effects of parity on ovarian cancer risk in mother/daughter pairs, and use simulations to study the performance of the estimates.

  View details for DOI 10.1002/gepi.10267

  View details for PubMedID 14557986

• Stage at diagnosis and survival in a multiethnic cohort of prostate cancer patients AMERICAN JOURNAL OF PUBLIC HEALTH Oakley-Girvan, I., Kolonel, L. N., Gallagher, R. P., Wu, A. H., Felberg, A., Whittemore, A. S. 2003; 93 (10): 1753-1759

  Abstract

  We evaluated the effects of socioeconomic status and comorbidity on stage of disease and survival among 1509 population-based prostate cancer patients.We applied logistic regression and Cox proportional hazards regression to data from Whites, African Americans, and Asian Americans who were diagnosed from 1987 to 1991.Patients with existing comorbid conditions were less likely than those without these conditions to be diagnosed with advanced cancer. Compared with Whites, African Americans (odds ratio [OR] = 1.5; 95% confidence interval [CI] = 1.1, 2.2) and foreign-born Asian Americans (OR = 1.6; 95% CI = 1.0, 2.4) were more likely to be diagnosed with advanced cancer. Among men with localized disease, prostate cancer death rates were higher for African Americans than for Whites (death rate ratio = 2.3; 95% CI = 1.2, 4.7).These findings support the need for further investigation of factors that affect access to and use of health care among African Americans and Asian Americans.

  View details for Web of Science ID 000185881100031

  View details for PubMedID 14534233

• Genetic association tests for family data with missing parental genotypes: A comparison GENETIC EPIDEMIOLOGY Whittemore, A. S., Halpern, J. 2003; 25 (1): 80-91

  Abstract

  We consider three tests for genetic association in data from nuclear families (the Family-Based Association Test (FBAT) test proposed by Rabinowitz and Laird ([2000] Hum. Hered. 50:211-223), a second test proposed by Rabinowitz ([2002] J. Am. Stat. Assoc. 97:742-758), and the Family Genotype Analysis Program (FGAP) nonfounder or partial score test proposed by Clayton ([1999] Am. J. Hum. Genet. 65:1170-1177) and Whittemore and Tu ([2000] Am. J. Hum. Genet. 66:1329-1340)). We show that each test statistic arises from the efficient score of the family data as the solution to a set of constraints on its null expectation. Moreover, the FBAT and Rabinowitz tests (but not the FGAP test) are locally the most powerful among all tests satisfying their constraints. We used simulations to examine how the three tests perform in situations when their assumptions are violated and the number of families is not huge. We found that the FBAT test tended to have less power than the other two tests, particularly when applied to families in whom all offspring were affected. The Rabinowitz and FGAP tests performed similarly, although the latter tended to extract more information from families containing one typed parent. While none of the tests showed good power to detect rare, recessively acting genes, the Rabinowitz test with a sample variance estimate performed particularly poorly in this case. However, the Rabinowitz test with a model-based variance had power comparable to that of the FGAP test, and more accurate type I error rates. We conclude that for the situations we considered, the Rabinowitz test with model-based variance has good power without forfeiting robustness against misspecification of parental genotype probabilities. However, its utility is limited by the lack of a simple algorithm to apply it to families with varying structures and phenotypes.

  View details for DOI 10.1002/gepi.10247

  View details for Web of Science ID 000183909000008

  View details for PubMedID 12813729

• Optimal designs for estimating penetrance of rare mutations of a disease-susceptibility gene GENETIC EPIDEMIOLOGY Gong, G., Whittemore, A. S. 2003; 24 (3): 173-180

  Abstract

  Many clinical decisions require accurate estimates of disease risks associated with mutations of known disease-susceptibility genes. Such risk estimation is difficult when the mutations are rare. We used computer simulations to compare the performance of estimates obtained from two types of designs based on family data. In the first (clinic-based designs), families are ascertained because they meet certain criteria concerning multiple disease occurrences among family members. In the second (population-based designs), families are sampled through a population-based registry of affected individuals called probands, with oversampling of probands whose families are more likely to segregate mutations. We generated family structures, genotypes, and phenotypes using models that reflect the frequencies and penetrances of mutations of the BRCA1/2 genes. We studied the effects of risk heterogeneity due to unmeasured, shared risk factors by including risk variation due to unmeasured genotypes of another gene. The simulations were chosen to mimic the ascertainment and selection processes commonly used in the two types of designs. We found that penetrance estimates from both designs are nearly unbiased in the absence of unmeasured shared risk factors, but are biased upward in the presence of such factors. The bias increases with increasing variation in risks across genotypes of the second gene. However, it is small compared to the standard error of the estimates. Standard errors from population-based designs are roughly twice those from clinic-based designs with the same number of families. Using the root-mean-square error as a measure of performance, we found that in all instances, the clinic-based designs gave more accurate estimates than did the population-based designs with the same numbers of families. Rough variance calculations suggest that clinic-based designs give more accurate estimates because they include more identified mutation carriers.

  View details for DOI 10.1002/gepi.10219

  View details for Web of Science ID 000182077700002

  View details for PubMedID 12652521

• BRCA1/2 mutation status influences somatic genetic progression in inherited and sporadic epithelial ovarian cancer cases CANCER RESEARCH Ramus, S. J., Pharoah, P. D., Harrington, P., Pye, C., Werness, B., Bobrow, L., Ayhan, A., Wells, D., Fishman, A., Gore, M., DiCioccio, R. A., Piver, M. S., Whittemore, A. S., Ponder, B. A., Gayther, S. A. 2003; 63 (2): 417-423

  Abstract

  Metaphase comparative genomic hybridization was used to analyze the spectrum of genetic alterations in 141 epithelial ovarian cancers from BRCA1 and BRCA2 mutation carriers, individuals with familial non-BRCA1/2 epithelial ovarian cancer, and women with nonfamilial epithelial ovarian cancer. Multiple genetic alterations were identified in almost all tumors. The high frequency with which some alterations were identified suggests the location of genes that are commonly altered during ovarian tumor development. In multiple chromosome regions, there were significant differences in alteration frequency between the four tumor types suggesting that BRCA1/2 mutation status and a family history of ovarian cancer influences the somatic genetic pathway of ovarian cancer progression. These findings were supported by hierarchical cluster analysis, which identified genetic events that tend to occur together during tumorigenesis and several alterations that were specific to tumors of a particular type. In addition, some genetic alterations were strongly associated with differences in tumor differentiation and disease stage. Taken together, these data provide molecular genetic evidence to support previous findings from histopathological studies, which suggest that clinical features of ovarian and breast tumors differ with respect to BRCA1/2 mutation status and/or cancer family history.

  View details for Web of Science ID 000180697500026

  View details for PubMedID 12543797

• Breast cancer in Marin County BREAST CANCER RESEARCH Whittemore, A. S. 2003; 5 (5): 232-234

  Abstract

  Two articles previously published in Breast Cancer Research illustrate the high rates of breast cancer in Marin County, a wealthy, urban county immediately northwest of the city of San Francisco. I herein comment on these articles, and on the political/psychological/scientific dilemma presented by regions with high cancer rates, such as Marin County. I discuss possible causes for such cancer 'clusters', and conclude with some thoughts about the future.

  View details for DOI 10.1186/bcr633

  View details for Web of Science ID 000184841000004

  View details for PubMedID 12927030

  View details for PubMedCentralID PMC314435

• Re: On the use of familial aggregation in population-based case probands for calculating penetrance JOURNAL OF THE NATIONAL CANCER INSTITUTE Whittemore, A. S., Gong, G. 2003; 95 (1): 76-77

  View details for Web of Science ID 000180079200019

  View details for PubMedID 12509408

• Observational studies and Randomized trials of hormone replacement therapy: What can we learn from them? EPIDEMIOLOGY Whittemore, A. S., McGuire, V. 2003; 14 (1): 8-10

  View details for Web of Science ID 000180166300004

  View details for PubMedID 12500037

• Analysis of the human progesterone receptor gene polymorphism PROGINS in Austrian ovarian cancer patients INTERNATIONAL JOURNAL OF CANCER Whittemore, A. S., McGuire, V. 2002; 101 (2): 202-202

  View details for DOI 10.1002/ijc.10571

  View details for Web of Science ID 000177622600015

  View details for PubMedID 12210000

• Comparison of techniques for the successful detection of BRCA1 mutations in fixed paraffin-embedded tissue CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Bernstein, J. L., Thompson, W. D., Casey, G., DiCioccio, R. A., Whittemore, A. S., Diep, A. T., Thakore, S. S., Vaziri, S., Xue, S. Y., Haile, R. W. 2002; 11 (9): 809-814

  Abstract

  Genomic DNA isolated from archived paraffin-embedded tissues (PETs) has important applicability in genetic epidemiological studies. To determine the accuracy of the sequence data, using DNA derived from PET among patients with known mutations characterized from blood, we conducted a blinded factorial experiment to simultaneously examine the influence of mutation type, age of the PET, PCR product type, and Taq DNA polymerase on BRCA1 gene mutation detection. The probability of detecting sequencing artifacts was also investigated. We found that: (a) gene detection was most accurate for newer PET; (b) high fidelity Taq with shorter PCR amplicon length yielded the highest mutation detection success rate and lowest artifact rate; and (c) base substitutions were more often correctly identified than frameshift mutations or wild-type sequences. We concluded that DNA derived from PET that archived for less than 18 years can be used successfully for detecting BRCA1 gene mutations if quality control is strictly maintained.

  View details for Web of Science ID 000177967900003

  View details for PubMedID 12223423

• Segregation analysis of prostate cancer in 1719 white, African-American and Asian-American families in the United States and Canada CANCER CAUSES & CONTROL Gong, G., Oakley-Girvan, I., Wu, A. H., Kolonel, L. N., John, E. M., West, D. W., Felberg, A., Gallagher, R. P., Whittemore, A. S. 2002; 13 (5): 471-482

  Abstract

  Some data suggest that brothers of prostate cancer patients have higher disease risk than their fathers, supporting an X-linked or recessive mode of inheritance. However, higher observed frequencies in brothers than fathers may merely reflect the strong temporal changes in US incidence rates.(a) to evaluate the fit of X-linked, recessive, and dominant modes of inheritance to prostate cancer incidence, specific for calendar year, age, and race, in population-based samples of US and Canadian families; and (b) to evaluate a simple multifactorial model for familial aggregation of prostate cancer due to shared low-penetrance variants of many genes or shared lifestyle factors.The data consist of reported prostate cancer incidence in first-degree relatives of 1,719 white, African-American, and Asian-American men with and without prostate cancer at ages <70 years. Model parameters were estimated by maximizing a pseudo-likelihood function of the data, and goodness of model fit was assessed by evaluating discrepancies between observed and expected numbers of pairs of relatives with prostate cancer.After adjusting for temporal trends in prostate cancer incidence rates we found that the X-linked model fit poorly. underpredicting the observed number of affected father-son pairs. This also was true of the recessive model, although the evidence for poor fit did not achieve statistical significance. In contrast, the dominant model provided adequate fit to the data. In this model the race-specific penetrance estimates for carriers of deleterious genotypes were similar among African-Americans and whites, but lower among Asian-Americans: risk by age 80 years for carriers born in 1900 was estimated as 75.3% for African-Americans and whites, and 44.4% for Asian-Americans. None of the Mendelian models fit the data better than did the simple multifactorial model.The good fit of the multifactorial model suggests that multiple genes, each having low penetrance, may be responsible for most inherited prostate cancer susceptibility, and that the contribution of rare highly penetrant mutations is small.

  View details for PubMedID 12146852

• Race, epithelial ovarian cancer survival, and membership in a large health maintenance organization EPIDEMIOLOGY McGuire, V., Herrinton, L., Whittemore, A. S. 2002; 13 (2): 231-234

  Abstract

  African-American ovarian cancer patients present with more advanced disease and have poorer survival than do white patients.To determine whether these differences occur among African-American and white patients who have equal access to medical care, we analyzed ovarian cancer patient characteristics separately for 1,587 members of the Kaiser Permanente Medical Plan of Northern California and 5,757 non-members.The distributions of disease stage at diagnosis were similar among African-American and white patients, both in the Kaiser plan and elsewhere. However, ovarian cancer death rates, adjusted for disease stage and age at diagnosis and for histology, were higher for African-American patients compared with white patients, regardless of Kaiser membership status. The death rate ratios for African-Americans compared with whites were 1.32 (95% CI = 1.02-1.70) for Kaiser members and 1.20 (95% CI = 1.04-1.40) for Kaiser non-members.Further research within an equal-access care system is needed to evaluate other important factors such as specialty of surgeon, extent of residual tumor after surgery, chemotherapy treatment, and postoperative management to determine whether these factors are contributing to the differences in survival between African-American and white ovarian cancer patients.

  View details for Web of Science ID 000174037800021

  View details for PubMedID 11880767

• Survival among US women with invasive epithelial ovarian cancer GYNECOLOGIC ONCOLOGY McGuire, V., Jesser, C. A., Whittemore, A. S. 2002; 84 (3): 399-403

  Abstract

  Invasive epithelial ovarian cancer is a highly fatal disease, diagnosed at advanced stages when survival is poor. Relatively little is known about the variation in survival across U.S. women of different race/ethnicities. To investigate this issue, we evaluated pathological characteristics and death rates due to invasive epithelial ovarian cancer in a population-based sample of patients from six racial/ethnic groups.The analysis included 38,012 women diagnosed with primary invasive epithelial ovarian cancer between 1973 and 1997 in the Surveillance, Epidemiology and End Results Program of the National Cancer Institute.Filipina patients were younger at diagnosis, more likely to have localized disease, and had more mucinous cancers than whites. African-Americans were more likely than whites to be diagnosed at older ages, with distant disease and with undifferentiated/unclassified cancers. After adjusting for age at diagnosis, stage of disease at diagnosis, and cancer histology, we found that, compared to whites, death rates were significantly elevated among African-Americans and significantly reduced among Hispanics and Filipina. We also found that death rates declined significantly with time since diagnosis among women with advanced disease.The declining death rates in women with advanced disease suggest the presence of considerable prognostic heterogeneity among these women, which could reflect differences in quality of care. This issue, as well as the survival disadvantage for African-American women and survival advantages for Hispanic and Filipina women, needs investigation.

  View details for DOI 10.1006/gyno.2001.6536

  View details for Web of Science ID 000174372100010

  View details for PubMedID 11855877

• Carbohydrates and colorectal cancer risk among Chinese in North America CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Borugian, M. J., Sheps, S. B., Whittemore, A. S., Wu, A. H., Potter, J. D., Gallagher, R. P. 2002; 11 (2): 187-193

  Abstract

  Previous studies have analyzed total carbohydrate as a dietary risk factor for colorectal cancer (CRC) but obtained conflicting results, perhaps attributable in part to the embedded potential confounder, fiber. The aim of this study was to analyze the nonfiber ("effective") carbohydrate component (eCarb) separately and to test the hypothesis that effective carbohydrate consumption is directly related to CRC risk. The data (473 cases and 1192 controls) were from a large, multicenter, case-control study of Chinese residing in North America. Multivariate logistic regression was used to perform a secondary analysis controlling for age; sex; consumption of fat, fiber, calcium, and total kilocalories; body mass (Quetelet's) index; family history; education; and years in North America. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate risk among subgroups by sex and cancer site. A statistically significant positive association was observed between eCarb consumption and risk of CRC in both men (OR, 1.7 comparing highest with lowest tertile of eCarb consumption; 95% CI, 1.1-2.7) and women (OR, 2.7; 95% CI, 1.5-4.8). As expected, the ORs for total carbohydrate were somewhat lower than those for effective carbohydrate, but the differences were not large. A sex difference in risk by colorectal subsite was observed, with risk concentrated in the right colon for women (OR, 6.5; 95% CI, 2.4-18.4) and in the rectum for men (OR, 2.4; 95% CI, 1.2-4.8). These data indicate that increased eCarb and total carbohydrate consumption are both associated with increased risk of CRC in both sexes, and that among women, relative risk appears greatest for the right colon, whereas among men, relative risk appears greatest for the rectum.

  View details for Web of Science ID 000174233100005

  View details for PubMedID 11867506

• Tests for genetic association using family data GENETIC EPIDEMIOLOGY Shih, M. C., Whittemore, A. S. 2002; 22 (2): 128-145

  Abstract

  We use likelihood-based score statistics to test for association between a disease and a diallelic polymorphism, based on data from arbitrary types of nuclear families. The Nonfounder statistic extends the transmission disequilibrium test (TDT) to accommodate affected and unaffected offspring, missing parental genotypes, phenotypes more general than qualitative traits, such as censored survival data and quantitative traits, and residual correlation of phenotypes within families. The Founder statistic compares observed or inferred parental genotypes to those expected in the general population. Here the genotypes of affected parents and those with many affected offspring are weighted more heavily than unaffected parents and those with few affected offspring. We illustrate the tests by applying them to data on a polymorphism of the SRD5A2 gene in nuclear families with multiple cases of prostate cancer. We also use simulations to compare the power of these family-based statistics to that of the score statistic based on Cox's partial likelihood for censored survival data, and find that the family-based statistics have considerably more power when there are many untyped parents. The software program FGAP for computing test statistics is available at http://www.stanford.edu/dept/HRP/epidemiology/FGAP.

  View details for Web of Science ID 000173390200003

  View details for PubMedID 11788959

• Comparison of DNA- and RNA-based methods for detection of truncating BRCA1 mutations HUMAN MUTATION Andrulis, I. L., Anton-Culver, H., Beck, J., Bove, B., Boyd, J., Buys, S., Godwin, A. K., Hopper, J. L., Li, F., Neuhausen, S. L., Ozcelik, H., Peel, D., Santella, R. M., Southey, M. C., van Orsouw, N. J., Venter, D. J., Vijg, J., Whittemore, A. S. 2002; 20 (1): 65-73

  Abstract

  A number of methods are used for mutational analysis of BRCA1, a large multi-exon gene. A comparison was made of five methods to detect mutations generating premature stop codons that are predicted to result in synthesis of a truncated protein in BRCA1. These included four DNA-based methods: two-dimensional gene scanning (TDGS), denaturing high performance liquid chromatography (DHPLC), enzymatic mutation detection (EMD), and single strand conformation polymorphism analysis (SSCP) and an RNA/DNA-based protein truncation test (PTT) with and without complementary 5' sequencing. DNA and RNA samples isolated from 21 coded lymphoblastoid cell line samples were tested. These specimens had previously been analyzed by direct automated DNA sequencing, considered to be the optimum method for mutation detection. The set of 21 cell lines included 14 samples with 13 unique frameshift or nonsense mutations, three samples with two unique splice site mutations, and four samples without deleterious mutations. The present study focused on the detection of protein-truncating mutations, those that have been reported most often to be disease-causing alterations that segregate with cancer in families. PTT with complementary 5' sequencing correctly identified all 15 deleterious mutations. Not surprisingly, the DNA-based techniques did not detect a deletion of exon 22. EMD and DHPLC identified all of the mutations with the exception of the exon 22 deletion. Two mutations were initially missed by TDGS, but could be detected after slight changes in the test design, and five truncating mutations were missed by SSCP. It will continue to be important to use complementary methods for mutational analysis.

  View details for DOI 10.1002/humu.10097

  View details for Web of Science ID 000176744500008

  View details for PubMedID 12112659

• Comparison of methods for detection of mutations in the BRCA1 gene. Bove, B. A., Ozcelik, H., Neuhausen, S., Boyd, J., Southey, M., Santella, R., Venter, D., Beck, J., Li, F., Buys, S., Andrulis, I. L., Godwin, A. K., Whittemore, A. CELL PRESS. 2001: 440–40

  View details for Web of Science ID 000171648901507

• Iodine and thyroid cancer risk among women in a multiethnic population: The Bay Area thyroid cancer study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Horn-Ross, P. L., Morris, J. S., Lee, M., West, D. W., Whittemore, A. S., McDougall, I. R., Nowels, K., Stewart, S. L., Spate, V. L., Shiau, A. C., Krone, M. R. 2001; 10 (9): 979-985

  Abstract

  Research on the relationship between iodine exposure and thyroid cancer risk is limited, and the findings are inconclusive. In most studies, fish/shellfish consumption has been used as a proxy measure of iodine exposure. The present study extends this research by quantifying dietary iodine exposure as well as incorporating a biomarker of long-term (1 year) exposure, i.e., from toenail clippings. This study is conducted in a multiethnic population with a wide variation in thyroid cancer incidence rates and substantial diversity in exposure. Women, ages 20-74, residing in the San Francisco Bay Area and diagnosed with thyroid cancer between 1995 and 1998 (1992-1998 for Asian women) were compared with women selected from the general population via random digit dialing. Interviews were conducted in six languages with 608 cases and 558 controls. The established risk factors for thyroid cancer were found to increase risk in this population: radiation to the head/neck [odds ratio (OR), 2.3; 95% confidence interval (CI), 0.97-5.5]; history of goiter/nodules (OR, 3.7; 95% CI, 2.5-5.6); and a family history of proliferative thyroid disease (OR, 2.5; 95% CI, 1.6-3.8). Contrary to our hypothesis, increased dietary iodine, most likely related to the use of multivitamin pills, was associated with a reduced risk of papillary thyroid cancer. This risk reduction was observed in "low-risk" women (i.e., women without any of the three established risk factors noted above; OR, 0.53; 95% CI, 0.33-0.85) but not in "high-risk" women, among whom a slight elevation in risk was seen (OR, 1.4; 95% CI, 0.56-3.4). However, no association with risk was observed in either group when the biomarker of exposure was evaluated. In addition, no ethnic differences in risk were observed. The authors conclude that iodine exposure appears to have, at most, a weak effect on the risk of papillary thyroid cancer.

  View details for Web of Science ID 000170899000011

  View details for PubMedID 11535551

• Re: Prostate cancer incidence and mortality in the United States and the United Kingdom JOURNAL OF THE NATIONAL CANCER INSTITUTE Shibata, A., Whittemore, A. S. 2001; 93 (14): 1109-1110

  View details for Web of Science ID 000169829000017

  View details for PubMedID 11459874

• Problems in the definition, interpretation, and evaluation of genetic heterogeneity AMERICAN JOURNAL OF HUMAN GENETICS Whittemore, A. S., Halpern, J. 2001; 68 (2): 457-465

  Abstract

  Suppose that we wish to classify families with multiple cases of disease into one of three categories: those that segregate mutations of a gene of interest, those which segregate mutations of other genes, and those whose disease is due to nonhereditary factors or chance. Among families in the first two categories (the hereditary families), we wish to estimate the proportion, p, of families that segregate mutations of the gene of interest. Although this proportion is a commonly accepted concept, it is well defined only with an unambiguous definition of "family." Even then, extraneous factors such as family sizes and structures can cause p to vary across different populations and, within a population, to be estimated differently by different studies. Restrictive assumptions about the disease are needed, in order to avoid this undesirable variation. The assumptions require that mutations of all disease-causing genes (i) have no effect on family size, (ii) have very low frequencies, and (iii) have penetrances that satisfy certain constraints. Despite the unverifiability of these assumptions, linkage studies often invoke them to estimate p, using the admixture likelihood introduced by Smith and discussed by Ott. We argue against this common practice, because (1) it also requires the stronger assumption of equal penetrances for all etiologically relevant genes; (2) even if all assumptions are met, estimates of p are sensitive to misspecification of the unknown phenocopy rate; (3) even if all the necessary assumptions are met and the phenocopy rate is correctly specified, estimates of p that are obtained by linkage programs such as HOMOG and GENEHUNTER are based on the wrong likelihood and therefore are biased in the presence of phenocopies. We show how to correct these estimates; but, nevertheless, we do not recommend the use of parametric heterogeneity models in linkage analysis, even merely as a tool for increasing the statistical power to detect linkage. This is because the assumptions required by these models cannot be verified, and their violation could actually decrease power. Instead, we suggest that estimation of p be postponed until the relevant genes have been identified. Then their frequencies and penetrances can be estimated on the basis of population-based samples and can be used to obtain more-robust estimates of p for specific populations.

  View details for Web of Science ID 000166524800015

  View details for PubMedID 11170893

• Allele-sharing among affected relatives: non-parametric methods for identifying genes STATISTICAL METHODS IN MEDICAL RESEARCH Shih, M. C., Whittemore, A. S. 2001; 10 (1): 27-55

  Abstract

  Non-parametric linkage analysis examines similarities among affected relatives in alleles of one or more genetic markers (pieces of DNA at known locations on a chromosome). The objective is to evaluate departures from the null hypothesis that the markers are not near a disease gene. Under the null hypothesis, Mendel's laws give the probabilities that a set of relatives exhibits a particular allele-sharing pattern, and the null hypothesis is rejected if the extent of allele sharing among affected relatives exceeds Mendelian expectation. Because the rationale for allele-sharing methods is intuitively plausible and easily grasped, geneticists have used these methods for more than 30 years, well before the advent of the large sets of polymorphic markers that have made linkage analysis so fruitful today. Here we describe methods for assessing whether the extent of marker allele sharing among affected relatives exceeds Mendelian expectation. We first quantify the notion of allele sharing and the probabilities of allele sharing in various sets of relatives. Then we describe allele sharing methods for affected sibs and more general sets of relatives. We also discuss related issues of test size and power. We conclude with a brief discussion of areas in need of further research.

  View details for Web of Science ID 000168123300003

  View details for PubMedID 11329690

• Survival in epithelial ovarian cancer patients with prior breast cancer AMERICAN JOURNAL OF EPIDEMIOLOGY McGuire, V., Whittemore, A. S., Norris, R., Oakley-Girvan, I. 2000; 152 (6): 528-532

  Abstract

  Ovarian cancer patients who carry germ-line BRCA1 mutations may have improved survival compared with ovarian cancer patients without these mutations. To evaluate this hypothesis, the authors compared survival in ovarian cancer patients who had a history of prior breast cancer with that of patients without such a history. Specifically, they used data from the population-based US Surveillance, Epidemiology, and End Results (SEER) Program to assess time to death from ovarian cancer among ovarian cancer patients with and without a prior breast cancer. All 25,637 White women diagnosed with invasive epithelial ovarian cancer in SEER registries between 1973 and 1995 were included. Of these, 824 women had had a prior breast cancer diagnosis. The ovarian cancer death rate among women with prior breast cancer was significantly lower than that of women with ovarian cancer only, adjusted for age and stage at ovarian cancer diagnosis. The survival advantage was most pronounced among older women and among those whose ovarian cancers were more advanced at the time of diagnosis. These results lend indirect support to prior findings of improved ovarian cancer survival in BRCA1 mutation carriers.

  View details for Web of Science ID 000089252100004

  View details for PubMedID 10997542

• Prostate cancer risk in relation to anthropometry and physical activity: The National Health and Nutrition Examination Survey I epidemiological follow-up study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Clarke, G., Whittemore, A. S. 2000; 9 (9): 875-881

  Abstract

  We studied the relationship of prostate cancer to anthropometry and self-reported physical activity among 5377 African-American and Caucasian participants in the National Health and Nutrition Examination Survey I cohort. The cohort was first examined between 1971 and 1975 and then followed prospectively through the Epidemiologic Follow-up Study in 1982-1984, 1986, 1987, and 1992. Men who reported low levels of nonrecreational physical activity had increased risk of prostate cancer compared with very active men. These findings were unchanged after adjustment for potential confounders and were stronger for African-Americans (relative risk, 3.7; 95% confidence interval, 1.7-8.4) than for Caucasians (relative risk, 1.7; confidence interval, 0.8-2.3). Lower levels of recreational activity were weakly associated with increased prostate cancer risk among African-Americans but not among Caucasians. Prostate cancer risk was unrelated to a variety of anthropometric variables. These results suggest that inactive men are at increased risk of prostate cancer.

  View details for Web of Science ID 000089392600003

  View details for PubMedID 11008903

• Re: "Differences in socioeconomic status and survival among white and black men with prostate cancer" - Reply AMERICAN JOURNAL OF EPIDEMIOLOGY Robbins, A. S., Whittemore, A. S., Thom, D. H. 2000; 152 (5): 494-494

  View details for Web of Science ID 000089024000016

• Correction Statistics in medicine Whittemore, A. S. 2000; 19 (9): 1251

  View details for PubMedID 10797520

• Detection of disease genes by use of family data. II. Application to nuclear families AMERICAN JOURNAL OF HUMAN GENETICS Tu, I. P., Balise, R. R., Whittemore, A. S. 2000; 66 (4): 1341-1350

  Abstract

  Two likelihood-based score statistics are used to detect association between a disease and a single diallelic polymorphism, on the basis of data from arbitrary types of nuclear families. The first statistic, the nonfounder statistic, extends the transmission/disequilibrium test to accommodate affected and unaffected offspring and missing parental genotypes. The second statistic, the founder statistic, compares observed or inferred parental genotypes with those of some reference population. In this comparison, the genotypes of affected parents or of those with many affected offspring are weighted more heavily than are the genotypes of unaffected parents or of those with few affected offspring. Genotypes of single unrelated cases and controls can be included in this analysis. We illustrate the two statistics by applying them to data on a polymorphism of the SDR5A2 gene in nuclear families with multiple cases of prostate cancer. We also use simulations to compare the power of the nonfounder statistic with that of the score statistic, on the basis of the conditional logistic regression of offspring genotypes.

  View details for Web of Science ID 000088373400016

  View details for PubMedID 10739759

• Detection of disease genes by use of family data. I. Likelihood-based theory AMERICAN JOURNAL OF HUMAN GENETICS Whittemore, A. S., Tu, I. P. 2000; 66 (4): 1328-1340

  Abstract

  We present a class of likelihood-based score statistics that accommodate genotypes of both unrelated individuals and families, thereby combining the advantages of case-control and family-based designs. The likelihood extends the one proposed by Schaid and colleagues (Schaid and Sommer 1993, 1994; Schaid 1996; Schaid and Li 1997) to arbitrary family structures with arbitrary patterns of missing data and to dense sets of multiple markers. The score statistic comprises two component test statistics. The first component statistic, the nonfounder statistic, evaluates disequilibrium in the transmission of marker alleles from parents to offspring. This statistic, when applied to nuclear families, generalizes the transmission/disequilibrium test to arbitrary numbers of affected and unaffected siblings, with or without typed parents. The second component statistic, the founder statistic, compares observed or inferred marker genotypes in the family founders with those of controls or those of some reference population. The founder statistic generalizes the statistics commonly used for case-control data. The strengths of the approach include both the ability to assess, by comparison of nonfounder and founder statistics, the potential bias resulting from population stratification and the ability to accommodate arbitrary family structures, thus eliminating the need for many different ad hoc tests. A limitation of the approach is the potential power loss and/or bias resulting from inappropriate assumptions on the distribution of founder genotypes. The systematic likelihood-based framework provided here should be useful in the evaluation of both the relative merits of case-control and various family-based designs and the relative merits of different tests applied to the same design. It should also be useful for genotype-disease association studies done with the use of a dense set of multiple markers.

  View details for Web of Science ID 000088373400015

  View details for PubMedID 10739758

• Declining ovarian cancer rates in US women in relation to parity and oral contraceptive use EPIDEMIOLOGY Gnagy, S., Ming, E. E., Devesa, S. S., Hartge, P., Whittemore, A. S. 2000; 11 (2): 102-105

  Abstract

  Ovarian cancer incidence and mortality rates have declined among U.S. women age 35-59 years during the period 1970-1995. Epidemiologic studies have shown that ovarian cancer risk decreases with increasing parity and increasing duration of oral contraceptive use. During this period, parity has declined while oral contraceptive use has increased. We compared temporal trends in observed ovarian cancer incidence rates with rates predicted by changes in parity and duration of oral contraceptive use to determine whether the changes in these characteristics could explain the declining rates in younger women. In addition, we wished to examine whether oral contraceptive use continues to be protective to postmenopausal women. To predict changes in rates between 1970 and 1995, we assumed that increases in parity and duration of oral contraceptive use induce proportional decreases in incidence rates. We found that the rates predicted by these assumptions agreed well with observed rates in young women (age 30-49) but were substantially lower than observed rates in older women (age 50-64). The data indicate that the relative decrease in incidence rates due to the protective effect of oral contraceptive use declines with age.

  View details for Web of Science ID 000085472700004

  View details for PubMedID 11021604

• Differences in socioeconomic status and survival among white and black men with prostate cancer AMERICAN JOURNAL OF EPIDEMIOLOGY Robbins, A. S., Whittemore, A. S., Thom, D. H. 2000; 151 (4): 409-416

  Abstract

  After diagnosis with prostate cancer, Black men in the United States have poorer survival than White men, even after controlling for differences in cancer stage. The extent to which these racial survival differences are due to biologic versus non-biologic factors is unclear, and it has been hypothesized that differences associated with socioeconomic status (SES) might account for much of the observed survival difference. The authors examined this hypothesis in a cohort study, using cancer registry and US Census data for White and Black men with incident prostate cancer (n = 23,334) who resided in 1,005 census tracts in the San Francisco Bay Area during 1973-1993. Separate analyses were conducted using two endpoints: death from prostate cancer and death from other causes. For each endpoint, death rate ratios (Blacks vs. Whites) were computed for men diagnosed at ages <65 years and at ages > or =65 years. These data suggest that differences associated with SES do not explain why Black men die from prostate cancer at a higher rate when compared with White men with this condition. However, among men with prostate cancer, SES-associated differences appear to explain almost all of the racial difference in risk of death from other causes.

  View details for Web of Science ID 000085474800010

  View details for PubMedID 10695600

• Estimating genetic influence on disease from population-based case-control data: Application to cancers of the breast and ovary STATISTICS IN MEDICINE Gong, G., Whittemore, A. S. 1999; 18 (23): 3321-3336

  Abstract

  We describe genetic mixture models and goodness-of-fit statistics for evaluating the joint effects of genetic and environmental factors on the risk of chronic diseases. We focus particularly on situations wherein the gene(s) of interest play roles in several diseases, and death due to one disease can censor the occurrence of others. We use the methods to investigate the risks of cancers of the breast and ovary associated with germline mutations of BRCA1, using data pooled from three population-based U.S. case-control studies of ovarian cancer. We evaluate the goodness-of-fit of the genetic models by comparing the predicted numbers of diseased mother-daughter and sister-sister pairs to the numbers observed. We also use simulations to examine the performance of estimates obtained from such complex mixture models, and the contribution of control families to the precision of parameter estimates.

  View details for Web of Science ID 000084077400014

  View details for PubMedID 10602154

• Genetically tailored preventive strategies: An effective plan for the twenty-first century? 90th Annual Meeting of the American-Association-for-Cancer-Research Whittemore, A. S. AMER ASSOC CANCER RESEARCH. 1999: 649–58

  Abstract

  A preventive strategy of considerable appeal would offer specific lifestyle changes and preventive interventions to people at increased cancer risk because of inherited susceptibility. The hope for such a strategy stems in part from the variation in risk among carriers of cancer-predisposing mutations. For example, despite the high risks of cancers of the breast and ovary among BRCA1 and BRCA2 mutation carriers, some 30% of these women are estimated to reach age 70 years without developing either cancer. We need to know what protects these women, compared with carriers who do develop these malignancies. Apart from chance, possible explanations include variation in type of mutation, in genotypes at other loci, or in potentially modifiable lifestyle characteristics. This article reviews our present knowledge about risks for cancers of the colorectum, female breast, and ovary in carriers of highly penetrant germ-line mutations of susceptibility genes. The paper also reviews our present knowledge about options for reducing these risks through changes in lifestyle, chemopreventive agents, and prophylactic surgery. It concludes with a discussion of what we need to know to offer those with inherited susceptibility safe, effective options for preventing these cancers and to provide a framework for deciding among the options.

  View details for Web of Science ID 000083705300002

• The Eighth AACR American Cancer Society Award lecture on cancer epidemiology and prevention. Genetically tailored preventive strategies: an effective plan for the twenty-first century? American Association for Cancer Research. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Whittemore, A. S. 1999; 8 (8): 649-58

  Abstract

  A preventive strategy of considerable appeal would offer specific lifestyle changes and preventive interventions to people at increased cancer risk because of inherited susceptibility. The hope for such a strategy stems in part from the variation in risk among carriers of cancer-predisposing mutations. For example, despite the high risks of cancers of the breast and ovary among BRCA1 and BRCA2 mutation carriers, some 30% of these women are estimated to reach age 70 years without developing either cancer. We need to know what protects these women, compared with carriers who do develop these malignancies. Apart from chance, possible explanations include variation in type of mutation, in genotypes at other loci, or in potentially modifiable lifestyle characteristics. This article reviews our present knowledge about risks for cancers of the colorectum, female breast, and ovary in carriers of highly penetrant germ-line mutations of susceptibility genes. The paper also reviews our present knowledge about options for reducing these risks through changes in lifestyle, chemopreventive agents, and prophylactic surgery. It concludes with a discussion of what we need to know to offer those with inherited susceptibility safe, effective options for preventing these cancers and to provide a framework for deciding among the options.

  View details for PubMedID 10744124

• Race, prostate cancer survival, and membership in a large health maintenance organization - Reply JOURNAL OF THE NATIONAL CANCER INSTITUTE Robbins, A. S., Whittemore, A. S., Van Den Eeden, S. K. 1999; 91 (9): 802-803

  View details for Web of Science ID 000080142100017

• Power of association and linkage tests when the disease alleles are unobserved AMERICAN JOURNAL OF HUMAN GENETICS Tu, I. P., Whittemore, A. S. 1999; 64 (2): 641-649

  Abstract

  Genomewide association studies have been advocated as a promising alternative to genomewide linkage scans for detection of small-effect genes in complex diseases. Comparisons of power and sample size between the two strategies have shown considerable advantages for the association studies. These comparisons assume that the set of markers includes the exact disease-related polymorphism. A concern, however, is that the power of an association study decreases when this is not the case, because of discrepant allele frequencies and less-than-maximum disequilibrium between the disease-related polymorphism and its nearest marker. Here, we quantify this concern by comparing the sample sizes needed by the two strategies when the markers exclude the disease-related polymorphism. For affected sib pairs and their parents, we found that incomplete disequilibrium and differing allele frequencies can have substantial negative impact on the power of association studies, resulting, in some circumstances, in little gain and even in loss of power, compared with linkage analysis. We provide some guidelines for choosing between strategies, for the detection of genes for complex diseases.

  View details for Web of Science ID 000078740600035

  View details for PubMedID 9973303

• Multipoint linkage analysis - A cautionary note HUMAN HEREDITY Halpern, J., Whittemore, A. S. 1999; 49 (4): 194-196

  Abstract

  Multipoint linkage analysis is commonly used to evaluate linkage of a disease to multiple markers in a small region. Multipoint analysis is particularly powerful when the IBD relations of family members at the trait locus are ambiguous. The increased power arises because, unlike single-marker analyses, multipoint analysis uses haplotype information from several markers to infer the IBD relations. We wish to temper this advantage with a cautionary note: multipoint analysis is sensitive to power loss due to misspecification of intermarker distances. Such misspecification is especially problematic when dealing with closely spaced markers. We present computer simulations comparing the power of single-point and multipoint analyses, both when IBD relations are ambiguous, and when the intermarker distances are misspecified. We conclude that when evaluating markers in a small region to confirm or refute previous findings, a situation in which p values of modest statistical significance are important, single marker analyses may provide more reliable measures of the strength of support for linkage than multipoint statistics.

  View details for Web of Science ID 000081857700004

  View details for PubMedID 10436380

• Study design in genetic epidemiology: theoretical and practical considerations. Journal of the National Cancer Institute. Monographs Whittemore, A. S., Nelson, L. M. 1999: 61-69

  Abstract

  Recent advances in molecular genetics have created new opportunities and challenges for genetic epidemiologists. Here we review some of the issues that arise when designing a study involving the genetic epidemiology of chronic diseases of late onset, such as cancer. We discuss two considerations that influence the choice of design. The first consideration is the study's goals. We describe the goals of identifying new susceptibility genes for a disease, of estimating important characteristics of known genes, and of learning how to prevent the disease in the genetically susceptible. We indicate how these goals affect the choice of design and present some guidelines for choosing designs that effectively address them. The second consideration is the set of practical constraints to successfully conducting the research. These contraints include problems of potential selection bias, reduced response rates, problems particular to family registries, problems particular to the cultures of various ethnic groups, and ethical issues. We indicate how these constraints affect the choice of design and discuss ways to deal with them.

  View details for PubMedID 10854488

• Prostate cancer incidence and mortality in the United States and the United Kingdom JOURNAL OF THE NATIONAL CANCER INSTITUTE Shibata, A., Ma, J., Whittemore, A. S. 1998; 90 (16): 1230-1231

  View details for Web of Science ID 000075476700014

  View details for PubMedID 9719085

• Race, prostate cancer survival, and membership in a large health maintenance organization JOURNAL OF THE NATIONAL CANCER INSTITUTE Robbins, A. S., Whittemore, A. S., Van Den Eeden, S. K. 1998; 90 (13): 986-990

  Abstract

  Population-based cancer registry data have shown that black men with prostate cancer have poorer stage-specific survival than white men, while studies in equal-access health care systems have not found racial differences in stage-specific survival. This study was designed to test the hypothesis that black men and white men with prostate cancer have equal stage-specific survival in equal-access health care systems.We conducted a cohort study using cancer registry data from all incident cases of prostate cancer occurring in a five-county San Francisco Bay Area region. Incident cases occurred among members (5263 cases, from January 1973 through June 1995) and nonmembers (16,019 cases, from January 1973 through December 1992) of the Kaiser Permanente Medical Care Program, a large health maintenance organization. Death rate ratios (DRRs, black men versus white men) for Kaiser members and nonmembers were computed for all stages combined (adjusting for age and stage) and for each stage (adjusting for age).Among Kaiser members, adjusted DRRs comparing black men with white men were as follows: all stages combined, 1.28 (95% confidence interval [CI] = 1.14-1.44); local stage, 1.23 (95% CI = 1.01-1.51); regional stage, 1.30 (95% CI = 0.97-1.75); and distant stage, 1.27 (95% CI = 1.07-1.50). Corresponding DRRs for nonmembers were as follows: all stages combined, 1.22 (95% CI = 1.14-1.30); local stage, 1.24 (95% CI = 1.09-1.41); regional stage, 1.48 (95% CI = 1.29-1.68); and distant stage, 1.01 (95% CI = 0.91-1.12).These results show poorer prostate cancer survival for black men compared with white men in an equal-access medical care setting. The findings are most consistent with the hypothesis of increased tumor virulence in blacks.

  View details for Web of Science ID 000074508800010

  View details for PubMedID 9665146

• Testing covariance structure in multivariate models: Application to family disease data JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION Whittemore, A. S., Halpern, J., Gong, G. 1998; 93 (442): 518-525

  View details for Web of Science ID 000074030600011

• Simple, robust linkage tests for affected sibs AMERICAN JOURNAL OF HUMAN GENETICS Whittemore, A. S., Tu, I. P. 1998; 62 (5): 1228-1242

  Abstract

  Parametric-linkage analysis applied to large pedigrees with many affected individuals has helped in the identification of highly penetrant genes; but, for diseases lacking a clear Mendelian inheritance pattern or caused by several genes of low to moderate penetrance, a more robust strategy is nonparametric analysis applied to small sets of affected relatives, such as affected sib pairs. Here we show that the robustness of affected-sib-pair tests is related to the shape of the constraint set for the sibs' identity-by-descent (IBD) probabilities. We also derive a set of constraints for the IBD probabilities of affected sib triples and use common features of the shapes of the two constrain sets to introduce new nonparametric tests (called "minmax" tests) that are more robust than those in current use. Asymptotic-power computations support the robustness of the proposed minmax tests.

  View details for Web of Science ID 000073487000027

  View details for PubMedID 9599188

• Serum levels of prostate-specific antigen among Japanese-American and native Japanese men JOURNAL OF THE NATIONAL CANCER INSTITUTE Shibata, A., Whittemore, A. S., Imai, K., Kolonel, L. N., Wu, A. H., John, E. H., Stamey, T. A., Paffenbarger, R. S. 1997; 89 (22): 1716-1720

  Abstract

  Fourfold to sixfold higher prostate cancer rates in Japanese-American men in the United States compared with Japanese men in Japan have been cited to support a role for environmental risk factors in the etiology of the disease. To examine the hypothesis that part or all of the elevated prostate cancer rates in Japanese-American men may reflect more intensive prostate cancer screening in the United States than in Japan, we compared prostate-specific antigen (PSA) levels in community-based samples of serum from men without prostate cancer.Japanese-American men aged 40-85 years and native Japanese men aged 40-89 years with no history of prostate cancer provided sera, respectively, in the United States from March 1990 through March 1992 (n = 237) or in Japan from January 1992 through December 1993 (n = 3522). Age-specific PSA levels were used to estimate the prevalences of undetected prostate cancer in the two populations.Age-specific mean PSA levels were significantly lower in Japanese-Americans than in native Japanese (two-sided P<.001). The prevalence of an elevated PSA level increased with age in both populations and exceeded 5% among men aged 60 years or more. Combined with data on prevalence of detected prostate cancer in the two populations, our data suggest that some 10.0% of Japanese-Americans aged 75 years have prostate cancer, with 31% of that fraction remaining undiagnosed. The corresponding estimates in Japan are a total cancer prevalence of 5.4%, of which 81% has not been detected clinically.The total cancer prevalence ratio 10.0/5.4 = 1.9 (95% confidence interval = 1.5-2.3) in Japanese-American men compared with Japanese men in Japan suggests an increased risk for Japanese-American men, but of less magnitude than the fourfold to sixfold increase indicated by the incidence data.

  View details for PubMedID 9390541

• Genetic predisposition to prostate cancer: Possible explanations for ethnic differences in risk PROSTATE Shibata, A., Whittemore, A. S. 1997; 32 (1): 65-72

  Abstract

  It seems unlikely that the large ethnic differences in prostate cancer risk can be explained completely by ethnic differences in diet or other lifestyle characteristics. Instead, the differences may be due to ethnic variation in endogenous factors, such as androgen metabolism or inherited susceptibility.We have reviewed the literature for evidence and support of ethnic variation in genetic susceptibility to prostate cancer as a reason for the ethnic differences in rates.We distinguish two types of ethnic variation: 1) variation in the prevalence of certain alleles of specific genes that confer modestly increased risk. Such variation might be reflected in ethnic differences in serum levels of androgens, their metabolites, or indicators of metabolism in the prostate; 2) variation in the prevalence of rare germline mutations conferring substantially increased risk. Such variation would be reflected in ethnic differences in familial aggregation of prostate cancer. We discuss the evidence in support of each of these two possibilities.Ethnic variation in polymorphic alleles of genes associated with modest fluctuations in risk could explain a large proportion of the ethnic difference in cancer risk. In contrast, rare mutations associated with substantially increased risk are likely to account for a smaller fraction of these differences.

  View details for Web of Science ID A1997XG77400009

  View details for PubMedID 9207959

• Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: Results from three US population-based case-control studies of ovarian cancer AMERICAN JOURNAL OF HUMAN GENETICS Whittemore, A. S., Gong, G., ITNYRE, J. 1997; 60 (3): 496-504

  Abstract

  We investigate the familial risks of cancers of the breast and ovary, using data pooled from three population-based case-control studies of ovarian cancer that were conducted in the United States. We base estimates of the frequency of mutations of BRCA1 (and possibly other genes) on the reported occurrence of breast cancer and ovarian cancer in the mothers and sisters of 922 women with incident ovarian cancer (cases) and in 922 women with no history of ovarian cancer (controls). Segregation analysis and goodness-of-fit testing of genetic models suggest that rare mutations (frequency .0014; 95% confidence interval .0002-.011) account for all the observed aggregation of breast cancer and ovarian cancer in these families. The estimated risk of breast cancer by age 80 years is 73.5% in mutation carriers and 6.8% in noncarriers. The corresponding estimates for ovarian cancer are 27.8% in carriers and 1.8% in noncarriers. For cancer risk in carriers, these estimates are lower than those obtained from families selected for high cancer prevalence. The estimated proportion of all U.S. cancer diagnoses, by age 80 years, that are due to germ-line BRCA1 mutations is 3.0% for breast cancer and 4.4% for ovarian cancer. Aggregation of breast cancer and ovarian cancer was less evident in the families of 169 cases with borderline ovarian cancers than in the families of cases with invasive cancers. Familial aggregation did not differ by the ethnicity of the probands, although the number of non-White and Hispanic cases (N = 99) was sparse.

  View details for Web of Science ID A1997WK40300005

  View details for PubMedID 9042908

• Multi-stage sampling in genetic epidemiology Workshop on Statistical Methods for Incomplete Covariate Data in Clinical and Epidemiological Studies Whittemore, A. S., Halpern, J. JOHN WILEY & SONS LTD. 1997: 153–67

  Abstract

  When data are expensive to collect, it can be cost-efficient to sample in two or more stages. In the first stage a simple random sample is drawn and then stratified according to some easily measured attribute. In each subsequent stage a random subset of previously selected units is sampled for more detailed observation, with a unit's sampling probability determined by its attributes as observed in the previous stages. These designs are useful in many medical studies; here we use them in genetic epidemiology. Two genetic studies illustrate the strengths and limitations of the approach. The first study evaluates nuclear and mitochondrial DNA in U.S. blacks. The goal is to estimate the relative contributions of white male genes and white female genes to the gene pool of African-Americans. This example shows that the Horvitz-Thompson estimators proposed for multi-stage designs can be inefficient, particularly when used with unnecessary stratification. The second example is a multi-stage study of familial prostate cancer. The goal is to gather pedigrees, blood samples and archived tissue for segregation and linkage analysis of familial prostate cancer data by first obtaining crude family data from prostate cancer cases and cancer-free controls. This second example shows the gains in efficiency from multi-stage sampling when the individual likelihood or quasilikelihood scores vary substantially across strata.

  View details for Web of Science ID A1997WA62500011

  View details for PubMedID 9004389

• Genome scanning for linkage: An overview AMERICAN JOURNAL OF HUMAN GENETICS Whittemore, A. S. 1996; 59 (3): 704-716

  Abstract

  Several different methods for linkage analysis are shown to arise from a single likelihood function L for the observed allele-sharing data at multiple markers in a chromosomal region. These include classical parametric lod score methods, nonparametric or "model-free" affected pedigree-member (APM) methods, and the Gaussian process method. Setting the methods in the context of the likelihood function L clarifies their underlying assumptions. A test statistic derived from L, the efficient score statistic, is introduced. It is asymptotically equivalent to the lod score, but it can be easier to compute when the penetrances and frequencies of alleles of the trait gene are not known. APM test statistics and the Gaussian lod score are shown to be special cases of efficient score statistics. This unified framework facilitates exploration of a range of models for the effects of a putative trait-predisposing gene, and it facilitates sensitivity analyses to examine the consequences of model misspecification.

  View details for Web of Science ID A1996VN62500025

  View details for PubMedID 8751872

• An analysis of correlated multivariate binary data: Application to familial cancers of the ovary and breast JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES C-APPLIED STATISTICS Betensky, R. A., Whittemore, A. S. 1996; 45 (4): 411-429

  View details for Web of Science ID A1996VV98800002

• VASECTOMY AND PROSTATE-CANCER - RESULTS FROM A MULTIETHNIC CASE-CONTROL STUDY JOURNAL OF THE NATIONAL CANCER INSTITUTE John, E. M., Whittemore, A. S., Wu, A. H., Kolonel, L. N., Hislop, T. G., Howe, G. R., West, D. W., Hankin, J., Dreon, D. M., Teh, C. Z., Burch, J. D., PAFFENBARGER, S. 1995; 87 (9): 662-669

  Abstract

  Vasectomy, a widely used form of contraception, has been associated in some studies with increased prostate cancer risk.We assessed this association on the basis of data collected in a large multiethnic case-control study of prostate cancer that was conducted in the United States (Los Angeles, San Francisco, and Hawaii) and Canada (Toronto and Vancouver).In home interviews conducted with newly diagnosed prostate cancer case patients and population control subjects, we obtained information on the participants' medical history, including a history of vasectomy and the age at which the procedure was performed, as well as other potential risk factors. Blood samples were collected from control subjects only and were assayed for concentration of sex hormones and sex hormone-binding globulin.The present analysis was based on 1642 prostate cancer patients and 1636 control subjects. A history of vasectomy was not significantly associated with prostate cancer risk among all racial/ethnic groups combined (odds ratio [OR] = 1.1; 95% confidence interval [CI] = 0.83-1.3), whites (OR = 0.94; 95% CI = 0.69-1.3), blacks (OR = 1.0; 95% CI = 0.59-1.8), or Chinese-Americans (OR = 0.96; 95% CI = 0.42-2.2). Among Japanese-Americans, the OR was 1.8 (95% CI = 0.97-3.4), but the statistically nonsignificant elevation in risk was limited to more educated men and those with localized cancers. ORs did not vary significantly by age at vasectomy or years since vasectomy. We found a lower serum concentration of sex hormone-binding globulin and a higher ratio of dihydrotestosterone to testosterone among vasectomized control subjects than among nonvasectomized control subjects.The findings of this study do not support previous reports of increased prostate cancer risk associated with vasectomy. However, the altered endocrine profiles of vasectomized control subjects seen in this cross-sectional comparison warrant further evaluation in longitudinal studies.

  View details for PubMedID 7538594

• PROSTATE-CANCER IN RELATION TO DIET, PHYSICAL-ACTIVITY, AND BODY-SIZE IN BLACKS, WHITES, AND ASIANS IN THE UNITED-STATES AND CANADA JOURNAL OF THE NATIONAL CANCER INSTITUTE Whittemore, A. S., Kolonel, L. N., Wu, A. H., John, E. M., Gallagher, R. P., Howe, G. R., Burch, J. D., Hankin, J., Dreon, D. M., West, D. W., Teh, C. Z., Paffenbarger, R. S. 1995; 87 (9): 652-661

  Abstract

  International and interethnic differences in prostate cancer incidence suggest an environmental, potentially modifiable etiology for the disease.We conducted a population-based case-control study of prostate cancer among blacks (very high risk), whites (high risk), and Asian-Americans (low risk) in Los Angeles, San Francisco, Hawaii, Vancouver, and Toronto. Our aim was to evaluate the roles of diet, physical activity patterns, body size, and migration characteristics on risk in these ethnic groups and to assess how much of the interethnic differences in risk might be attributed to interethnic differences in such lifestyle characteristics.We used a common protocol and questionnaire to administer personal interviews to 1655 black, white, Chinese-American, and Japanese-American case patients diagnosed during 1987-1991 with histologically confirmed prostate carcinoma and to 1645 population-based control subjects matched to case patients by age, ethnicity, and region of residence. Sera collected from 1127 control subjects were analyzed for levels of prostate-specific antigen (PSA) to permit comparison of case patients with control subjects lacking serological evidence of prostate disease. Odds ratios were estimated using conditional logistic regression. We estimated the proportion of prostate cancer attributable to certain risk factors and the proportion of interethnic risk differences attributable to interethnic differences in risk-factor prevalence.A positive statistically significant association of prostate cancer risk and total fat intake was found for all ethnic groups combined. This association was attributable to energy from saturated fats; after adjusting for saturated fat, risk was associated only weakly with monounsaturated fat and was unrelated to protein, carbohydrate, polyunsaturated fat, and total food energy. Saturated fat intake was associated with higher risks for Asian-Americans than for blacks and whites. In all ethnic groups combined, the risk tended to be higher when only case patients with advanced disease were compared with control subjects with normal PSA levels. Among foreign-born Asian-Americans, risk increased independently with years of residence in North America and with saturated fat intake. Crude estimates suggest that differences in saturated fat intake account for about 10% of black-white differences and about 15% of white-Asian-American differences in prostate cancer incidence. Risk was not consistently associated with intake of any micronutrients, body mass, or physical activity patterns.These data support a causal role in prostate cancer for saturated fat intake but suggest that other factors are largely responsible for interethnic differences in risk.

  View details for PubMedID 7752270

• CHRONIC OBSTRUCTIVE PULMONARY-DISEASE IN LIFELONG NONSMOKERS - RESULTS FROM NHANES AMERICAN JOURNAL OF PUBLIC HEALTH Whittemore, A. S., Perlin, S. A., DICICCIO, Y. 1995; 85 (5): 702-706

  Abstract

  The prevalence of chronic obstructive pulmonary disease was evaluated in 12,980 lifelong nonsmoking adults who participated in one of three National US Health and Nutrition Examination Surveys. Also evaluated were the relationships between chronic obstructive pulmonary disease and age, sex, ethnicity, education, income, and certain environmental and occupational factors. Overall, 4% of men and 5% of women reported physician-diagnosed chronic obstructive pulmonary disease. Prevalence increased with age and with decreasing household income, was higher in Whites than in non-Whites, and was particularly high in Hispanic women. Further research is needed to explain the excess risk for chronic obstructive pulmonary disease in economically disadvantaged nonsmokers, and to assess the role of environmental tobacco smoke in nonsmokers' risk for the disease.

  View details for Web of Science ID A1995QW83900018

  View details for PubMedID 7733432

• FAMILY HISTORY AND PROSTATE-CANCER RISK IN BLACK, WHITE, AND ASIAN MEN IN THE UNITED-STATES AND CANADA AMERICAN JOURNAL OF EPIDEMIOLOGY Whittemore, A. S., Wu, A. H., Kolonel, L. N., John, E. M., Gallagher, R. P., Howe, G. R., West, D. W., Teh, C. Z., Stamey, T. 1995; 141 (8): 732-740

  Abstract

  Increased risk of prostate cancer in men with a family history of the disease has been observed consistently in epidemiologic studies. However, most studies have been confined to white men; little is known about familial aggregation of prostate cancer in populations with unusually high incidence, such as African Americans, or in populations with low incidence, such as Asian-Americans. The authors report results from a population-based case-control study of prostate cancer among blacks, whites, and Asian-Americans in the United States and Canada. Controls were matched to cases on age (5-year groups), ethnicity (black, white, Chinese-American, Japanese-American), and region of residence (Los Angeles, San Francisco, Hawaii, Vancouver, Toronto). In the combined group of participants, 5% of controls and 13% of cases reported a father, brother, or son with prostate cancer. These prevalences were somewhat lower among Asian-Americans than among blacks or whites. A positive family history was associated with a statistically significant two- to threefold increase in risk in each of the three ethnic groups. The overall odds ratio associated with such a family history, adjusted for age and ethnicity, was 2.5 (95% confidence interval 1.9-3.3). This odds ratio varied by neither ethnicity nor age of the participants. Sera from 1,087 controls were used to examine the relations between family history and serum concentrations of androgens and prostate-specific antigen. The concentrations of sex hormone-binding globulin were slightly higher in men with than without a positive family history. Prostate-specific antigen concentrations were unrelated to family history.

  View details for PubMedID 7535977

• PROSTATE-SPECIFIC ANTIGEN AS PREDICTOR OF PROSTATE-CANCER IN BLACK-MEN AND WHITE MEN JOURNAL OF THE NATIONAL CANCER INSTITUTE Whittemore, A. S., Lele, C., Friedman, G. D., Stamey, T., Vogelman, J. H., Orentreich, N. 1995; 87 (5): 354-360

  Abstract

  The increasing incidence of prostate cancer creates complex issues in health care management and cost containment. There is a need to evaluate serial measurements of prostate-specific antigen (PSA) as a marker for long-term risk of clinically important prostate cancer (stages B through D).We used a nested case-control design within a retrospective cohort study to evaluate serial PSA concentrations in relation to subsequent prostate cancer diagnoses.Participants included 40 black and 96 white men with subsequent diagnoses of prostate cancer and 84 black and 100 white men without such diagnoses (control subjects) in a multiphasic health screening program conducted by the Kaiser Permanente Medical Care Program of Northern California. Serial serum samples were collected 1.5-23 years before prostate cancer diagnosis.Median serum PSA concentrations, specific for age and subsequent cancer status, were similar in blacks and whites. Concentrations in control subjects increased exponentially with age, with a doubling time of 24.9 years. Concentrations in men with stage A cancer were similar to those in control subjects. Until about 13 years before diagnosis, PSA in men with subsequent cancer stages B through D increased exponentially with age, with a doubling time similar to that of control subjects. Thereafter, the PSA concentrations increased exponentially, with a doubling time of 4.3 years. Rapid increase in PSA concentration started about 1.5 years earlier for men with stage D cancer than for men with stage B or C cancer. The single PSA measurement drawn closest to diagnosis was a more sensitive marker of stages B through D cancer within the next 7 years than was any index of change that also took account of earlier PSA readings.These data suggest that 1) age-specific PSA concentrations are similar in black men and white men and 2) current PSA concentration, specific for age, outperforms changes in past concentrations in identifying the man who will develop stage B, C, or D cancer within 7 years, albeit at the cost of a slightly higher rate of false-positive results. This interpretation needs confirmation in other data containing many serial PSA measurements within a few years of diagnosis.

  View details for Web of Science ID A1995QH57000008

  View details for PubMedID 7531773

• SEGREGATION ANALYSIS OF CASE-CONTROL DATA USING GENERALIZED ESTIMATING EQUATIONS BIOMETRICS Whittemore, A. S., Gong, G. 1994; 50 (4): 1073-1087

  Abstract

  Generalized estimating equations (GEEs) (Liang and Zeger, 1986, Biometrika 73, 13-22) are used to fit genetic models to binary disease data for families of subjects in case-control studies. The GEEs include model specification of both the disease probabilities and the two-way (and possibly three-way) correlation coefficients of the family disease data. These quantities are modelled as nonlinear functions of unobserved genotypes, observed environmental covariates, and the unknown parameters; the functions reflect the method used to ascertain the family data. Goodness of fit is tested by allowing more flexible forms for the correlation coefficients, regressing them against covariates specific to the relevant pair (or triple) of family members. The approach is applied to family data obtained from simulated and real case-control studies. This semiparametric approach is less dependent on unverifiable assumptions and more computationally tractable than other methods for segregation analysis.

  View details for Web of Science ID A1994QP05000015

  View details for PubMedID 7786989

• CHARACTERISTICS RELATING TO OVARIAN-CANCER RISK - IMPLICATIONS FOR PREVENTION AND DETECTION NIH Consensus Development Conference on Ovarian Cancer: Screening, Treatment, and Follow-Up Whittemore, A. S. ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS. 1994: S15–S19

  Abstract

  Approximately 20,000 women are diagnosed with ovarian cancer in the United States each year, and some 12,000 women die because of it. Epithelial ovarian cancer, the most common histopathologic type, is uncommon before age 40 years, after which incidence rates increase steeply until age 70-79 years and then decrease somewhat. In the United States, the lifetime risk from birth to age 85 years is about 1.5%. There is general agreement that residence in North America or northern Europe, nulliparity, and having a mother or sister with ovarian cancer are associated with an elevated risk, and that increasing number of pregnancies (whether or not full term), increasing length of oral contraceptive use, and increasing duration of lactation are protective. A history of breast or endometrial cancer appears to be associated with a slight elevation in risk. Apart from oral contraceptive use, none of these characteristics can be modified easily to reduce ovarian cancer risk. However, long-term oral contraceptive use before the menopause could prevent as much as half of all ovarian cancer. At present, the subgroup of the population at highest risk consists of women with a mother or sister with the disease; the lifetime ovarian cancer risk in these women is about 9%. A small fraction of them have families with multiple cases of ovarian cancer and early-onset breast cancer, due largely or entirely to mutated alleles of the gene BRCA1. These women, who have a lifetime risk of breast or ovarian cancer of 85-100%, need aggressive screening and possibly prophylactic surgery.

  View details for Web of Science ID A1994QF35200003

  View details for PubMedID 7835800

• RATES AND RISKS OF OVARIAN-CANCER IN SUBGROUPS OF WHITE WOMEN IN THE UNITED-STATES OBSTETRICS AND GYNECOLOGY Hartge, P., Whittemore, A. S., ITNYRE, J., McGowan, L., Cramer, D., CASAGRANDE, J. T., Kelsey, J. L., Lee, M., Lee, N. C., Lyon, J. L., Marshall, J. R., Nasca, P. C., Paffenbarger, R. S., Rosenberg, L., Weiss, N. S. 1994; 84 (5): 760-764

  View details for Web of Science ID A1994PN55100005

• USE OF BIOLOGICAL MARKERS IN RISK ASSESSMENT RISK ANALYSIS McMillan, A., Whittemore, A. S., Silvers, A., DICICCIO, Y. 1994; 14 (5): 807-813

  Abstract

  Measurements of intermediate end points in the carcinogenic process may reduce uncertainty in human risk assessment from bioassay data, by identifying sources of interspecies variation and dose nonlinearity. This paper describes desirable properties of such markers: persistence, predictive power, temporal relevance, and consistency across dose rate and species. We illustrate these properties by evaluating markers for squamous cell nasal carcinoma in rodents exposed to formaldehyde. We also discuss design issues for bioassays that evaluate markers and tumors simultaneously at necropsy.

  View details for Web of Science ID A1994PT37000013

  View details for PubMedID 7800865

• COMPARISON OF DIETARY HABITS, PHYSICAL-ACTIVITY AND BODY-SIZE AMONG CHINESE IN NORTH-AMERICA AND CHINA INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Lee, M. M., WUWILLIAMS, A., Whittemore, A. S., Zheng, S., Gallagher, R., Teh, C. Z., Zhou, L., Wang, X. H., Chen, K., Ling, C. D., JIAO, D. A., Jung, D., Paffenbarger, R. S. 1994; 23 (5): 984-990

  Abstract

  Chinese in North America have higher rates of many chronic diseases than do Chinese in Asia. However, there is a lack of data among comparisons of the environmental and lifestyle factors for Chinese in China and Chinese residing in North America.We examined self-reported dietary nutrient intakes, physical activity patterns and body mass index of 2488 healthy Chinese men and women residing in North America (US and Canada) and in the People's Republic of China.On average, Chinese in China consumed more calories (males 2904 kcal in China, versus 2201 kcal in North America; females 2317 Kcal in China, versus 1795 Kcal in North America and more carbohydrate, but less fat (males 72.2 g in China versus 84.5 g in North America, females 56.6 g in China versus 70.8 g in North America), protein, vitamin A, beta-carotene and vitamin C than did Chinese in North America. Per cent calories from fat was 35% for Chinese in North America and 22% for Chinese in China. In contrast, the per cent of calories from carbohydrates was 62-68% in China and 48% in North America. Chinese in China reported spending more time in vigorous activity, sleeping and walking but less hours in sitting than Chinese in North America. Chinese in China weighted less and were leaner than North American Chinese.These differences in nutrient intakes, physical activity and body size of Chinese living on two different continents suggest possible explanations for observed differences in chronic disease rates in the two populations.

  View details for Web of Science ID A1994PT30300014

  View details for PubMedID 7860179

• PROBABILITY OF GENE IDENTITY BY DESCENT - COMPUTATION AND APPLICATIONS BIOMETRICS Whittemore, A. S., Halpern, J. 1994; 50 (1): 109-117

  Abstract

  Two genes at a given locus are identical by descent (IBD) if both have been inherited from a common ancestor. We present an algorithm for computing the probabilities of all IBD relationships among the genes of pedigree members. We show how to use these probabilities to calculate the probability of any combination of genotypes or phenotypes for the pedigree members. Applications to linkage analysis and genetic counseling are illustrated with examples. The algorithm also can be used to calculate the generalized kinship coefficients proposed by others.

  View details for Web of Science ID A1994NH26500010

  View details for PubMedID 8086594

• A CLASS OF TESTS FOR LINKAGE USING AFFECTED PEDIGREE MEMBERS BIOMETRICS Whittemore, A. S., Halpern, J. 1994; 50 (1): 118-127

  Abstract

  We describe a class of nonparametric tests for linkage between a marker and a gene assumed to exist and to govern susceptibility to a disease. The tests are formed by assigning a score to each possible pattern of marker allele sharing (identity-by-descent) among affected pedigree members, and then averaging the scores over all patterns compatible with the observed marker genotype and genealogical relationship of the affected members. Different score functions give different tests. One function, which examines marker allele similarity across pairs of affected pedigree members, gives a test similar to that of Fimmers et al. (1989, in Multipoint Mapping and Linkage Based on Affected Pedigree Members: Genetic Analysis Workshop, R. C. Elston, M. A. Spence, S. E. Hodge, and J. W. MacCluer (eds), 123-128; City: Alan R. Liss). A second function examines allele similarity across arbitrary subsets, not just pairs, of affected members. The resulting test can be more powerful than the one based solely on pairs of affected members. The approach has several advantages: it does not require knowledge of the mode of disease inheritance; it does not require unambiguous determination of identity-by-descent at the marker; it does not suffer from variability due to chance allele similarity among affected members who are unrelated, such as spouses; it allows marker genotypes of unaffected members to contribute information on allele sharing among the affected; it permits calculation of exact P-values. Computational requirements limit the tests to many pedigrees with few (< 16) affected members.

  View details for Web of Science ID A1994NH26500011

  View details for PubMedID 8086596

• Epidemiology and primary prevention of cancers of the breast, endometrium, and ovary. A brief overview. Annals of epidemiology Kelsey, J. L., Whittemore, A. S. 1994; 4 (2): 89-95

  Abstract

  Cancers of the breast, endometrium, and ovary account for 41% of incident cancers among women. Many risk factors for breast cancer have been identified, but most are associated with only modest elevations in risk. Also, of all the risk factors identified, few are likely to be affected by intervention programs. The pathogenesis of breast cancer is not well understood, but estrogen and possibly estrogen plus progesterone are likely to be etiologically involved. For endometrial cancer, a major etiologic pathway is exposure to estrogen without cyclic exposure to progesterone. Most of the established risk factors for endometrial cancer appear to affect risk at least in part through this pathway. Only a few risk factors for ovarian cancer have been identified. The two most commonly suggested etiologic mechanisms for ovarian cancer are (a) that suppression of ovulation reduces risk and (b) that suppression of pituitary gonadotropins reduces risk. Each hypothesis is consistent with some, but not all, of the data. Prospects for the primary prevention of these cancers are discouraging at present because few of the risk factors identified to date are readily subject to modification, especially for breast cancer, and the underlying etiologies of these cancers are not well understood, particularly for breast and ovarian cancers.

  View details for PubMedID 8205289

• PROSTATE-CANCER CANCER SURVEYS Whittemore, A. S. 1994; 20: 309-322

  Abstract

  Trends in prostate cancer incidence and mortality are examined for men in England, Italy, Japan, Sweden and the USA. Incidence rose during the period 1968-1972 to 1983-1987 in all these populations. A substantial portion of this increase may be due to increased detection rates. However, mortality also has risen during this period in most of the populations. Although some of the increased mortality may be due to changes in death certification, the possibility of real increases in incidence of aggressive disease cannot be excluded. Large international and interethnic differences are evident for both incidence and mortality, in all time periods. Interpretation of the differences in incidence is complicated by international and interethnic differences in detection rates. The differences in mortality are unlikely to be due entirely to differences in death certification. The temporal rise in incidence demonstrated by all these populations suggests worldwide increases in health care costs for prostate cancer. Since a large part of the increased incidence seems to be due to increased detection rates of localized disease that would otherwise have remained asymptomatic, the increased costs may not be associated with concomitant reductions in morbidity and mortality.

  View details for Web of Science ID A1994PG61800017

• Prostate cancer. Cancer surveys Whittemore, A. S. 1994; 19-20: 309-22

  Abstract

  Trends in prostate cancer incidence and mortality are examined for men in England, Italy, Japan, Sweden and the USA. Incidence rose during the period 1968-1972 to 1983-1987 in all these populations. A substantial portion of this increase may be due to increased detection rates. However, mortality also has risen during this period in most of the populations. Although some of the increased mortality may be due to changes in death certification, the possibility of real increases in incidence of aggressive disease cannot be excluded. Large international and interethnic differences are evident for both incidence and mortality, in all time periods. Interpretation of the differences in incidence is complicated by international and interethnic differences in detection rates. The differences in mortality are unlikely to be due entirely to differences in death certification. The temporal rise in incidence demonstrated by all these populations suggests worldwide increases in health care costs for prostate cancer. Since a large part of the increased incidence seems to be due to increased detection rates of localized disease that would otherwise have remained asymptomatic, the increased costs may not be associated with concomitant reductions in morbidity and mortality.

  View details for PubMedID 7895221

• THE DESCRIPTIVE EPIDEMIOLOGY OF PROSTATE CANCER - AN UPDATE 5th Tokyo Symposium on Prostate Cancer - Fundamental Approaches to the Diagnosis and Treatment for Prostate Cancer and BPH Whittemore, A. S. ADENINE PRESS. 1994: 37–47

  View details for Web of Science ID A1994BB74L00005

• FERTILITY DRUGS AND RISK OF OVARIAN-CANCER HUMAN REPRODUCTION Whittemore, A. S. 1993; 8 (7): 999-1000

  View details for Web of Science ID A1993LK72800006

  View details for PubMedID 8408508

• LOCALIZED PROSTATE-CANCER - RELATIONSHIP OF TUMOR VOLUME TO CLINICAL-SIGNIFICANCE FOR TREATMENT OF PROSTATE-CANCER 1ST NATIONAL CONF ON PROSTATE CANCER Stamey, T. A., Freiha, F. S., McNeal, J. E., REDWINE, E. A., Whittemore, A. S., Schmid, H. P. WILEY-LISS. 1993: 933–38

  Abstract

  Using the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute and American total mortality rates, the authors calculated the probability at birth of having a diagnosis of prostate cancer within a man's life to be 8.8% and then subtracted the incidence of microscopic Stage A cancers too small to ever be clinically significant. This gave a final probability of 8%.Prostates were examined after 139 consecutive unselected cystoprostatectomies from patients with bladder cancers in whom it was unknown whether they had prostate cancer. Prostate cancer was found in 55 patients (40%); the volume of the largest cancer in each specimen was determined using histologic morphometry. The authors identified the 8% of these 139 cytoprostatectomy specimens with the largest volume of prostate cancer.The largest 11 of the 55 cancers represented 7.9% of the total 139 samples. These cancers ranged in volume from 0.5-6.1 ml, representing only 20% of all patients with prostate cancer.If the strong evidence is accepted that cancer progression is proportional to cancer volume, it was concluded that prostate cancers larger than 0.5 ml appear to correspond to the 8% of men who will be diagnosed with a clinically significant carcinoma, as derived previously. Conversely, those 80% of prostate cancers smaller than 0.5 ml probably are not likely to reach a clinically significant size in view of the long doubling time of this cancer.

  View details for Web of Science ID A1993KM67400007

  View details for PubMedID 7679045

• CHARACTERISTICS RELATING TO OVARIAN-CANCER RISK - COLLABORATIVE ANALYSIS OF 7 UNITED-STATES CASE-CONTROL STUDIES - EPITHELIAL OVARIAN-CANCER IN BLACK-WOMEN JOURNAL OF THE NATIONAL CANCER INSTITUTE John, E. M., Whittemore, A. S., Harris, R., ITNYRE, J. 1993; 85 (2): 142-147

  Abstract

  Previous epidemiologic studies of ovarian cancer have focused chiefly on White women, who have a higher incidence of ovarian cancer than Black women. No study has previously examined risk factors for ovarian cancer among Black women.This study was designed to evaluate the risk of epithelial ovarian cancer in Black women in relation to reproductive characteristics such as pregnancy, oral contraceptive use, and breast-feeding, and to determine whether differences in reproductive factors between Black and White women account for differences in ovarian cancer incidence.Combining interview data from seven case-control studies, we compared reproductive characteristics of 110 Black case subjects with a diagnosis of epithelial ovarian cancer between 1971 and 1986 with characteristics of 251 Black population control subjects and 114 Black hospital control subjects. We also compared the prevalence of reproductive factors in 246 Black population control subjects and 4378 White population control subjects and estimated the fraction of Black-White differences in ovarian cancer incidence attributable to racial differences in prevalence of these characteristics.Decreased risks of epithelial ovarian cancer in Black women were associated with parity of four or higher (odds ratio [OR] = 0.53; 95% confidence interval [CI] = 0.25-1.1), breast-feeding for 6 months or longer (OR = 0.85; 95% CI = 0.36-2.0), and use of oral contraceptives for 6 years or longer (OR = 0.62; 95% CI = 0.24-1.6). A greater proportion of Black women (48%) than White women (27%) reported four or more term pregnancies, and Black women (62%) were more likely than White women (53%) to have breast-fed their children. Oral contraceptive use was more common among White women (59%) than Black women (51%).Differences in the prevalence of other factors related to ovarian cancer risk or differences in genetic susceptibility must explain most of the Black-White differences in incidence of ovarian cancer.

  View details for PubMedID 8418303

• PERSONAL CHARACTERISTICS RELATING TO RISK OF INVASIVE EPITHELIAL OVARIAN-CANCER IN OLDER WOMEN IN THE UNITED-STATES WORKING CONF ON PERSPECTIVES ON OVARIAN CANCER IN OLDER-AGED WOMEN : CURRENT KNOWLEDGE AND RECOMMENDATIONS FOR RESEARCH Whittemore, A. S. WILEY-LISS. 1993: 558–65

  Abstract

  The ovarian cancer incidence rate is higher for women over 55 years of age than for younger women, but it increases less rapidly with age after age 55 years than before. This slower rate of increase suggests that the postmenopausal ovary may be less exposed or less susceptible than the functioning one to endogenous or exogenous carcinogens. For example, it is not exposed to mitotic stimuli at follicle rupture, which may increase the likelihood of malignancy.Findings from a collaborative analysis of 12 U.S. case-control studies are used to examine associations between invasive epithelial ovarian cancer and certain reproductive and hormonal characteristics, and to determine if those associations change as women age.Ovarian cancer risk reductions were associated with pregnancy (regardless of outcome), lactation, and oral contraceptive use. The percentage risk reduction associated with pregnancy was smaller for older women than younger women, although the absolute magnitude of the risk reduction increased with age. In contrast, the percentage risk reduction associated with oral contraceptive use was greater for older women. The total duration of ovulation was strongly associated with increased risk in women under 55 years of age, but not in older women.The greater protection to older women associated with oral contraceptive use suggests that the early high-potency contraceptive formulations used by these women may have been more protective than recent ones. The sparsity of strong risk factors in older women emphasizes the need for sensitive and specific markers for early detection of ovarian malignancy in this age group.

  View details for Web of Science ID A1993KH50600009

  View details for PubMedID 8420677

• USE OF NHANES DATA TO ASSIGN NUTRIENT DENSITIES TO FOOD GROUPS IN A MULTIETHNIC DIET HISTORY QUESTIONNAIRE NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL Dreon, D. M., John, E. M., DICICCIO, Y., Whittemore, A. S. 1993; 20 (3): 223-230

  Abstract

  In epidemiological studies of diet and chronic disease, a brief yet comprehensive diet history questionnaire must aggregate some foods into food groups. A nutrient density is assigned to each food group by averaging the densities of its constituent foods. A person's intake of a given nutrient is then estimated by multiplying the reported consumption of each food group by its average nutrient density and summing over food groups. These calculations could introduce bias in multiethnic studies, if the average nutrient densities assigned to food groups are inappropriate for some ethnic populations. This issue is examined here for intakes of total fat, saturated fat, and vitamin A for U.S. blacks and whites. We used 24-hour diet recall data from the Second National Health and Nutrition Examination Survey (NHANES II) to assess black-white differences in relative frequency of consumption of foods within food groups of a diet history questionnaire. We also calculated ethnic-specific average nutrient densities for each food group by weighting the densities of its foods in proportion to their frequency of consumption by black and white NHANES II participants. We found black-white differences in the frequency of consumption of foods within 14 food groups. However, blacks and whites had different average total fat densities for only 1 of the 14 food groups, no difference in saturated fat densities for any food group, and different vitamin A densities for 2 food groups. Among blacks and whites, there is no advantage to calculating ethnic-specific average nutrient densities for food groups comprised of foods with similar densities.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for PubMedID 8108272

• DIETARY-INTAKE OF FIBER AND DECREASED RISK OF CANCERS OF THE COLON AND RECTUM - EVIDENCE FROM THE COMBINED ANALYSIS OF 13 CASE-CONTROL STUDIES JOURNAL OF THE NATIONAL CANCER INSTITUTE Howe, G. R., Benito, E., CASTELLETO, R., CORNEE, J., Esteve, J., Gallagher, R. P., ISCOVICH, J. M., JIAO, D. A., Kaaks, R., Kune, G. A., Kune, S., LABBE, K. A., Lee, H. P., Lee, M., Miller, A. B., Peters, R. K., Potter, J. D., Riboli, E., Slattery, M. L., Trichopoulos, D., Tuyns, A., Tzonou, A., Whittemore, A. S., WUWILLIAMS, A. H., Zheng, S. 1992; 84 (24): 1887-1896

  Abstract

  Colorectal cancer is a major public health problem in both North America and western Europe, and incidence and mortality rates are rapidly increasing in many previously low-risk countries. It has been hypothesized that increased intakes of fiber, vitamin C, and beta carotene could decrease the risk of colorectal cancer.The objective of this study was to examine the effects of fiber, vitamin C, and beta-carotene intakes on colorectal cancer risk in a combined analysis of data from 13 case-control studies previously conducted in populations with differing colorectal cancer rates and dietary practices. The study was designed to estimate risks in the pooled data, to test the consistency of the associations across the studies, and to examine interactions of the effects of the nutrients with cancer site, sex, and age.Original data records for 5287 case subjects with colorectal cancer and 10,470 control subjects without disease were combined. Logistic regression analysis was used to estimate relative risks and confidence intervals for intakes of fiber, vitamin C, and beta carotene, with the effects of study, sex, and age group being adjusted by stratification.Risk decreased as fiber intake increased; relative risks were 0.79, 0.69, 0.63, and 0.53 for the four highest quintiles of intake compared with the lowest quintile (trend, P < .0001). The inverse association with fiber is seen in 12 of the 13 studies and is similar in magnitude for left- and right-sided colon and rectal cancers, for men and for women, and for different age groups. In contrast, after adjustment for fiber intake, only weak inverse associations are seen for the intakes of vitamin C and beta carotene.This analysis provides substantive evidence that intake of fiber-rich foods is inversely related to risk of cancers of both the colon and rectum.If causality is assumed, we estimate that risk of colorectal cancer in the U.S. population could be reduced about 31% (50,000 cases annually) by an average increase in fiber intake from food sources of about 13 g/d, corresponding to an average increase of about 70%.

  View details for Web of Science ID A1992KB98400012

  View details for PubMedID 1334153

• CHARACTERISTICS RELATING TO OVARIAN-CANCER RISK - COLLABORATIVE ANALYSIS OF 12 UNITED-STATES CASE-CONTROL STUDIES .3. EPITHELIAL TUMORS OF LOW MALIGNANT POTENTIAL IN WHITE WOMEN AMERICAN JOURNAL OF EPIDEMIOLOGY Harris, R., Whittemore, A. S., ITNYRE, J. 1992; 136 (10): 1204-1211

  Abstract

  Epithelial ovarian neoplasms of low malignant potential, also called borderline ovarian tumors, have various features of malignancy, but they do not invade the ovarian stroma. Women with these tumors usually are younger when diagnosed and have better prognoses than do women with invasive tumors. There have been few epidemiologic studies of borderline tumors, and it is unclear whether there are etiologic differences between the two types of tumor behavior. Combined data from nine case-control studies, conducted from 1974 to 1986 and representing 327 white women with tumors of low malignant potential and 4,144 white controls, were used to evaluate the relation between these tumors and personal characteristics related to invasive ovarian cancer. The risk profile for tumors of low malignant potential was found to be similar to that for invasive tumors, with two exceptions: Compared with that of invasive tumors, risk of borderline tumors was less clearly reduced among women who had used oral contraceptives and more clearly elevated among women with a history of infertility.

  View details for Web of Science ID A1992KG47200003

  View details for PubMedID 1476142

• CHARACTERISTICS RELATING TO OVARIAN-CANCER RISK - COLLABORATIVE ANALYSIS OF 12 UNITED-STATES CASE-CONTROL STUDIES .1. METHODS AMERICAN JOURNAL OF EPIDEMIOLOGY Whittemore, A. S., Harris, R., ITNYRE, J., Halpern, J. 1992; 136 (10): 1175-1183

  Abstract

  Data from 12 US case-control studies of ovarian cancer, conducted during the period 1956-1986 and representing some 3,000 cases and 10,000 controls, were pooled and reanalyzed. Separate analyses were conducted for four subgroups of the pooled data: invasive epithelial ovarian cancers in white women; epithelial ovarian cancers of low malignant potential in white women, epithelial ovarian cancers in black women, and nonepithelial ovarian cancers. This paper gives a brief description of the participating studies and describes the methods used in the collaborative analysis.

  View details for Web of Science ID A1992KG47200001

  View details for PubMedID 1476140

• CHARACTERISTICS RELATING TO OVARIAN-CANCER RISK - COLLABORATIVE ANALYSIS OF 12 UNITED-STATES CASE-CONTROL STUDIES .2. INVASIVE EPITHELIAL OVARIAN CANCERS IN WHITE WOMEN AMERICAN JOURNAL OF EPIDEMIOLOGY Whittemore, A. S., Harris, R., ITNYRE, J. 1992; 136 (10): 1184-1203

  Abstract

  Data collected from 2,197 white ovarian cancer patients and 8,893 white controls in 12 US case-control studies conducted in the period 1956-1986 were used to evaluate the relation of invasive epithelial ovarian cancer to reproductive and menstrual characteristics, exogenous estrogen use, and prior pelvic surgeries. Clear trends of decreasing risk were evident with increasing number of pregnancies (regardless of outcome) and increasing duration of breast feeding and oral contraceptive use. Ovarian dysfunction leading to both infertility and malignancy is an unlikely explanation for these trends for several reasons: 1) The trends were evident even among the highly parous; 2) risk among nulliparous women did not vary by marital status or gravidity; and 3) risk among ever-married women showed little relation to length of longest pregnancy attempt or history of clinically diagnosed infertility. Risk was increased among women who had used fertility drugs and among women with long total duration of premenopausal sexual activity without birth control; these associations were particularly strong among the nulligravid. No consistent trends in risk were seen with age at menarche, age at menopause, or duration of estrogen replacement therapy. A history of tubal ligation or of hysterectomy with ovarian conservation was associated with reduced ovarian cancer risk. These observations suggest that pregnancy, breast feeding, and oral contraceptive use induce biological changes that protect against ovarian malignancy, that, at most, a small fraction of the excess ovarian cancer risk among nulliparous women is due to infertility, and that any increased risk associated with infertility may be due to the use of fertility drugs.

  View details for Web of Science ID A1992KG47200002

  View details for PubMedID 1476141

• CHARACTERISTICS RELATING TO OVARIAN-CANCER RISK - COLLABORATIVE ANALYSIS OF 12 UNITED-STATES CASE-CONTROL STUDIES .4. THE PATHOGENESIS OF EPITHELIAL OVARIAN-CANCER AMERICAN JOURNAL OF EPIDEMIOLOGY Whittemore, A. S., Harris, R., ITNYRE, J. 1992; 136 (10): 1212-1220

  Abstract

  Two hypotheses have been proposed to explain the reduced risk of epithelial ovarian cancer associated with pregnancy and oral contraceptive use. The first states that some sequelae of ovulation increase the likelihood of malignancy and that pregnancies and oral contraceptives protect by suppressing ovulation. The second hypothesis states that circulating levels of pituitary gonadotropins increase the risk of malignancy and that pregnancies and oral contraceptives protect by suppressing secretion of these hormones. The authors evaluate the two hypotheses in light of combined data from 12 United States case-control studies of epithelial ovarian cancer in white women conducted from 1956 to 1986. While a number of observations support both hypotheses, there are exceptions. Differential risk reduction associated with pregnancy and oral contraceptive use (pregnancy being the more effective in young women and the less effective in older women) conflicts with the first "ovulation" hypothesis, while reduced risk associated with breast feeding and absence of altered risk associated with estrogen replacement therapy conflicts with the second "gonadotropin" hypothesis. Several findings would not have been predicted by either hypothesis, e.g., only weak trends relate cancer risk to age at menarche, and, among older women, no clear trends relate risk to age at menopause. Odds ratio attenuation due to errors in reporting personal characteristics may be responsible for some of these inconsistencies. Multidisciplinary research is needed to clarify the etiologic roles of ovulation and gonadotropin stimulation, both of which may enhance carcinogenesis in the ovarian epithelium.

  View details for Web of Science ID A1992KG47200004

  View details for PubMedID 1476143

• CUTANEOUS MELANOMA AT LAWRENCE-LIVERMORE-NATIONAL-LABORATORY - COMPARISON WITH RATES IN 2 SAN-FRANCISCO BAY AREA COUNTIES CANCER CAUSES & CONTROL Gong, G., Whittemore, A. S., West, D., Moore, D. H. 1992; 3 (3): 191-197

  Abstract

  During the period 1974 through 1985, employees at Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States) were diagnosed with cutaneous malignant melanoma at approximately three times the rate of the surrounding community. We investigated two explanations for this excess: the first explanation examined was that the recorded incidence of the neighboring community underestimates actual incidence. We estimated the amount of excess attributable to underreporting by using data from a survey conducted among San Francisco Bay Area clinicians and pathologists to determine previously unrecorded occurrences. We found that underreporting has negligible impact on melanoma incidence. The second explanation examined was that heightened medical awareness of the disease among LLNL employees and their physicians has led to greater detection. We found that LLNL melanomas are thinner than those from the surrounding community and that no excess was observed if we limited our attention to thicker, more invasive melanomas.

  View details for Web of Science ID A1992HU58700001

  View details for PubMedID 1610965

• LOW-GRADE, LATENT PROSTATE-CANCER VOLUME - PREDICTOR OF CLINICAL CANCER INCIDENCE JOURNAL OF THE NATIONAL CANCER INSTITUTE Whittemore, A. S., Keller, J. B., Betensky, R. 1991; 83 (17): 1231-1235

  Abstract

  We hypothesize that each cell in low-grade (Gleason grade 1-3) prostate cancer tissue is at risk of transformation into a cell which produces a high-grade (Gleason grade 4-5) clinical cancer after a short period of growth. As a consequence, the volume of low-grade, latent cancer tissue in the prostate glands of men at any age determines their incidence rate for high-grade, clinical cancer a few years later. Autopsy and incidence data for both white men and black men support this conclusion, with a tumor growth period of about 7 years. The transformation rate is similar for black men and for white men, about 0.024 high-grade cancers per year per cm3 of low-grade, latent cancer volume. Our hypothesis explains the infrequent occurrence of clinical cancer despite the high prevalence of latent cancer, the steep rise of clinical cancer incidence with age despite the slow rise of latent cancer prevalence with age, and the disparities in clinical cancer incidence among some populations despite their similar latent cancer prevalence. This hypothesis suggests that low-grade cancer volume is a critical determinant of clinical cancer risk.

  View details for Web of Science ID A1991GD15200012

  View details for PubMedID 1870149

• FAMILY DATA DETERMINE ALL PARAMETERS IN MENDELIAN INCOMPLETE PENETRANCE MODELS ANNALS OF HUMAN GENETICS Whittemore, A. S., Keller, J. B., Ward, M. J. 1991; 55: 175-177

  Abstract

  We show that data on the frequency of occurrence of an hereditary trait in family members can be used to determine all four parameters in a Mendelian genetic model with incomplete penetrance. Thus previous statements in the literature that such data can determine only three combinations of the parameters are incorrect.

  View details for Web of Science ID A1991FV08800009

  View details for PubMedID 1952809

• URINARY CADMIUM AND BLOOD-PRESSURE - RESULTS FROM THE NHANES-II SURVEY ENVIRONMENTAL HEALTH PERSPECTIVES Whittemore, A. S., DICICCIO, Y., Provenzano, G. 1991; 91: 133-140

  Abstract

  Relationships between urinary cadmium levels and blood pressure were examined in a sample of 951 adult men and women who participated in the Second National Health and Nutritional Examination Survey (NHANES II). Among all participants, positive relationships were seen between urinary cadmium levels and both systolic and diastolic blood pressure (p less than 0.05 and p less than 0.01, respectively), after adjusting for age, sex, race, relative body weight, smoking status, and hypertensive medication use. However, analyses for subgroups determined by sex and smoking status were inconsistent. Among current smokers, urinary cadmium levels were significantly positively associated with both systolic and diastolic blood pressure for women, and with diastolic blood pressure for men. Yet among former smokers and lifelong nonsmokers of both sexes, urinary cadmium was not significantly associated with either systolic or diastolic blood pressure. Evidence that some hypertensive medications increase urinary cadmium excretion suggests that the positive associations seen among current smokers may reflect high urinary cadmium levels among hypertensives induced by hypertensive treatment. After treated hypertensives were removed from the analysis, regression coefficients relating blood pressure to cadmium dropped by a factor of two and lost statistical significance. We conclude that the present data provide little support for a causal association between systemic cadmium and hypertension at nonoccupational exposure levels. Further, conflicting results of previous studies may reflect failure to control adequately for age, smoking status, and hypertensive treatment.

  View details for Web of Science ID A1991FD60400014

  View details for PubMedID 2040243

• THE IMPORTANCE OF MODELS IN THE ASSESSMENT OF SYNERGY JOURNAL OF CLINICAL EPIDEMIOLOGY Hlatky, M. A., Whittemore, A. S. 1991; 44 (12): 1287-1288

  View details for Web of Science ID A1991GY65900002

  View details for PubMedID 1753259

• DIET, PHYSICAL-ACTIVITY, AND COLORECTAL-CANCER AMONG CHINESE IN NORTH-AMERICA AND CHINA JOURNAL OF THE NATIONAL CANCER INSTITUTE Whittemore, A. S., WUWILLIAMS, A. H., Lee, M., Zheng, S., Gallagher, R. P., JIAO, D. A., Zhou, L., Wang, X. H., Chen, K., Jung, D., Teh, C. Z., Ling, C. D., Xu, J. Y., Paffenbarger, R. S., Henderson, B. E. 1990; 82 (11): 915-926

  Abstract

  In a population-based case-control study of colorectal cancer among Chinese men and women in western North America and the People's Republic of China, a common protocol was used to assess past life-style characteristics of 905 cases diagnosed during 1981-1986 and 2,488 controls. Risks for cancers of both the colon and rectum increased with increased food energy from fat, protein, carbohydrate, and all energy sources combined, for both sexes and on both continents. Yet, in multivariate analysis, colorectal cancer risk was significantly associated only with saturated fat; no relationships were seen with other dietary sources of energy. Colon cancer risk was elevated among men employed in sedentary occupations. On both continents and in both sexes, risks for cancers of both the colon and rectum increased with increasing time spent sitting. Further, the association between colorectal cancer risk and saturated fat was stronger among the sedentary than among the active. Risk among sedentary Chinese Americans of either sex increased more than fourfold from the lowest to the highest category of saturated fat intake. Among migrants to North America, risk increased with increasing years lived in North America. These observations suggest (a) that colorectal cancer risk increases with duration of exposure to a sedentary life-style and a diet rich in saturated fat; (b) that higher incidence among Chinese-American men relative to women is due to longer duration of these habits among men, who have lived longer in North America; and (c) that higher risk among Chinese Americans of both sexes relative to risk among the general population in China is due to differences in such habits. Attributable risk calculations suggest that, if these associations are causal, saturated fat intakes exceeding 10 g/day, particularly in combination with physical inactivity, could account for 60% of colorectal cancer incidence among Chinese-American men and 40% among Chinese-American women.

  View details for Web of Science ID A1990DG12800012

  View details for PubMedID 2342126

• TESTING ODDS-RATIO EQUALITY FOR SEVERAL DISEASES BIOMETRIKA Whittemore, A. S., Halpern, J. 1989; 76 (4): 795-798

  View details for Web of Science ID A1989CD39700018

• ERRORS-IN-VARIABLES REGRESSION USING STEIN ESTIMATES AMERICAN STATISTICIAN Whittemore, A. S. 1989; 43 (4): 226-228

  View details for Web of Science ID A1989CQ03200008

• MYCOSIS-FUNGOIDES IN RELATION TO ENVIRONMENTAL EXPOSURES AND IMMUNE-RESPONSE - A CASE-CONTROL STUDY JOURNAL OF THE NATIONAL CANCER INSTITUTE Whittemore, A. S., Holly, E. A., Lee, I. M., Abel, E. A., ADAMS, R. M., Nickoloff, B. J., Bley, L., Peters, J. M., Gibney, C. 1989; 81 (20): 1560-1567

  Abstract

  Mycosis fungoides is a cutaneous T-cell lymphoma of unknown etiology, thought to be a rare sequela of chronic antigenic stimulation that may occur, for example, with exposure to contact allergens. To explore this possibility, we interviewed 174 patients with mycosis fungoides and 294 randomly selected control subjects in the San Francisco, Los Angeles, and Seattle areas concerning their lifetime histories of employment, chemical exposures, allergy, atopy, and certain medical conditions. Patients reported higher prevalence of cancers other than the non-Hodgkin's lymphomas and skin cancers (relative risk = 3.3, P less than .001) and were more likely than controls to burn when exposed to the sun (for nonblacks, relative risk = 1.7, P = .01). The latter difference may reflect a manifestation rather than a precursor of the disease. We found no consistent or biologically plausible differences between patients and controls with respect to types of jobs held, or to occupational or vocational exposures to chemicals. These findings do not support the hypothesis that persistent antigenic stimulation by contact allergens is etiologically important in the pathogenesis of mycosis fungoides.

  View details for Web of Science ID A1989AU61300013

  View details for PubMedID 2795681

• COLORECTAL-CANCER INCIDENCE AMONG CHINESE IN NORTH-AMERICA AND THE PEOPLES-REPUBLIC-OF-CHINA - VARIATION WITH SEX, AGE AND ANATOMICAL SITE INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Whittemore, A. S. 1989; 18 (3): 563-568

  Abstract

  Age-specific incidence rates for cancers of the colon and rectum are presented for Chinese in the western United States and Canada (high risk area), and in Shanghai, the People's Republic of China (low risk area). These rates are compared to those among North American whites. Among Chinese, rate differences between high and low risk areas are greater for colon cancer than rectal cancer, are greater for men than women, and increase with age. The most striking finding is the high colon cancer incidence among older Chinese-American men, compared to Chinese-American women. Colon cancer rates among elderly Chinese-American men equal those of whites, which are seven times the corresponding rates in China. By contrast, colon cancer rates among older Chinese-American women are intermediate between those of whites and those in China, and are only three to four times the rates in China. Rectal cancer rate differences for Chinese men also exceed those for Chinese women. However, they are less dramatic than for colon cancer, with elderly Chinese-American men having roughly double the rates in China, and with women exhibiting little variation between continents or ethnic groups. Male:female (M:F) rate ratios increase with age for both continents, both ethnic groups, and both colon and rectum. The colon cancer M:F ratios among Chinese-Americans exceed the others, reaching two in the older age groups. These observations suggest sex-specific aetiological exposures, or sex-specific susceptibilities to common exposures, among Chinese-Americans.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1989CA15200011

  View details for PubMedID 2807658

• EPITHELIAL OVARIAN-CANCER AND THE ABILITY TO CONCEIVE CANCER RESEARCH Whittemore, A. S., Wu, M. L., Paffenbarger, R. S., SARLES, D. L., Kampert, J. B., Grosser, S., Jung, D. L., Ballon, S., Hendrickson, M., MOHLEBOETANI, J. 1989; 49 (14): 4047-4052

  Abstract

  Relationships between ovarian cancer and ability to conceive were explored in a case-control study of 188 women with histologically confirmed epithelial ovarian cancer and 539 control women in the San Francisco Bay Area. Control women consisted of two groups: those hospitalized without cancer, matched to cases by age, race, and hospital of diagnosis (n = 280); and those selected from the general population by random digital dialing, matched to cases by age, race, and telephone prefix (n = 259). Ovarian cancer risk among nulliparous (but not parous) women was positively associated with a history of unsuccessful attempts to conceive, of physician-diagnosed infertility, and of doubts about ability to conceive. Among all women, risk increased with increasing years of unprotected intercourse (P value for trend = 0.02). Risk among women having 10 or more yr of unprotected intercourse was 1.8 relative to that among women having less than 2 such yr (P = 0.01). This association was independent of parity, oral contraceptive use, and estimated years of ovulation, each associated with ovarian cancer. Further, duration of unprotected intercourse combined multiplicatively with each of these latter characteristics in increasing ovarian cancer risk. For example, while cancer risk exhibited a 2-fold range from lowest to highest years of unprotected intercourse and a 4-fold range from lowest to highest years of ovulation, risk among women in the highest joint category of these characteristics was 8 times that of women in the lowest category. We believe that some abnormality of ovulation that reduces the likelihood of conception plays a role in epithelial ovarian cancer.

  View details for Web of Science ID A1989AE49800059

  View details for PubMedID 2736545

• CANCER RISK ASSESSMENT AND PREVENTION - WHERE DO WE STAND ENVIRONMENTAL HEALTH PERSPECTIVES Whittemore, A. S. 1989; 81: 95-101

  Abstract

  This paper reviews selected aspects of progress and setbacks in cancer risk assessment and prevention during the four decades since the founding in 1947 of the Institute of Environmental Medicine at the New York University Medical Center. The period has been marked by substantial gains in quantifying the risks posed by exposures to known human carcinogens such as tobacco and ionizing radiation. By contrast, the search for sensitive and specific laboratory screens for human carcinogens has met setbacks, and epidemiological data still are needed to monitor the adverse effects of environmental exposures. The determination of acceptable levels of exposure to potential human carcinogens remains a formidable task, one for which no scientific framework yet exists. Future challenges in cancer risk assessment include the validation and use of biological markers of exposure and effective monitoring of risk among exposed populations. Future challenges in cancer prevention include the elimination of tobacco consumption and the acquisition of knowledge needed to prevent nutritionally and hormonally related cancers such as cancers of the bowel, prostate, and breast.

  View details for Web of Science ID A1989AA49000019

  View details for PubMedID 2667993

• PERSONAL AND ENVIRONMENTAL CHARACTERISTICS RELATED TO EPITHELIAL OVARIAN-CANCER - .1. REPRODUCTIVE AND MENSTRUAL EVENTS AND ORAL-CONTRACEPTIVE USE AMERICAN JOURNAL OF EPIDEMIOLOGY Wu, M. L., Whittemore, A. S., Paffenbarger, R. S., SARLES, D. L., Kampert, J. B., Grosser, S., Jung, D. L., Ballon, S., Hendrickson, M., MOHLEBOETANI, J. 1988; 128 (6): 1216-1227

  Abstract

  In two case-control studies conducted in the six-county San Francisco Bay Area, 111 women diagnosed with epithelial ovarian carcinoma in 1974-1977 and 188 women diagnosed in 1983-1985 were interviewed concerning their menstrual, sexual, and reproductive histories. For comparison, interviews were conducted with 752 control women admitted to the same hospitals within six months of the cases; for cases diagnosed in the later period, interviews were also conducted with an additional 259 population-based controls selected by random digit dialing. Controls were matched to cases by age and race. Qualitative and quantitative findings were similar for the two studies. In the combined data, cases were more likely than their matched controls to have been nulliparous, to have undergone menarche at an early age, and to have refrained from using oral contraceptives. Menopause occurred slightly later for cases than for controls, but the differences were not statistically significant. Neither age at first term pregnancy (20 or more weeks gestation) nor number of term pregnancies was predictive of ovarian cancer risk. The protection afforded by oral contraceptive use was independent of parity, and it increased with increasing duration of use. There were no trends in risk with time since last oral contraceptive use or with time since first use, after adjustment for duration of use. These observations suggest that oral contraceptive use decreases risk for ovarian cancer, rather than merely indicates fertility, which may itself decrease risk of developing the disease. The authors combined reproductive characteristics and oral contraceptive use to estimate a woman's total duration of ovulation, which was positively associated with ovarian cancer risk (p less than 0.001 for trend). These observations support the concept that the greater the duration of ovulation or accompanying endocrinologic phenomena, the greater a woman's risk for ovarian cancer.

  View details for Web of Science ID A1988R305200004

  View details for PubMedID 3195563

• APPROXIMATIONS FOR REGRESSION WITH COVARIATE MEASUREMENT ERROR JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION Whittemore, A. S., Keller, J. B. 1988; 83 (404): 1057-1066

  View details for Web of Science ID A1988R852000020

• PERSONAL AND ENVIRONMENTAL CHARACTERISTICS RELATED TO EPITHELIAL OVARIAN-CANCER .2. EXPOSURES TO TALCUM POWDER, TOBACCO, ALCOHOL, AND COFFEE AMERICAN JOURNAL OF EPIDEMIOLOGY Whittemore, A. S., Wu, M. L., Paffenbarger, R. S., SARLES, D. L., Kampert, J. B., Grosser, S., Jung, D. L., Ballon, S., Hendrickson, M. 1988; 128 (6): 1228-1240

  Abstract

  Vaginal exposures to talc and other particulates may play an etiologic role in epithelial ovarian cancer. Surgical sterilization may protect against ovarian cancer by blocking entry of such particulates into the peritoneal cavity. The authors assessed histories of talcum powder use, tubal sterilization, and hysterectomy with ovarian conservation in 188 women in the San Francisco Bay Area with epithelial ovarian cancers diagnosed in 1983-1985 and in 539 control women. To investigate the roles of blood-borne environmental exposures on ovarian cancer risk, they assessed lifetime consumption of coffee, tobacco, and alcohol in these women. Of the 539 controls, 280 were hospitalized women without overt cancer, and 259 were chosen from the general population by random digit telephone dialing. Ninety-seven (52%) of the cancer patients habitually used talcum powder on the perineum, compared with 247 (46%) of the controls. Adjusted for parity, the relative risk (RR) = 1.40, p = 0.06. There were no statistically significant trends with increasing frequency or duration of talc use, and patients did not differ from controls in use of talc on sanitary pads and/or contraceptive diaphragms. Fewer ovarian cancer patients (7%) than controls (13%) reported prior fallopian tube ligation (RR, adjusted for parity, = 0.56, p = 0.06), and fewer patients (20%) than controls (28%) reported prior hysterectomy (RR = 0.66, p = 0.05). The protective effect of hysterectomy was confined to those who underwent this surgery 10 or more years prior to interview and to those who had not undergone prior tubal sterilization. Consumption of cigarettes and alcohol did not differ between cases and controls. By contrast, 11 (6%) cases never regularly consumed coffee, compared with 31 (11%) hospital controls and 26 (10%) population controls (RR, adjusted for smoking, = 2.2, p = 0.03, for the comparison using all controls). Overall, ovarian cancer risk among women who had drunk coffee for more than 40 years was 3.4 times that of women who had never regularly consumed coffee (p less than 0.01). However, the data exhibited no clear trends in risk with increasing consumption. Although risk ratios relating duration of coffee drinking to ovarian cancer were unaffected by adjustment for several characteristics, further study is needed to exclude potential confounding by other unmeasured characteristics.

  View details for Web of Science ID A1988R305200005

  View details for PubMedID 3195564

• ERRORS IN REPORTED DIETARY INTAKES .2. LONG-TERM RECALL AMERICAN JOURNAL OF EPIDEMIOLOGY Wu, M. L., Whittemore, A. S., Jung, D. L. 1988; 128 (5): 1137-1145

  Abstract

  Inconsistent results among case-control studies of diet and cancer may reflect discrepancies between dietary reports based on current habits and actual intakes from the time of cancer initiation in the distant past. To examine the validity of reported past and current diet as measures of past diet, the authors queried 873 men and women in three northern California communities about their diet 11 years earlier in 1972 and about their current diet in 1983. They used the same dietary history questionnaire that had been administered to the subjects in 1972. Retrospectively recalled and currently reported nutrient intakes and measures of body size were compared with original reports obtained in 1972. Mean values of recalled nutrient intakes agreed with mean values of intakes reported in 1972. The agreement held for each sex, community, and nutrient examined. By contrast, mean values of current intakes were smaller than those reported in 1972. Correlation coefficients showed closer agreement between recalled and original intakes than between current and original intakes. Nevertheless, recalled intakes correlated more closely with current intakes than with original ones. Analysis of variance was used to partition the variation in recalled and original intakes into components due to interpersonal variation in true intakes, errors in recall, and residual reporting error. Interpersonal variation accounted for only 20-40% of the variation in dietary intakes, with most of the balance due to reporting error. For comparison, interpersonal variation accounted for 70-85% of the variance of recalled and original reports of body size. These results suggest that inconsistencies among case-control studies of diet may be due to large random measurement errors in individual dietary intakes. The apparent validity and reproducibility of mean dietary measures, averaged over large populations, suggests the need for new designs for studies of diet and disease.

  View details for Web of Science ID A1988Q806700018

  View details for PubMedID 3189287

• COMBINED EFFECT OF CHILDBEARING, MENSTRUAL EVENTS, AND BODY SIZE ON AGE-SPECIFIC BREAST-CANCER RISK AMERICAN JOURNAL OF EPIDEMIOLOGY Kampert, J. B., Whittemore, A. S., Paffenbarger, R. S. 1988; 128 (5): 962-979

  Abstract

  Pike et al. (Nature 1983;303:767-70) and Moolgavkar et al. (JNCI 1980;65:59-69) proposed quantitative theories for the effect on age-specific breast cancer risk of ages at menarche, first childbirth, and menopause. Here the incidence rate functions predicted by these theories are fit to data for 1,884 women of all ages with breast cancer and 3,432 matched controls admitted to San Francisco Bay area hospitals in 1970-1977. A third function describing age-specific breast cancer risk based on the timing of childbearing and menstrual events is presented, and its fit to the data is compared with that of the functions of Pike et al. and Moolgavkar et al. None of the three fully accounted for the protective effects of early age at first childbirth in premenopausal women or of early age at menopause in parous postmenopausal women. To account for the effects of total parity and body mass (Quetelet) index on risk of breast cancer occurrence, the authors developed a fourth incidence rate function by extending the third. Goodness of fit to the data of the fourth function is demonstrated. Age-specific relative risks of breast cancer according to childbearing, menstrual events, and body size are estimated from the fourth function. The main qualitative findings are that 1) the protective effects of late menarche and of early first full-term pregnancy are greater in premenopausal than in postmenopausal women; 2) first full-term pregnancy initially boosts the level of risk, but incidence rates increase with age more slowly thereafter; 3) among the parous, multiparity is protective both in premenopausal and postmenopausal women, regardless of age at first full-term pregnancy; 4) both nulliparous and lean women are more protected by early menopause than are parous and overweight women; 5) increased body mass index is protective before, but detrimental after, menopause; and 6) postmenopausal incidence rates increase with age more rapidly among overweight than among lean women.

  View details for Web of Science ID A1988Q806700002

  View details for PubMedID 3189296

• BODY SIZE, REPRODUCTIVE FACTORS, AND BREAST-CANCER SURVIVAL PREVENTIVE MEDICINE MOHLEBOETANI, J. C., Grosser, S., Whittemore, A. S., Malec, M., Kampert, J. B., Paffenbarger, R. S. 1988; 17 (5): 634-642

  Abstract

  Mortality rates among 838 white female breast cancer patients were examined for relationships to personal characteristics assessed at time of diagnosis. These included weight and body mass index, oral contraceptive use, and prior menstrual and reproductive events. Multivariate analyses were used to determine the importance of these characteristics in predicting death rates specific for age and extent of disease at time of diagnosis. Weight was associated with poor prognosis among premenopausal patients, but not among postmenopausal patients. Premenopausal women weighing more than 140 lbs at diagnosis had death rates 1.7 times those of lighter women (P = 0.04). This effect was not explained by differences in the distribution of disease stage between the two groups. Body mass index was positively associated with mortality in both premenopausal and postmenopausal patients. In the entire group, the death rate ratio was 1.4 (P = 0.02) for obese (body mass index greater than 30.4 X 10(-3) lbs/in.2) vs lean women. Among premenopausal patients, parous women had higher mortality rates than nulliparous women (death rate ratio = 2.0, P = 0.06). Although the data were sparse, death rates were higher for women having a full-term pregnancy within 2 years of diagnosis than for premenopausal women with earlier pregnancies. Oral contraceptive use, age at menarche, age at first full term birth, and age at menopause were unrelated to mortality.

  View details for Web of Science ID A1988Q962700008

  View details for PubMedID 3237661

• EFFECT OF CIGARETTE-SMOKING IN EPIDEMIOLOGICAL-STUDIES OF LUNG-CANCER STATISTICS IN MEDICINE Whittemore, A. S. 1988; 7 (1-2): 223-238

  Abstract

  This paper describes a method for adjusting the analysis of occupational/environmental lung cancer risks for the effects of cigarette smoking in cohort and case-control studies. The method uses a function that relates an individual's death rate to his age and cigarette smoking history. Two such functions are examined. The first depends on total packs of cigarettes smoked and age. The second, based on the multistage theory of carcinogenesis, depends on age, age at start of smoking, and subsequent smoking rates. The lung cancer rates predicted by these two functions are compared to those observed in cohort studies of male British physicians and U.S. veterans, and in a case-control study of non-Hispanic white men in New Mexico. Neither of the cohort data sets distinguished the fit of the two functions. The New Mexico data were fit better by the second function, though both functions overpredicted death rates among ex-smokers. Each function explained substantially more variation in the New Mexico data than did any of several logistic regression models involving categorical variables for age and smoking.

  View details for Web of Science ID A1988M095800021

  View details for PubMedID 3353605

• RISK-FACTORS AND SURVIVAL - DISCUSSION STATISTICS IN MEDICINE Breslow, N., BYAR, D., Cupples, L. A., Vollmer, W. M., Prentice, R. L., Mantel, N., Anderson, K., Whittemore, A., Segal, M., Lagakos, S. W., Lebowitz, M. D., Bates, D., Halperin, M., Kalbfleisch, J. D. 1988; 7 (1-2): 297-302

  View details for Web of Science ID A1988M095800027

• SPECIAL TOPICS - DISCUSSION STATISTICS IN MEDICINE Breslow, N., Zeger, S., Prentice, R. L., Province, M. A., Louis, T. A., Speizer, F. E., Flournoy, N., Whittemore, A., Ware, J. H., Feinleib, M., Lebowitz, M. D., Laird, N. M. 1988; 7 (1-2): 199-202

  View details for Web of Science ID A1988M095800018

• Methods for analyzing occupational cohort data with application to lung cancer in U.S. uranium miners. Journal of chronic diseases Halpern, J., Whittemore, A. S. 1987; 40: 79S-88S

  Abstract

  We used two methods to examine how lung cancer death rates vary with cumulative exposures to radiation and tobacco among U.S. uranium miners. We assumed that exposures act proportionately on age-specific death rates among nonsmokers who are unexposed to uranium. The two methods produced similar results when death rate ratios were taken to be the product of radiation and tobacco effects. The estimates were discrepant when death rate ratios were taken to be the sum of radiation and tobacco effects. Both methods indicated better fit for the multiplicative model, as judged by the maximized loglikelihood values. Death rates estimated in this way for white males in the absence of mining and smoking increased only weakly with age. This weak relation suggests that our models of death rates fit poorly. It may be that cumulative exposures are inappropriate measures of the effects of radiation and tobacco on lung cancer death rates.

  View details for PubMedID 3667869

• METHODS FOR ANALYZING OCCUPATIONAL COHORT DATA WITH APPLICATION TO LUNG-CANCER IN UNITED-STATES URANIUM MINERS JOURNAL OF CHRONIC DISEASES Halpern, J., Whittemore, A. S. 1987; 40: S79-S88

  View details for Web of Science ID A1987L004600010

• METHODS OLD AND NEW FOR ANALYZING OCCUPATIONAL COHORT DATA AMERICAN JOURNAL OF INDUSTRIAL MEDICINE Whittemore, A. S. 1987; 12 (3): 233-248

  Abstract

  The person-years approach to analyzing mortality data from occupational cohorts was introduced in the midtwentieth century. It cross-classifies all observed deaths and observation times into cells, computes the number of expected deaths for each cell based on referenced mortality rates, and then examines the ratio of total number of observed deaths to total number of expected deaths (the standardized mortality ratio). The maximum likelihood method of statistical inference was developed in the early twentieth century. However, only recently has it been applied to the analysis of occupational cohort data. When so applied, it provides estimates of measures of association between exposures and disease by maximizing the probability of the observed data. This paper shows how recent developments in the use of this tool justify and extend the person-years approach. In particular, problems with the standardized mortality ratio cited in the literature are shown to result from reliance on assumptions that are inappropriate for the data at hand. Methods for testing these assumptions are described. The discussion is illustrated with examples from occupational cohort studies of lung cancer.

  View details for Web of Science ID A1987J748300001

  View details for PubMedID 3674019

• ERRORS IN REPORTED DIETARY INTAKES .1. SHORT-TERM RECALL AMERICAN JOURNAL OF EPIDEMIOLOGY Wu, M. L., Whittemore, A. S., Jung, D. L. 1986; 124 (5): 826-835

  Abstract

  Measures for quantifying reproducibility and between-subject variability of nutrient intake data are applied to intakes reported in two interviews (1-3 months apart) by 44 male and 17 female healthy white subjects aged 45-75 years. Intakes were assessed by three methods: a dietary history that included consumption frequency and serving size for 71 food items (dietary history method); a combination of individual consumption frequencies with sex-specific mean serving sizes (frequency method); an extrapolation from frequencies and serving sizes of all foods reported for a "typical day" in the specified time period (typical day method). Intake variation within subjects, between subjects, and between methods was assessed by analysis of variance for each sex and for each of the nutrients: total calories, protein, fat, vitamin A, and protein and fat as percentage of total calories. Dietary history-assessed intakes exceeded those assessed by the other two methods. The dietary history versus frequency excess was greater than the dietary history versus typical day excess for calories, fat, and protein, while the reverse was true for vitamin A and fat as percentage of total calories. The typical day method was unreliable for vitamin A because it occasionally produced extremely high, unreproducible intakes. The intraclass correlation coefficient was used to measure a method's ability to distinguish interpersonal variation from within-person error. The frequency method produced less within-person error than did the dietary history method for all nutrients. For absolute intakes, the frequency method produced less interpersonal variation than did the dietary history method, while for relative intakes, the reverse was true. Females reported intakes with less within-person error than did males, and the interpersonal spread of their intakes was smaller. Consequences of these findings for the power and sensitivity of studies on the role of dietary factors in the etiology of chronic disease are explored.

  View details for Web of Science ID A1986E498300014

  View details for PubMedID 3766514

• AN ANALYSIS OF CONTAMINATED WELL WATER AND HEALTH-EFFECTS IN WOBURN, MASSACHUSETTS - COMMENT JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION Whittemore, A. S. 1986; 81 (395): 609-610

  View details for Web of Science ID A1986D958800005

• REGRESSION-MODELS FOR COHORT MORTALITY STUDIES MATHEMATICAL MODELLING Whittemore, A. S. 1986; 7 (9-12): 1365-1373

  View details for Web of Science ID A1986F488000014

• CHRONIC DISEASE IN FORMER COLLEGE-STUDENTS .26. EARLY PRECURSORS OF SITE-SPECIFIC CANCERS IN COLLEGE MEN AND WOMEN JOURNAL OF THE NATIONAL CANCER INSTITUTE Whittemore, A. S., Paffenbarger, R. S., Anderson, K., Lee, J. E. 1985; 74 (1): 43-51

  View details for Web of Science ID A1985ABH4100006

• ANALYZING COHORT MORTALITY DATA AMERICAN STATISTICIAN Whittemore, A. S. 1985; 39 (4): 437-441

  View details for Web of Science ID A1985AUU1100018

• EARLY PRECURSORS OF UROGENITAL CANCERS IN FORMER COLLEGE MEN .27. JOURNAL OF UROLOGY Whittemore, A. S., Paffenbarger, R. S., Anderson, K., Lee, J. E. 1984; 132 (6): 1256-1261

  Abstract

  Physical and social characteristics recorded at college physical examination or reported at subsequent alumni questionnaire in 1962 or 1966 by 47,271 male former students from Harvard University and the University of Pennsylvania were reviewed for their relationship to risk for cancers of the kidney, bladder, prostate and testis. The records of 213 subjects who died with 1 of these cancers in a 16-50 year followup period and of 280 subjects who reported such a cancer by mail questionnaire in 1976 or 1977 were compared with those of 1,972 matched classmates who were known to be alive and cancer-free at the time subjects with cancer had died or were diagnosed. Students with a record of proteinuria at college physical examination experienced increased risk of kidney cancer. Higher levels of body weight during college were associated with elevated risks of kidney and bladder cancers; however, increased weight in 1962/1966 related only to kidney cancer. A history of cigarette smoking as reported by questionnaire in 1962/1966 predicted increased occurrence of bladder cancer. Students with a history of tonsillectomy at college entrance experienced increased risk of prostate cancer, and those who reported cancer history in 1 or both parents were at increased risk for testicular cancer. These and other findings are presented as clues deserving further exploration for any etiological significance they may hold for the cancer sites studied.

  View details for Web of Science ID A1984TU33500061

  View details for PubMedID 6502830

• LUNG-CANCER MORTALITY AMONG UNITED-STATES URANIUM MINERS - A REAPPRAISAL JOURNAL OF THE NATIONAL CANCER INSTITUTE Whittemore, A. S., McMillan, A. 1983; 71 (3): 489-499

  Abstract

  This report examines lung cancer mortality among a cohort of white underground uranium miners in the Colorado plateau and is based on mortality follow-up through December 31, 1977. The analytic methods represent a miner's annual age-specific lung cancer mortality rate as the (unspecified) rate among nonsmoking men born at the same time and with no mining history, multiplied by the relative risk factor R. This factor depends on the miner's total exposures to radon daughters [in working level months (WLM) and to cigarettes (in packs), accumulated from start of exposure until 10 years before his current age. Among those examined, the relative risk function giving the highest likelihood of the data was R = (1 + 0.31 X 10(-2) WLM)(1 + 0.51 X 10(-3) packs). This multiplicative function specifies that ratios of mortality rates for miners versus nonminers with similar age and smoking characteristics do not depend on smoking status. By contrast, differences between miners' and nonminers' mortality rates are substantially higher for smokers than for nonsmokers. The data rejected (P = .01) several additive functions for R that specify relative risk as a sum of components due to radiation and to cigarette smoking. Cumulative exposures to both radiation and cigarettes gave better fits to the data than did average annual exposure rates. Age at start of underground mining had no effect on risk, after controlling for age at lung cancer death, year of birth, and cumulative radiation and smoking exposures.

  View details for Web of Science ID A1983RM22500012

  View details for PubMedID 6577225

• ESTIMATING ATTRIBUTABLE RISK FROM CASE-CONTROL STUDIES AMERICAN JOURNAL OF EPIDEMIOLOGY Whittemore, A. S. 1983; 117 (1): 76-85

  Abstract

  Levin's measure of attributable risk is extended to account for confounding. Maximum likelihood estimates and confidence intervals for this extended measure are presented. The estimates and confidence intervals apply both to matched and to stratified case-control studies. The statistical methods are illustrated by the use of data from a study of factors of womanhood as related to breast cancer, and data from a study of cigarette smoking as related to bladder cancer. The results of computer simulations are used to describe the behavior of the estimates and confidence intervals when sample size is small relative to the number of strata of the confounding factor.

  View details for Web of Science ID A1983PX20000011

  View details for PubMedID 6823955

• TRANSFORMATIONS TO LINEARITY IN BINARY REGRESSION SIAM JOURNAL ON APPLIED MATHEMATICS Whittemore, A. S. 1983; 43 (4): 703-710

  View details for Web of Science ID A1983RE33800006

• EARLY PRECURSORS OF PANCREATIC-CANCER IN COLLEGE MEN JOURNAL OF CHRONIC DISEASES Whittemore, A. S., Paffenbarger, R. S., Anderson, K., Halpern, J. 1983; 36 (3): 251-256

  Abstract

  From college data on 50,000 male former students, the records of 126 men who died of pancreatic cancer in a 16-50 yr follow-up period were compared with those of 504 surviving classmates with respect to physical and social characteristics. Return mail questionnaires received from 30,000 surviving alumni in 1962 or 1966 also were reviewed for characteristics that might predict altered risk of pancreatic cancer. Strong positive associations were found for cigarette smoking as reported both during college (p less than 0.001) and at time of questionnaire return (p = 0.03). Smoking 10 or more cigarettes per day during college corresponded to a relative risk of 2.6 with 95% confidence limits 1.5 to 4.6, and a positive smoking history at questionnaire return yielded a relative risk of 2.4 (1.1-5.1). No association was found for collegiate coffee drinking, either before or after adjustment for cigarette smoking. The relative risk for coffee drinking adjusted for smoking was 1.1 (0.7-1.8). In contrast, collegiate tea consumption was associated with a reduction in pancreatic cancer risk. The relative risk for tea drinking adjusted for smoking was 0.5 (0.3-0.9). Men who at college physical examination complained of occasional abdominal pain or discomfort had increased relative risk of pancreatic cancer (3.1 : 1.1-9.0) in the follow-up period.

  View details for Web of Science ID A1983QH65000004

  View details for PubMedID 6826689

• OSTEOSARCOMAS AMONG BEAGLES EXPOSED TO PU-239 RADIATION RESEARCH Whittemore, A. S., McMillan, A. 1982; 90 (1): 41-56

  View details for Web of Science ID A1982NH16600004

  View details for PubMedID 6950452

• A CASE-CONTROL STUDY OF PANCREATIC-CARCINOMA JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY HAINES, A. P., Moss, A. R., Whittemore, A., Quivey, J. 1982; 103 (1): 93-97

  Abstract

  The hospital records of 60 female and 56 male pancreatic cancer patients and 232 age-, race-, sex-, and hospital-matched controls were reviewed for evidence of prior thyroid disease, cholecystectomy, appendectomy, alcohol consumption and among females, for diseases for the endometrium and ovary. No statistically significant differences were detected between case and control groups. It may be of interest, however, that there were four patients with a history of thyrotoxicosis among the pancreatic cancer patients and only one in the control group. In females, a history of thyroidectomy was somewhat more common among the patients than the controls.

  View details for Web of Science ID A1982NJ82900010

  View details for PubMedID 7076720

• HANDEDNESS AND BREAST-CANCER LATERALITY - TESTING A HYPOTHESIS HUMAN BIOLOGY Howard, J., Petrakis, N. L., BROSS, I. D., Whittemore, A. S. 1982; 54 (2): 365-371

  View details for Web of Science ID A1982NT05400014

  View details for PubMedID 7095801

• REGRESSION-ANALYSIS OF CYTOPATHOLOGICAL DATA BIOMETRICS Whittemore, A. S., McLarty, J. W., Fortson, N., Anderson, K. 1982; 38 (4): 899-905

  Abstract

  Epithelial cells from the human body are frequently labelled according to one of several ordered levels of abnormality, ranging from normal to malignant. The label of the most abnormal cell in a specimen determines the score for the specimen. This paper presents a model for the regression of specimen scores against continuous and discrete variables, as in host exposure to carcinogens. Application to data and tests for adequacy of model fit are illustrated using sputum specimens obtained from a cohort of former asbestos workers.

  View details for Web of Science ID A1982QF89700002

  View details for PubMedID 7168794

• SAMPLE-SIZE FOR LOGISTIC-REGRESSION WITH SMALL RESPONSE PROBABILITY JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION Whittemore, A. S. 1981; 76 (373): 27-32

  View details for Web of Science ID A1981LL12000005

• AIR-POLLUTION AND RESPIRATORY-DISEASE ANNUAL REVIEW OF PUBLIC HEALTH Whittemore, A. S. 1981; 2: 397-429

  View details for Web of Science ID A1981LQ55200017

  View details for PubMedID 7348558

• ASTHMA AND AIR-POLLUTION IN THE LOS-ANGELES AREA AMERICAN JOURNAL OF PUBLIC HEALTH Whittemore, A. S., Korn, E. L. 1980; 70 (7): 687-696

  Abstract

  Daily asthma attack diaries of 16 panels of asthmatics residing in the Los Angeles area were collected by the Environmental Protection Agency for 34-week periods during the years 1972-1975. There data are examined here for the relationship between daily attack occurrence and daily levels of photochemical oxidant, total suspended particulates, minimum temperature, relative humidity, and average wind speed. A separate multiple logistic regression is used for each panelist's attack data. Variables representing the presence or absence of attack on the preceding day, as well as day of week and time since the start of the study, are included in the regressions. The most significant predictor of attacks was the presence of an attack on the preceding day. On the average, the panelists tended to have increased attacks on days with high oxidant and particulate pollution, on cool days, and during the first two months of the study. Panelists' attack propensity also differed by day of week; in particular they had more attacks on Saturdays (the last day of the weekly reporting period) than on Sundays. Each panelist's regression coefficients are classified according to age, sex, hay fever status, and self-assessed attack precursors; this classification is used to examine subgroups among the panelists with high coefficients corresponding to the above factors.

  View details for Web of Science ID A1980JX88700004

  View details for PubMedID 7386702

• MATHEMATICAL-MODELS OF CANCER AND THEIR USE IN RISK ASSESSMENT JOURNAL OF ENVIRONMENTAL PATHOLOGY AND TOXICOLOGY Whittemore, A. S. 1979; 3 (1-2): 353-362

  Abstract

  Cancer risk assessment necessarily involves the use of mathematical models. Although risk estimates can be extremely sensitive to underlying assumptions in such models, the assumptions are frequently overlooked when a particular model is used. This paper presents four examples to illustrate how the alteration of assumptions can have a large effect on risk estimates. Ways of avoiding undue model dependence are discussed.

  View details for Web of Science ID A1979JK54300022

  View details for PubMedID 547018

• METHODS FOR ANALYZING PANEL STUDIES OF ACUTE HEALTH-EFFECTS OF AIR-POLLUTION BIOMETRICS Korn, E. L., Whittemore, A. S. 1979; 35 (4): 795-802

  Abstract

  New methods are presented for analyzing repeated binary health measurements of individuals exposed to varying levels of air pollution. The methods involve a separate logistic regression of response against environmental covariates for each individual. Parameters reflecting individual susceptibility to pollutants and weather are estimated using Cox's regression techniques (1970, 1972a). The individual parameters are combined to yield summary estimates of environmental effects. The approach does not require independence of successive health measurements. It is illustrated with data on asthma and air pollution in the Los Angeles area.

  View details for Web of Science ID A1979HX66000009

  View details for PubMedID 526525

• QUANTITATIVE THEORIES OF CARCINOGENESIS SIAM REVIEW Whittemore, A., Keller, J. B. 1978; 20 (1): 1-30

  View details for Web of Science ID A1978EN69400001

• COLLAPSIBILITY OF MULTIDIMENSIONAL CONTINGENCY-TABLES JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-METHODOLOGICAL Whittemore, A. S. 1978; 40 (3): 328-340

  View details for Web of Science ID A1978GK25000007

• AGE DISTRIBUTION OF HUMAN CANCER FOR CARCINOGENIC EXPOSURES OF VARYING INTENSITY AMERICAN JOURNAL OF EPIDEMIOLOGY Whittemore, A. S. 1977; 106 (5): 418-432

  Abstract

  The time and age dependence of cancer incidence rates resulting from various type of carcinogenic exposure are calculated and compared with observed cancer incidence rates. Implications for the detection of increased cancer incidence are discussed. The calculations assume that exposure affects one of several changes necessary for malignant cell transformation.

  View details for Web of Science ID A1977EB18200010

  View details for PubMedID 920729