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1. p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study

Author: Köbel, Martin, Kang, Eun-Young, Weir, Ashley, Rambau, Peter F, Lee, Cheng-Han, Nelson, Gregg S, Ghatage, Prafull, Meagher, Nicola S, Riggan, Marjorie J, Alsop, Jennifer, Anglesio, Michael S, Beckmann, Matthias W, Bisinotto, Christiani, Boisen, Michelle, Boros, Jessica, Brand, Alison H, Brooks-Wilson, Angela, Carney, Michael E, Coulson, Penny, Courtney-Brooks, Madeleine, Cushing-Haugen, Kara L, Cybulski, Cezary, Deen, Suha, El-Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Fereday, Sian, AOCS Group, Fischer, Anna, Gayther, Simon A, Barquin-Garcia, Arantzazu, Gentry-Maharaj, Aleksandra, Gilks, C Blake, Gronwald, Helena, Grube, Marcel, Harnett, Paul R, Harris, Holly R, Hartkopf, Andreas D, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Huang, Yajue, Jakubowska, Anna, Jimenez-Linan, Mercedes, Jones, Michael E, Kennedy, Catherine J, Kluz, Tomasz, Koziak, Jennifer M, Lesnock, Jaime, Lester, Jenny, Lubiński, Jan, Longacre, Teri A, Lycke, Maria, Mateoiu, Constantina, McCauley, Bryan M, McGuire, Valerie, Ney, Britta, Olawaiye, Alexander, Orsulic, Sandra, Osorio, Ana, Paz-Ares, Luis, Ramón Y Cajal, Teresa, Rothstein, Joseph H, Ruebner, Matthias, Schoemaker, Minouk J, Shah, Mitul, Sharma, Raghwa, Sherman, Mark E, Shvetsov, Yurii B, Singh, Naveena, Steed, Helen, Storr, Sarah J, Talhouk, Aline, Traficante, Nadia, Wang, Chen, Whittemore, Alice S, Widschwendter, Martin, Wilkens, Lynne R, Winham, Stacey J, Benitez, Javier, Berchuck, Andrew, Bowtell, David D, Candido Dos Reis, Francisco J, Campbell, Ian, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Fasching, Peter A, Fortner, Renée T, García, María J, Goodman, Marc T, Goode, Ellen L, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kelemen, Linda E, Kommoss, Stefan, Le, Nhu D, Martin, Stewart G, Menon, Usha, Modugno, Francesmary, Pharoah, Paul Dp, Schildkraut, Joellen M, Sieh, Weiva, Staebler, Annette, Sundfeldt, Karin, Swerdlow, Anthony J, Ramus, Susan J, Brenton, James D, Köbel, Martin [0000-0002-6615-2037], Weir, Ashley [0000-0002-3072-2616], Anglesio, Michael S [0000-0003-1639-5003], Erber, Ramona [0000-0003-0315-1229], Gilks, C Blake [0000-0001-7889-8250], Shvetsov, Yurii B [0000-0001-5131-9618], Campbell, Ian [0000-0002-7773-4155], Huntsman, David G [0000-0003-4934-3322], and Apollo - University of Cambridge Repository
Subjects: clear cell, p53, Ovarian Neoplasms, ovarian cancer, high-grade serous carcinoma, Humans, Female, TP53, prognosis, Tumor Suppressor Protein p53, Carcinoma, Ovarian Epithelial, endometrioid, Carcinoma, Endometrioid
Abstract: Funder: Biomedical Research Centre, Funder: European Regional Development Fund, Funder: Mayo Foundation for Medical Education and Research, Funder: Pomeranian Medical University, Funder: Pomorski Uniwersytet Medyczny W Szczecinie, Funder: Cancer Council NSW, Funder: Cancer Institute NSW, Funder: Deutsches Krebsforschungszentrum, Funder: The BC Cancer Foundation, Funder: University College London Hospitals Biomedical Research Centre, Funder: Breast Cancer Now, Funder: Cancer Council Tasmania, Funder: Clinical Academic Reserve, Funder: ELAN Funds of the University of Erlangen-Nuremberg, Funder: Fondo Europeo de Desarrollo Regional, Funder: National Institute for Health Research (NIHR), Funder: National Institute for Health and Care Research, Funder: Ovarian Cancer Australia, Funder: Queensland Cancer Fund, Funder: Cancer Council New South Wales, Funder: Fred C. and Katherine B. Andersen Foundation, Funder: German Cancer Research Center, Funder: Institute of Cancer Research, Funder: Mayo Foundation, Funder: Minnesota Ovarian Cancer Alliance, Funder: Peter MacCallum Foundation, Funder: University of Cambridge, Funder: Cancer Foundation of Western Australia, Funder: VGH and UBC Hospital Foundation, Funder: Cancer Council Victoria, Funder: NHS, Funder: UK National Institute for Health Research, Funder: Cancer Council South Australia, Funder: Oak Foundation, Funder: Sydney West Translational Cancer Research Centre, 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.
Published: 2023

2. p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study

Author: Köbel, Martin, Kang, Eun‐Young, Weir, Ashley, Rambau, Peter F, Lee, Cheng‐Han, Nelson, Gregg S, Ghatage, Prafull, Meagher, Nicola S, Riggan, Marjorie J, Alsop, Jennifer, Anglesio, Michael S, Beckmann, Matthias W, Bisinotto, Christiani, Boisen, Michelle, Boros, Jessica, Brand, Alison H, Brooks‐Wilson, Angela, Carney, Michael E, Coulson, Penny, Courtney‐Brooks, Madeleine, Cushing‐Haugen, Kara L, Cybulski, Cezary, Deen, Suha, El‐Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Fereday, Sian, Fischer, Anna, Gayther, Simon A, Barquin‐Garcia, Arantzazu, Gentry‐Maharaj, Aleksandra, Gilks, C Blake, Gronwald, Helena, Grube, Marcel, Harnett, Paul R, Harris, Holly R, Hartkopf, Andreas D, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Huang, Yajue, Jakubowska, Anna, Jimenez‐Linan, Mercedes, Jones, Michael E, Kennedy, Catherine J, Kluz, Tomasz, Koziak, Jennifer M, Lesnock, Jaime, Lester, Jenny, Lubiński, Jan, Longacre, Teri A, Lycke, Maria, Mateoiu, Constantina, McCauley, Bryan M, McGuire, Valerie, Ney, Britta, Olawaiye, Alexander, Orsulic, Sandra, Osorio, Ana, Paz‐Ares, Luis, Ramón Y Cajal, Teresa, Rothstein, Joseph H, Ruebner, Matthias, Schoemaker, Minouk J, Shah, Mitul, Sharma, Raghwa, Sherman, Mark E, Shvetsov, Yurii B, Singh, Naveena, Steed, Helen, Storr, Sarah J, Talhouk, Aline, Traficante, Nadia, Wang, Chen, Whittemore, Alice S, Widschwendter, Martin, Wilkens, Lynne R, Winham, Stacey J, Benitez, Javier, Berchuck, Andrew, Bowtell, David D, Candido Dos Reis, Francisco J, Campbell, Ian, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Fasching, Peter A, Fortner, Renée T, García, María J, Goodman, Marc T, Goode, Ellen L, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kelemen, Linda E, Kommoss, Stefan, Le, Nhu D, Martin, Stewart G, Menon, Usha, Modugno, Francesmary, Pharoah, Paul DP, Schildkraut, Joellen M, Sieh, Weiva, Staebler, Annette, Sundfeldt, Karin, Swerdlow, Anthony J, Ramus, Susan J, Brenton, James D, Köbel, Martin [0000-0002-6615-2037], Weir, Ashley [0000-0002-3072-2616], Anglesio, Michael S [0000-0003-1639-5003], Erber, Ramona [0000-0003-0315-1229], Gilks, C Blake [0000-0001-7889-8250], Shvetsov, Yurii B [0000-0001-5131-9618], Campbell, Ian [0000-0002-7773-4155], Huntsman, David G [0000-0003-4934-3322], and Apollo - University of Cambridge Repository
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 [HGSC], endometrioid [EC] and clear cell carcinomas [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6678 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, cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93% (4630/4957) 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 (HR=2.18, 95% CI 1.36-3.47, p=0.0011) as well as with CCC (HR=1.57, 95% CI 1.11-2.22, p=0.012). Abnormal p53 was also associated with shorter overall survival in FIGO 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., CRUK
Published: 2023
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3. Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2

Author: O’Mahony, Denise G., Ramus, Susan J., Southey, Melissa C., Meagher, Nicola S., Hadjisavvas, Andreas, John, Esther M., Hamann, Ute, Imyanitov, Evgeny N., Andrulis, Irene L., Sharma, Priyanka, Daly, Mary B., Hake, Christopher R., Weitzel, Jeffrey N., Jakubowska, Anna, Godwin, Andrew K., Arason, Adalgeir, Bane, Anita, Simard, Jacques, Soucy, Penny, Caligo, Maria A., Mai, Phuong L., Claes, Kathleen B. M., Teixeira, Manuel R., Chung, Wendy K., Lazaro, Conxi, Hulick, Peter J., Toland, Amanda E., Pedersen, Inge Sokilde, Mourits, Marian J. E., Neuhausen, Susan L., Vega, Ana, de la Hoya, Miguel, Nevanlinna, Heli, Dhawan, Mallika, Zampiga, Valentina, Danesi, Rita, Varesco, Liliana, Gismondi, Viviana, Vellone, Valerio Gaetano, James, Paul A., Janavičius, Ramūnas, Nikitina-Zake, Liene, Nielsen, Finn Cilius, van Overeem Hansen, Thomas, Pejovic, Tanja, Borg, Ake, Rantala, Johanna, Offit, Kenneth, Montagna, Marco, Nathanson, Katherine L., Domchek, Susan M., Osorio, Ana, García, María J., Karlan, Beth Y., Lesueur, Fabienne, De Fazio, Anna, Bowtell, David, McGuffog, Lesley, Leslie, Goska, Parsons, Michael T., Dörk, Thilo, Speith, Lisa-Marie, dos Santos, Elizabeth Santana, da Costa, Alexandre André B. A., Radice, Paolo, Peterlongo, Paolo, Papi, Laura, Engel, Christoph, Hahnen, Eric, Schmutzler, Rita K., Wappenschmidt, Barbara, Easton, Douglas F., Tischkowitz, Marc, Singer, Christian F., Tan, Yen Yen, Whittemore, Alice S., Sieh, Weiva, Brenton, James D., Yannoukakos, Drakoulis, Fostira, Florentia, Konstantopoulou, Irene, Soukupova, Jana, Vocka, Michal, Chenevix-Trench, Georgia, Pharoah, Paul D. P., Antoniou, Antonis C., Goldgar, David E., Spurdle, Amanda B., and Michailidou, Kyriaki
Abstract: Background: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system. Methods: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong). Results: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis. Conclusions: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.
Published: 2023

4. Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

Author: Devries, Amber A, Dennis, Joe, Tyrer, Jonathan P, Peng, Pei-chen, Coetzee, Simon G, Reyes, Alberto L, Plummer, Jasmine T, Davis, Brian D, Chen, Stephanie S, Dezem, Felipe Segato, Aben, Katja K H, Anton-culver, Hoda, Antonenkova, Natalia N, Beckmann, Matthias W, Beeghly-fadiel, Alicia, Berchuck, Andrew, Bogdanova, Natalia V, Bogdanova-markov, Nadja, Brenton, James D, Butzow, Ralf, Campbell, Ian, Chang-claude, Jenny, Chenevix-trench, G, Cook, Linda S, Defazio, A, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Eliassen, A Heather, Fasching, Peter A, Fortner, Renée T, Giles, Graham G, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Webb, P, 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, Green, A, Gertig, D, Traficante, N, Fereday, S, Moore, S, Hung, J, Harrap, K, Sadkowsky, T, Pandeya, N, Malt, M, Robertson, R, Bergh, T Vanden, 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, Proietto, A, Braye, S, Shannon, J, Stewart, J, Begbie, S, Håkansson, Niclas, Hildebrandt, Michelle A T, Huff, Chad, Huntsman, David G, Jensen, Allan, Kar, Siddhartha, Karlan, Beth Y, Khusnutdinova, Elza K, Kiemeney, Lambertus A, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Le, Nhu D, Lubiński, Jan, May, Taymaa, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Monteiro, Alvaro N, Moysich, Kirsten B, Odunsi, Kunle, Olsson, Håkan, Pearce, Celeste L, Pejovic, Tanja, Ramus, Susan J, Riboli, Elio, Riggan, Marjorie J, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, V Wendy, Sieh, Weiva, Song, Honglin, Sutphen, Rebecca, Terry, Kathryn L, Thompson, Pamela J, Titus, Linda, Tworoger, Shelley S, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Webb, Penelope M, Wentzensen, Nicolas, Whittemore, Alice S, Wolk, Alicja, Wu, Anna H, Ziogas, Argyrios, Freedman, Matthew L, Lawrenson, Kate, Pharoah, Paul D P, Easton, Douglas F, Gayther, Simon A, Jones, Michelle R, Helsinki University Hospital Area, Clinicum, Department of Pathology, and HUSLAB
Subjects: Cancer Research, GENES, DNA Copy Number Variations, SUSCEPTIBILITY LOCI, 3122 Cancers, Carcinoma, Ovarian Epithelial, Polymorphism, Single Nucleotide, BREAST, Humans, Genetic Predisposition to Disease, BRCA2 MUTATIONS, GENOME-WIDE ASSOCIATION, Alleles, Ovarian Neoplasms, Cancer och onkologi, Science & Technology, IDENTIFICATION, REARRANGEMENTS, COMMON VARIANTS, GERMLINE MUTATIONS, DELETIONS, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Cancer and Oncology, Female, Life Sciences & Biomedicine, Genome-Wide Association Study
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 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.
Published: 2022

5. Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

Author: DeVries, Amber A, Dennis, Joe, Tyrer, Jonathan P, Peng, Pei-Chen, Coetzee, Simon G, Reyes, Alberto L, Plummer, Jasmine T, Davis, Brian D, Chen, Stephanie S, Dezem, Felipe Segato, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia N, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Berchuck, Andrew, Bogdanova, Natalia V, Bogdanova-Markov, Nadja, Brenton, James D, Butzow, Ralf, Campbell, Ian, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Dörk, Thilo, Eccles, Diana M, Eliassen, A Heather, Fasching, Peter A, Fortner, Renée T, Giles, Graham G, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, OPAL Study Group, AOCS Group, Håkansson, Niclas, Hildebrandt, Michelle AT, Huff, Chad, Huntsman, David G, Jensen, Allan, Kar, Siddhartha, Karlan, Beth Y, Khusnutdinova, Elza K, Kiemeney, Lambertus A, Kjaer, Susanne K, Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Le, Nhu D, Lubiński, Jan, May, Taymaa, Menon, Usha, Milne, Roger L, Modugno, Francesmary, Monteiro, Alvaro N, Moysich, Kirsten B, Odunsi, Kunle, Olsson, Håkan, Pearce, Celeste L, Pejovic, Tanja, Ramus, Susan J, Riboli, Elio, Riggan, Marjorie J, Romieu, Isabelle, Sandler, Dale P, Schildkraut, Joellen M, Setiawan, V Wendy, Sieh, Weiva, Song, Honglin, Sutphen, Rebecca, Terry, Kathryn L, Thompson, Pamela J, Titus, Linda, Tworoger, Shelley S, Van Nieuwenhuysen, Els, Edwards, Digna Velez, Webb, Penelope M, Wentzensen, Nicolas, Whittemore, Alice S, Wolk, Alicja, Wu, Anna H, Ziogas, Argyrios, Freedman, Matthew L, Lawrenson, Kate, Pharoah, Paul DP, Easton, Douglas F, Gayther, Simon A, and Jones, Michelle R
Subjects: Ovarian Neoplasms, DNA Copy Number Variations, Prevention, Carcinoma, Human Genome, Oncology and Carcinogenesis, AOCS Group, Single Nucleotide, Ovarian Cancer, Rare Diseases, Ovarian Epithelial, OPAL Study Group, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Female, Genetic Testing, Oncology & Carcinogenesis, Polymorphism, Aetiology, Alleles, Genome-Wide Association Study, Cancer
Abstract: BackgroundKnown 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.MethodsSingle 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.ResultsWe 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
Published: 2022

6. Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Author: Dareng, Eileen O., Tyrer, Jonathan P., Barnes, Daniel R., Jones, Michelle R., Yang, Xin, Aben, Katja K. H., Adank, Muriel A., Agata, Simona, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Aravantinos, Gerasimos, Arun, Banu K., Augustinsson, Annelie, Balmaña, Judith, Bandera, Elisa V., Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Bernardini, Marcus Q., Bjorge, Line, Black, Amanda, Bogdanova, Natalia V., Bonanni, Bernardo, Borg, Ake, Brenton, James D., Budzilowska, Agnieszka, Butzow, Ralf, Buys, Saundra S., Cai, Hui, Caligo, Maria A., Campbell, Ian, Cannioto, Rikki, Cassingham, Hayley, Chang-Claude, Jenny, Chanock, Stephen J., Chen, Kexin, Chiew, Yoke-Eng, Chung, Wendy K., Claes, Kathleen, Colonna, Sarah, Lesueur, Fabienne, Mebirouk, Noura, Engel, Christoph, Schmutzler, Rita K., Davies, Eleanor, Eccles, Diana M., Evans, D. Gareth, Cook, Linda S., Couch, Fergus J., Daly, Mary B., Dao, Fanny, de la Hoya, Miguel, de Putter, Robin, Dennis, Joe, DePersia, Allison, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Doherty, Jennifer A., Domchek, Susan M., Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eliassen, Heather A., Evans, Gareth D., Fasching, Peter A., Flanagan, James M., Fortner, Renée T., Machackova, Eva, Friedman, Eitan, Ganz, Patricia A., Garber, Judy, Gensini, Francesca, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hamann, Ute, Hansen, Thomas V. O., Harris, Holly R., Hartman, Mikael, Heitz, Florian, Hildebrandt, Michelle A. T., Høgdall, Estrid, Høgdall, Claus K., Hopper, John L., Huang, Ruea-Yea, Huff, Chad, Hulick, Peter J., Huntsman, David G., Imyanitov, Evgeny N., Chenevix-Trench, Georgia, van der Hout, Annemieke H., Isaacs, Claudine, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jensen, Allan, Johannsson, Oskar Th., John, Esther M., Jones, Michael E., Kang, Daehee, Karlan, Beth Y., Karnezis, Anthony, Kelemen, Linda E., Khusnutdinova, Elza, Kiemeney, Lambertus A., Kim, Byoung-Gie, Kjaer, Susanne K., Komenaka, Ian, Kupryjanczyk, Jolanta, Kurian, Allison W., Kwong, Ava, Lambrechts, Diether, Larson, Melissa C., Lazaro, Conxi, Le, Nhu D., Leslie, Goska, Lester, Jenny, Levine, Douglas A., Li, Lian, Li, Jingmei, Loud, Jennifer T., Lu, Karen H., Lubiński, Jan, Mai, Phuong L., Manoukian, Siranoush, Marks, Jeffrey R., Matsuno, Rayna Kim, Matsuo, Keitaro, May, Taymaa, McGuffog, Lesley, McLaughlin, John R., McNeish, Iain A., Menon, Usha, Miller, Austin, Milne, Roger L., Minlikeeva, Albina, Modugno, Francesmary, Montagna, Marco, Moysich, Kirsten B., Munro, Elizabeth, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Nielsen, Henriette Roed, Nielsen, Finn C., Nikitina-Zake, Liene, Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olbrecht, Siel, Olopade, Olufunmilayo I., Olson, Sara H., Olsson, Håkan, Osorio, Ana, Papi, Laura, Park, Sue K., Parsons, Michael T., Pathak, Harsha, Pedersen, Inge Sokilde, Peixoto, Ana, Pejovic, Tanja, Perez-Segura, Pedro, Permuth, Jennifer B., Peshkin, Beth, Peterlongo, Paolo, Piskorz, Anna, Prokofyeva, Darya, Radice, Paolo, Rantala, Johanna, Riggan, Marjorie J., Risch, Harvey A., Rodriguez-Antona, Cristina, Ross, Eric, Rossing, Mary Anne, Runnebaum, Ingo, Sandler, Dale P., Santamariña, Marta, Soucy, Penny, Setiawan, V. Wendy, Shan, Kang, Sieh, Weiva, Simard, Jacques, Singer, Christian F., Sokolenko, Anna P., Song, Honglin, Southey, Melissa C., Steed, Helen, Stoppa-Lyonnet, Dominique, Sutphen, Rebecca, Swerdlow, Anthony J., Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo Hwang, Terry, Kathryn L., Terry, Mary Beth, Thompson, Pamela J., Thomsen, Liv Cecilie Vestrheim, Titus, Linda, Trabert, Britton, Travis, Ruth, Tworoger, Shelley S., Valen, Ellen, van Altena, Anne M., Van Nieuwenhuysen, Els, Edwards, Digna Velez, Vierkant, Robert A., Wang, Frances, Webb, Penelope M., Weinberg, Clarice R., Wentzensen, Nicolas, White, Emily, Whittemore, Alice S., Winham, Stacey J., Wolk, Alicja, Woo, Yin-Ling, Wu, Anna H., Yan, Li, Yannoukakos, Drakoulis, Zheng, Wei, Ziogas, Argyrios, Lawrenson, Kate, deFazio, Anna, Ramus, Susan J., Pearce, Celeste L., Monteiro, Alvaro N., Cunningham, Julie M., Goode, Ellen L., Schildkraut, Joellen M., Berchuck, Andrew, Gayther, Simon A., Pharoah, Paul D. P., Claes, Kathleen B. M., Thomassen, Mads, Thull, Darcy L., Tischkowitz, Marc, Toland, Amanda E., Torres, Diana, Tung, Nadine, van Rensburg, Elizabeth J., Vega, Ana, Wappenschmidt, Barbara, Weitzel, Jeffrey N., Zavaglia, Katia M., Zorn, Kristin K., Sellers, Thomas A., Antoniou, Antonis C., Kleibl, Zdenek, Easton, Douglas, DeFazio, Anna, Cunningham, Julie, GEMO Study Collaborators, [missing], GC-HBOC Study Collaborators, [missing], EMBRACE Collaborators, [missing], OPAL Study Group, [missing], AOCS Group, [missing], KConFab Investigators, [missing], HEBON Investigators, [missing], The OCAC Consortium, [missing], The CIMBA Consortium, [missing], Clinicum, Department of Pathology, HUSLAB, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, Faculteit Medische Wetenschappen/UMCG, Institut Català de la Salut, [Dareng EO, Barnes DR, Yang X] University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Cambridge, UK. [Tyrer JP] University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Oncology, Cambridge, UK. [Jones MR] Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [Aben KKH] Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands. Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands. [Balmaña J] Hereditary cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Ovarian Cancer Action, and National Institute for Health Research
Subjects: Male, Biochemistry & Molecular Biology, OCAC Consortium, Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], Breast Neoplasms, Ovaris - Càncer - Aspectes genètics, Carcinoma, Ovarian Epithelial, SUSCEPTIBILITY, Polymorphism, Single Nucleotide, GEMO Study Collaborators, Risk Factors, OPAL Study Group, Other subheadings::Other subheadings::/genetics [Other subheadings], Medicine and Health Sciences, Genetics, Ovaris - Càncer - Propensió, Humans, Genetic Predisposition to Disease, Prospective Studies, EMBRACE Collaborators, GC-HBOC Study Collaborators, Genetics (clinical), HEBON Investigators, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], Medicinsk genetik, Ovarian Neoplasms, Genetics & Heredity, 0604 Genetics, Science & Technology, Otros calificadores::Otros calificadores::/genética [Otros calificadores], 1184 Genetics, developmental biology, physiology, Neoplasms::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms::Carcinoma, Ovarian Epithelial [DISEASES], 1103 Clinical Sciences, Bayes Theorem, AOCS Group, neoplasias::neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas::carcinoma epitelial de ovario [ENFERMEDADES], Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Carcinoma, Ovarian Epithelial/genetics, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], CIMBA Consortium, 1182 Biochemistry, cell and molecular biology, Female, KConFab Investigators, Ovarian Neoplasms/epidemiology, Medical Genetics, Life Sciences & Biomedicine
Abstract: Clinical genetics; Genetic markers; Risk factors Genética clínica; Marcadores genéticos; Factores de riesgo Genètica clínica; Marcadors genètics; Factors de risc 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.
Published: 2022

7. Identification of novel epithelial ovarian cancer loci in women of African ancestry

Author: Manichaikul, Ani, Peres, Lauren C, Wang, Xin-Qun, Barnard, Mollie E, Chyn, Deanna, Sheng, Xin, Du, Zhaohui, Tyrer, Jonathan, Dennis, Joseph, Schwartz, Ann G, Cote, Michele L, Peters, Edward, Moorman, Patricia G, Bondy, Melissa, Barnholtz-Sloan, Jill S, Terry, Paul, Alberg, Anthony J, Bandera, Elisa V, Funkhouser, Ellen, Wu, Anna H, Pearce, Celeste Leigh, Pike, Malcom, Setiawan, Veronica Wendy, Haiman, Christopher A, African American Breast Cancer Consortium (AABC), African Ancestry Prostate Cancer Consortium (AAPC), Palmer, Julie R, LeMarchand, Loic, Wilkens, Lynne R, Berchuck, Andrew, Doherty, Jennifer A, Modugno, Francesmary, Ness, Roberta, Moysich, Kirsten, Karlan, Beth Y, Whittemore, Alice S, McGuire, Valerie, Sieh, Weiva, Lawrenson, Kate, Gayther, Simon, Sellers, Thomas A, Pharoah, Paul, Schildkraut, Joellen M, African American Cancer Epidemiology Study (AACES) and the Ovarian Cancer Association Consortium (OCAC), Peres, Lauren C [0000-0002-6620-8600], Du, Zhaohui [0000-0002-7125-8928], Barnholtz-Sloan, Jill S [0000-0001-6190-9304], Pearce, Celeste Leigh [0000-0002-8023-7846], Pike, Malcom [0000-0003-4891-1199], Modugno, Francesmary [0000-0003-0637-1534], Lawrenson, Kate [0000-0002-6469-2515], Schildkraut, Joellen M [0000-0002-0990-9339], and Apollo - University of Cambridge Repository
Subjects: Follistatin, endocrine system diseases, Oncology and Carcinogenesis, Black People, Breast Neoplasms, Carcinoma, Ovarian Epithelial, Polymorphism, Single Nucleotide, African Ancestry Prostate Cancer Consortium, White People, Rare Diseases, Antigens, Neoplasm, Clinical Research, Ovarian Epithelial, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Antigens, Polymorphism, Aetiology, genome wide association study, Cancer, eQTLs, Prevention, Carcinoma, Aldo-Keto Reductase Family 1 Member C3, African American Cancer Epidemiology Study (AACES) and the Ovarian Cancer Association Consortium, African American Breast Cancer Consortium, Single Nucleotide, United States, Neoplasm Proteins, Ovarian Cancer, Black or African American, ovarian cancer, African ancestry, gene expression, Neoplasm, Female, Genome-Wide Association Study, Biotechnology
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 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
Published: 2020

8. Association between ambient air pollution and breast cancer risk: The multiethnic cohort study

Author: Cheng, Iona, Tseng, Chiuchen, Wu, Jun, Yang, Juan, Conroy, Shannon M, Shariff-Marco, Salma, Li, Lianfa, Hertz, Andrew, Gomez, Scarlett Lin, Le Marchand, Loïc, Whittemore, Alice S, Stram, Daniel O, Ritz, Beate, and Wu, Anna H
Subjects: Time Factors, Life on Land, air pollution, Oncology and Carcinogenesis, Breast Neoplasms, California, Cohort Studies, breast cancer, Risk Factors, Clinical Research, Humans, 2.2 Factors relating to the physical environment, Climate-Related Exposures and Conditions, Prospective Studies, Oncology & Carcinogenesis, Aetiology, Aged, Cancer, Air Pollutants, Asian, Incidence, Prevention, Middle Aged, multiethnic cohort, Black or African American, Female, Particulate Matter, epidemiology, Follow-Up Studies
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 μg/m3 ) determined by kriging. However, among women who lived within 500 m of major roads, significantly increased risks were observed with NOx (hazard ratio [HR] = 1.35, 95% confidence interval [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 the risk of breast cancer is warranted.
Published: 2020

9. Accuracy of Risk Estimates from the iPrevent Breast Cancer Risk Assessment and Management Tool

Author: Phillips, Kelly-Anne, Liao, Yuyan, Milne, Roger L, MacInnis, Robert J, Collins, Ian M, Buchsbaum, Richard, Weideman, Prue C, Bickerstaffe, Adrian, Nesci, Stephanie, Chung, Wendy K, Southey, Melissa C, Knight, Julia A, Whittemore, Alice S, Dite, Gillian S, Goldgar, David, Giles, Graham G, Glendon, Gord, Cuzick, Jack, Antoniou, Antonis C, Andrulis, Irene L, John, Esther M, Daly, Mary B, Buys, Saundra S, Hopper, John L, Terry, Mary Beth, kConFab Investigators, Phillips, Kelly-Anne [0000-0002-0475-1771], Milne, Roger L [0000-0001-5764-7268], Collins, Ian M [0000-0001-6936-0942], Weideman, Prue C [0000-0002-3672-5201], Dite, Gillian S [0000-0002-2448-2548], Giles, Graham G [0000-0003-4946-9099], and Apollo - University of Cambridge Repository
Subjects: kConFab Investigators
Abstract: BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Published: 2019

10. Genome-wide association study of germline variants and breast cancer-specific mortality

Author: Escala-Garcia, Maria, Guo, Qi, Dörk, Thilo, Canisius, Sander, Keeman, Renske, Dennis, Joe, Beesley, Jonathan, Lecarpentier, Julie, Bolla, Manjeet K, Wang, Qin, Abraham, Jean, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Auer, Paul L, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Blomqvist, Carl, Boeckx, Bram, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brentnall, Adam, Brinton, Louise, Broberg, Per, Brock, Ian W, Brucker, Sara Y, Burwinkel, Barbara, Caldas, Carlos, Caldés, Trinidad, Campa, Daniele, Canzian, Federico, Carracedo, Angel, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Cheng, Ting-Yuan David, Chin, Suet-Feung, Clarke, Christine L, NBCS Collaborators, Cordina-Duverger, Emilie, Couch, Fergus J, Cox, David G, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dunn, Janet A, Dunning, Alison M, Durcan, Lorraine, Dwek, Miriam, Earl, Helena M, Ekici, Arif B, Eliassen, A Heather, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Figueroa, Jonine, Flesch-Janys, Dieter, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, Galle, Eva, Gapstur, Susan M, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, George, Angela, Georgoulias, Vassilios, Giles, Graham G, Glendon, Gord, Goldgar, David E, González-Neira, Anna, Alnæs, Grethe I Grenaker, Grip, Mervi, Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hankinson, Susan, Harkness, Elaine F, Harrington, Patricia A, Hart, Steven N, Hartikainen, Jaana M, Hein, Alexander, Hillemanns, Peter, Hiller, Louise, Holleczek, Bernd, Hollestelle, Antoinette, Hooning, Maartje J, Hoover, Robert N, Hopper, John L, Howell, Anthony, Huang, Guanmengqian, Humphreys, Keith, Hunter, David J, Janni, Wolfgang, John, Esther M, Jones, Michael E, Jukkola-Vuorinen, Arja, Jung, Audrey, Kaaks, Rudolf, Kabisch, Maria, Kaczmarek, Katarzyna, Kerin, Michael J, Khan, Sofia, Khusnutdinova, Elza, Kiiski, Johanna I, Kitahara, Cari M, Knight, Julia A, Ko, Yon-Dschun, Koppert, Linetta B, Kosma, Veli-Matti, Kraft, Peter, Kristensen, Vessela N, Krüger, Ute, Kühl, Tabea, Lambrechts, Diether, Le Marchand, Loic, Lee, Eunjung, Lejbkowicz, Flavio, Li, Lian, Lindblom, Annika, Lindström, Sara, Linet, Martha, Lissowska, Jolanta, Lo, Wing-Yee, Loibl, Sibylle, Lubiński, Jan, Lux, Michael P, MacInnis, Robert J, Maierthaler, Melanie, Maishman, Tom, Makalic, Enes, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Mavroudis, Dimitrios, McLean, Catriona, Meindl, Alfons, Middha, Pooja, Miller, Nicola, Milne, Roger L, Moreno, Fernando, Mulligan, Anna Marie, Mulot, Claire, Nassir, Rami, Neuhausen, Susan L, Newman, William T, Nielsen, Sune F, Nordestgaard, Børge G, Norman, Aaron, Olsson, Håkan, Orr, Nick, Pankratz, V Shane, Park-Simon, Tjoung-Won, Perez, Jose IA, Pérez-Barrios, Clara, Peterlongo, Paolo, Petridis, Christos, Pinchev, Mila, Prajzendanc, Karoliona, Prentice, Ross, Presneau, Nadege, Prokofieva, Darya, Pylkäs, Katri, Rack, Brigitte, Radice, Paolo, Ramachandran, Dhanya, Rennert, Gadi, Rennert, Hedy S, Rhenius, Valerie, Romero, Atocha, Roylance, Rebecca, Saloustros, Emmanouil, Sawyer, Elinor J, Schmidt, Daniel F, Schmutzler, Rita K, Schneeweiss, Andreas, Schoemaker, Minouk J, Schumacher, Fredrick, Schwentner, Lukas, Scott, Rodney J, Scott, Christopher, Seynaeve, Caroline, Shah, Mitul, Simard, Jacques, Smeets, Ann, Sohn, Christof, Southey, Melissa C, Swerdlow, Anthony J, Talhouk, Aline, Tamimi, Rulla M, Tapper, William J, Teixeira, Manuel R, Tengström, Maria, Terry, Mary Beth, Thöne, Kathrin, Tollenaar, Rob AEM, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Turman, Constance, Turnbull, Clare, Ulmer, Hans-Ulrich, Untch, Michael, Vachon, Celine, van Asperen, Christi J, van den Ouweland, Ans MW, van Veen, Elke M, Wendt, Camilla, Whittemore, Alice S, Willett, Walter, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R, Zhang, Yan, Easton, Douglas F, Fasching, Peter A, Nevanlinna, Heli, Eccles, Diana M, Pharoah, Paul DP, Schmidt, Marjanka K, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Abraham, Jean [0000-0003-0688-4807], Caldas, Carlos [0000-0003-3547-1489], Chin, Suet-Feung [0000-0001-5697-1082], Dunning, Alison [0000-0001-6651-7166], Earl, Helena [0000-0003-1549-8094], Rhenius, Valerie [0000-0003-4215-3235], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: Receptors, Estrogen, Genetic Variation, Humans, Bayes Theorem, Breast Neoplasms, Female, Prognosis, Chromosomes, Human, Pair 7, White People, Genome-Wide Association Study, Proportional Hazards Models
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
Published: 2019

11. Genome-wide association study of germline variants and breast cancer-specific mortality

Author: Escala-Garcia, Maria, Guo, Qi, Dörk, Thilo, Canisius, Sander, Keeman, Renske, Dennis, Joe, Beesley, Jonathan, Lecarpentier, Julie, Bolla, Manjeet K, Wang, Qin, Abraham, Jean, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Auer, Paul L, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Blomqvist, Carl, Boeckx, Bram, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brentnall, Adam, Brinton, Louise, Broberg, Per, Brock, Ian W, Brucker, Sara Y, Burwinkel, Barbara, Caldas, Carlos, Caldés, Trinidad, Campa, Daniele, Canzian, Federico, Carracedo, Angel, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Cheng, Ting-Yuan David, Chin, Suet-Feung, Clarke, Christine L, NBCS Collaborators, Cordina-Duverger, Emilie, Couch, Fergus J, Cox, David G, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dunn, Janet A, Dunning, Alison M, Durcan, Lorraine, Dwek, Miriam, Earl, Helena M, Ekici, Arif B, Eliassen, A Heather, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Figueroa, Jonine, Flesch-Janys, Dieter, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, Galle, Eva, Gapstur, Susan M, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, George, Angela, Georgoulias, Vassilios, Giles, Graham G, Glendon, Gord, Goldgar, David E, González-Neira, Anna, Alnæs, Grethe I Grenaker, Grip, Mervi, Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hankinson, Susan, Harkness, Elaine F, Harrington, Patricia A, Hart, Steven N, Hartikainen, Jaana M, Hein, Alexander, Hillemanns, Peter, Hiller, Louise, Holleczek, Bernd, Hollestelle, Antoinette, Hooning, Maartje J, Hoover, Robert N, Hopper, John L, Howell, Anthony, Huang, Guanmengqian, Humphreys, Keith, Hunter, David J, Janni, Wolfgang, John, Esther M, Jones, Michael E, Jukkola-Vuorinen, Arja, Jung, Audrey, Kaaks, Rudolf, Kabisch, Maria, Kaczmarek, Katarzyna, Kerin, Michael J, Khan, Sofia, Khusnutdinova, Elza, Kiiski, Johanna I, Kitahara, Cari M, Knight, Julia A, Ko, Yon-Dschun, Koppert, Linetta B, Kosma, Veli-Matti, Kraft, Peter, Kristensen, Vessela N, Krüger, Ute, Kühl, Tabea, Lambrechts, Diether, Le Marchand, Loic, Lee, Eunjung, Lejbkowicz, Flavio, Li, Lian, Lindblom, Annika, Lindström, Sara, Linet, Martha, Lissowska, Jolanta, Lo, Wing-Yee, Loibl, Sibylle, Lubiński, Jan, Lux, Michael P, MacInnis, Robert J, Maierthaler, Melanie, Maishman, Tom, Makalic, Enes, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Mavroudis, Dimitrios, McLean, Catriona, Meindl, Alfons, Middha, Pooja, Miller, Nicola, Milne, Roger L, Moreno, Fernando, Mulligan, Anna Marie, Mulot, Claire, Nassir, Rami, Neuhausen, Susan L, Newman, William T, Nielsen, Sune F, Nordestgaard, Børge G, Norman, Aaron, Olsson, Håkan, Orr, Nick, Pankratz, V Shane, Park-Simon, Tjoung-Won, Perez, Jose IA, Pérez-Barrios, Clara, Peterlongo, Paolo, Petridis, Christos, Pinchev, Mila, Prajzendanc, Karoliona, Prentice, Ross, Presneau, Nadege, Prokofieva, Darya, Pylkäs, Katri, Rack, Brigitte, Radice, Paolo, Ramachandran, Dhanya, Rennert, Gadi, Rennert, Hedy S, Rhenius, Valerie, Romero, Atocha, Roylance, Rebecca, Saloustros, Emmanouil, Sawyer, Elinor J, Schmidt, Daniel F, Schmutzler, Rita K, Schneeweiss, Andreas, Schoemaker, Minouk J, Schumacher, Fredrick, Schwentner, Lukas, Scott, Rodney J, Scott, Christopher, Seynaeve, Caroline, Shah, Mitul, Simard, Jacques, Smeets, Ann, Sohn, Christof, Southey, Melissa C, Swerdlow, Anthony J, Talhouk, Aline, Tamimi, Rulla M, Tapper, William J, Teixeira, Manuel R, Tengström, Maria, Terry, Mary Beth, Thöne, Kathrin, Tollenaar, Rob AEM, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Turman, Constance, Turnbull, Clare, Ulmer, Hans-Ulrich, Untch, Michael, Vachon, Celine, Van Asperen, Christi J, Van Den Ouweland, Ans MW, Van Veen, Elke M, Wendt, Camilla, Whittemore, Alice S, Willett, Walter, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R, Zhang, Yan, Easton, Douglas F, Fasching, Peter A, Nevanlinna, Heli, Eccles, Diana M, Pharoah, Paul DP, and Schmidt, Marjanka K
Subjects: Receptors, Estrogen, Genetic Variation, Humans, Bayes Theorem, Breast Neoplasms, Female, Prognosis, Chromosomes, Human, Pair 7, White People, Genome-Wide Association Study, Proportional Hazards Models
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.
Published: 2019
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12. Publisher Correction: Shared heritability and functional enrichment across six solid cancers (Nature Communications, (2019), 10, 1, (431), 10.1038/s41467-018-08054-4)

Author: Jiang, Xia, Finucane, Hilary K., Schumacher, Fredrick R., Schmit, Stephanie L., Tyrer, Jonathan P., Han, Younghun, Michailidou, Kyriaki, Lesseur, Corina, Kuchenbaecker, Karoline B., Dennis, Joe, Conti, David V., Casey, Graham, Gaudet, Mia M., Huyghe, Jeroen R., Albanes, Demetrius, Aldrich, Melinda C., Andrew, Angeline S., Andrulis, Irene L., Anton-Culver, Hoda, Antoniou, Antonis C., Antonenkova, Natalia N., Arnold, Susanne M., Aronson, Kristan J., Arun, Banu K., Bandera, Elisa V., Barkardottir, Rosa B., Barnes, Daniel R., Batra, Jyotsna, Beckmann, Matthias W., Benitez, Javier, Benlloch, Sara, Berchuck, Andrew, Berndt, Sonja I., Bickeböller, Heike, Bien, Stephanie A., Blomqvist, Carl, Boccia, Stefania, Bogdanova, Natalia V., Bojesen, Stig E., Bolla, Manjeet K., Brauch, Hiltrud, Brenner, Hermann, Brenton, James D., Brook, Mark N., Brunet, Joan, Brunnström, Hans, Buchanan, Daniel D., Burwinkel, Barbara, Butzow, Ralf, Cadoni, Gabriella, Caldés, Trinidad, Caligo, Maria A., Campbell, Ian, Campbell, Peter T., Cancel-Tassin, Géraldine, Cannon-Albright, Lisa, Campa, Daniele, Caporaso, Neil, Carvalho, André L., Chan, Andrew T., Chang-Claude, Jenny, Chanock, Stephen J., Chen, Chu, Christiani, David C., Claes, Kathleen B.M., Claessens, Frank, Clements, Judith, Collée, J. Margriet, Correa, Marcia Cruz, Couch, Fergus J., Cox, Angela, Cunningham, Julie M., Cybulski, Cezary, Czene, Kamila, Daly, Mary B., deFazio, Anna, Devilee, Peter, Diez, Orland, Gago-Dominguez, Manuela, Donovan, Jenny L., Dörk, Thilo, Duell, Eric J., Dunning, Alison M., Dwek, Miriam, Eccles, Diana M., Edlund, Christopher K., Edwards, Digna R.Velez, Ellberg, Carolina, Evans, D. Gareth, Fasching, Peter A., Ferris, Robert L., Liloglou, Triantafillos, Figueiredo, Jane C., Fletcher, Olivia, Fortner, Renée T., Fostira, Florentia, Franceschi, Silvia, Friedman, Eitan, Gallinger, Steven J., Ganz, Patricia A., Garber, Judy, García-Sáenz, José A., Gayther, Simon A., Giles, Graham G., Godwin, Andrew K., Goldberg, Mark S., Goldgar, David E., Goode, Ellen L., Goodman, Marc T., Goodman, Gary, Grankvist, Kjell, Greene, Mark H., Gronberg, Henrik, Gronwald, Jacek, Guénel, Pascal, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hamdy, Freddie C., Hamilton, Robert J., Hampe, Jochen, Haugen, Aage, Heitz, Florian, Herrero, Rolando, Hillemanns, Peter, Hoffmeister, Michael, Høgdall, Estrid, Hong, Yun Chul, Hopper, John L., Houlston, Richard, Hulick, Peter J., Hunter, David J., Huntsman, David G., Idos, Gregory, Imyanitov, Evgeny N., Ingles, Sue Ann, Isaacs, Claudine, Jakubowska, Anna, James, Paul, Jenkins, Mark A., Johansson, Mattias, Johansson, Mikael, John, Esther M., Joshi, Amit D., Kaneva, Radka, Karlan, Beth Y., Kelemen, Linda E., Kühl, Tabea, Khaw, Kay Tee, Khusnutdinova, Elza, Kibel, Adam S., Kiemeney, Lambertus A., Kim, Jeri, Kjaer, Susanne K., Knight, Julia A., Kogevinas, Manolis, Kote-Jarai, Zsofia, Koutros, Stella, Kristensen, Vessela N., Kupryjanczyk, Jolanta, Lacko, Martin, Lam, Stephan, Lambrechts, Diether, Landi, Maria Teresa, Lazarus, Philip, Le, Nhu D., Lee, Eunjung, Lejbkowicz, Flavio, Lenz, Heinz Josef, Leslie, Goska, Lessel, Davor, Lester, Jenny, Levine, Douglas A., Li, Li, Li, Christopher I., Lindblom, Annika, Lindor, Noralane M., Liu, Geoffrey, Loupakis, Fotios, Lubiński, Jan, Maehle, Lovise, Maier, Christiane, Mannermaa, Arto, Marchand, Loic Le, Margolin, Sara, May, Taymaa, McGuffog, Lesley, Meindl, Alfons, Middha, Pooja, Miller, Austin, Milne, Roger L., MacInnis, Robert J., Modugno, Francesmary, Montagna, Marco, Moreno, Victor, Moysich, Kirsten B., Mucci, Lorelei, Muir, Kenneth, Mulligan, Anna Marie, Nathanson, Katherine L., Neal, David E., Ness, Andrew R., Neuhausen, Susan L., Nevanlinna, Heli, Newcomb, Polly A., Newcomb, Lisa F., Nielsen, Finn Cilius, Nikitina-Zake, Liene, Nordestgaard, Børge G., Nussbaum, Robert L., Offit, Kenneth, Olah, Edith, Olama, Ali Amin Al, Olopade, Olufunmilayo I., Olshan, Andrew F., Olsson, Håkan, Osorio, Ana, Pandha, Hardev, Park, Jong Y., Pashayan, Nora, Parsons, Michael T., Pejovic, Tanja, Penney, Kathryn L., Peters, Wilbert H.M., Phelan, Catherine M., Phipps, Amanda I., Plaseska-Karanfilska, Dijana, Pring, Miranda, Prokofyeva, Darya, Radice, Paolo, Stefansson, Kari, Ramus, Susan J., Raskin, Leon, Rennert, Gad, Rennert, Hedy S., van Rensburg, Elizabeth J., Riggan, Marjorie J., Risch, Harvey A., Risch, Angela, Roobol, Monique J., Rosenstein, Barry S., Rossing, Mary Anne, De Ruyck, Kim, Saloustros, Emmanouil, Sandler, Dale P., Sawyer, Elinor J., Schabath, Matthew B., Schleutker, Johanna, Schmidt, Marjanka K., Setiawan, V. Wendy, Shen, Hongbing, Siegel, Erin M., Sieh, Weiva, Singer, Christian F., Slattery, Martha L., Sorensen, Karina Dalsgaard, Southey, Melissa C., Spurdle, Amanda B., Stanford, Janet L., Stevens, Victoria L., Stintzing, Sebastian, Stone, Jennifer, Sundfeldt, Karin, Sutphen, Rebecca, Swerdlow, Anthony J., Tajara, Eloiza H., Tangen, Catherine M., Tardon, Adonina, Taylor, Jack A., Teare, M. Dawn, Teixeira, Manuel R., Terry, Mary Beth, Terry, Kathryn L., Thibodeau, Stephen N., Thomassen, Mads, Bjørge, Line, Tischkowitz, Marc, Toland, Amanda E., Torres, Diana, Townsend, Paul A., Travis, Ruth C., Tung, Nadine, Tworoger, Shelley S., Ulrich, Cornelia M., Usmani, Nawaid, Vachon, Celine M., Van Nieuwenhuysen, Els, Vega, Ana, Aguado-Barrera, Miguel Elías, Wang, Qin, Webb, Penelope M., Weinberg, Clarice R., Weinstein, Stephanie, Weissler, Mark C., Weitzel, Jeffrey N., West, Catharine M.L., White, Emily, Whittemore, Alice S., Wichmann, H. Erich, Wiklund, Fredrik, Winqvist, Robert, Wolk, Alicja, Woll, Penella, Woods, Michael, Wu, Anna H., Wu, Xifeng, Yannoukakos, Drakoulis, Zheng, Wei, Zienolddiny, Shanbeh, Ziogas, Argyrios, Zorn, Kristin K., Lane, Jacqueline M., Saxena, Richa, Thomas, Duncan, Hung, Rayjean J., Diergaarde, Brenda, McKay, James, Peters, Ulrike, Hsu, Li, García-Closas, Montserrat, Eeles, Rosalind A., Chenevix-Trench, Georgia, Brennan, Paul J., Haiman, Christopher A., Simard, Jacques, Easton, Douglas F., Gruber, Stephen B., Pharoah, Paul D.P., Price, Alkes L., Pasaniuc, Bogdan, Amos, Christopher I., Kraft, Peter, and Lindström, Sara
Subjects: head and neck, Settore MED/31 - OTORINOLARINGOIATRIA
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2019

13. Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study

Author: Dixon-Suen, Suzanne C, Nagle, Christina M, Thrift, Aaron P, Pharoah, Paul DP, Ewing, Ailith, Pearce, Celeste Leigh, Zheng, Wei, Australian Ovarian Cancer Study Group, Chenevix-Trench, Georgia, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Lambrechts, Sandrina, Van Nieuwenhuysen, Els, Rossing, Mary Anne, Doherty, Jennifer A, Wicklund, Kristine G, Chang-Claude, Jenny, Jung, Audrey Y, Moysich, Kirsten B, Odunsi, Kunle, Goodman, Marc T, Wilkens, Lynne R, Thompson, Pamela J, Shvetsov, Yurii B, Dörk, Thilo, Park-Simon, Tjoung-Won, Hillemanns, Peter, Bogdanova, Natalia, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Leminen, Arto, Modugno, Francesmary, Ness, Roberta B, Edwards, Robert P, Kelley, Joseph L, Heitz, Florian, du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Karlan, Beth Y, Lester, Jenny, Orsulic, Sandra, Rimel, Bobbie J, Kjær, Susanne K, Høgdall, Estrid, Jensen, Allan, Goode, Ellen L, Fridley, Brooke L, Cunningham, Julie M, Winham, Stacey J, Giles, Graham G, Bruinsma, Fiona, Milne, Roger L, Southey, Melissa C, Hildebrandt, Michelle AT, Wu, Xifeng, Lu, Karen H, Liang, Dong, Levine, Douglas A, Bisogna, Maria, Schildkraut, Joellen M, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Bandera, Elisa V, Olson, Sara H, Salvesen, Helga B, Thomsen, Liv Cecilie Vestrheim, Kopperud, Reidun K, Bjorge, Line, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bruegl, Amanda, Cook, Linda S, Le, Nhu D, Swenerton, Kenneth D, Brooks-Wilson, Angela, Kelemen, Linda E, Lubiński, Jan, Huzarski, Tomasz, Gronwald, Jacek, Menkiszak, Janusz, Wentzensen, Nicolas, Brinton, Louise, Yang, Hannah, Lissowska, Jolanta, Høgdall, Claus K, Lundvall, Lene, Song, Honglin, Tyrer, Jonathan P, Campbell, Ian, Eccles, Diana, Paul, James, Glasspool, Rosalind, Siddiqui, Nadeem, and Whittemore, Alice S
Subjects: Australian Ovarian Cancer Study Group, Adult, Adolescent, Ovarian Cancer Association Consortium, Oncology and Carcinogenesis, Young Adult, Rare Diseases, Risk Factors, Clinical Research, Ovarian Epithelial, 80 and over, Genetics, Humans, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Aged, Cancer, Ovarian Neoplasms, Geography, Carcinoma, Middle Aged, Mendelian Randomization Analysis, Body Height, Ovarian Cancer, Case-Control Studies, Public Health and Health Services, Female
Abstract: BackgroundObservational 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.MethodsWe 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 geneticrisk 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.ResultsGreater 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.ConclusionsWomen 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.
Published: 2018

14. Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study

Author: Dixon-Suen, Suzanne C, Nagle, Christina M, Thrift, Aaron P, Pharoah, Paul DP, Ewing, Ailith, Pearce, Celeste Leigh, Zheng, Wei, Australian Ovarian Cancer Study Group, Chenevix-Trench, Georgia, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Lambrechts, Sandrina, Van Nieuwenhuysen, Els, Rossing, Mary Anne, Doherty, Jennifer A, Wicklund, Kristine G, Chang-Claude, Jenny, Jung, Audrey Y, Moysich, Kirsten B, Odunsi, Kunle, Goodman, Marc T, Wilkens, Lynne R, Thompson, Pamela J, Shvetsov, Yurii B, Dörk, Thilo, Park-Simon, Tjoung-Won, Hillemanns, Peter, Bogdanova, Natalia, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Leminen, Arto, Modugno, Francesmary, Ness, Roberta B, Edwards, Robert P, Kelley, Joseph L, Heitz, Florian, du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Karlan, Beth Y, Lester, Jenny, Orsulic, Sandra, Rimel, Bobbie J, Kjær, Susanne K, Høgdall, Estrid, Jensen, Allan, Goode, Ellen L, Fridley, Brooke L, Cunningham, Julie M, Winham, Stacey J, Giles, Graham G, Bruinsma, Fiona, Milne, Roger L, Southey, Melissa C, Hildebrandt, Michelle AT, Wu, Xifeng, Lu, Karen H, Liang, Dong, Levine, Douglas A, Bisogna, Maria, Schildkraut, Joellen M, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Bandera, Elisa V, Olson, Sara H, Salvesen, Helga B, Thomsen, Liv Cecilie Vestrheim, Kopperud, Reidun K, Bjorge, Line, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bruegl, Amanda, Cook, Linda S, Le, Nhu D, Swenerton, Kenneth D, Brooks-Wilson, Angela, Kelemen, Linda E, Lubiński, Jan, Huzarski, Tomasz, Gronwald, Jacek, Menkiszak, Janusz, Wentzensen, Nicolas, Brinton, Louise, Yang, Hannah, Lissowska, Jolanta, Høgdall, Claus K, Lundvall, Lene, Song, Honglin, Tyrer, Jonathan P, Campbell, Ian, Eccles, Diana, Paul, James, Glasspool, Rosalind, Siddiqui, Nadeem, Whittemore, Alice S, Sieh, Weiva, McGuire, Valerie, Rothstein, Joseph H, Narod, Steven A, Phelan, Catherine, Risch, Harvey A, McLaughlin, John R, Anton-Culver, Hoda, Ziogas, Argyrios, Menon, Usha, Gayther, Simon A, Ramus, Susan J, Gentry-Maharaj, Aleksandra, Wu, Anna H, Pike, Malcolm C, Tseng, Chiu-Chen, Kupryjanczyk, Jolanta, Dansonka-Mieszkowska, Agnieszka, Budzilowska, Agnieszka, Rzepecka, Iwona K, Webb, Penelope M, Ovarian Cancer Association Consortium, Dixon-Suen, Suzanne C [0000-0003-3714-8386], Zheng, Wei [0000-0003-1226-070X], Brinton, Louise [0000-0003-3853-8562], Glasspool, Rosalind [0000-0002-5000-1680], and Apollo - University of Cambridge Repository
Subjects: Adult, Aged, 80 and over, Ovarian Neoplasms, Adolescent, Geography, Carcinoma, Ovarian Epithelial, Mendelian Randomization Analysis, Middle Aged, Body Height, Young Adult, Risk Factors, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Aged
Abstract: BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Published: 2018

15. MyD88 and TLR4 Expression in Epithelial Ovarian Cancer

Author: Block, Matthew S, Vierkant, Robert A, Rambau, Peter F, Winham, Stacey J, Wagner, Philipp, Traficante, Nadia, Tołoczko, Aleksandra, Tiezzi, Daniel G, Taran, Florin Andrei, Sinn, Peter, Sieh, Weiva, Sharma, Raghwa, Rothstein, Joseph H, Ramón Y Cajal, Teresa, Paz-Ares, Luis, Oszurek, Oleg, Orsulic, Sandra, Ness, Roberta B, Nelson, Gregg, Modugno, Francesmary, Menkiszak, Janusz, McGuire, Valerie, McCauley, Bryan M, Mack, Marie, Lubiński, Jan, Longacre, Teri A, Li, Zheng, Lester, Jenny, Kennedy, Catherine J, Kalli, Kimberly R, Jung, Audrey Y, Johnatty, Sharon E, Jimenez-Linan, Mercedes, Jensen, Allan, Intermaggio, Maria P, Hung, Jillian, Herpel, Esther, Hernandez, Brenda Y, Hartkopf, Andreas D, Harnett, Paul R, Ghatage, Prafull, García-Bueno, José M, Gao, Bo, Fereday, Sian, Eilber, Ursula, Edwards, Robert P, de Sousa, Christiani B, de Andrade, Jurandyr M, Chudecka-Głaz, Anita, Chenevix-Trench, Georgia, Cazorla, Alicia, Brucker, Sara Y, Australian Ovarian Cancer Study Group, Alsop, Jennifer, Whittemore, Alice S, Steed, Helen, Staebler, Annette, Moysich, Kirsten B, Menon, Usha, Koziak, Jennifer M, Kommoss, Stefan, Kjaer, Susanne K, Kelemen, Linda E, Karlan, Beth Y, Huntsman, David G, Høgdall, Estrid, Gronwald, Jacek, Goodman, Marc T, Gilks, Blake, García, María José, Fasching, Peter A, de Fazio, Anna, Deen, Suha, Chang-Claude, Jenny, Candido Dos Reis, Francisco J, Campbell, Ian G, Brenton, James D, Bowtell, David D, Benítez, Javier, Pharoah, Paul DP, Köbel, Martin, Ramus, Susan J, Goode, Ellen L, Brenton, James [0000-0002-5738-6683], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: Australian Ovarian Cancer Study Group, Ovarian Neoplasms, Adult, Tumor, Carcinoma, Carcinoma, Ovarian Epithelial, Middle Aged, Immunohistochemistry, Survival Analysis, Medical and Health Sciences, Ovarian Cancer, Toll-Like Receptor 4, Rare Diseases, Clinical Research, Tissue Array Analysis, Ovarian Epithelial, Myeloid Differentiation Factor 88, Biomarkers, Tumor, Humans, Female, Biomarkers, Cancer, Aged
Abstract: OBJECTIVE: 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. PATIENTS AND METHODS: 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). RESULTS: Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P
Published: 2018

16. Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

Author: Ovarian Tumor Tissue Analysis (OTTA) Consortium, Goode, Ellen L, Block, Matthew S, Kalli, Kimberly R, Vierkant, Robert A, Chen, Wenqian, Fogarty, Zachary C, Gentry-Maharaj, Aleksandra, Tołoczko, Aleksandra, Hein, Alexander, Bouligny, Aliecia L, Jensen, Allan, Osorio, Ana, Hartkopf, Andreas, Ryan, Andy, Chudecka-Głaz, Anita, Magliocco, Anthony M, Hartmann, Arndt, Jung, Audrey Y, Gao, Bo, Hernandez, Brenda Y, Fridley, Brooke L, McCauley, Bryan M, Kennedy, Catherine J, Wang, Chen, Karpinskyj, Chloe, de Sousa, Christiani B, Tiezzi, Daniel G, Wachter, David L, Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Nelson, Gregg, Lubiński, Jan, Menkiszak, Janusz, Alsop, Jennifer, Lester, Jenny, García-Donas, Jesús, Nation, Jill, Hung, Jillian, Palacios, José, Rothstein, Joseph H, Kelley, Joseph L, de Andrade, Jurandyr M, Robles-Díaz, Luis, Intermaggio, Maria P, Widschwendter, Martin, Beckmann, Matthias W, Ruebner, Matthias, Jimenez-Linan, Mercedes, Singh, Naveena, Oszurek, Oleg, Harnett, Paul R, Rambau, Peter F, Sinn, Peter, Wagner, Philipp, Ghatage, Prafull, Sharma, Raghwa, Edwards, Robert P, Ness, Roberta B, Orsulic, Sandra, Brucker, Sara Y, Johnatty, Sharon E, Longacre, Teri A, Ursula, Eilber, McGuire, Valerie, Sieh, Weiva, Natanzon, Yanina, Li, Zheng, Whittemore, Alice S, Anna, deFazio, Staebler, Annette, Karlan, Beth Y, Gilks, Blake, Bowtell, David D, Høgdall, Estrid, Candido dos Reis, Francisco J, Steed, Helen, Campbell, Ian G, Gronwald, Jacek, Benítez, Javier, Koziak, Jennifer M, Chang-Claude, Jenny, Moysich, Kirsten B, Kelemen, Linda E, Cook, Linda S, Goodman, Marc T, García, María José, Fasching, Peter A, Kommoss, Stefan, Deen, Suha, Kjaer, Susanne K, Menon, Usha, Brenton, James D, Pharoah, Paul DP, Chenevix-Trench, Georgia, Huntsman, David G, Winham, Stacey J, Köbel, Martin, Ramus, Susan J, Brenton, James [0000-0002-5738-6683], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: CD8 Antigens, Oncology and Carcinogenesis, Cystadenocarcinoma, chemical and pharmacologic phenomena, Carcinoma, Ovarian Epithelial, Cohort Studies, Vaccine Related, Lymphocytes, Tumor-Infiltrating, Rare Diseases, Clinical Research, Ovarian Epithelial, Humans, Lymphocytes, Tumor-Infiltrating, Prospective Studies, Ovarian Tumor Tissue Analysis (OTTA) Consortium, Cancer, Ovarian Neoplasms, BRCA2 Protein, Prevention, Carcinoma, Serous, Middle Aged, Survival Analysis, Cystadenocarcinoma, Serous, Ovarian Cancer, Treatment Outcome, Mutation, Public Health and Health Services, Female, Neoplasm Grading
Abstract: IMPORTANCE: 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. OBJECTIVE: To define the prognostic role of CD8+ TILs in epithelial ovarian cancer. DESIGN, SETTING, AND PARTICIPANTS: 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. EXPOSURES: 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. MAIN OUTCOMES AND MEASURES: Overall survival time. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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.
Published: 2017

17. Investigating the genetic relationship between Alzheimer’s disease and cancer using GWAS summary statistics

Author: Feng, Yen Chen Anne, Cho, Kelly, Lindstrom, Sara, Kraft, Peter, Cormack, Jean, Blalock, Kendra, Campbell, Peter T., Casey, Graham, Conti, David V., Edlund, Christopher K., Figueiredo, Jane, James Gauderman, W., Gong, Jian, Green, Roger C., Gruber, Stephen B., Harju, John F., Harrison, Tabitha A., Jacobs, Eric J, Jenkins, Mark A., Jiao, Shuo, Li, Li, Lin, Yi, Manion, Frank J., Moreno, Victor, Mukherjee, Bhramar, Peters, Ulrike, Raskin, Leon, Schumacher, Fredrick R., Seminara, Daniela, Severi, Gianluca, Stenzel, Stephanie L., Thomas, Duncan C., Hopper, John L., Southey, Melissa C., Makalic, Enes, Schmidt, Daniel F., Fletcher, Olivia, Peto, Julian, Gibson, Lorna, Dos-Santos-Silva, Isabel, Hunter, David J., Lindström, Sara, Ahsan, Habib, Whittemore, Alice S., Waisfisz, Quinten, Meijers-Heijboer, Hanne, Adank, Muriel A., van der Luijt, Rob B., Uitterlinden, Andre G, IGAP Consortium, Colorectal Transdisciplinary Study (CORECT), Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE), Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE), and Transdisciplinary Research in Cancer of the Lung (TRICL)
Subjects: Genetics, Genetics(clinical)
Abstract: Growing evidence from both epidemiology and basic science suggest an inverse association between Alzheimer’s disease (AD) and cancer. We examined the genetic relationship between AD and various cancer types using GWAS summary statistics from the IGAP and GAME-ON consortia. Sample size ranged from 9931 to 54,162; SNPs were imputed to the 1000 Genomes European panel. Our results based on cross-trait LD Score regression showed a significant positive genetic correlation between AD and five cancers combined (colon, breast, prostate, ovarian, lung; rg = 0.17, P = 0.04), and specifically with breast cancer (ER-negative and overall; rg = 0.21 and 0.18, P = 0.035 and 0.034) and lung cancer (adenocarcinoma, squamous cell carcinoma and overall; rg = 0.31, 0.38 and 0.30, P = 0.029, 0.016, and 0.006). Estimating the genetic correlation in specific functional categories revealed mixed positive and negative signals, notably stronger at annotations associated with increased enhancer activity. This suggests a role of gene expression regulators in the shared genetic etiology between AD and cancer, and that some shared variants modulate disease risk concordantly while others have effects in opposite directions. Due to power issues, we did not detect cross-phenotype associations at individual SNPs. This genetic overlap is not likely driven by a handful of major loci. Our study is the first to examine the co-heritability of AD and cancer leveraging large-scale GWAS results. The functional categories highlighted in this study need further investigation to illustrate the details of the genetic sharing and to bridge between different levels of associations.
Published: 2017

18. Investigating the genetic relationship between Alzheimer’s disease and cancer using GWAS summary statistics

Author: Feng, Yen Chen Anne, Cho, Kelly, Lindstrom, Sara, Kraft, Peter, Cormack, Jean, Blalock, Kendra, Campbell, Peter T., Casey, Graham, Conti, David V., Edlund, Christopher K., Figueiredo, Jane, James Gauderman, W., Gong, Jian, Green, Roger C., Gruber, Stephen B., Harju, John F., Harrison, Tabitha A., Jacobs, Eric J, Jenkins, Mark A., Jiao, Shuo, Li, Li, Lin, Yi, Manion, Frank J., Moreno, Victor, Mukherjee, Bhramar, Peters, Ulrike, Raskin, Leon, Schumacher, Fredrick R., Seminara, Daniela, Severi, Gianluca, Stenzel, Stephanie L., Thomas, Duncan C., Hopper, John L., Southey, Melissa C., Makalic, Enes, Schmidt, Daniel F., Fletcher, Olivia, Peto, Julian, Gibson, Lorna, Dos-Santos-Silva, Isabel, Hunter, David J., Lindström, Sara, Ahsan, Habib, Whittemore, Alice S., Waisfisz, Quinten, Meijers-Heijboer, Hanne, Adank, Muriel A., van der Luijt, Rob B., Uitterlinden, Andre G, IGAP Consortium, Colorectal Transdisciplinary Study (CORECT), Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE), CCA - Cancer biology and immunology, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
Subjects: 0301 basic medicine, Male, Genome-wide association study, Single-nucleotide polymorphism, Disease, Biology, Genetic correlation, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Alzheimer Disease, Neoplasms, Genetics, medicine, Humans, Genetics(clinical), 1000 Genomes Project, Genetics (clinical), Cancer, medicine.disease, 030104 developmental biology, Adenocarcinoma, Female, Genome-Wide Association Study
Abstract: Growing evidence from both epidemiology and basic science suggest an inverse association between Alzheimer’s disease (AD) and cancer. We examined the genetic relationship between AD and various cancer types using GWAS summary statistics from the IGAP and GAME-ON consortia. Sample size ranged from 9931 to 54,162; SNPs were imputed to the 1000 Genomes European panel. Our results based on cross-trait LD Score regression showed a significant positive genetic correlation between AD and five cancers combined (colon, breast, prostate, ovarian, lung; r g = 0.17, P = 0.04), and specifically with breast cancer (ER-negative and overall; r g = 0.21 and 0.18, P = 0.035 and 0.034) and lung cancer (adenocarcinoma, squamous cell carcinoma and overall; r g = 0.31, 0.38 and 0.30, P = 0.029, 0.016, and 0.006). Estimating the genetic correlation in specific functional categories revealed mixed positive and negative signals, notably stronger at annotations associated with increased enhancer activity. This suggests a role of gene expression regulators in the shared genetic etiology between AD and cancer, and that some shared variants modulate disease risk concordantly while others have effects in opposite directions. Due to power issues, we did not detect cross-phenotype associations at individual SNPs. This genetic overlap is not likely driven by a handful of major loci. Our study is the first to examine the co-heritability of AD and cancer leveraging large-scale GWAS results. The functional categories highlighted in this study need further investigation to illustrate the details of the genetic sharing and to bridge between different levels of associations.
Published: 2017

19. Germline whole exome sequencing and large-scale replication identifies FANCM as a likely high grade serous ovarian cancer susceptibility gene

Author: Dicks, Ed, Song, Honglin, Ramus, Susan J., Van Oudenhove, Elke, Tyrer, Jonathan P., Intermaggio, Maria P., Kar, Siddhartha, Harrington, Patricia, Bowtell, David D., Study Group, Aocs, Cicek, Mine S., Cunningham, Julie M., Fridley, Brooke L., Alsop, Jennifer, Jimenez-Linan, Mercedes, Piskorz, Anna, Goranova, Teodora, Kent, Emma, Siddiqui, Nadeem, Paul, James, Crawford, Robin, Poblete, Samantha, Lele, Shashi, Sucheston-Campbell, Lara, Moysich, Kirsten B., Sieh, Weiva, McGuire, Valerie, Lester, Jenny, Odunsi, Kunle, Whittemore, Alice S., Bogdanova, Natalia, Dürst, Matthias, Hillemanns, Peter, Karlan, Beth Y., Gentry-Maharaj, Aleksandra, Menon, Usha, Tischkowitz, Marc, Levine, Douglas, Brenton, James D., Dörk, Thilo, Goode, Ellen L., Gayther, Simon A., Pharoah, Paul D.P., Dicks, Ed [0000-0002-0617-0401], Song, Honglin [0000-0001-5076-7371], Tyrer, Jonathan [0000-0003-3724-4757], Tischkowitz, Marc [0000-0002-7880-0628], Brenton, James [0000-0002-5738-6683], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, DNA repair, Oncology and Carcinogenesis, Genome-wide association study, VARIANTS, Biology, BREAST, Germline, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, Clinical Research, Medicine and Health Sciences, LOCUS, Genetics, CONFER SUSCEPTIBILITY, 2.1 Biological and endogenous factors, FANCL, susceptibility genes, FANCM, Genetic Testing, GENOME-WIDE ASSOCIATION, Mutation frequency, Aetiology, Exome sequencing, Cancer, next generation sequencing, RAD51C, MUTATIONS, Prevention, Human Genome, BRCA2, RISKS, 3. Good health, 030104 developmental biology, Good Health and Well Being, ovarian cancer, Oncology, 030220 oncology & carcinogenesis, Cancer research
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 = 1.8x10(-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.
Published: 2017

20. RE: 'RISK PREDICTION FOR EPITHELIAL OVARIAN CANCER IN 11 UNITED STATES–BASED CASE-CONTROL STUDIES: INCORPORATION OF EPIDEMIOLOGIC RISK FACTORS AND 17 CONFIRMED GENETIC LOCI'

Author: Clyde, Merlise A, Weber, Rachel Palmieri, Iversen, Edwin S, Poole, Elizabeth M, Doherty, Jennifer A, Goodman, Marc T, Ness, Roberta B, Risch, Harvey A, Rossing, Mary Anne, Terry, Kathryn L, Wentzensen, Nicolas, Whittemore, Alice S, Anton-Culver, Hoda, Bandera, Elisa V, Berchuck, Andrew, Carney, Michael E, Cramer, Daniel W, Cunningham, Julie M, Cushing-Haugen, Kara L, Edwards, Robert P, Fridley, Brooke L, Goode, Ellen L, Lurie, Galina, McGuire, Valerie, Modugno, Francesmary, Moysich, Kirsten B, Olson, Sara H, Pearce, Celeste Leigh, Pike, Malcolm C, Rothstein, Joseph H, Sellers, Thomas A, Sieh, Weiva, Stram, Daniel, Thompson, Pamela J, Vierkant, RobertA, Wicklund, KristineG, Wu, Anna H, Ziogas, Argyrios, Pharoah, Paul D, Tworoger, Shelley S, Schildkraut, Joellen M, and Consortium, Ovarian Canc Assoc
Subjects: Epidemiology, Medical and Health Sciences, Mathematical Sciences
Published: 2017

21. No Evidence That Genetic Variation in the Myeloid-Derived Suppressor Cell Pathway Influences Ovarian Cancer Survival

Author: Sucheston-Campbell, Lara E, Cannioto, Rikki, Clay, Alyssa I, Etter, John Lewis, Eng, Kevin H, Liu, Song, Battaglia, Sebastiano, Hu, Qiang, Szender, J Brian, Minlikeeva, Albina, Joseph, Janine M, Mayor, Paul, Abrams, Scott I, Segal, Brahm H, Wallace, Paul K, Soh, Kah Teong, Zsiros, Emese, Anton-Culver, Hoda, Bandera, Elisa V, Beckmann, Matthias W, Berchuck, Andrew, Bjorge, Line, Bruegl, Amanda, Campbell, Ian G, Campbell, Shawn Patrice, Chenevix-Trench, Georgia, Cramer, Daniel W, Dansonka-Mieszkowska, Agnieszka, Dao, Fanny, Diergaarde, Brenda, Doerk, Thilo, Doherty, Jennifer A, du Bois, Andreas, Eccles, Diana, Engelholm, Svend Aage, Fasching, Peter A, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Glasspool, Rosalind M, Goodman, Marc T, Gronwald, Jacek, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hillemmanns, Peter, Høgdall, Claus, Høgdall, Estrid VS, Huzarski, Tomasz, Jensen, Allan, Johnatty, Sharon E, Jung, Audrey, Karlan, Beth Y, Klapdor, Reudiger, Kluz, Tomasz, Konopka, Bożena, Kjær, Susanne Krüger, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lester, Jenny, Lubiński, Jan, Levine, Douglas A, Lundvall, Lene, McGuire, Valerie, McNeish, Iain A, Menon, Usha, Modugno, Francesmary, Ness, Roberta B, Orsulic, Sandra, Paul, James, Pearce, Celeste Leigh, Pejovic, Tanja, Pharoah, Paul, Ramus, Susan J, Rothstein, Joseph, Rossing, Mary Anne, Rübner, Matthias, Schildkraut, Joellen M, Schmalfeldt, Barbara, Schwaab, Ira, Siddiqui, Nadeem, Sieh, Weiva, Sobiczewski, Piotr, Song, Honglin, Terry, Kathryn L, Van Nieuwenhuysen, Els, Vanderstichele, Adriaan, Vergote, Ignace, Walsh, Christine S, Webb, Penelope M, Wentzensen, Nicolas, Whittemore, Alice S, Wu, Anna H, Ziogas, Argyrios, Odunsi, Kunle, Chang-Claude, Jenny, Goode, Ellen L, Moysich, Kirsten B, and Australian Ovarian Cancer Study
Subjects: Ovarian Neoplasms, endocrine system diseases, Epidemiology, Myeloid-Derived Suppressor Cells, Prevention, Carcinoma, Glandular and Epithelial, Genetic Variation, Australian Ovarian Cancer Study, Medical and Health Sciences, female genital diseases and pregnancy complications, Ovarian Cancer, Rare Diseases, Clinical Research, Neoplasms, Ovarian Epithelial, Genetics, Humans, 2.1 Biological and endogenous factors, Female, Genetic Testing, Aetiology, Genetic Association Studies, Cancer
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.
Published: 2017

22. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

Author: Milne, Roger L., Kuchenbaecker, Karoline B., Michailidou, Kyriaki, Beesley, Jonathan, Kar, Siddhartha, Lindstrom, Sara, Hui, Shirley, Lemaçon, Audrey, Soucy, Penny, Dennis, Joe, Jiang, Xia, Rostamianfar, Asha, Finucane, Hilary, Bolla, Manjeet K., McGuffog, Lesley, Wang, Qin, Aalfs, Cora M., Abctctb, Investigators, Adams, Marcia, Adlard, Julian, Agata, Simona, Ahmed, Shahana, Ahsan, Habibul, Aittom, Kristiina Äki, Fares, Al Ejeh, Allen, Jamie, Ambrosone, Christine B., Amos, Christopher I., Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Arndt, Volker, Arnold, Norbert, Aronson, Kristan J., Auber, Bernd, Auer, Paul L., Ausems, Margreet G.M., Azzollini, Jacopo, François, Bacot, Balma, Judith Nã, Barile, Monica, Barjhoux, Laure, Barkardottir, Rosa B., Barrdahl, Myrto, Barnes, Daniel, Barrowdale, Daniel, Baynes, Caroline, Beckmann, Matthias W., Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Bignon, Yves Jean, Blazer, Kathleen R., Blok, Marinus J., Blomqvist, Carl, Blot, William, Bobolis, Kristie, Boeckx, Bram, Bogdanova, Natalia V., Bojesen, Anders, Bojesen, Stig E., Bonanni, Bernardo, Anne-Lise, Børresen Dale, Bozsik, Aniko, Bradbury, Angela R., Brand, Judith S., Brauch, Hiltrud, Brenner, Hermann, Brigitte, Bressac De Paillerets, Brewer, Carole, Brinton, Louise, Broberg, Per, Angela, Brooks Wilson, Brunet, Joan, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S., Byun, Jinyoung, Cai, Qiuyin, Cald, Trinidad És, Caligo, Maria A., Campbell, Ian, Canzian, Federico, Caron, Olivier, Carracedo, Angel, Carter, Brian D., Esteban, Castelao, Castera, Laurent, Virginie, Caux Moncoutier, Chan, Salina B., Jenny, Chang Claude, Chanock, Stephen J., Chen, Xiaoqing, Cheng, Ting Yuan David, Chiquette, Jocelyne, Christiansen, Hans, Claes, Kathleen B., Clarke, Christine L., Conner, Thomas, Conroy, Don M., Cook, Jackie, Cordina-Duverger, Emilie, Cornelissen, Sten, Coupier, Isabelle, Cox, Angela, Cox, David G., Cross, Simon S., Cuk, Katarina, Cunningham, J. M., Czene, Kamila, Daly, Mary B., Damiola, Francesca, Darabi, Hatef, Davidson, Rosemarie, Leeneer, Kim De L., Devilee, Peter, Dicks, Ed, Diez, Orland, Ding, Yuan Chun, Ditsch, Nina, Doheny, Kimberly F., Domchek, Susan M., Dorfling, Cecilia M., Dörk, Thilo, Dos-Santos-Silva, Isabel, Dubois, Stéphane, Dugué, Pierre Antoine, Dumont, Martine, Dunning, Alison M., Durcan, Lorraine, Dwek, Miriam, Dworniczak, Bernd, Eccles, Diana, Eeles, Ros, Ehrencrona, Hans, Eilber, Ursula, Ejlertsen, Bent, Ekici, Arif B., Eliassen, A. Heather, Engel, Christoph, Eriksson, Mikael, Fachal, Laura, Faivre, Laurence, Fasching, Peter A., Faust, Ulrike, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Foulkes, William D., Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gabrielson, Marike, Gaddam, Pragna, Gammon, Marilie D., Ganz, Patricia A., Gapstur, Susan M., Garber, Judy, Garcia-Barberan, Vanesa, Garciá-Saénz, José A., Gaudet, Mia M., Gauthier-Villars, Marion, Gehrig, Andrea, Georgoulias, Vassilios, Gerdes, Anne Marie, Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goldberg, Mark S., Goldgar, David E., González-Neira, Anna, Goodfellow, Paul, Greene, Mark H., Grenaker, Grethe Alnæs I., Grip, Mervi, Gronwald, Jacek, Grundy, Anne, Gschwantler, Daphne Kaulich, Guénel, Pascal, Guo, Qi, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hallberg, Emily, Hamann, Ute, Hamel, Nathalie, Hankinson, Susan, Hansen, Thomas V., Harrington, Patricia, Hart, Steven N., Hartikainen, Jaana M., Healey, Catherine S., Hein, Alexander, Helbig, Sonja, Henderson, Alex, Heyworth, Jane, Hicks, Belynda, Hillemanns, Peter, Hodgson, Shirley, Hogervorst, Frans B., Hollestelle, Antoinette, Hooning, Maartje J., Hoover, Bob, Hopper, John L., Hu, Chunling, Huang, Guanmengqian, Hulick, Peter J., Humphreys, Keith, Hunter, David J., Imyanitov, Evgeny N., Isaacs, Claudine, Iwasaki, Motoki, Izatt, Louise, Jakubowska, Anna, James, Paul, Janavicius, Ramunas, Janni, Wolfgang, Jensen, Uffe Birk, John, Esther M., Johnson, Nichola, Jones, Kristine, Jones, Michael, Jukkola-Vuorinen, Arja, Kaaks, Rudolf, Kabisch, Maria, Kaczmarek, Katarzyna, Kang, Daehee, Kast, Karin, Keeman, Renske, Kerin, Michael J., Kets, Carolien M., Keupers, Mac Hteld, Khan, Sofia, Khusnutdinova, Elza, Kiiski, Johanna I., Kim, Sung Won, Knight, Julia A., Konstantopoulou, Irene, Kosma, Veli Matti, Kristensen, Vessela N., Kruse, Torben A., Kwong, Ava, Lænkholm, Anne Vibeke, Laitman, Yael, Lalloo, Fiona, Lambrechts, Diether, Landsman, Keren, Lasset, Christine, Lazaro, Conxi, Marchand, Loic Le, Lindström, Sara, Al-Ejeh, Fares, Margreet, G. M.Ausems, Bacot, François, Børresen-Dale, Anne Lise, Bressac-De, Brigitte Paillerets, Brooks-Wilson, Angela, Castelao, J. Esteban, Caux-Moncoutier, Virginie, Chang-Claude, Jenny, McLaes, Kathleen B., Leeneer, Kim De, Dieter, Flesch Janys, Gschwantler-Kaulich, Daphne, Keupers, MacHteld, Lecarpentier, Julie, Lee, Andrew, Lee, Eunjung, Won, Jong Lee, Lee, Min Hyuk, Lejbkowicz, Flavio, Lesueur, Fabienne, Li, Jingmei, Lilyquist, Jenna, Lincoln, Anne, Lindblom, Annika, Lissowska, Jolanta, Lo, Wing Yee, Loibl, Sibylle, Long, Jirong, Loud, Jennifer T., Lubinski, Jan, Luccarini, Craig, Lush, Michael, MacInnis, Robert J., Maishman, Tom, Makalic, Enes, Kostovska, Ivana Maleva, Malone, Kathleen E., Siranoush, Manoukian, Manson, Joann E., Margolin, Sara, Martens, John W., Martinez, Maria Elena, Matsuo, Keitaro, Mavroudis, Dimitrios, Mazoyer, Sylvie, McLean, Catriona, Meijers-Heijboer, Hanne, Menéndez, Primitiva, Meyer, Jeffery, Miao, Hui, Miller, Austin, Miller, Nicola, Mitchell, Gillian, Montagna, Marco, Muir, Kenneth, Mulligan, Anna Marie, Mulot, Claire, Nadesan, Sue, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Nevelsteen, Ines, Niederacher, Dieter, Nielsen, Sune F., Nordestgaard, Børge G., Norman, Aaron, Nussbaum, Robert L., Olah, Edith, Olopade, Olufunmilayo I., Olson, Janet E., Olswold, Curtis, Ong, Kai Ren, Oosterwijk, Jan C., Orr, Nick, Osorio, Ana, Pankratz, V. Shane, Papi, Laura, Park-Simon, Tjoung Won, Paulsson-Karlsson, Ylva, Lloyd, Rachel, Pedersen, Inge Søkilde, Peissel, Bernard, Peixoto, Ana, Perez, Jose I., Peterlongo, Paolo, Peto, Julian, Pfeiler, Georg, Phelan, Catherine M., Pinchev, Mila, Plaseska-Karanfilska, Dijana, Poppe, Bruce, Porteous, Mary E., Prentice, Ross, Presneau, Nadege, Prokofieva, Darya, Pugh, Elizabeth, Pujana, Miquel Angel, Pylkäs, Katri, Rack, Brigitte, Radice, Paolo, Rahman, Nazneen, Rantala, Johanna, Rappaport-Fuerhauser, Christine, Rennert, Gad, Rennert, Hedy S., Rhenius, Valerie, Rhiem, Kerstin, Richardson, Andrea, Rodriguez, Gustavo C., Romero, Atocha, Romm, Jane, Rookus, Matti A., Rudolph, Anja, Ruediger, Thomas, Saloustros, Emmanouil, Sanders, Joyce, Sandler, Dale P., Sangrajrang, Suleeporn, Sawyer, Elinor J., Schmidt, Daniel F., Schoemaker, Minouk J., Schumacher, Fredrick, Schürmann, Peter, Schwentner, Lukas, Scott, Christopher, Scott, Rodney J., Seal, Sheila, Senter, Leigha, Seynaeve, Caroline, Shah, Mitul, Sharma, Priyanka, Shen, Chen Yang, Sheng, Xin, Shimelis, Hermela, Shrubsole, Martha J., Shu, Xiao Ou, Side, Lucy E., Singer, Christian F., Sohn, Christof, Southey, Melissa C., Spinelli, John J., Spurdle, Amanda B., Stegmaier, Christa, Stoppa-Lyonnet, Dominique, Sukiennicki, Grzegorz, Surowy, Harald, Sutter, Christian, Swerdlow, Anthony, Szabo, Csilla I., Tamimi, Rulla M., Tan, Yen Y., Taylor, Jack A., Tejada, Maria Isabel, Tengström, Maria, Teo, Soo H., Terry, Mary B., Tessier, Daniel C., Teul, Alex E., Thöne, Kathrin, Thull, Darcy L., Tibiletti, Maria Grazia, Tihomirova, Laima, Tischkowitz, Marc, Toland, Amanda E., Tollenaar, Rob A.M., Tomlinson, Ian, Tong, Ling, Torres, Diana, Tranchant, Martine, Truong, Thérèse, Tucker, Kathy, Tung, Nadine, Tyrer, Jonathan, Ulmer, Hans Ulrich, Vachon, Celine, Christi, Van Asperen J., Den Berg, David Van, Ouweland, Ans M.Vanden, Rensburg, Elizabeth J., Varesco, Liliana, Varon-Mateeva, Raymonda, Vega, Ana, Viel, Alessandra, Vijai, Joseph, Vincent, Daniel, Vollenweider, Jason, Walker, Lisa, Wang, Zhaoming, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weinberg, Clarice R., Weitzel, Jeffrey N., Wendt, Camilla, Wesseling, Jelle, Whittemore, Alice S., Wijnen, Juul T., Willett, Walter, Winqvist, Robert, Wolk, Alicja, Wu, Anna H., Xia, Lucy, Yang, Xiaohong R., Yannoukakos, Drakoulis, Zaffaroni, Daniela, Zheng, Wei, Zhu, Bin, Ziogas, Argyrios, Ziv, Elad, Zorn, Kristin K., Gago-Dominguez, Manuela, Mannermaa, Arto, Olsson, Håkan, Teixeira, Manuel R., Stone, Jennifer, Offit, Kenneth, Ottini, Laura, Park, Sue K., Thomassen, Mads, Hall, Per, Meindl, Alfons, Schmutzler, Rita K., Droit, Arnaud, Bader, Gary D., Pharoah, Paul D., Couch, Fergus J., Easton, Douglas F., Kraft, Peter, Chenevix-Trench, Georgia, Garciá-Closas, Montserrat, Schmidt, Marjanka K., Antoniou, Antonis C., Simard, Jacques, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Human Genetics, CCA - Cancer biology and immunology, Epidemiology and Data Science, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, Amsterdam Reproduction & Development (AR&D), Clinical Genetics, Medical Oncology, Internal Medicine, Obstetrics & Gynecology, MUMC+: DA KG Lab Centraal Lab (9), and RS: GROW - R4 - Reproductive and Perinatal Medicine
Subjects: 0301 basic medicine, Oncology, Estrogen receptor, Genome-wide association study, consortium, Gene mutation, DISEASE, Breast cancer, Risk Factors, Receptors, common variants, BRCA2 MUTATION CARRIERS, Medicine and Health Sciences, CONFER SUSCEPTIBILITY, skin and connective tissue diseases, ovarian cancers, BRCA1 Protein, COMMON VARIANTS, Single Nucleotide, OVARIAN CANCERS, 3. Good health, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Receptors, Estrogen, functional variants, Female, estrogen receptor, SNPs, EXPRESSION, medicine.medical_specialty, Heterozygote, SUSCEPTIBILITY LOCI, European Continental Ancestry Group, Breast cancer, estrogen receptor, SNPs, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, White People, Article, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, expression, medicine, Genetic predisposition, Genetics, Journal Article, Humans, Genetic Predisposition to Disease, ddc:610, Risk factor, Polymorphism, GENOME-WIDE ASSOCIATION, FUNCTIONAL VARIANTS, disease, CONSORTIUM, Case-control study, Biology and Life Sciences, medicine.disease, confer susceptibility, Estrogen, susceptibility loci, 030104 developmental biology, Mutation, genome-wide association, brca2 mutation carriers, Genome-Wide Association Study
Abstract: Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease1. 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 BRCA1mutation 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.
Published: 2017

23. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Author: Phelan, Catherine M. Kuchenbaecker, Karoline B. Tyrer, Jonathan P. Kar, Siddhartha P. Lawrenson, Kate Winham, Stacey J. and Dennis, Joe Pirie, Ailith Riggan, Marjorie J. Chornokur, Ganna Earp, Madalene A. Lyra, Jr., Paulo C. Lee, Janet M. and Coetzee, Simon Beesley, Jonathan McGuffog, Lesley Soucy, Penny Dicks, Ed Lee, Andrew Barrowdale, Daniel and Lecarpentier, Julie Leslie, Goska Aalfs, Cora M. Aben, Katja K. H. Adams, Marcia Adlard, Julian Andrulis, Irene L. and Anton-Culver, Hoda Antonenkova, Natalia Aravantinos, Gerasimos and Arnold, Norbert Arun, Banu K. Arver, Brita Azzollini, Jacopo Balmana, Judith Banerjee, Susana N. Barjhoux, Laure and Barkardottir, Rosa B. Bean, Yukie Beckmann, Matthias W. and Beeghly-Fadiel, Alicia Benitez, Javier Bermisheva, Marina and Bernardini, Marcus Q. Birrer, Michael J. Bjorge, Line Black, Amanda Blankstein, Kenneth Blok, Marinus J. Bodelon, Clara and Bogdanova, Natalia Bojesen, Anders Bonanni, Bernardo and Borg, Ake Bradbury, Angela R. Brenton, James D. Brewer, Carole Brinton, Louise Broberg, Per Brooks-Wilson, Angela and Bruinsma, Fiona Brunet, Joan Buecher, Bruno Butzow, Ralf and Buys, Saundra S. Caldes, Trinidad Caligo, Maria A. and Campbell, Ian Cannioto, Rikki Carney, Michael E. Cescon, Terence Chan, Salina B. Chang-Claude, Jenny Chanock, Stephen and Chen, Xiao Qing Chiew, Yoke-Eng Chiquette, Jocelyne and Chung, Wendy K. Claes, Kathleen B. M. Conner, Thomas Cook, Linda S. Cook, Jackie Cramer, Daniel W. Cunningham, Julie M. and D'Aloisio, Aimee A. Daly, Mary B. Damiola, Francesca and Damirovna, Sakaeva Dina Dansonka-Mieszkowska, Agnieszka Dao, Fanny Davidson, Rosemarie DeFazio, Anna Delnatte, Capucine and Doheny, Kimberly F. Diez, Orland Ding, Yuan Chun and Doherty, Jennifer Anne Domchek, Susan M. Dorfling, Cecilia M. and Dork, Thilo Dossus, Laure Duran, Mercedes Durst, Matthias Dworniczak, Bernd Eccles, Diana Edwards, Todd and Eeles, Ros Eilber, Ursula Ejlertsen, Bent Ekici, Arif B. and Ellis, Steve Elvira, Mingajeva Eng, Kevin H. Engel, Christoph Evans, D. Gareth Fasching, Peter A. Ferguson, Sarah Ferrer, Sandra Fert Flanagan, James M. Fogarty, Zachary C. Fortner, Renee T. Fostira, Florentia Foulkes, William D. Fountzilas, George Fridley, Brooke L. Friebel, Tara M. Friedman, Eitan Frost, Debra Ganz, Patricia A. and Garber, Judy Garcia, Maria J. Garcia-Barberan, Vanesa and Gehrig, Andrea Gentry-Maharaj, Aleksandra Gerdes, Anne-Marie and Giles, Graham G. Glasspool, Rosalind Glendon, Gord Godwin, Andrew K. Goldgar, David E. Goranova, Teodora Gore, Martin and Greene, Mark H. Gronwald, Jacek Gruber, Stephen Hahnen, Eric Haiman, Christopher A. Hakansson, Niclas Hamann, Ute and Hansen, Thomas V. O. Harrington, Patricia A. Harris, Holly R. Hauke, Jan Hein, Alexander Henderson, Alex and Hildebrandt, Michelle A. T. Hillemanns, Peter Hodgson, Shirley and Hogdall, Claus K. Hogdall, Estrid Hogervorst, Frans B. L. and Holland, Helene Hooning, Maartje J. Hosking, Karen and Huang, Ruea-Yea Hulick, Peter J. Hung, Jillian Hunter, David J. Huntsman, David G. Huzarski, Tomasz Imyanitov, Evgeny N. and Isaacs, Claudine Iversen, Edwin S. Izatt, Louise and Izquierdo, Angel Jakubowska, Anna James, Paul Janavicius, Ramunas Jernetz, Mats Jensen, Allan Jensen, Uffe Birk and John, Esther M. Johnatty, Sharon Jones, Michael E. Kannisto, Paivi Karlan, Beth Y. Karnezis, Anthony Kast, Karin and Kennedy, Catherine J. Khusnutdinova, Elza Kiemeney, Lambertus A. and Kiiski, Johanna I. Kim, Sung-Won Kjaer, Susanne K. and Kobel, Martin Kopperud, Reidun K. Kruse, Torben A. and Kupryjanczyk, Jolanta Kwong, Ava Laitman, Yael Lambrechts, Diether Larranaga, Nerea Larson, Melissa C. Lazaro, Conxi and Le, Nhu D. Le Marchand, Loic Lee, Jong Won Lele, Shashikant B. Leminen, Arto Leroux, Dominique Lester, Jenny and Lesueur, Fabienne Levine, Douglas A. Liang, Dong and Liebrich, Clemens Lilyquist, Jenna Lipworth, Loren and Lissowska, Jolanta Lu, Karen H. Lubinski, Jan Luccarini, Craig Lundvall, Lene Mai, Phuong L. Mendoza-Fandino, Gustavo and Manoukian, Siranoush Massuger, Leon F. A. G. May, Taymaa and Mazoyer, Sylvie McAlpine, Jessica N. McGuire, Valerie and McLaughlin, John R. McNeish, Iain Meijers-Heijboer, Hanne and Meindl, Alfons Menon, Usha Mensenkamp, Arjen R. Merritt, Melissa A. Milne, Roger L. Mitchell, Gillian Modugno, Francesmary Moes-Sosnowska, Joanna Moffitt, Melissa and Montagna, Marco Moysich, Kirsten B. Mulligan, Anna Marie and Musinsky, Jacob Nathanson, Katherine L. Nedergaard, Lotte and Ness, Roberta B. Neuhausen, Susan L. Nevanlinna, Heli and Niederacher, Dieter Nussbaum, Robert L. Odunsi, Kunle Olah, Edith Olopade, Olufunmilayo I. Olsson, Hakan Olswold, Curtis and O'Malley, David M. Ong, Kai-ren Onland-Moret, N. Charlotte and Orr, Nicholas Orsulic, Sandra Osorio, Ana Palli, Domenico Papi, Laura Park-Simon, Tjoung-Won Paul, James and Pearce, Celeste L. Pedersen, Inge Sokilde Peeters, Petra H. M. and Peissel, Bernard Peixoto, Ana Pejovic, Tanja Pelttari, Liisa M. Permuth, Jennifer B. Peterlongo, Paolo Pezzani, Lidia Pfeiler, Georg Phillips, Kelly-Anne Piedmonte, Marion and Pike, Malcolm C. Piskorz, Anna M. Poblete, Samantha R. and Pocza, Timea Poole, Elizabeth M. Poppe, Bruce Porteous, Mary E. Prieur, Fabienne Prokofyeva, Darya Pugh, Elizabeth and Pujana, Miquel Angel Pujol, Pascal Radice, Paolo Rantala, Johanna Rappaport-Fuerhauser, Christine Rennert, Gad Rhiem, Kerstin Rice, Patricia Richardson, Andrea Robson, Mark and Rodriguez, Gustavo C. Rodriguez-Antona, Cristina Romm, Jane and Rookus, Matti A. Rossing, Mary Anne Rothstein, Joseph H. and Rudolph, Anja Runnebaum, Ingo B. Salvesen, Helga B. Sandler, Dale P. Schoemaker, Minouk J. Senter, Leigha Setiawan, V. Wendy Severi, Gianluca Sharma, Priyanka Shelford, Tameka and Siddiqui, Nadeem Side, Lucy E. Sieh, Weiva Singer, Christian F. Sobol, Hagay Song, Honglin Southey, Melissa C. and Spurdle, Amanda B. Stadler, Zsofia Steinemann, Doris and Stoppa-Lyonnet, Dominique Sucheston-Campbell, Lara E. and Sukiennicki, Grzegorz Sutphen, Rebecca Sutter, Christian and Swerdlow, Anthony J. Szabo, Csilla I. Szafron, Lukasz Tan, Yen Y. Taylor, Jack A. Tea, Muy-Kheng Teixeira, Manuel R. and Teo, Soo-Hwang Terry, Kathryn L. Thompson, Pamela J. and Thomsen, Liv Cecilie Vestrheim Thull, Darcy L. Tihomirova, Laima and Tinker, Anna V. Tischkowitz, Marc Tognazzo, Silvia and Toland, Amanda Ewart Tone, Alicia Trabert, Britton Travis, Ruth C. Trichopoulou, Antonia Tung, Nadine Tworoger, Shelley S. Van Altena, Anne M. Van den Berg, David van der Hout, Annemarie H. van der Luijt, Rob B. Van Heetvelde, Mattias and Van Nieuwenhuysen, Els Van Rensburg, Elizabeth J. and Vanderstichele, Adriaan Varon-Mateeva, Raymonda Vega, Ana and Edwards, Digna Velez Vergote, Ignace Vierkant, Robert A. and Vijai, Joseph Vratimos, Athanassios Walker, Lisa Walsh, Christine Wand, Dorothea Wang-Gohrke, Shan Wappenschmidt, Barbara Webb, Penelope M. Weinberg, Clarice R. Weitzel, Jeffrey N. Wentzensen, Nicolas Whittemore, Alice S. Wijnen, Juul T. Wilkens, Lynne R. Wolk, Alicja Woo, Michelle Wu, Xifeng Wu, Anna H. Yang, Hannah Yannoukakos, Drakoulis and Ziogas, Argyrios Zorn, Kristin K. Narod, Steven A. Easton, Douglas F. Amos, Christopher I. Schildkraut, Joellen M. and Ramus, Susan J. Ottini, Laura Goodman, Marc T. Park-, Sue K. and Kelemen, Linda E. Risch, Harvey A. Thomassen, Mads and Offit, Kenneth Simard, Jacques Schmutzler, Rita Katharina and Hazelett, Dennis Monteiro, Alvaro N. Couch, Fergus J. and Berchuck, Andrew Chenevix-Trench, Georgia Goode, Ellen L. and Sellers, Thomas A. Gayther, Simon A. Antoniou, Antonis C. and Pharoah, Paul D. P. AOCS Study Grp EMEMBRACE Study GEMO Study Collaborators HEBON Study KConFab Investigators OPAL Study Grp
Subjects: endocrine system diseases, female genital diseases and pregnancy complications
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.
Published: 2017

24. Risk Prediction for Epithelial Ovarian Cancer in 11 United States-Based Case-Control Studies: Incorporation of Epidemiologic Risk Factors and 17 Confirmed Genetic Loci

Author: Clyde, Merlise A, Palmieri Weber, Rachel, Iversen, Edwin S, Poole, Elizabeth M, Doherty, Jennifer A, Goodman, Marc T, Ness, Roberta B, Risch, Harvey A, Rossing, Mary Anne, Terry, Kathryn L, Wentzensen, Nicolas, Whittemore, Alice S, Anton-Culver, Hoda, Bandera, Elisa V, Berchuck, Andrew, Carney, Michael E, Cramer, Daniel W, Cunningham, Julie M, Cushing-Haugen, Kara L, Edwards, Robert P, Fridley, Brooke L, Goode, Ellen L, Lurie, Galina, McGuire, Valerie, Modugno, Francesmary, Moysich, Kirsten B, Olson, Sara H, Pearce, Celeste Leigh, Pike, Malcolm C, Rothstein, Joseph H, Sellers, Thomas A, Sieh, Weiva, Stram, Daniel, Thompson, Pamela J, Vierkant, Robert A, Wicklund, Kristine G, Wu, Anna H, Ziogas, Argyrios, Tworoger, Shelley S, Schildkraut, Joellen M, and on behalf of the Ovarian Cancer Association Consortium
Subjects: Ovarian Neoplasms, Adult, model evaluation, genetic risk polymorphisms, Epidemiology, Middle Aged, Carcinoma, Ovarian Epithelial, Risk Assessment, Polymorphism, Single Nucleotide, Medical and Health Sciences, United States, Mathematical Sciences, Logistic Models, ovarian cancer, risk model, Risk Factors, Genetic Loci, Area Under Curve, Case-Control Studies, Humans, Genetic Predisposition to Disease, Female, Neoplasms, Glandular and Epithelial, on behalf of the Ovarian Cancer Association Consortium, Aged
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.
Published: 2016

25. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author: Kar, Siddhartha P, Beesley, Jonathan, Amin Al Olama, Ali, Michailidou, Kyriaki, Tyrer, Jonathan, Kote-Jarai, ZSofia, Lawrenson, Kate, Lindstrom, Sara, Ramus, Susan J, Thompson, Deborah J, ABCTB Investigators, Kibel, Adam S, Dansonka-Mieszkowska, Agnieszka, Michael, Agnieszka, Dieffenbach, Aida K, Gentry-Maharaj, Aleksandra, Whittemore, Alice S, Wolk, Alicja, Monteiro, Alvaro, Peixoto, Ana, Kierzek, Andrzej, Cox, Angela, Rudolph, Anja, Gonzalez-Neira, Anna, Wu, Anna H, Lindblom, Annika, Swerdlow, Anthony, AOCS Study Group & Australian Cancer Study (Ovarian Cancer), APCB BioResource, Ziogas, Argyrios, Ekici, Arif B, Burwinkel, Barbara, Karlan, Beth Y, Nordestgaard, Børge G, Blomqvist, Carl, Phelan, Catherine, McLean, Catriona, Pearce, Celeste Leigh, Vachon, Celine, Cybulski, Cezary, Slavov, Chavdar, Stegmaier, Christa, Maier, Christiane, Ambrosone, Christine B, Høgdall, Claus K, Teerlink, Craig C, Kang, Daehee, Tessier, Daniel C, Schaid, Daniel J, Stram, Daniel O, Cramer, Daniel W, Neal, David E, Eccles, Diana, Flesch-Janys, Dieter, Edwards, Digna R Velez, Wokozorczyk, Dominika, Levine, Douglas A, Yannoukakos, Drakoulis, Sawyer, Elinor J, Bandera, Elisa V, Poole, Elizabeth M, Goode, Ellen L, Khusnutdinova, Elza, Høgdall, Estrid, Song, Fengju, Bruinsma, Fiona, Heitz, Florian, Modugno, Francesmary, Hamdy, Freddie C, Wiklund, Fredrik, Giles, Graham G, Olsson, Håkan, Wildiers, Hans, Ulmer, Hans-Ulrich, Pandha, Hardev, Risch, Harvey A, Darabi, Hatef, Salvesen, Helga B, Nevanlinna, Heli, Gronberg, Henrik, Brenner, Hermann, Brauch, Hiltrud, Anton-Culver, Hoda, Song, Honglin, Lim, Hui-Yi, McNeish, Iain, Campbell, Ian, Vergote, Ignace, Gronwald, Jacek, Lubiński, Jan, Stanford, Janet L, Benítez, Javier, Doherty, Jennifer A, Permuth, Jennifer B, Chang-Claude, Jenny, Donovan, Jenny L, Dennis, Joe, Schildkraut, Joellen M, Schleutker, Johanna, and Hopper, John L
Subjects: AOCS Study Group & Australian Cancer Study, Male, Urologic Diseases, Aging, Enhancer Elements, Quantitative Trait Loci, Oncology and Carcinogenesis, ABCTB Investigators, Datasets as Topic, Breast Neoplasms, NBCS Investigators, APCB BioResource, PRACTICAL consortium, Rare Diseases, Meta-Analysis as Topic, Genetic, Breast Cancer, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Gene Regulatory Networks, Aetiology, Polymorphism, Cancer, Ovarian Neoplasms, Prostate Cancer, Human Genome, Prostatic Neoplasms, Chromosome Mapping, Single Nucleotide, Ovarian Cancer, Organ Specificity, Genetic Loci, Case-Control Studies, kConFab Investigators, Female, GENICA Network, Signal Transduction, Genome-Wide Association Study
Abstract: UnlabelledBreast, 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.SignificanceWe 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.
Published: 2016

26. Assessment of Multifactor Gene-Environment Interactions and Ovarian Cancer Risk: Candidate Genes, Obesity, and Hormone-Related Risk Factors

Author: Usset, Joseph L, Raghavan, Rama, Tyrer, Jonathan P, McGuire, Valerie, Sieh, Weiva, Webb, Penelope, Chang-Claude, Jenny, Rudolph, Anja, Anton-Culver, Hoda, Berchuck, Andrew, Brinton, Louise, Cunningham, Julie M, DeFazio, Anna, Doherty, Jennifer A, Edwards, Robert P, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Goodman, Marc T, Høgdall, Estrid, Jensen, Allan, Johnatty, Sharon E, Kiemeney, Lambertus A, Kjaer, Susanne K, Larson, Melissa C, Lurie, Galina, Massuger, Leon, Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Pike, Malcolm C, Ramus, Susan J, Rossing, Mary Anne, Rothstein, Joseph, Song, Honglin, Thompson, Pamela J, van den Berg, David J, Vierkant, Robert A, Wang-Gohrke, Shan, Wentzensen, Nicolas, Whittemore, Alice S, Wilkens, Lynne R, Wu, Anna H, Yang, Hannah, Pearce, Celeste Leigh, Schildkraut, Joellen M, Pharoah, Paul, Goode, Ellen L, Fridley, Brooke L, and Ovarian Cancer Association Consortium and the Australian Cancer Study
Subjects: Ovarian Neoplasms, Epidemiology, Prevention, Contraception/Reproduction, Single Nucleotide, Middle Aged, Estrogen, Medical and Health Sciences, Ovarian Cancer, Rare Diseases, Risk Factors, Clinical Research, Genetics, Ovarian Cancer Association Consortium and the Australian Cancer Study, Humans, 2.1 Biological and endogenous factors, Female, Gene-Environment Interaction, Obesity, Polymorphism, Aetiology, Cancer, Nutrition
Abstract: BackgroundMany 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.MethodsWe 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.ResultsSNPs 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)).ConclusionsWe 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.ImpactAssessment 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.
Published: 2016

27. The association between socioeconomic status and tumour stage at diagnosis of ovarian cancer: A pooled analysis of 18 case-control studies

Author: Præstegaard, Camilla, Kjaer, Susanne K, Nielsen, Thor SS, Jensen, Signe M, Webb, Penelope M, Nagle, Christina M, Høgdall, Estrid, Risch, Harvey A, Rossing, Mary Anne, Doherty, Jennifer A, Wicklund, Kristine G, Goodman, Marc T, Modugno, Francesmary, Moysich, Kirsten, Ness, Roberta B, Edwards, Robert P, Goode, Ellen L, Winham, Stacey J, Fridley, Brooke L, Cramer, Daniel W, Terry, Kathryn L, Schildkraut, Joellen M, Berchuck, Andrew, Bandera, Elisa V, Paddock, Lisa, Kiemeney, Lambertus A, Massuger, Leon F, Wentzensen, Nicolas, Pharoah, Paul, Song, Honglin, Whittemore, Alice S, McGuire, Valerie, Sieh, Weiva, Rothstein, Joseph, Anton-Culver, Hoda, Ziogas, Argyrios, Menon, Usha, Gayther, Simon A, Ramus, Susan J, Gentry-Maharaj, Aleksandra, Wu, Anna H, Pearce, Celeste L, Pike, Malcolm C, Lee, Alice W, Chang-Claude, Jenny, Jensen, Allan, and Ovarian Cancer Association Consortium
Subjects: Ovarian Neoplasms, Delayed Diagnosis, Epidemiology, Ovarian Cancer Association Consortium, Oncology and Carcinogenesis, Middle Aged, Carcinoma, Ovarian Epithelial, Pooled analysis, Tumour stage, Logistic Models, Social Class, Ovarian cancer, Case-Control Studies, Socioeconomic status, Odds Ratio, Public Health and Health Services, Humans, Female, Neoplasms, Glandular and Epithelial, Oncology & Carcinogenesis, Aged
Abstract: PURPOSE: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. METHODS: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. RESULTS: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. CONCLUSION: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.
Published: 2016

28. PPM1D Mosaic Truncating Variants in Ovarian Cancer Cases May Be Treatment-Related Somatic Mutations

Author: Pharoah, Paul DP, Song, Honglin, Dicks, Ed, Intermaggio, Maria P, Harrington, Patricia, Baynes, Caroline, Alsop, Kathryn, Australian Ovarian Cancer Study Group, Bogdanova, Natalia, Cicek, Mine S, Cunningham, Julie M, Fridley, Brooke L, Gentry-Maharaj, Aleksandra, Hillemanns, Peter, Lele, Shashi, Lester, Jenny, McGuire, Valerie, Moysich, Kirsten B, Poblete, Samantha, Sieh, Weiva, Sucheston-Campbell, Lara, Widschwendter, Martin, Ovarian Cancer Association Consortium, Whittemore, Alice S, Dörk, Thilo, Menon, Usha, Odunsi, Kunle, Goode, Ellen L, Karlan, Beth Y, Bowtell, David D, Gayther, Simon A, and Ramus, Susan J
Subjects: Australian Ovarian Cancer Study Group, Adult, Ovarian Cancer Association Consortium, Oncology and Carcinogenesis, Antineoplastic Agents, Polymerase Chain Reaction, Rare Diseases, Gene Frequency, Clinical Research, Genetics, Phosphoprotein Phosphatases, 2.1 Biological and endogenous factors, Humans, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Aetiology, Cancer, Aged, Ovarian Neoplasms, Mosaicism, Human Genome, High-Throughput Nucleotide Sequencing, Middle Aged, Ovarian Cancer, Protein Phosphatase 2C, Case-Control Studies, Mutation, Female
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.
Published: 2016

29. Cross-cancer genome-wide analysis of lung, ovary, breast, prostate and colorectal cancer reveals novel pleiotropic associations

Author: Fehringer, Gordon, Kraft, Peter, Pharoah, Paul D, Eeles, Rosalind A, Chatterjee, Nilanjan, Schumacher, Fredrick R, Schildkraut, Joellen M, Lindstrom, Sara, Brennan, Paul, Bickeboller, Heike, Houlston, Richard S, Landi, Maria Teresa, Caporaso, Neil, Risch, Angela, Al Olama, Ali Amin, Berndt, Sonja I, Giovannucci, Edward L, Gronberg, Henrik, Kote-Jarai, Zsofia, Ma, Jing, Muir, Kenneth, Stampfer, Meir J, Stevens, Victoria L, Wiklund, Fredrik, Willett, Walter C, Goode, Ellen L, Permuth, Jennifer B, Risch, Harvey A, Reid, Brett M, Bezieau, Stephane, Brenner, Hermann, Chan, Andrew T, Chang-Claude, Jenny, Hudson, Thomas J, Kocarnik, Jonathan K, Newcomb, Polly A, Schoen, Robert E, Slattery, Martha L, White, Emily, Adank, Muriel A, Ahsan, Habibul, Aittomaki, Kristiina, Baglietto, Laura, Blomquist, Carl, Canzian, Federico, Czene, Kamila, dos-Santos-Silva, Isabel, Eliassen, A Heather, Figueroa, Jonine D, Flesch-Janys, Dieter, Fletcher, Olivia, Garcia-Closas, Montserrat, Gaudet, Mia M, Johnson, Nichola, Hall, Per, Hazra, Aditi, Hein, Rebecca, Hofman, Albert, Hopper, John L, Irwanto, Astrid, Johansson, Mattias, Kaaks, Rudolf, Kibriya, Muhammad G, Lichtner, Peter, Liu, Jianjun, Lund, Eiliv, Makalic, Enes, Meindl, Alfons, Muller-Myhsok, Bertram, Muranen, Taru A, Nevanlinna, Heli, Peeters, Petra H, Peto, Julian, Prentice, Ross L, Rahman, Nazneen, Sanchez, Maria Jose, Schmidt, Daniel F, Schmutzler, Rita K, Southey, Melissa C, Tamimi, Rulla, Travis, Ruth C, Turnbull, Clare, Uitterlinden, Andre G, Wang, Zhaoming, Whittemore, Alice S, Yang, Xiaohong R, Zheng, Wei, Buchanan, Daniel D, Casey, Graham, Conti, David V, Edlund, Christopher K, Gallinger, Steven, Haile, Robert W, Jenkins, Mark, Le Marchand, Loic, Li, Li, Lindor, Noralene M, Schmit, Stephanie L, Thibodeau, Stephen N, Woods, Michael O, Rafnar, Thorunn, Gudmundsson, Julius, Stacey, Simon N, Stefansson, Kari, Sulem, Patrick, Chen, Y Ann, Tyrer, Jonathan P, Christiani, David C, Wei, Yongyue, Shen, Hongbing, Hu, Zhibin, Shu, Xiao-Ou, Shiraishi, Kouya, Takahashi, Atsushi, Bosse, Yohan, Obeidat, Ma'en, Nickle, David, Timens, Wim, Freedman, Matthew L, Li, Qiyuan, Seminara, Daniela, Chanock, Stephen J, Gong, Jian, Peters, Ulrike, Gruber, Stephen B, Amos, Christopher I, Sellers, Thomas A, Easton, Douglas F, Hunter, David J, Haiman, Christopher A, Henderson, Brian E, Hung, Rayjean J, OCAC, Consortium, PRACTICAL, Res, Hereditary Breast Ovarian Canc, Transdisciplinary, Colorectal, Canc, African Amer Breast, Canc, African Ancestry Prostate, Medical Oncology, Epidemiology, Internal Medicine, Surgery, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Groningen Research Institute for Asthma and COPD (GRIAC)
Subjects: 0301 basic medicine, Oncology, Male, medicine.medical_specialty, Cancer Research, Lung Neoplasms, SUSCEPTIBILITY LOCI, Genotype, IDENTIFIES 2, Colorectal cancer, Locus (genetics), Genome-wide association study, Breast Neoplasms, Article, 03 medical and health sciences, Prostate cancer, AFRICAN ANCESTRY, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Journal Article, AGGRESSIVE PROSTATE, Humans, GENETIC POLYMORPHISMS, Lung cancer, METAANALYSIS, Ovarian Neoplasms, business.industry, COMMON VARIANTS, Prostatic Neoplasms, CELL CARCINOMA, medicine.disease, RISK LOCI, 3. Good health, 030104 developmental biology, Expression quantitative trait loci, Adenocarcinoma, Female, business, Colorectal Neoplasms, GASTRIC-CANCER, Genome-Wide Association Study
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.
Published: 2016

30. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Author: Hampras, Shalaka S., Sucheston-Campbell, Lara E., Cannioto, Rikki, Chang-Claude, Jenny, Modugno, Francesmary, Dörk, Thilo, Hillemanns, Peter, Preus, Leah, Knutson, Keith L., Wallace, Paul K., Hong, Chi-Chen, Friel, Grace, Davis, Warren, Nesline, Mary, Pearce, Celeste L., Kelemen, Linda E., Goodman, Marc T., Bandera, Elisa V., Terry, Kathryn L., Schoof, Nils, Eng, Kevin H., Clay, Alyssa, Singh, Prashant K., Joseph, Janine M., Aben, Katja K.H., Anton-Culver, Hoda, Antonenkova, Natalia, Baker, Helen, Bean, Yukie, Beckmann, Matthias W., Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A., Brooks-Wilson, Angela, Bruinsma, Fiona, Butzow, Ralf, Campbell, Ian G., Carty, Karen, Cook, Linda S., Cramer, Daniel W., Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Dennis, Joe, Despierre, Evelyn, Dicks, Ed, Doherty, Jennifer A., du Bois, Andreas, Dürst, Matthias, Easton, Doug, Eccles, Diana, Edwards, Robert P., Ekici, Arif B., Fasching, Peter A., Fridley, Brooke L., Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G., Glasspool, Rosalind, Gronwald, Jacek, Harrington, Patricia, Harter, Philipp, Hasmad, Hanis Nazihah, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle A.T., Hogdall, Claus, Hogdall, Estrid, Hosono, Satoyo, Iversen, Edwin S., Jakubowska, Anna, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y., Kellar, Melissa, Kelley, Joseph L., Kiemeney, Lambertus A., Klapdor, Rüdiger, Kolomeyevskaya, Nonna, Krakstad, Camilla, Kjaer, Susanne K., Kruszka, Bridget, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D., Lee, Alice W., Lele, Shashikant, Leminen, Arto, Lester, Jenny, Levine, Douglas A., Liang, Dong, Lissowska, Jolanta, Liu, Song, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon F.A.G., Matsuo, Keitaro, McGuire, Valeria, McLaughlin, John R., Mcneish, Iain, Menon, Usha, Moes-Sosnowska, Joanna, Narod, Steven A., Nedergaard, Lotte, Nevalinna, Heli, Nickels, Stefan, Nevanlinna, Heli, Olson, Sara H., Orlow, Irene, Weber, Rachel Palmieri, Paul, James, Pejovic, Tanja, Pelttari, Liisa M., Perkins, Barbara, Permuth-Wey, Jenny, Pike, Malcolm C., Plisiecka-Halasa, Joanna, Poole, Elizabeth M., Risch, Harvey A., Rossing, Mary Anne, Rothstein, Joseph H., Rudolph, Anja, Runnebaum, Ingo B., Rzepecka, Iwona K., Salvesen, Helga B., Schernhammer, Eva, Schmitt, Kristina, Schwaab, Ira, Shu, Xiao-Ou, Shvetsov, Yurii B., Siddiqui, Nadeem, Sieh, Weiva, Song, Honglin, Southey, Melissa C., Tangen, Ingvild L., Teo, Soo-Hwang, Thompson, Pamela J., Timorek, Agnieszka, Tsai, Ya-Yu, Tworoger, Shelley S., Tyrer, Jonathan, van Altena, Anna M., Vergote, Ignace, Vierkant, Robert A., Walsh, Christine, Wang-Gohrke, Shan, Wentzensen, Nicolas, Whittemore, Alice S., Wicklund, Kristine G., Wilkens, Lynne R., Wu, Anna H., Wu, Xifeng, Woo, Yin-Ling, Yang, Hannah, Zheng, Wei, Ziogas, Argyrios, Gayther, Simon A., Ramus, Susan J., Sellers, Thomas A., Schildkraut, Joellen M., Phelan, Catherine M., Berchuck, Andrew, Chenevix-Trench, Georgia, Cunningham, Julie M., Pharoah, Paul P., Ness, Roberta B., Odunsi, Kunle, Goode, Ellen L., and Moysich, Kirsten B.
Subjects: endocrine system diseases, female genital diseases and pregnancy complications
Abstract: Background: 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.\ud Methods: 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.\ud Results: 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).\ud Conclusions: 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.
Published: 2016

31. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

Author: Lawrenson, Kate, Kar, Siddhartha, McCue, Karen, Kuchenbaeker, Karoline, Michailidou, Kyriaki, Tyrer, Jonathan, Beesley, Jonathan, Ramus, Susan J., Li, Qiyuan, Delgado, Melissa K., Lee, Janet M., Aittomäki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Arun, Banu K., Arver, Brita, Bandera, Elisa V., Barile, Monica, Barkardottir, Rosa B., Barrowdale, Daniel, Beckmann, Matthias W., Benitez, Javier, Berchuck, Andrew, Bisogna, Maria, Bjorge, Line, Blomqvist, Carl, Blot, William, Bogdanova, Natalia, Bojesen, Anders, Bojesen, Stig E., Bolla, Manjeet K., Bonanni, Bernardo, Børresen-Dale, Anne Lise, Brauch, Hiltrud, Brennan, Paul, Brenner, Hermann, Bruinsma, Fiona, Brunet, Joan, Buhari, Shaik Ahmad, Burwinkel, Barbara, Butzow, Ralf, Buys, Saundra S., Cai, Qiuyin, Caldes, Trinidad, Campbell, Ian, Canniotto, Rikki, Chang-Claude, Jenny, Chiquette, Jocelyne, Choi, Ji Yeob, Claes, Kathleen B M, Cook, Linda S., Cox, Angela, Cramer, Daniel W., Cross, Simon S., Cybulski, Cezary, Czene, Kamila, Daly, Mary B., Damiola, Francesca, Dansonka-Mieszkowska, Agnieszka, Darabi, Hatef, Dennis, Joe, Devilee, Peter, Diez, Orland, Doherty, Jennifer A., Domchek, Susan M., Dorfling, Cecilia M., Dörk, Thilo, Dumont, Martine, Ehrencrona, Hans, Ejlertsen, Bent, Ellis, Steve, Engel, Christoph, Lee, Eunjung, Evans, D. Gareth, Fasching, Peter A., Feliubadalo, Lidia, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Foretova, Lenka, Fostira, Florentia, Foulkes, William D., Fridley, Brooke L., Friedman, Eitan, Frost, Debra, Gambino, Gaetana, Ganz, Patricia A., Garber, Judy, García-Closas, Montserrat, Gentry-Maharaj, Aleksandra, Ghoussaini, Maya, Giles, Graham G., Glasspool, Rosalind, Godwin, Andrew K., Goldberg, Mark S., Goldgar, David E., González-Neira, Anna, Goode, Ellen L., Goodman, Marc T., Greene, Mark H., Gronwald, Jacek, Guénel, Pascal, Haiman, Christopher A., Hall, Per, Hallberg, Emily, Hamann, Ute, Hansen, Thomas V O, Harrington, Patricia A., Hartman, Mikael, Hassan, Norhashimah, Healey, Sue, Heitz, Florian, Herzog, Josef, Høgdall, Estrid, Høgdall, Claus K., Hogervorst, Frans B L, Hollestelle, Antoinette, Hopper, John L., Hulick, Peter J., Huzarski, Tomasz, Imyanitov, Evgeny N., Isaacs, Claudine, Ito, Hidemi, Jakubowska, Anna, Janavicius, Ramunas, Jensen, Allan, John, Esther M., Johnson, Nichola, Kabisch, Maria, Kang, Daehee, Kapuscinski, Miroslav, Karlan, Beth Y., Khan, Sofia, Kiemeney, Lambertus A., Kjaer, Susanne Kruger, Knight, Julia A., Konstantopoulou, Irene, Kosma, Veli Matti, Kristensen, Vessela, Kupryjanczyk, Jolanta, Kwong, Ava, De La Hoya, Miguel, Laitman, Yael, Lambrechts, Diether, Le, Nhu, De Leeneer, Kim, Lester, Jenny, Levine, Douglas A., Li, Jingmei, Lindblom, Annika, Long, Jirong, Lophatananon, Artitaya, Loud, Jennifer T., Lu, Karen, Lubinski, Jan, Mannermaa, Arto, Manoukian, Siranoush, Le Marchand, Loic, Margolin, Sara, Marme, Frederik, Massuger, Leon F A G, Matsuo, Keitaro, Mazoyer, Sylvie, McGuffog, Lesley, McLean, Catriona, McNeish, Iain, Meindl, Alfons, Menon, Usha, Mensenkamp, Arjen R., Milne, Roger L., Montagna, Marco, Moysich, Kirsten B., Muir, Kenneth, Mulligan, Anna Marie, Nathanson, Katherine L., Ness, Roberta B., Neuhausen, Susan L., Nevanlinna, Heli, Nord, Silje, Nussbaum, Robert L., Odunsi, Kunle, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Olson, Janet E., Olswold, Curtis, O'Malley, David, Orlow, Irene, Orr, Nick, Osorio, Ana, Park, Sue Kyung, Pearce, Celeste L., Pejovic, Tanja, Peterlongo, Paolo, Pfeiler, Georg, Phelan, Catherine M., Poole, Elizabeth M., Pylkäs, Katri, Radice, Paolo, Rantala, Johanna, Rashid, Muhammad Usman, Rennert, Gad, Rhenius, Valerie, Rhiem, Kerstin, Risch, Harvey A., Rodriguez, Gus, Rossing, Mary Anne, Rudolph, Anja, Salvesen, Helga B., Sangrajrang, Suleeporn, Sawyer, Elinor J., Schildkraut, Joellen M., Schmidt, Marjanka K., Schmutzler, Rita K., Sellers, Thomas A., Seynaeve, Caroline, Shah, Mitul, Shen, Chen Yang, Shu, Xiao Ou, Sieh, Weiva, Singer, Christian F., Sinilnikova, Olga M., Slager, Susan, Song, Honglin, Soucy, Penny, Southey, Melissa C., Stenmark-Askmalm, Marie, Stoppa-Lyonnet, Dominique, Sutter, Christian, Swerdlow, Anthony, Tchatchou, Sandrine, Teixeira, Manuel R., Teo, Soo H., Terry, Kathryn L., Terry, Mary Beth, Thomassen, Mads, Tibiletti, Maria Grazia, Tihomirova, Laima, Tognazzo, Silvia, Toland, Amanda Ewart, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Tseng, Chiu Chen, Tung, Nadine, Tworoger, Shelley S., Vachon, Celine, Van Den Ouweland, Ans M W, Van Doorn, Helena C., Van Rensburg, Elizabeth J., Van't Veer, Laura J., Vanderstichele, Adriaan, Vergote, Ignace, Vijai, Joseph, Wang, Qin, Wang-Gohrke, Shan, Weitzel, Jeffrey N., Wentzensen, Nicolas, Whittemore, Alice S., Wildiers, Hans, Winqvist, Robert, Wu, Anna H., Yannoukakos, Drakoulis, Yoon, Sook Yee, Yu, Jyh Cherng, Zheng, Wei, Zheng, Ying, Khanna, Kum Kum, Simard, Jacques, Monteiro, Alvaro N., French, Juliet D., Couch, Fergus J., Freedman, Matthew L., Easton, Douglas F., Dunning, Alison M., Pharoah, Paul D., Edwards, Stacey L., Chenevix-Trench, Georgia, Antoniou, Antonis C., Gayther, Simon A., Bowtell, David, DeFazio, Anna, Webb, Penny, Collonge-Rame, Marie Agnès, Damette, Alexandre, Barouk-Simonet, Emmanuelle, Bonnet, Françoise, Bubien, Virginie, Sevenet, Nicolas, Longy, Michel, Berthet, Pascaline, Vaur, Dominique, Castera, Laurent, Ferrer, Sandra Fert, Bignon, Yves Jean, Uhrhammer, Nancy, Coron, Fanny, Faivre, Laurence, Baurand, Amandine, Jacquot, Caroline, Bertolone, Geoffrey, Lizard, Sarab, Leroux, Dominique, Dreyfus, Hélène, Rebischung, Christine, Peysselon, Magalie, Peyrat, Jean Philippe, Fournier, Joëlle, Révillion, Françoise, Adenis, Claude, Vénat-Bouvet, Laurence, Léone, Mélanie, Boutry-Kryza, Nadia, Calender, Alain, Giraud, Sophie, Verny-Pierre, Carole, Lasset, Christine, Bonadona, Valérie, Barjhoux, Laure, Sobol, Hagay, Bourdon, Violaine, Noguchi, Tetsuro, Remenieras, Audrey, Coupier, Isabelle, Pujol, Pascal, Sokolowska, Johanna, Bronner, Myriam, Delnatte, Capucine, Bézieau, Stéphane, Mari, Véronique, Gauthier-Villars, Marion, Buecher, Bruno, Rouleau, Etienne, Golmard, Lisa, Moncoutier, Virginie, Belotti, Muriel, De Pauw, Antoine, Elan, Camille, Fourme, Emmanuelle, Birot, Anne Marie, Saule, Claire, Laurent, Maïté, Houdayer, Claude, Lesueur, Fabienne, Mebirouk, Noura, Coulet, Florence, Colas, Chrystelle, Soubrier, Florent, Warcoin, Mathilde, Prieur, Fabienne, Lebrun, Marine, Kientz, Caroline, Muller, Danièle, Fricker, Jean Pierre, Toulas, Christine, Guimbaud, Rosine, Gladieff, Laurence, Feillel, Viviane, Mortemousque, Isabelle, Bressac-De-Paillerets, Brigitte, Caron, Olivier, Guillaud-Bataille, Marine, Gregory, Helen, Miedzybrodzka, Zosia, Morrison, Patrick J., Donaldson, Alan, Rogers, Mark T., Kennedy, M. John, Porteous, Mary E., Brady, Angela, Barwell, Julian, Foo, Claire, Lalloo, Fiona, Side, Lucy E., Eason, Jacqueline, Henderson, Alex, Walker, Lisa, Cook, Jackie, Snape, Katie, Murray, Alex, McCann, Emma, Rookus, M. A., Van Leeuwen, F. E., Van Der Kolk, L. E., Schmidt, M. K., Russell, N. S., De Lange, J. L., Wijnands, R., Collée, J. M., Hooning, M. J., Seynaeve, C., Van Deurzen, C. H M, Obdeijn, I. M., Van Asperen, C. J., Tollenaar, R. A E M, Van Cronenburg, T. C T E F, Kets, C. M., Ausems, M. G E M, Van Der Pol, C. C., Van Os, T. A M, Waisfisz, Q., Meijers-Heijboer, H. E J, Gómez-Garcia, E. B., Oosterwijk, J. C., Mourits, M. J., De Bock, G. H., Vasen, H. F., Siesling, S., Verloop, J., Overbeek, L. I H, Fox, Stephen, Kirk, Judy, Lindeman, Geoff, Price, Melanie, NIH - National Cancer Institute (NCI) (Estados Unidos), National Health and Medical Research Council (Australia), Victorian Health Promotion Foundation, Dutch Cancer Society (Holanda), Breast Cancer Research Trust, Instituto de Salud Carlos III, Lon V. Smith Foundation, Federal Ministry of Education & Research (Alemania), Finlands Akademi (Finlandia), United States Army Medical Research and Development Command, California Breast Cancer Research Program, German Cancer Aid, Canadian Institutes of Health Research, Ministère de Économie, Innovation et Exportation (Canadá), Ministry of Higher Education (Malasia), National Medical Research Council (Singapur), University of Oulu (Finlandia), Yorkshire Cancer Research, Hellenic Cooperative Oncology Group, California Cancer Research Program, Danish Cancer Society, Ministry of Science and Higher Education (Polonia), Asociación Española Contra el Cáncer, University of Kansas. Cancer Center (Estados Unidos), Hungarian Research Grants, Norwegian EEA Financial Mechanism, Canadian Breast Cancer Network, NIH - National Cancer Institute (NCI). Specialized Programs of Research Excellence (SPOREs) (Estados Unidos), Congressionally Directed Medical Research Programs (Estados Unidos), NRG Oncology National (Estados Unidos), Unión Europea. Comisión Europea. 7 Programa Marco, Medical Oncology, Obstetrics & Gynecology, Clinical Genetics, 1 Department of Preventive Medicine, Keck School of MediCenter, Kansas City, Kansas 66160, USA. 90 Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel-Hashomer 52621, Israel. 91 Section of Genetic Oncology, Department of Laboratory Medicine, University and University Hospital of Pisa, Pisa 56126, Italy. 92 UCLA Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Center, Los Angeles, California 90024, USA. 93 Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. 94 Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK. 95Women’s Cancer, UCL EGA Institute for Women’s Health, London WC1E 6AU, UK. 96 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia. 97 Cancer Research UK Clinical Trials Unit, The BeatsonWest of Scotland Cancer Centre, Glasgow G12 0YN, UK. 98 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160, USA. 99 Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montreal, Que´bec H3A 1A1, Canada. 100 Department of Medicine, McGill University, Montreal, Que´bec H3A 1A1, Canada. 101 Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA. 102 Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55902, USA. 103 Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. 104Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. 105 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland 20892, USA. 106 Department of Genetics and Pathology, Pomeranian Medical University, 70-204 Szczecin, Poland. 107 Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, 94805 Villejuif, France. 108 University Paris- Sud, 91405 Villejuif, France. 109 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. 110 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark. 111 Department of Oncology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK. 112 Saw Swee Hock School of Public Health, National University of Singapore Singapore 119077, Singapore. 113 Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, 50603 Kuala Lumpur, Malaysia. 114 Cancer Research Initiatives Foundation, Subang Jaya, 47500 Selangor, Malaysia. 115 Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, 45136 Essen, Germany. 116 Department of Gynecology and Gynecologic Oncology, Dr Horst Schmidt Kliniken Wiesbaden, 65199 Wiesbaden, Germany. 117 Clinical Cancer Genetics, for the City of Hope Clinical Cancer Genetics Community Research Network, Duarte California 91010, USA. 118 Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, 2730 Copenhagen, Denmark. 119 Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark. 120 Department of Gynecology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark. 121 Family Cancer Clinic, Netherlands Cancer Institute, 1006 Amsterdam, The Netherlands. 122 Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, 3015 Rotterdam, The Netherlands. 123 Center for Medical Genetics, NorthShore University Health System, Evanston, Illinois 60201, USA. 124 N.N. Petrov Institute of Oncology, St Petersburg 197758, Russia. 125 Lombardi Comprehensive Cancer Center, Georgetown University, Washington District of Columbia 20057, USA. 126 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Aichi 464-8681, Japan. 127 State Research Institute Centre for Innovative Medicine, LT-01102 Vilnius, Lithuania. 128 Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California 94538, USA. 129 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 08826, Korea. 130 Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria 3010, Australia. 131Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. 132 Radboud University Medical Centre, Radboud Institute for Health Sciences, 6500 Nijmegen, The Netherlands. 133 Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. 134 Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario M5T 3M7, Canada. 135 Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, 70210 Kuopio, Finland. 136 Cancer Center, Kuopio University Hospital, 70210 Kuopio, Finland. 137 Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, 70210 Kuopio, Finland. 138 Department of Clinical Molecular Biology, Oslo University Hospital, University of Oslo, 1478 Oslo, Norway. 139 The Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong, China. 140 Department of Surgery, The University of Hong Kong, Hong Kong, China. 141Vesalius Research Center, VIB, 3000 Leuven, Belgium. 142 Laboratory for Translational Genetics, Department of Oncology, University of Leuven, 3000 Leuven, Belgium. 143 Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 77 Stockholm, Sweden. 144 Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK. 145 Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. 146 Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), 20133 Milan, Italy. 147 University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA. 148 Department of Oncology - Pathology, Karolinska Institutet, SE- 171 77 Stockholm, Sweden. 149 National Center for Tumour Diseases, University of Heidelberg, 69117 Heidelberg, Germany. 150 Department of Gynaecology, Radboud University Medical Centre, 6500 Nijmegen, The Netherlands. 151 Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka 812-8582, Japan. 152 Anatomical Pathology, The Alfred Hospital, Melbourne, Victoria 3004, Australia. 153 Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow G61 1BD, UK. 154 Division of Gynaecology and Obstetrics, Technische Universita¨t Mu¨nchen, 81675 Munich, Germany. 155 Department of Human Genetics, Radboud University Medical Centre, 6500 Nijmegen, The Netherlands. 156 Immunology and Molecular Oncology Unit, Instituto Oncologico Veneto IOV, IRCCS, 35128 Padua, Italy. 157 Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. 158 Institute of Population Health, University of Manchester, Manchester M13 9PL, UK. 159 Laboratory Medicine Program, University Health Network, Toronto, Ontario M5G 1L7, Canada. 160 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1L7, Canada. 161 The University of Texas School of Public Health, Houston, Texas 77030, USA. 162 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California 91010, USA. 163 Department of Medicine and Genetics, University of California, San Francisco, California 94143, USA. 164 Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. 165 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York 10065, USA. 166 Department of Molecular Genetics, National Institute of Oncology, 1122 Budapest, Hungary. 167 Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois 60637, USA. 168 The Ohio State University and the James Cancer Center, Columbus, Ohio 43210, USA. 169 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York 10017, USA. 170 Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Centre (CNIO), 28019 Madrid, Spain. 171 Biomedical Network on Rare Diseases (CIBERER), 28029 Madrid, Spain. 172 Department of Surgery, Seoul National University College of Medicine, Seoul, 03080 Korea. 173 Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon 97239, USA. 174 Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon 97239, USA. 175 IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, 16 20139 Milan, Italy. 176 Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria. 177 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida 33606, USA. 178 Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. 179 Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, Massachusetts 02115, USA. 180 Laboratory of Cancer Genetics and Tumour Biology, Northern Finland Laboratory Centre NordLab, FI-90014 Oulu, Finland. 181 Laboratory of Cancer Genetics and Tumour Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, FI-90014 Oulu, Finland. 182 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT),cine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA. 2 Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK. 3 QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia. 4 Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge CB1 8RN, UK. 5 Medical College, Xiamen University, Xiamen 361102, China. 6 Department of Medical Oncology, The Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. 7 Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki 00029 HUS, Finland. 8 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario Canada, M5G 1X5. 9 Department of Molecular Genetics, University of Toronto, Toronto, OntarioCanada, M5S 1A8. 10 Department of Epidemiology, Genetic Epidemiology Research Institute, School of Medicine, University of California Irvine, Irvine, California 92697, USA. 11 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany. 12 University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. 13 Department of Oncology, Karolinska University Hospital, Stockholm 171 77, Sweden. 14 Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA. 15 Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan 20141, Italy. 16 Department of Pathology, Landspitali University Hospital and BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik 600169- 2039, Iceland. 17 University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen 91054, Germany. 18 Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid E-28029, Spain. 19 Centro de Investigacio´n en Red de Enfermedades Raras, Valencia 28029, Spain. 20 Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina 27710, USA. 21 Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York 10065, USA. 22 Department of Gynecology and Obstetrics, Haukeland University Hospital, 5021 Bergen, Norway. 23 Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, N-5020 Bergen, Norway. 24 Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki FIN-00029, Finland. 25 Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA. 26 International Epidemiology Institute, Rockville, Maryland 20850, USA. 27 Gynaecology Research Unit, Hannover Medical School, Hannover D-30625, Germany. 28 Department of Clinical Genetics, Vejle Hospital, Vejle 7100, Denmark. 29 Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark. 30 Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev 2730, Denmark. 31 Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev 2730, Denmark. 32 Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo N-0310, Norway. 33 K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo N-0310, Norway. 34 Dr Margarete Fischer- Bosch-Institute of Clinical Pharmacology, Stuttgart D-70376, Germany. 35 University of Tu¨bingen, Tu¨bingen 72074, Germany. 36 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. 37 International Agency for Research on Cancer, Lyon 69008, France. 38 Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg 69121, Germany. 39 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3004, Australia. 40 Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d’Investigacio´ Biome`dica de Girona), Catalan Institute of Oncology, Girona 08908, Spain. 41 Department of Surgery, National University Health System, Singapore 119077, Singapore. 42 Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. 43 Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg 69120, Germany. 44 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki 00029 HUS, Finland. 45 Department of Pathology, Helsinki University Central Hospital, Helsinki 00029, Finland. 46 Department of Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA. 47 Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigacio´n Sanitaria del Hospital Clı ´nico San Carlos), Madrid 28040, Spain. 48 Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria 3002, Australia. 49 Cancer Pathology & Prevention, Division of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo 14263, New York, USA. 50 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69121, Germany. 51 University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany. 52 Unite´ de recherche en sante´ des populations, Centre des maladies du sein Descheˆnes-Fabia, Centre de recherche FRSQ du Centre hospitalier affilie´ universitaire de Que´bec, Que´bec City, Que´bec Canada, G1J 1Z4. 53 Cancer Research Institute, Seoul National University, Seoul 08826, Korea. 54 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea. 55 Center for Medical Genetics, Ghent University, Ghent 9000, Belgium. 56 Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico 87131, USA. 57 Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield S10 2TN, UK. 58 Harvard HT Chan School of Public Health, Boston, Massachusetts 02115, USA. 59 Obstetrics and Gynecology Epidemiology Center, Brigham andWomen’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. 60 Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield S10 2TN, UK. 61 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 70-115, Poland. 62 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden. 63 Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. 64 INSERM U1052, CNRS UMR5286, Universite´ Lyon, Centre de Recherche en Cance´rologie de Lyon, Lyon 69373, France. 65 Department of Pathology and Laboratory Diagnostics the Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology,Warsaw 44-101, Poland. 66 Department of Pathology, Leiden University Medical Center, Leiden 2333, The Netherlands. 67 Department of Human Genetics, Leiden University Medical Center, Leiden 2333, The Netherlands. 68 Oncogenetics Group, University Hospital Vall d’Hebron, Vall d’Hebron Institute of Oncology (VHIO) and Universitat Auto`noma de Barcelona, Barcelona, 186 Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), Center for Molecular Medicine Cologne (CMMC), University Hospital of Cologne, 50931 Cologne, Germany. 187Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut 06510, USA. 188Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, Illinois 60201, USA. 189 Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. 190Department of Epidemiology, University of Washington, Seattle, Washington 98109, USA. 191National Cancer Institute, Bangkok 10400, Thailand. 192 Research Oncology, Guy’s Hospital, King’s College London, London SE1 9RT, UK. 193Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. 194 Cancer Control and Population Sciences, Duke Cancer Institute, Durham, North Carolina 27710, USA. 195Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands. 196Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, 50676 Cologne, Germany. 197 Center for Integrated Oncology, University Hospital of Cologne, 50676 Cologne, Germany. 198 Center for Molecular Medicine, University Hospital of Cologne, 50676 Cologne, Germany. 199 Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, 50676 Cologne, Germany. 200 Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan. 201 School of Public Health, China Medical University, Taichung 404, Taiwan. 202Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford California 94305, USA. 203 Unite´ Mixte de Ge´ne´tique Constitutionnelle des Cancers Fre´quents, Hospices Civils de Lyon – Centre Le´on Be´rard, Lyon 69008, France. 204 INSERM U1052, CNRS UMR5286, Universite´ Lyon 1, Centre de Recherche en Cance´rologie de Lyon, Lyon 69003, France. 205Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia. 206Division of Clinical Genetics, Department of Clinical and Experimental Medicine, Linko¨ping University, 581 83 Linko¨ping, Sweden. 207 Institut Curie, Department of Tumour Biology, Paris, France, Institut Curie, INSERM U830, 75248 Paris, France. 208Universite´ Paris Descartes, Sorbonne Paris Cite´, 75270 Paris, France. 209 Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, 69120 Heidelberg, Germany. 210Department of Genetics, Portuguese Oncology Institute, Porto 4200-072, Portugal. 211 Biomedical Sciences Institute (ICBAS), Porto University, Porto 4099-002, Portugal. 212Department of Epidemiology, Mailman School of Public Health, Columbia University, New York 10027, USA. 213Department of Clinical Genetics, Odense University Hospital, 5000 Odense C, Denmark. 214UO Anatomia Patologica, Ospedale di Circolo-Universita` dell’Insubria, 21100 Varese, Italy. 215 Latvian Biomedical Research and Study Centre, Riga LV-1067, Latvia. 216 Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico), 64 - 35128 Padua, Italy. 217Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio 43210, USA. 218Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford OX3 7BN, UK. 219 Institute of Human Genetics, Pontificia Universidad Javeriana, Cra. 7 #40-62 Bogota, Colombia. 220Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. 221Department of Clinical Genetics, Erasmus University Medical Center, 3015 CE Rotterdam, The Netherlands. 222Department of Gynecology, Family Cancer Clinic, Erasmus MC Cancer Institute, 3015 CE Rotterdam, The Netherlands. 223Division of Gynecological Oncology, Department of Oncology, University Hospitals Leuven, B-3000 Leuven, Belgium. 224University Hospital Ulm, 89069 Ulm, Germany. 225Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda Maryland 20892, USA. 226 Multidisciplinary Breast Center, Department of General Medical Oncology, University Hospitals Leuven, B-3000 Leuven, Belgium. 227 Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research ‘Demokritos’, Athens 153 10, Greece. 228 Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 47500 Subang Jaya, Malaysia. 229 University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya Medical Centre, University Malaya, 59100 Kuala Lumpur, Malaysia. 230Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114 Taiwan. 231 Shanghai Center for Disease Control and Prevention, Shanghai, China. 232 Cancer Epidemiology Program, Division of Population Sciences, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA. 233Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA. 234 Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. 235 Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia. 236 Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK. 237 Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3052, Australia. 238 Department of Gynaecological Oncology, Westmead Institute for Cancer Research, Westmead Hospital Westmead, New South Wales 2145, Australia., Tyrer, Jonathan [0000-0003-3724-4757], Dennis, Joe [0000-0003-4591-1214], Rhenius, Valerie [0000-0003-4215-3235], Song, Honglin [0000-0001-5076-7371], Wang, Jean [0000-0002-9139-0627], Easton, Douglas [0000-0003-2444-3247], Dunning, Alison [0000-0001-6651-7166], Pharoah, Paul [0000-0001-8494-732X], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Epidemiology and Data Science, EMGO - Quality of care, Anesthesiology, Human genetics, CCA - Cancer biology, and VU University medical center
Subjects: endocrine system diseases, Messenger, IDENTIFIES 3, MODIFIERS, Brjóstakrabbamein, BRCA2 MUTATION CARRIERS, Medicine and Health Sciences, GWAS, INVESTIGATORS, African Continental Ancestry Group, Asian Continental Ancestry Group, Breast Neoplasms, Chromosomes, Human, Pair 19, Female, Genome-Wide Association Study, Genotype, Humans, Ovarian Neoplasms, RNA, Messenger, Alleles, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, skin and connective tissue diseases, COMMON VARIANTS, EPITHELIAL-CELLS, Single Nucleotide, female genital diseases and pregnancy complications, NAF12, Medical Genetics, Human, endocrine system, Science, Chromosomes, Human, Pair 19/genetics, Black People, Breast Neoplasms/genetics, Chromosomes, Article, Ovarian Neoplasms/genetics, SDG 3 - Good Health and Well-being, Asian People, REVEALS, Polymorphism, GENOME-WIDE ASSOCIATION, Krabbamein, Medicinsk genetik, Cancer och onkologi, Pair 19, Arfgengi, GENE, Eggjastokkar, Cancer and Oncology, RNA, BRCA1 Protein/genetics
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, A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.
Published: 2016

32. Common variants at 19p13 are associated with susceptibility to ovarian cancer (vol 42, pg 880, 2010)

Author: Bolton, Kelly L, Tyrer, Jonathan, Song, Honglin, Ramus, Susan J, Notaridou, Maria, Jones, Chris, Sher, Tanya, Gentry-Maharaj, Aleksandra, Wozniak, Eva, Tsai, Ya-Yu, Weidhaas, Joanne, Paik, Daniel, Van den Berg, David J, Stram, Daniel O, Pearce, Celeste Leigh, Wu, Anna H, Brewster, Wendy, Anton-Culver, Hoda, Ziogas, Argyrios, Narod, Steven A, Levine, Douglas A, Kaye, Stanley B, Brown, Robert, Paul, Jim, Flanagan, James, Sieh, Weiva, McGuire, Valerie, Whittemore, Alice S, Campbell, Ian, Gore, Martin E, Lissowska, Jolanta, Yang, Hanna P, Medrek, Krzysztof, Gronwald, Jacek, Lubinski, Jan, Jakubowska, Anna, Le, Nhu D, Cook, Linda S, Kelemen, Linda E, Brooks-Wilson, Angela, Massuger, Leon FAG, Kiemeney, Lambertus A, Aben, Katja KH, van Altena, Anne M, Houlston, Richard, Tomlinson, Ian, Palmieri, Rachel T, Moorman, Patricia G, Schildkraut, Joellen, Iversen, Edwin S, Phelan, Catherine, Vierkant, Robert A, Cunningham, Julie M, Goode, Ellen L, Fridley, Brooke L, Kruger-Kjaer, Susan, Blaeker, Jan, Hogdall, Estrid, Hogdall, Claus, Gross, Jenny, Karlan, Beth Y, Ness, Roberta B, Edwards, Robert P, Odunsi, Kunle, Moyisch, Kirsten B, Baker, Julie A, Modugno, Francesmary, Heikkinenen, Tuomas, Butzow, Ralf, Nevanlinna, Heli, Leminen, Arto, Bogdanova, Natalia, Antonenkova, Natalia, Doerk, Thilo, Hillemanns, Peter, Duerst, Matthias, Runnebaum, Ingo, Thompson, Pamela J, Carney, Michael E, Goodman, Marc T, Lurie, Galina, Wang-Gohrke, Shan, Hein, Rebecca, Chang-Claude, Jenny, Rossing, Mary Anne, Cushing-Haugen, Kara L, Doherty, Jennifer, Chen, Chu, Rafnar, Thorunn, Besenbacher, Soren, Sulem, Patrick, Stefansson, Kari, Birrer, Michael J, Terry, Kathryn L, Hernandez, Dena, Cramer, Daniel W, Vergote, Ignace, Amant, Frederic, Lambrechts, Diether, and Despierre, Evelyn
Subjects: Biological Sciences, Medical and Health Sciences, Developmental Biology
Published: 2016

33. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

Author: Southey, Melissa C, Goldgar, David E, Winqvist, Robert, Pylkäs, Katri, Couch, Fergus, Tischkowitz, Marc, Foulkes, William D, Dennis, Joe, Michailidou, Kyriaki, van Rensburg, Elizabeth J, Heikkinen, Tuomas, Nevanlinna, Heli, Hopper, John L, Dörk, Thilo, Claes, Kathleen Bm, Reis-Filho, Jorge, Teo, Zhi Ling, Radice, Paolo, Catucci, Irene, Peterlongo, Paolo, Tsimiklis, Helen, Odefrey, Fabrice A, Dowty, James G, Schmidt, Marjanka K, Broeks, Annegien, Hogervorst, Frans B, Verhoef, Senno, Carpenter, Jane, Clarke, Christine, Scott, Rodney J, Fasching, Peter A, Haeberle, Lothar, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, Dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Bolla, Manjeet K, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Marme, Federik, Burwinkel, Barbara, Yang, Rongxi, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Sanchez, Marie, Bojesen, Stig, Nielsen, Sune F, Flyger, Henrik, Benitez, Javier, Zamora, M Pilar, Perez, Jose Ignacio Arias, Menéndez, Primitiva, Anton-Culver, Hoda, Neuhausen, Susan, Ziogas, Argyrios, Clarke, Christina A, Brenner, Hermann, Arndt, Volker, Stegmaier, Christa, Brauch, Hiltrud, Brüning, Thomas, Ko, Yon-Dschun, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia V, Antonenkova, Natalia N, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Spurdle, Amanda B, Investigators, kConFab, Australian Ovarian Cancer Study Group, Wauters, Els, Smeets, Dominiek, Beuselinck, Benoit, Floris, Giuseppe, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Olson, Janet E, Vachon, Celine, Pankratz, Vernon S, McLean, Catriona, Haiman, Christopher A, Henderson, Brian E, Schumacher, Fredrick, Le Marchand, Loic, Kristensen, Vessela, Alnæs, Grethe Grenaker, Zheng, Wei, Hunter, David J, Lindstrom, Sara, Hankinson, Susan E, Kraft, Peter, Andrulis, Irene, Knight, Julia A, Glendon, Gord, Mulligan, Anna Marie, Jukkola-Vuorinen, Arja, Grip, Mervi, Kauppila, Saila, Devilee, Peter, Tollenaar, Robert AEM, Seynaeve, Caroline, Hollestelle, Antoinette, Garcia-Closas, Montserrat, Figueroa, Jonine, Chanock, Stephen J, Lissowska, Jolanta, Czene, Kamila, Darabi, Hatef, Eriksson, Mikael, Eccles, Diana M, Rafiq, Sajjad, Tapper, William J, Gerty, Sue M, Hooning, Maartje J, Martens, John WM, Collée, J Margriet, Tilanus-Linthorst, Madeleine, Hall, Per, Li, Jingmei, Brand, Judith S, Humphreys, Keith, Cox, Angela, Reed, Malcolm WR, Luccarini, Craig, Baynes, Caroline, Dunning, Alison M, Hamann, Ute, Torres, Diana, Ulmer, Hans Ulrich, Rüdiger, Thomas, Jakubowska, Anna, Lubinski, Jan, Jaworska, Katarzyna, Durda, Katarzyna, Slager, Susan, Toland, Amanda E, Ambrosone, Christine B, Yannoukakos, Drakoulis, Swerdlow, Anthony, Ashworth, Alan, Orr, Nick, Jones, Michael, González-Neira, Anna, Pita, Guillermo, Alonso, M Rosario, Álvarez, Nuria, Herrero, Daniel, Tessier, Daniel C, Vincent, Daniel, Bacot, Francois, Simard, Jacques, Dumont, Martine, Soucy, Penny, Eeles, Rosalind, Muir, Kenneth, Wiklund, Fredrik, Gronberg, Henrik, Schleutker, Johanna, Nordestgaard, Børge G, Weischer, Maren, Travis, Ruth C, Neal, David, Donovan, Jenny L, Hamdy, Freddie C, Khaw, Kay-Tee, Stanford, Janet L, Blot, William J, Thibodeau, Stephen, Schaid, Daniel J, Kelley, Joseph L, Maier, Christiane, Kibel, Adam S, Cybulski, Cezary, Cannon-Albright, Lisa, Butterbach, Katja, Park, Jong, Kaneva, Radka, Batra, Jyotsna, Teixeira, Manuel R, Kote-Jarai, Zsofia, Olama, Ali Amin Al, Benlloch, Sara, Renner, Stefan P, Hartmann, Arndt, Hein, Alexander, Ruebner, Matthias, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Lambretchs, Sandrina, Doherty, Jennifer A, Rossing, Mary Anne, Nickels, Stefan, Eilber, Ursula, Wang-Gohrke, Shan, Odunsi, Kunle, Sucheston-Campbell, Lara E, Friel, Grace, Lurie, Galina, Killeen, Jeffrey L, Wilkens, Lynne R, Goodman, Marc T, Runnebaum, Ingo, Hillemanns, Peter A, Pelttari, Liisa M, Butzow, Ralf, Modugno, Francesmary, Edwards, Robert P, Ness, Roberta B, Moysich, Kirsten B, du Bois, Andreas, Heitz, Florian, Harter, Philipp, Kommoss, Stefan, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Jensen, Allan, Kjaer, Susanne Krüger, Høgdall, Estrid, Peissel, Bernard, Bonanni, Bernardo, Bernard, Loris, Goode, Ellen L, Fridley, Brooke L, Vierkant, Robert A, Cunningham, Julie M, Larson, Melissa C, Fogarty, Zachary C, Kalli, Kimberly R, Liang, Dong, Lu, Karen H, Hildebrandt, Michelle AT, Wu, Xifeng, Levine, Douglas A, Dao, Fanny, Bisogna, Maria, Berchuck, Andrew, Iversen, Edwin S, Marks, Jeffrey R, Akushevich, Lucy, Cramer, Daniel W, Schildkraut, Joellen, Terry, Kathryn L, Poole, Elizabeth M, Stampfer, Meir, Tworoger, Shelley S, Bandera, Elisa V, Orlow, Irene, Olson, Sara H, Bjorge, Line, Salvesen, Helga B, van Altena, Anne M, Aben, Katja KH, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bean, Yukie, Brooks-Wilson, Angela, Kelemen, Linda E, Cook, Linda S, Le, Nhu D, Górski, Bohdan, Gronwald, Jacek, Menkiszak, Janusz, Høgdall, Claus K, Lundvall, Lene, Nedergaard, Lotte, Engelholm, Svend Aage, Dicks, Ed, Tyrer, Jonathan, Campbell, Ian, McNeish, Iain, Paul, James, Siddiqui, Nadeem, Glasspool, Rosalind, Whittemore, Alice S, Rothstein, Joseph H, McGuire, Valerie, Sieh, Weiva, Cai, Hui, Shu, Xiao-Ou, Teten, Rachel T, Sutphen, Rebecca, McLaughlin, John R, Narod, Steven A, Phelan, Catherine M, Monteiro, Alvaro N, Fenstermacher, David, Lin, Hui-Yi, Permuth, Jennifer B, Sellers, Thomas A, Chen, Y Ann, Tsai, Ya-Yu, Chen, Zhihua, Gentry-Maharaj, Aleksandra, Gayther, Simon A, Ramus, Susan J, Menon, Usha, Wu, Anna H, Pearce, Celeste L, Van Den Berg, David, Pike, Malcolm C, Dansonka-Mieszkowska, Agnieszka, Plisiecka-Halasa, Joanna, Moes-Sosnowska, Joanna, Kupryjanczyk, Jolanta, Pharoah, Paul Dp, Song, Honglin, Winship, Ingrid, Chenevix-Trench, Georgia, Giles, Graham G, Tavtigian, Sean V, Easton, Doug F, Milne, Roger L, Clinical Genetics, Neurology, Medical Oncology, Surgery, Erasmus MC other, Clinicum, Department of Obstetrics and Gynecology, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Department of Oncology, Department of Pathology, HUS Gynecology and Obstetrics, Tischkowitz, Marc [0000-0002-7880-0628], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Khaw, Kay-Tee [0000-0002-8802-2903], Amin Al Olama, Ali [0000-0002-7178-3431], Dicks, Ed [0000-0002-0617-0401], Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], Song, Honglin [0000-0001-5076-7371], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Oncology, Male, Ataxia Telangiectasia Mutated Proteins, prostate-cancer, Prostate cancer, 0302 clinical medicine, brca1, Medizinische Fakultät, Medicine and Health Sciences, skin and connective tissue diseases, Genetics (clinical), Ovarian Neoplasms, education.field_of_study, brca2-interacting protein, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], 1184 Genetics, developmental biology, physiology, Nuclear Proteins, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, PROSTATE-CANCER, Cancer: prostate, Multicenter Study, ovarian-cancer, Centre for Surgical Research, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, ovary [Cancer], Female, Fanconi Anemia Complementation Group N Protein, metaanalysis, Risk, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Population, 3122 Cancers, cancer predisposition, Breast Neoplasms, OVARIAN-CANCER, BRCA2-INTERACTING PROTEIN, Cancer: ovary, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, prostate [Cancer], medicine, Cancer Genetics, Genetics, Journal Article, breast [Cancer], BREAST-CANCER, Humans, Genetic Predisposition to Disease, ddc:610, education, gene, CHEK2, FAMILY REGISTRY, METAANALYSIS, breast-cancer, Genetic Association Studies, business.industry, MUTATIONS, Cancer: breast, Tumor Suppressor Proteins, Case-control study, Cancer, Prostatic Neoplasms, medicine.disease, BRCA1, mutations, GENE, susceptibility loci, Checkpoint Kinase 2, 030104 developmental biology, Relative risk, Case-Control Studies, Mutation, family registry, Ovarian cancer, business
Abstract: Background: 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.Methods: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2c.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.Results: 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.Conclusions: 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.
Published: 2016

34. Corrigendum: Common variants at 19p13 are associated with susceptibility to ovarian cancer

Author: Bolton, Kelly L, Tyrer, Jonathan, Song, Honglin, Ramus, Susan J, Notaridou, Maria, Jones, Chris, Sher, Tanya, Gentry-Maharaj, Aleksandra, Wozniak, Eva, Tsai, Ya-Yu, Weidhaas, Joanne, Paik, Daniel, Van Den Berg, David J, Stram, Daniel O, Pearce, Celeste Leigh, Wu, Anna H, Brewster, Wendy, Anton-Culver, Hoda, Ziogas, Argyrios, Narod, Steven A, Levine, Douglas A, Kaye, Stanley B, Brown, Robert, Paul, Jim, Flanagan, James, Sieh, Weiva, McGuire, Valerie, Whittemore, Alice S, Campbell, Ian, Gore, Martin E, Lissowska, Jolanta, Yang, Hanna P, Medrek, Krzysztof, Gronwald, Jacek, Lubinski, Jan, Jakubowska, Anna, Le, Nhu D, Cook, Linda S, Kelemen, Linda E, Brooks-Wilson, Angela, Massuger, Leon FAG, Kiemeney, Lambertus A, Aben, Katja KH, van Altena, Anne M, Houlston, Richard, Tomlinson, Ian, Palmieri, Rachel T, Moorman, Patricia G, Schildkraut, Joellen, Iversen, Edwin S, Phelan, Catherine, Vierkant, Robert A, Cunningham, Julie M, Goode, Ellen L, Fridley, Brooke L, Kruger-Kjaer, Susan, Blaeker, Jan, Hogdall, Estrid, Hogdall, Claus, Gross, Jenny, Karlan, Beth Y, Ness, Roberta B, Edwards, Robert P, Odunsi, Kunle, Moyisch, Kirsten B, Baker, Julie A, Modugno, Francesmary, Heikkinenen, Tuomas, Butzow, Ralf, Nevanlinna, Heli, Leminen, Arto, Bogdanova, Natalia, Antonenkova, Natalia, Doerk, Thilo, Hillemanns, Peter, Dürst, Matthias, Runnebaum, Ingo, Thompson, Pamela J, Carney, Michael E, Goodman, Marc T, Lurie, Galina, Wang-Gohrke, Shan, Hein, Rebecca, Chang-Claude, Jenny, Rossing, Mary Anne, Cushing-Haugen, Kara L, Doherty, Jennifer, Chen, Chu, Rafnar, Thorunn, Besenbacher, Soren, Sulem, Patrick, Stefansson, Kari, Birrer, Michael J, Terry, Kathryn L, Hernandez, Dena, Cramer, Daniel W, Vergote, Ignace, Amant, Frederic, Lambrechts, Diether, and Despierre, Evelyn
Subjects: Australian Ovarian Cancer Study Group, Rare Diseases, Biological Sciences, Medical and Health Sciences, Ovarian Cancer, Cancer, Developmental Biology
Published: 2016

35. Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations: Cancer Research

Author: Fehringer, G., Kraft, P., Pharoah, Paul D. P., Eeles, Rosalind A., Chatterjee, N., Schumacher, Fredrick R., Schildkraut, Joellen M., Lindstrom, S., Brennan, P., Bickeboller, H., Houlston, Richard S., Landi, M.T., Caporaso, N., Risch, A., Al Olama, A. A., Berndt, Sonja I, Giovannucci, E.L., Gronberg, H., Kote-Jarai, Zsofia, Ma, Jun, Muir, K., Stampfer, M. J., Stevens, V.L., Wiklund, Fredrik, Willett, W.C., Goode, Ellen L., Permuth, J. B., Risch, Harvey A., Reid, B. M., Bezieau, S., Brenner, H., Chan, T.A., Chang-Claude, J., Hudson, T.J., Kocarnik, J. K., Newcomb, Polly 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., Johnson, N., Hall, P., Hazra, A., Hein, R., Hofman, A., Hopper, John L., Irwanto, A., Johansson, M., Kaaks, R., Kibriya, M.G., Lichtner, P., Liu, J., Lund, E., Makalic, E., Meindl, A., Muller-Myhsok, B., Muranen, Taru A., Nevanlinna, H., Peeters, Petra H., Peto, J., Prentice, R. L., Rahman, N., Sanchez, Anthony M. J., Schmidt, Daniel F., Schmutzler, Rita K., Southey, Melissa C., Tamimi, R., Travis, R.C., Turnbull, C., Uitterlinden, A. G., Wang, M. -Z., Whittemore, Alice S., Yang, X. H. R., Zheng, W., Buchanan, D. D., Casey, G., Conti, David V., Edlund, Christopher 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, A.Y., Tyrer, Jonathan P, Christiani, David C., Wei, Y., Shen, H. B., Hu, Z. B., Shu, X.O., Shiraishi, K., Takahashi, A., Bosse, Y., Obeidat, M., Nickle, D., Timens, W., Freedman, Matthew L., Li, Y.Q., Seminara, D., Chanock, Stephen J, Gong, J., Peters, U., Gruber, Stephen B., Amos, Christopher I., Sellers, Thomas A., Easton, Douglas F., Hunter, David J., Haiman, Christopher A., Henderson, B.E., Hung, Rayjean J., [Unknown], Ocac, Consortium, Practical, Hereditary Breast Ovarian Canc, Res, Colorectal, Transdisciplinary, African Amer Breast, Canc, African Ancestry Prostate, Canc, Human genetics, and CCA - Cancer biology
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 atCDKN2B-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. (C) 2016 AACR.
Published: 2016

36. Common variants at 19p13 are associated with susceptibility to ovarian cancer (vol 42, pg 880, 2010)

Author: Bolton, Kelly L., Tyrer, Jonathan, Song, Honglin, Ramus, Susan J., Notaridou, Maria, Jones, Chris, Sher, Tanya, Gentry-Maharaj, Aleksandra, Wozniak, Eva, Tsai, Ya-Yu, Weidhaas, Joanne, Paik, Daniel, van den Berg, David J., Stram, Daniel O., Pearce, Celeste Leigh, Wu, Anna H., Brewster, Wendy, Anton-Culver, Hoda, Ziogas, Argyrios, Narod, Steven A., Levine, Douglas A., Kaye, Stanley B., Brown, Robert, Paul, Jim, Flanagan, James, Sieh, Weiva, McGuire, Valerie, Whittemore, Alice S., Campbell, Ian, Gore, Martin E., Lissowska, Jolanta, Yang, Hanna P., Medrek, Krzysztof, Gronwald, Jacek, Lubinski, Jan, Jakubowska, Anna, Le, Nhu D., Cook, Linda S., Kelemen, Linda E., Brooks-Wilson, Angela, Massuger, Leon F. A. G., Kiemeney, Lambertus A., Aben, Katja K. H., van Altena, Anne M., Houlston, Richard, Tomlinson, Ian, Palmieri, Rachel T., Moorman, Patricia G., Schildkraut, Joellen, Iversen, Edwin S., Phelan, Catherine, Vierkant, Robert A., Cunningham, Julie M., Goode, Ellen L., Fridley, Brooke L., Kruger-Kjaer, Susan, Blaeker, Jan, Hogdall, Estrid, Hogdall, Claus, Gross, Jenny, Karlan, Beth Y., Ness, Roberta B., Edwards, Robert P., Odunsi, Kunle, Moyisch, Kirsten B., Baker, Julie A., Modugno, Francesmary, Heikkinenen, Tuomas, Butzow, Ralf, Nevanlinna, Heli, Leminen, Arto, Bogdanova, Natalia, Antonenkova, Natalia, Doerk, Thilo, Hillemanns, Peter, Dürst, Matthias, Runnebaum, Ingo, Thompson, Pamela J., Carney, Michael E., Goodman, Marc T., Lurie, Galina, Wang-Gohrke, Shan, Hein, Rebecca, Chang-Claude, Jenny, Rossing, Mary Anne, Cushing-Haugen, Kara L., Doherty, Jennifer, Chen, Chu, Rafnar, Thorunn, Besenbacher, Soren, Sulem, Patrick, Stefansson, Kari, Birrer, Michael J., Terry, Kathryn L., Hernandez, Dena, Cramer, Daniel W., Vergote, Ignace, Amant, Frederic, Lambrechts, Diether, Despierre, Evelyn, Fasching, Peter A., Beckmann, Matthias W., Thiel, Falk C., Ekici, Arif B., Chen, Xiaoqing, Johnatty, Sharon E., Webb, Penelope M., Beesley, Jonathan, Chanock, Stephen, Garcia-Closas, Montserrat, Sellers, Tom, Easton, Douglas F., Berchuck, Andrew, Chenevix-Trench, Georgia, Pharoah, Paul D. P., Gayther, Simon A., and Other departments
Published: 2016

37. Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium

Author: Johnatty, Sharon E., Tyrer, Jonathan P., Kar, Siddhartha, Beesley, Jonathan, Lu, Yi, Gao, Bo, Fasching, Peter A., Hein, Alexander, Ekici, Arif B., Beckmann, Matthias W., Lambrechts, Diether, Nieuwenhuysen, Els Van, Vergote, Ignace, Lambrechts, Sandrina, Rossing, Mary Anne, Doherty, Jennifer A., Chang-Claude, Jenny, Modugno, Francesmary, Ness, Roberta B., Moysich, Kirsten B., Levine, Douglas A., Kiemeney, Lambertus A., Massuger, Leon F.A.G., Gronwald, Jacek, Lubiński, Jan, Jakubowska, Anna, Cybulski, Cezary, Brinton, Louise, Lissowska, Jolanta, Wentzensen, Nicolas, Song, Honglin, Rhenius, Valerie, Campbell, Ian, Eccles, Diana, Sieh, Weiva, Whittemore, Alice S., McGuire, Valerie, Rothstein, Joseph H., Sutphen, Rebecca, Anton-Culver, Hoda, Ziogas, Argyrios, Gayther, Simon A., Gentry-Maharaj, Aleksandra, Menon, Usha, Ramus, Susan J., Pearce, Celeste L, Pike, Malcolm C, Stram, Daniel O., Wu, Anna H., Kupryjanczyk, Jolanta, Dansonka-Mieszkowska, Agnieszka, Rzepecka, Iwona K., Spiewankiewicz, Beata, Goodman, Marc T., Wilkens, Lynne R., Carney, Michael E., Thompson, Pamela J, Heitz, Florian, du Bois, Andreas, Schwaab, Ira, Harter, Philipp, Pisterer, Jacobus, Hillemanns, Peter, Karlan, Beth Y., Walsh, Christine, Lester, Jenny, Orsulic, Sandra, Winham, Stacey J, Earp, Madalene, Larson, Melissa C., Fogarty, Zachary C., Høgdall, Estrid, Jensen, Allan, Kjaer, Susanne Kruger, Fridley, Brooke L., Cunningham, Julie M., Vierkant, Robert A., Schildkraut, Joellen M., Iversen, Edwin S., Terry, Kathryn L., Cramer, Daniel W., Bandera, Elisa V., Orlow, Irene, Pejovic, Tanja, Bean, Yukie, Høgdall, Claus, Lundvall, Lene, McNeish, Ian, Paul, James, Carty, Karen, Siddiqui, Nadeem, Glasspool, Rosalind, Sellers, Thomas, Kennedy, Catherine, Chiew, Yoke-Eng, Berchuck, Andrew, MacGregor, Stuart, deFazio, Anna, Pharoah, Paul D.P., Goode, Ellen L., Webb, Penelope M., and Chenevix-Trench, Georgia
Subjects: Oncology, Cancer Research, Genome-wide association study, AGO Study Group, Kaplan-Meier Estimate, Carcinoma, Ovarian Epithelial, Bioinformatics, chemistry.chemical_compound, Neoplasms, Ovarian Epithelial, 2.1 Biological and endogenous factors, Neoplasms, Glandular and Epithelial, Aetiology, Cancer, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Glandular and Epithelial, Single Nucleotide, Prognosis, Ovarian Cancer, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Australian Ovarian Cancer Study Group, medicine.medical_specialty, Genotype, Quantitative Trait Loci, Oncology and Carcinogenesis, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, Rare Diseases, Meta-Analysis as Topic, Clinical Research, Internal medicine, Carcinoma, medicine, Genetics, SNP, Humans, Progression-free survival, Oncology & Carcinogenesis, Polymorphism, Alleles, business.industry, Human Genome, Computational Biology, medicine.disease, Carboplatin, Patient Outcome Assessment, Regimen, Orphan Drug, chemistry, Ovarian cancer, business, Genome-Wide Association Study
Abstract: Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. Experimental Design: We analyzed approximately 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 first-line 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. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. Results: Five SNPs were significantly associated (P ≤ 1.0 × 10−5) 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 noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10−6). ENCODE ChIP-seq data at 1q22 for normal ovary show 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 high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤6 × 10−3). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res; 21(23); 5264–76. ©2015 AACR.
Published: 2015

38. The Effects of Common Genetic Variants in Oncogenes on Ovarian Cancer Survival

Author: Quaye, Lydia, Gayther, Simon A, Ramus, Susan J, Di Cioccio, Richard A, McGuire, Valerie, Hogdall, Estrid, Hogdall, Claus, Blaakær, Jan, Easton, Douglas F, Ponder, Bruce A J, Jacobs, Ian, Kjaer, Susanne Kruger, Whittemore, Alice S, Pearce, Celeste Leigh, Pharoah, Paul D P, and Song, Honglin
Subjects: Proto-Oncogene Proteins B-raf, Oncology, endocrine system, Cancer Research, medicine.medical_specialty, Genotype, endocrine system diseases, Colorectal cancer, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins p21(ras), Proto-Oncogene Proteins, Internal medicine, medicine, Humans, Survival rate, Proportional Hazards Models, Ovarian Neoplasms, Proportional hazards model, Hazard ratio, Cancer, Oncogenes, medicine.disease, female genital diseases and pregnancy complications, Survival Rate, Minor allele frequency, Endocrinology, ras Proteins, Female, KRAS, Ovarian cancer
Abstract: Purpose: The 5-year survival rate for invasive epithelial ovarian cancer is Experimental Design: 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). Results: 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). Conclusion: Common genetic variants in the BRAF and KRAS oncogenes may be important in the prediction of survival in patients with invasive epithelial ovarian cancer.
Published: 2008

39. Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer

Author: Ramus, Susan J, Song, Honglin, Dicks, Ed, Tyrer, Jonathan P, Rosenthal, Adam N, Intermaggio, Maria P, Fraser, Lindsay, Gentry-Maharaj, Aleksandra, Hayward, Jane, Philpott, Susan, Anderson, Christopher, Edlund, Christopher K, Conti, David, Harrington, Patricia, Barrowdale, Daniel, Bowtell, David D, Alsop, Kathryn, Mitchell, Gillian, AOCS Study Group, Cicek, Mine S, Cunningham, Julie M, Fridley, Brooke L, Alsop, Jennifer, Jimenez-Linan, Mercedes, Poblete, Samantha, Lele, Shashi, Sucheston-Campbell, Lara, Moysich, Kirsten B, Sieh, Weiva, McGuire, Valerie, Lester, Jenny, Bogdanova, Natalia, Dürst, Matthias, Hillemanns, Peter, Ovarian Cancer Association Consortium, Odunsi, Kunle, Whittemore, Alice S, Karlan, Beth Y, Dörk, Thilo, Goode, Ellen L, Menon, Usha, Jacobs, Ian J, Antoniou, Antonis C, Pharoah, Paul DP, and Gayther, Simon A
Subjects: Risk, Adult, Ovarian Cancer Association Consortium, Ubiquitin-Protein Ligases, European Continental Ancestry Group, Oncology and Carcinogenesis, Cell Cycle Proteins, White People, Rare Diseases, Predictive Value of Tests, Clinical Research, Neoplasms, Ovarian Epithelial, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Aetiology, Germ-Line Mutation, Aged, Cancer, Ovarian Neoplasms, Tumor Suppressor Proteins, Prevention, Carcinoma, Human Genome, Glandular and Epithelial, Nuclear Proteins, High-Throughput Nucleotide Sequencing, AOCS Study Group, Middle Aged, United States, Fanconi Anemia Complementation Group Proteins, Ovarian Cancer, DNA-Binding Proteins, Good Health and Well Being, Mutation, Female, Missense, Fanconi Anemia Complementation Group N Protein, RNA Helicases
Abstract: BACKGROUND: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. METHODS: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. RESULTS: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)). CONCLUSIONS: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.
Published: 2015

40. Genome-wide significant risk associations for mucinous ovarian carcinoma (vol 47, pg 888, 2015)

Author: Kelemen, Linda E., Lawrenson, Kate, Tyrer, Jonathan, Li, Qiyuan, Lee, Janet M., Seo, Ji-Heui, Phelan, Catherine M., Beesley, Jonathan, Chen, Xiaoqing, Spindler, Tassja J., Aben, Katja K. H., Anton-Culver, Hoda, Antonenkova, Natalia, Baker, Helen, Bandera, Elisa V., Bean, Yukie, Beckmann, Matthias W., Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A., Brooks-Wilson, Angela, Bruinsma, Fiona, Butzow, Ralf, Campbell, Ian G., Carty, Karen, Chang-Claude, Jenny, Chen, Y. Ann, Chen, Zhihua, Cook, Linda S., Cramer, Daniel W., Cunningham, Julie M., Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Dennis, Joe, Dicks, Ed, Doherty, Jennifer A., Doerk, Thilo, Du Bois, Andreas, Duerst, Matthias, Eccles, Diana, Easton, Douglas T., Edwards, Robert P., Eilber, Ursula, Ekici, Arif B., Engelholm, Svend Aage, Fasching, Peter A., Fridley, Brooke L., Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G., Glasspool, Rosalind, Goode, Ellen L., Goodman, Marc T., Grownwald, Jacek, Harrington, Patricia, Harter, Philipp, Hasmad, Hanis Nazihah, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle A. T., Hillemanns, Peter, Hogdall, Estrid, Hogdall, Claus, Hosono, Satoyo, Iversen, Edwin S., Jakubowska, Anna, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y., Kellar, Melissa, Kelley, Joseph L., Lambertus Kiemeney, Krakstad, Camilla, Kjaer, Susanne K., Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D., Lee, Alice W., Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A., Liang, Dong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon F. A. G., Matsuo, Keitaro, Mcguire, Valerie, Mclaughlin, John R., Mcneish, Iain, Menon, Usha, Modugno, Francesmary, Moes-Sosnowska, Joanna, Moysich, Kirsten B., Narod, Steven A., Nedergaard, Lotte, Ness, Roberta B., Nevanlinna, Heli, Adenan, Noor Azmi Mat, Odunsi, Kunle, Olson, Sara H., Orlow, Irene, Orsulic, Sandra, Weber, Rachel Palmieri, Paul, James, Pearce, Celeste Leigh, Pejovic, Tanja, Pelttari, Liisa M., Permuth-Wey, Jennifer, Pike, Malcolm C., Poole, Elizabeth M., Ramus, Susan J., Risch, Harvey A., Rosen, Barry, Rossing, Mary Anne, Rothstein, Joseph H., Rudolph, Anja, Runnebaum, Ingo B., Rzepecka, Iwona K., Salvesen, Helga B., Schildkraut, Joellen M., Schwaab, Ira, Shu, Xiao-Ou, Shvetsov, Yurii B., Siddiqui, Nadeem, Sieh, Weiva, Song, Honglin, Southey, Melissa C., Sucheston, Lara, Tangen, Ingvild L., Teo, Soo-Hwang, Terry, Kathryn L., Thompson, Pamela J., Tworoger, Shelley S., Altena, Anne M., Nieuwenhuysen, Els, Vergote, Ignace, Vierkant, Robert A., Wang-Gohrke, Shan, Walsh, Christine, Wentzensen, Nicolas, Whittemore, Alice S., Wicklund, Kristine G., Wilkens, Lynne R., Sawicki, Wlodzimierz, Woo, Yin-Ling, Wu, Xifeng, Wu, Anna H., Yang, Hannah, Zheng, Wei, Ziogas, Argyrios, Sellers, Thomas A., Freedman, Matthew L., Chenevix-Trench, Georgia, Pharoah, Paul D. P., Gayther, Simon A., Berchuck, Andrew, Australian Canc Study, Australian Ovarian Canc Study Grp, and Ovarian Canc Assoc Consortium
Published: 2015

41. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Author: Michailidou, Kyriaki, Beesley, Jonathan, Lindstrom, Sara, Canisius, Sander, Dennis, Joe, Lush, Michael J., Maranian, Mel J., Bolla, Manjeet K., Wang, Qin, Shah, Mitul, Perkins, Barbara J., Czene, Kamila, Eriksson, Mikael, Darabi, Hatef, Brand, Judith S., Bojesen, Stig E., Nordestgaard, Borge G., Flyger, Henrik, Nielsen, Sune F., Rahman, Nazneen, Turnbull, Clare, Fletcher, Olivia, Peto, Julian, Gibson, Lorna, dos-Santos-Silva, Isabel, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Eilber, Ursula, Behrens, Sabine, Nevanlinna, Heli, Muranen, Taru A., Aittomaki, Kristiina, Blomqvist, Carl, Khan, Sofia, Aaltonen, Kirsimari, Ahsan, Habibul, Kibriya, Muhammad G., Whittemore, Alice S., John, Esther M., Malone, Kathleen E., Gammon, Marilie D., Santella, Regina M., Ursin, Giske, Makalic, Enes, Schmidt, Daniel F., Casey, Graham, Hunter, David J., van der Luijt, Rob B., Peeters, Petra, BOCS, KConFab Investigators, AOCS Grp, NBCS, and GENICA Network
Subjects: RISK, ESTROGEN, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Journal Article, CONFER SUSCEPTIBILITY, COMMON VARIANTS, ALLELES, GENOTYPE IMPUTATION, CHEK2-ASTERISK-1100DELC, BRCA1, OVARIAN-CANCER, METAANALYSIS
Abstract: Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining similar to 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
Published: 2015

42. Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer

Author: Candido-dos-Reis, Francisco J, Song, Honglin, Goode, Ellen L, Cunningham, Julie M, Fridley, Brooke L, Larson, Melissa C, Alsop, Kathryn, Dicks, Ed, Harrington, Patricia, Ramus, Susan J, de Fazio, Anna, Mitchell, Gillian, Fereday, Sian, Bolton, Kelly L, Gourley, Charlie, Michie, Caroline, Karlan, Beth, Lester, Jenny, Walsh, Christine, Cass, Ilana, Olsson, Håkan, Gore, Martin, Benitez, Javier J, Garcia, Maria J, Andrulis, Irene, Mulligan, Anna Marie, Glendon, Gord, Blanco, Ignacio, Lazaro, Conxi, Whittemore, Alice S, McGuire, Valerie, Sieh, Weiva, Montagna, Marco, Alducci, Elisa, Sadetzki, Siegal, Chetrit, Angela, Kwong, Ava, Kjaer, Susanne K, Jensen, Allan, Høgdall, Estrid, Neuhausen, Susan, Nussbaum, Robert, Daly, Mary, Greene, Mark H, Mai, Phuong L, Loud, Jennifer T, Moysich, Kirsten, Toland, Amanda E, Lambrechts, Diether, Ellis, Steve, Frost, Debra, Brenton, James D, Tischkowitz, Marc, Easton, Douglas F, Antoniou, Antonis, Chenevix-Trench, Georgia, Gayther, Simon A, Bowtell, David, Pharoah, Paul DP, for EMBRACE, kConFab Investigators, and Australian Ovarian Cancer Study Group
Subjects: Australian Ovarian Cancer Study Group, Clinical Trials and Supportive Activities, Oncology and Carcinogenesis, Rare Diseases, Clinical Research, Neoplasms, Ovarian Epithelial, Breast Cancer, Genetics, Humans, Oncology & Carcinogenesis, Germ-Line Mutation, Neoplasm Staging, Aged, Cancer, Ovarian Neoplasms, for EMBRACE, Prevention, Carcinoma, Glandular and Epithelial, Middle Aged, Prognosis, BRCA1, Survival Analysis, BRCA2, Ovarian Cancer, Good Health and Well Being, Genes, kConFab Investigators, Female, Neoplasm Grading
Abstract: PurposeTo analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis.Experimental designWe 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 analyzed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analyzed using Fine and Gray model.ResultsThe combined 10-year overall survival rate was 30% [95% confidence interval (CI), 28%-31%] for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The HR for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the HR was 0.42 at time zero and increased over time (predicted to become greater than 1 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.ConclusionsBRCA1/2 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.
Published: 2015

43. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

Author: Lawrenson, Kate, Iversen, Edwin S., Tyrer, Jonathan, Weber, Rachel Palmieri, Concannon, Patrick, Hazelett, Dennis J., Li, Qiyuan, Marks, Jeffrey R., Berchuck, Andrew, Lee, Janet M., Aben, Katja K.H., Anton-Culver, Hoda, Antonenkova, Natalia, Bandera, Elisa V., Bean, Yukie, Beckmann, Matthias W., Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A., Brooks-Wilson, Angela, Bruinsma, Fiona, Butzow, Ralf, Campbell, Ian G., Carty, Karen, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Chen, Ann, Cook, Linda S., Cramer, Daniel W., Cunningham, Julie M., Cybulski, Cezary, Plisiecka-Halasa, Joanna, Dennis, Joe, Dicks, Ed, Doherty, Jennifer A., Dörk, Thilo, du Bois, Andreas, Eccles, Diana, Easton, Douglas T., Edwards, Robert P., Eilber, Ursula, Ekici, Arif B., Fasching, Peter A., Fridley, Brooke L., Gao, Yu-Tang, Gentry-Maharaj, Aleksandra, Giles, Graham G., Glasspool, Rosalind, Goode, Ellen L., Goodman, Marc T., Gronwald, Jacek, Harter, Philipp, Hasmad, Hanis Nazihah, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle A.T., Hillemanns, Peter, Hogdall, Estrid, Hogdall, Claus, Hosono, Satoyo, Jakubowska, Anna, Paul, James, Jensen, Allan, Karlan, Beth Y., Kjaer, Susanne Kruger, Kelemen, Linda E., Kellar, Melissa, Kelley, Joseph L., Kiemeney, Lambertus A., Krakstad, Camilla, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D., Lee, Alice W., Cannioto, Rikki, Leminen, Arto, Lester, Jenny, Levine, Douglas A., Liang, Dong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon F.A.G., Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R., Nevanlinna, Heli, McNeish, Iain, Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B., Narod, Steven A., Nedergaard, Lotte, Ness, Roberta B., Noor Azmi, Mat Adenan, Odunsi, Kunle, Olson, Sara H., Orlow, Irene, Orsulic, Sandra, Pearce, Celeste L., Pejovic, Tanja, Pelttari, Liisa M., Permuth-Wey, Jennifer, Phelan, Catherine M., Pike, Malcolm C., Poole, Elizabeth M., Ramus, Susan J., Risch, Harvey A., Rosen, Barry, Rossing, Mary Anne, Rothstein, Joseph H., Rudolph, Anja, Runnebaum, Ingo B., Rzepecka, Iwona K., Salvesen, Helga B., Budzilowska, Agnieszka, Sellers, Thomas A., Shu, Xiao-Ou, Shvetsov, Yurii B., Siddiqui, Nadeem, Sieh, Weiva, Song, Honglin, Southey, Melissa C., Sucheston, Lara, Tangen, Ingvild L., Teo, Soo-Hwang, Terry, Kathryn L., Thompson, Pamela J., Timorek, Agnieszka, Tworoger, Shelley S., Van Nieuwenhuysen, Els, Vergote, Ignace, Vierkant, Robert A., Wang-Gohrke, Shan, Walsh, Christine, Wentzensen, Nicolas, Whittemore, Alice S., Wicklund, Kristine G., Wilkens, Lynne R., Woo, Yin-Ling, Wu, Xifeng, Wu, Anna H., Yang, Hannah, Zheng, Wei, Ziogas, Argyrios, Coetzee, Gerhard A., Freedman, Matthew L., Monteiro, Alvaro N.A., Moes-Sosnowska, Joanna, Kupryjanczyk, Jolanta, Pharoah, Paul D., Gayther, Simon A., and Schildkraut, Joellen M.
Subjects: endocrine system diseases, Medizinische Fakultät, ddc:610, female genital diseases and pregnancy complications
Abstract: Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10–7). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r 2 with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11–1.24, P = 1.1×10−7). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10−8). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r 2 = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10-8). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.
Published: 2015

44. Variation in NF-κB signaling pathways and survival in invasive epithelial ovarian cancer

Author: Block, Matthew S, Charbonneau, Bridget, Vierkant, Robert A, Fogarty, Zachary, Bamlet, William R, Pharoah, Paul DP, Georgia Chenevix-Trench, for AOCS, ACS Group, Rossing, Mary Anne, Cramer, Daniel, Pearce, Celeste Leigh, Schildkraut, Joellen, Menon, Usha, Kjaer, Susanne K, Levine, Douglas A, Gronwald, Jacek, Culver, Hoda Anton, Whittemore, Alice S, Karlan, Beth Y, Lambrechts, Diether, Wentzensen, Nicolas, Kupryjanczyk, Jolanta, Chang-Claude, Jenny, Bandera, Elisa V, Hogdall, Estrid, Heitz, Florian, Kaye, Stanley B, Fasching, Peter A, Campbell, Ian, Goodman, Marc T, Pejovic, Tanja, Bean, Yukie T, Hays, Laura E, Lurie, Galina, Eccles, Diana, Hein, Alexander, Beckmann, Matthias W, Ekici, Arif B, Paul, James, Brown, Robert, Flanagan, James M, Harter, Philipp, du Bois, Andreas, Schwaab, Ira, Hogdall, Claus K, Lundvall, Lene, Olson, Sara H, Orlow, Irene, Paddock, Lisa E, Rudolph, Anja, Eilber, Ursula, Dansonka-Mieszkowska, Agnieszka, Rzepecka, Iwona K, Ziolkowska-Seta, Izabela, Brinton, Louise A, Yang, Hannah, Garcia-Closas, Montserrat, Despierre, Evelyn, Lambrechts, Sandrina, Vergote, Ignace, Walsh, Christine S, Lester, Jenny, Sieh, Weiva, McGuire, Valerie, Rothstein, Joseph H, Ziogas, Argyrios, Lubiński, Jan, Cybulski, Cezary, Menkiszak, Janusz, Jensen, Allan, Gayther, Simon A, Ramus, Susan J, Gentry-Maharaj, Aleksandra, Berchuck, Andrew, Wu, Anna H, Pike, Malcolm C, Van Den Berg, David, Terry, Kathryn L, Vitonis, Allison F, Ramirez, Starr M, Rider, David N, Knutson, Keith L, Sellers, Thomas A, Phelan, Catherine M, Doherty, Jennifer A, Johnatty, Sharon E, deFazio, Anna, Song, Honglin, Tyrer, Jonathan, Kalli, Kimberly R, Fridley, Brooke L, Cunningham, Julie M, and Goode, Ellen L
Subjects: Adult, endocrine system diseases, Genotype, Epidemiology, Medical and Health Sciences, ACS Group, Georgia Chenevix-Trench, Rare Diseases, Neoplasms, Ovarian Epithelial, Genetics, Humans, 2.1 Biological and endogenous factors, Neoplasm Invasiveness, Aetiology, Polymorphism, Proportional Hazards Models, Aged, Cancer, Ovarian Neoplasms, Prevention, Inflammatory and immune system, Carcinoma, NF-kappa B, Glandular and Epithelial, Single Nucleotide, Middle Aged, female genital diseases and pregnancy complications, Ovarian Cancer, for AOCS, Female, Signal Transduction
Abstract: Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (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 < 2.5 × 10(-5)). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41-2.35; P = 4.13 × 10(-6)] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56-0.82; P = 2.33 × 10(-5)). Other associations of note included TNF receptor-associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77-0.92; P = 6.49 × 10(-5)) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26-0.73; P = 4.56 × 10(-4)). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.
Published: 2014

45. DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Osorio, Ana, Milne, Roger L., Kuchenbaecker, Karoline, Vaclová, Tereza, Pita, Guillermo, Alonso, Rosario, Peterlongo, Paolo, Blanco Guillermo, Ignacio, De la Hoya, Miguel, Durán, Mercedes, Diez, Orland, Ramon y Cajal, Teresa, Konstantopoulou, Irene, Martínez-Bouzas, Cristina, Andrés Conejero, Raquel, Soucy, Penny, McGuffog, Lesley, Barrowdale, Daniel, Lee, Andrew, SWE-BRCA, None, Arver, Brita, Rantala, Johanna, Loman, Niklas, Ehrencrona, Hans, Olopade, Olufunmilayo I., Beattie, Mary S., Domchek, Susan M., Nathanson, Katherine, Rebbeck, Timothy R., Arun, Banu K., Karlan, Beth Y., Walsh, Christine, Lester, Jenny, John, Esther M., Whittemore, Alice S., Daly, Mary B., Southey, Melissa, Hopper, John L, Terry, Mary Beth, Buys, Saundra, Janavicius, Ramunas, Dorfling, Cecilia M., van Rensburg, Elizabeth J., Steele, Linda, Neuhausen, Susan L., Ding, Yuan Chun, Hansen, Thomas v. O., Jønson, Lars, Ejlertsen, Bent, Gerdes, Anne-Marie, Infante, Mar, Herráez, Belén, Moreno, Leticia Thais, Weitzel, Jeffrey N., Herzog, Josef, Weeman, Kisa, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniela, Scuvera, Giulietta, Bonanni, Bernardo, Mariette, Frederique, Volorio, Sara, Viel, Alessandra, Varesco, Liliana, Papi, Laura, Ottini, Laura, Tibiletti, Maria Grazia, Radice, Paolo, Yannoukakos, Drakoulis, Garber, Judy, Ellis, Steve, Frost, Debra, Platte, Radka, Fineberg, Elena, Evans, Gareth, Lalloo, Fiona, Izatt, Louise, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Eccles, Diana M, Cook, Jackie, Hodgson, Shirley, Brewer, Carole, Tischkowitz, Marc, Douglas, Fiona, Porteous, Mary, Side, Lucy, Walker, Lisa, Morrison, Patrick, Donaldson, Alan, Kennedy, John, Foo, Claire, Godwin, Andrew K., Schmutzler, Rita Katharina, Wappenschmidt, Barbara, Rhiem, Kerstin, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hans Jörg, Niederacher, Dieter, Sutter, Christian, Wang-Gohrke, Shan, Steinemann, Doris, Preisler-Adams, Sabine, Kast, Karin, Varon-Mateeva, Raymonda, Gehrig, Andrea, Stoppa-Lyonnet, Dominique, Sinilnikova, Olga M., Mazoyer, Sylvie, Damiola, Francesca, Poppe, Bruce, Claes, Kathleen, Piedmonte, Marion, Tucker, Kathy, Backes, Floor, Rodríguez, Gustavo, Brewster, Wendy, Wakeley, Katie, Rutherford, Thomas, Caldes, Trinidad, Nevanlinna, Heli, Aittomäki, Kristiina, Rookus, Matti A., van Os, Theo A. M., van der Kolk, Lizet, de Lange, J. L., Meijers-Heijboer, Hanne E. J., van der Hout, A. H., van Asperen, Christi J., Gómez Garcia, Encarna B., Hoogerbrugge, Nicoline, Collée, J. Margriet, van Deurzen, Carolien H. M., van der Luijt, Rob B., Devilee, Peter, HEBON, None, Olah, Edith, Lázaro, Conxi, Teulé, Alex, Menéndez, Mireia, Jakubowska, Anna, Cybulski, Cezary, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska-Bieniek, Katarzyna, Johannsson, Oskar Th., Maugard, Christine, Montagna, Marco, Tognazzo, Silvia, Teixeira, Manuel R., Healey, Sue, Investigators, kConFab, Olswold, Curtis, Guidugli, Lucia, Lindor, Noralane, Slager, Susan, Szabo, Csilla I., Vijai, Joseph, Robson, Mark, Kauff, Noah, Zhang, Liying, Rau-Murthy, Rohini, Fink-Retter, Anneliese, Singer, Christian F., Rappaport, Christine, Geschwantler Kaulich, Daphne, Pfeiler, Georg, Tea, Muy-Kheng, Berger, Andreas, Phelan, Catherine M., Greene, Mark H., Mai, Phuong L., Lejbkowicz, Flavio, Andrulis, Irene L., Mulligan, Anna Marie, Glendon, Gord, Toland, Amanda Ewart, Bojesen, Anders, Pedersen, Inge Sokilde, Sunde, Lone, Thomassen, Mads, Kruse, Torben A., Jensen, Uffe Birk, Friedman, Eitan, Laitman, Yael, Shimon, Shani Paluch, Simard, Jacques, Easton, Douglas F., Offit, Kenneth, Couch, Fergus J., Chenevix-Trench, Georgia, Antoniou, Antonis C., Benitez, Javier, Universitat Autònoma de Barcelona, Pediatric Surgery, Clinical Genetics, Pathology, Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain, Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain. 2Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia. 3Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. 4Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain. 5Genotyping Unit (CeGen), Spanish National Cancer Centre (CNIO), Madrid, Spain. 6IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy. 7Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain. 8Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain. 9Institute of Biology and Molecular Genetics, Universidad de Valladolid (IBGM-UVA), Valladolid, Spain. 10Oncogenetics Laboratory, University Hospital Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Institut de Recerca (VHIR), and Universitat Autonoma de Barcelona, Barcelona, Spain. 11Oncology Service, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 12Molecular Diagnostics Laboratory IRRP, National Centre for Scientific Research Demokritos Aghia Paraskevi Attikis, Athens, Greece. 13Molecular Genetics Laboratory (Department of Biochemistry), Cruces Hospital Barakaldo, Bizkaia, Spain. 14Medical Oncology Service, Hospital Clínico Lozano Blesa, San Juan Bosco, Zaragoza, Spain. 15Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Canada. 16Department of Oncology, Lund University, Lund, Sweden. 17Department of Oncology, Karolinska University Hospital, Stockholm, Sweden. 18Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. 19Department of Oncology, Lund University Hospital, Lund, Sweden. 20Department of Clinical Genetics, Lund University Hospital, Lund, Sweden. 21Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois, United States of America. 22Departments of Medicine, Epidemiology, and Biostatistics, University of California, San Francisco, San Francisco, California, United States of America. 23Abramson Cancer Center and Department of Medicine, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America. 24Abramson Cancer Center and Center for Clinical Epidemiology and Biostatistics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America. 25University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. 26Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America. 27Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, United States of America. 28Department of Health Research & Policy, Stanford University School of Medicine, Stanford, California, United States of America. 29Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America. 30Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Australia. 31Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Victoria, Australia. 32Department of Epidemiology, Columbia University, New York, New York, United States of America. 33Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America. 34Vilnius University Hospital Santariskiu Clinics, Hematology, oncology and transfusion medicine center, Department of Molecular and Regenerative Medicine, Vilnius, Lithuania. 35Department of Genetics, University of Pretoria, Pretoria, South Africa. 36Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, United States of America. 37Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 38Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 39Department of Clinical Genetics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 40Clinical Cancer Genetics, City of Hope, Duarte, California, United States of America. 41Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy. 42Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy. 43IFOM, Fondazione Istituto FIRC di Oncologia Molecolare and Cogentech Cancer Genetic Test Laboratory, Milan, Italy. 44Division of Experimental Oncology 1, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy. 45Unit of Hereditary Cancer, Department of Epidemiology, Prevention and Special Functions, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. 46Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy. 47Department of Molecular Medicine, 'Sapienza' University, Rome, Italy. 48UO Anatomia Patologica, Ospedale di Circolo-Università dell'Insubria, Varese, Italy. 49Unit of Molecular bases of genetic risk and genetic testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy. 50Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. 51Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom. 52South East Thames Regional Genetics Service, Guy's Hospital London, United Kingdom. 53Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, United Kingdom. 54Yorkshire Regional Genetics Service, Leeds, United Kingdom. 55Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, United Kingdom. 56West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, United Kingdom. 57Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom. 58Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, United Kingdom. 59Clinical Genetics Department, St Georges Hospital, University of London, London, United Kingdom. 60Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, United Kingdom. 61Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrookes Hospital, Cambridge, United Kingdom. 62Institute of Human Genetics, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom. 63South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, United Kingdom. 64North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom. 65Oxford Regional Genetics Service, Churchill Hospital, Oxford, United Kingdom. 66Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, United Kingdom. 67South West Regional Genetics Service, Bristol, United Kingdom. 68Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin and St James's Hospital, Dublin, Eire. 69Cheshire & Merseyside Clinical Genetics Service, Liverpool Women's NHS Foundation Trust, Liverpool, United Kingdom. 70Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, United States of America. 71Centre of Familial Breast and Ovarian Cancer and Centre for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany. 72Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. 73Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany. 74Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. 75Institute of Human Genetics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. 76Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany. 77Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany. 78Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany. 79Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany. 80Institute of Human Genetics, University of Münster, Münster, Germany. 81Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany. 82Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Berlin, Germany. 83Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Würzburg, Germany. 84Institut Curie, Department of Tumour Biology, Paris, France, Institut Curie, INSERM U830, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 85Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, Lyon, France, INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France. 86INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France. 87Center for Medical Genetics, Ghent University, Ghent, Belgium. 88Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, New York, United States of America. 89Prince of Wales Hospital. Sydney, Australia. 90Ohio State University, Columbus Cancer Council, Columbus, Ohio, United States of America. 91Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, Illinois, United States of America. 92Division of Gynecologic Oncology, NorthShore University HealthSystem, Chicago, Illinois, United States of America. 93For Tufts Medical Center, Boston, Massachusetts, United States of America. 94Yale University School of Medicine, New Haven, Connecticut, United States of America. 95Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. 96Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands. 97Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands. 98Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands. 99Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands. 100University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands. 101Department of Clinical Genetics, Leiden University Medical Center Leiden, Leiden, The Netherlands. 102Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands. 103Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 104Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands. 105Department of Pathology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands. 106Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 107Department of Human Genetics & Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. 108The Hereditary Breast and Ovarian Cancer Research Group, Netherlands Cancer Institute, Amsterdam, The Netherlands. 109Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary. 110Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain. 111Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland. 112Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland, Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland. 113Department of Oncology, Landspitali University Hospital and BMC, Faculty of Medicine, University of Iceland, Reykjavik Iceland. 114Laboratoire de Diagnostic Génétique et Service d'Onco-hématologie, Hopitaux Universitaire de Strasbourg, CHRU Nouvel Hôpital Civil, Strasbourg, France. 115Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy. 116Department of Genetics, Portuguese Oncology Institute, Porto, and Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal. 117Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia. 118Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Peter MacCallum Cancer Center, Melbourne, Australia. 119Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America. 120Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America. 121Center for Individualized Medicine, Mayo Clinic, Scottsdale, Arizona, United States of America. 122Center for Translational Cancer Research, Department of Biological Sciences, University of Delaware, Newark, Delaware, United States of America. 123Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America, Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. 124Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. 125Diagnostic Molecular Genetics Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. 126Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. 127Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, United States of America. 128Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States of America. 129Clalit National Israeli Cancer Control Center, Haifa, Israel. 130Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, and Cancer Care Ontario, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. 131Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada, Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada. 132Ontario Cancer Genetics Network: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. 133Division of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America. 134Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark. 135Section of Molecular Diagnostics, Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark. 136Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark. 137Department of Clinical Genetics, Odense University Hospital, Odense, Denmark. 138Sheba Medical Center, Tel Aviv, Israel. 139Canada Research Chair in Oncogenetics, Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Canada. 140Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America. 141Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain, Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain, Genotyping Unit (CeGen), Spanish National Cancer Centre (CNIO), Madrid, Spain., SWE-BRCA, Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, Instituto de Salud Carlos III, Unión Europea, Cancer Research UK (Reino Unido), United States of Department of Health & Human Services, Canadian Institutes of Health Research, Susan G. Komen Breast Cancer Foundation, Ralph and Marion Falk Medical Research Trust, Research Council (Lituania), University of Kansas. Cancer Center (Estados Unidos), National Institute for Health Research (Reino Unido), Deutsche Krebshilfe, Finlands Akademi (Finlandia), Dutch Cancer Society (Holanda), Dutch Research Council (Holanda), Pink Ribbons Project, Hungarian Scientific Research Fund (Hungría), Canadian Breast Cancer Network, Ministère du Développement économique, de Innovation et de Exportation (Canadá), Westat (Estados Unidos), Department of Obstetrics and Gynecology, Clinicum, Universitat de Barcelona, Human Genetics, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Lee, Andrew [0000-0003-0677-0252], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Human genetics, CCA - Oncogenesis, Fundación Mutua Madrileña Automovilista, Fundacion Asociacion Espanola Contra el Cancer (AECC), Instituto de Salud Carlos III - ISCIII, European Union (EU), Cancer Research UK, United States Department of Health & Human Services National Institutes of Health (NIH) - USA, Canadian Institutes of Health Research (CIHR), Research Council of Lithuania, University of Kansas Cancer Center, National Institute for Health Research (NIHR), Academy of Finland, KWF Kankerbestrijding, Netherlands Organization for Scientific Research (NWO), Pink Ribbon grant, Orszagos Tudomanyos Kutatasi Alapprogramok (OTKA), Canadian Breast Cancer Research Alliance-grant, Ministry of Economic Development, Innovation and Export Trade, and Westat, Inc, Rockville, MD
Subjects: Cancer Research, 24 Ciencias de la Vida, DNA Repair, endocrine system diseases, ADN, Càncer d'ovari, Synthetic lethality, BRCA1 Protein/genetics, DNA Glycosylases, 0302 clinical medicine, DNA Glycosylases/genetics, Brjóstakrabbamein, Genotype, Medicine and Health Sciences, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Glicosilasas, INVESTIGATORS, skin and connective tissue diseases, OGG1, Genetics (clinical), Genetics, DAMAGE, Aged, 80 and over, Ovarian Neoplasms, 0303 health sciences, BRCA1 Protein, SINGLE-NUCLEOTIDE POLYMORPHISMS, COMMON VARIANTS, Base excision repair, Middle Aged, BRCA2 Protein, 3. Good health, 030220 oncology & carcinogenesis, NEIL2, Female, Medical Genetics, Research Article, BRCA1, BRCA2, Adult, Risk, Ovarian Neoplasms/genetics, lcsh:QH426-470, Adolescent, DNA repair, education, Single-nucleotide polymorphism, Breast Neoplasms, DNA Repair/genetics, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, OVARIAN-CANCER, 03 medical and health sciences, Polymorphism, Single Nucleotide/genetics, SDG 3 - Good Health and Well-being, Ovarian cancer, Cancer Genetics, BREAST-CANCER, Humans, Genetic Predisposition to Disease, ddc:610, Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Aged, BRCA2 Protein/genetics, CONSORTIUM, Biology and Life Sciences, Arfgengi, lcsh:Genetics, DNA glycosylase, Cancer research, 3111 Biomedicine, GENETIC MODIFIERS, Genètica
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, Author Summary Women harboring a germ-line mutation in the BRCA1 or BRCA2 genes have a high lifetime risk to develop breast and/or ovarian cancer. However, not all carriers develop cancer and high variability exists regarding age of onset of the disease and type of tumor. One of the causes of this variability lies in other genetic factors that modulate the phenotype, the so-called modifier genes. Identification of these genes might have important implications for risk assessment and decision making regarding prevention of the disease. Given that BRCA1 and BRCA2 participate in the repair of DNA double strand breaks, here we have investigated whether variations, Single Nucleotide Polymorphisms (SNPs), in genes participating in other DNA repair pathway may be associated with cancer risk in BRCA carriers. We have selected the Base Excision Repair pathway because BRCA defective cells are extremely sensitive to the inhibition of one of its components, PARP1. Thanks to a large international collaborative effort, we have been able to identify at least two SNPs that are associated with increased cancer risk in BRCA1 and BRCA2 mutation carriers respectively. These findings could have implications not only for risk assessment, but also for treatment of BRCA1/2 mutation carriers with PARP inhibitors.
Published: 2014

46. Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome

Author: Charbonneau, Bridget, Moysich, Kirsten B, Kalli, Kimberly R, Oberg, Ann L, Vierkant, Robert A, Fogarty, Zachary C, Block, Matthew S, Maurer, Matthew J, Goergen, Krista M, Fridley, Brooke L, Cunningham, Julie M, Rider, David N, Preston, Claudia, Hartmann, Lynn C, Lawrenson, Kate, Wang, Chen, Tyrer, Jonathan, Song, Honglin, deFazio, Anna, Johnatty, Sharon E, Doherty, Jennifer A, Phelan, Catherine M, Sellers, Thomas A, Ramirez, Starr M, Vitonis, Allison F, Terry, Kathryn L, Van Den Berg, David, Pike, Malcolm C, Wu, Anna H, Berchuck, Andrew, Gentry-Maharaj, Aleksandra, Ramus, Susan J, Diergaarde, Brenda, Shen, Howard, Jensen, Allan, Menkiszak, Janusz, Cybulski, Cezary, Lubiłski, Jan, Ziogas, Argyrios, Rothstein, Joseph H, McGuire, Valerie, Sieh, Weiva, Lester, Jenny, Walsh, Christine, Vergote, Ignace, Lambrechts, Sandrina, Despierre, Evelyn, Garcia-Closas, Montserrat, Yang, Hannah, Brinton, Louise A, Spiewankiewicz, Beata, Rzepecka, Iwona K, Dansonka-Mieszkowska, Agnieszka, Seibold, Petra, Rudolph, Anja, Paddock, Lisa E, Orlow, Irene, Lundvall, Lene, Olson, Sara H, Hogdall, Claus K, Schwaab, Ira, du Bois, Andreas, Harter, Philipp, Flanagan, James M, Brown, Robert, Paul, James, Ekici, Arif B, Beckmann, Matthias W, Hein, Alexander, Eccles, Diana, Lurie, Galina, Hays, Laura E, Bean, Yukie T, Pejovic, Tanja, Goodman, Marc T, Campbell, Ian, Fasching, Peter A, Konecny, Gottfried, Kaye, Stanley B, Heitz, Florian, Hogdall, Estrid, Bandera, Elisa V, Chang-Claude, Jenny, Kupryjanczyk, Jolanta, Wentzensen, Nicolas, Lambrechts, Diether, Karlan, Beth Y, Whittemore, Alice S, Culver, Hoda Anton, Gronwald, Jacek, Levine, Douglas A, Kjaer, Susanne K, Menon, Usha, Schildkraut, Joellen M, Pearce, Celeste Leigh, Cramer, Daniel W, Rossing, Mary Anne, Chenevix-Trench, Georgia, AOCS group, and ACS
Subjects: T-Lymphocytes, Immunology, Oncology and Carcinogenesis, Gene Expression, AOCS group, Rare Diseases, Genetics, Humans, 2.1 Biological and endogenous factors, Neoplasm Invasiveness, Genetic Predisposition to Disease, Aetiology, Polymorphism, Germ-Line Mutation, Cancer, Ovarian Neoplasms, Gene Expression Profiling, Interleukin-2 Receptor alpha Subunit, Genetic Variation, Single Nucleotide, Pharmacology and Pharmaceutical Sciences, ACS, Prognosis, Regulatory, Ovarian Cancer, Patient Outcome Assessment, Female, Neoplasm Grading
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.
Published: 2014

47. DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers

Author: Osorio, Ana, Milne, Roger L, Kuchenbaecker, Karoline, Vaclová, Tereza, Pita, Guillermo, Alonso, Rosario, Peterlongo, Paolo, Blanco, Ignacio, de la Hoya, Miguel, Duran, Mercedes, Díez, Orland, Ramón Y Cajal, Teresa, Konstantopoulou, Irene, Martínez-Bouzas, Cristina, Andrés Conejero, Raquel, Soucy, Penny, McGuffog, Lesley, Barrowdale, Daniel, Lee, Andrew, SWE-BRCA, Arver, Brita, Rantala, Johanna, Loman, Niklas, Ehrencrona, Hans, Olopade, Olufunmilayo I, Beattie, Mary S, Domchek, Susan M, Nathanson, Katherine, Rebbeck, Timothy R, Arun, Banu K, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, John, Esther M, Whittemore, Alice S, Daly, Mary B, Southey, Melissa, Hopper, John, Terry, Mary B, Buys, Saundra S, Janavicius, Ramunas, Dorfling, Cecilia M, van Rensburg, Elizabeth J, Steele, Linda, Neuhausen, Susan L, Ding, Yuan Chun, Hansen, Thomas VO, Jønson, Lars, Ejlertsen, Bent, Gerdes, Anne-Marie, Infante, Mar, Herráez, Belén, Moreno, Leticia Thais, Weitzel, Jeffrey N, Herzog, Josef, Weeman, Kisa, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniela, Scuvera, Giulietta, Bonanni, Bernardo, Mariette, Frederique, Volorio, Sara, Viel, Alessandra, Varesco, Liliana, Papi, Laura, Ottini, Laura, Tibiletti, Maria Grazia, Radice, Paolo, Yannoukakos, Drakoulis, Garber, Judy, Ellis, Steve, Frost, Debra, Platte, Radka, Fineberg, Elena, Evans, Gareth, Lalloo, Fiona, Izatt, Louise, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Eccles, Diana, Cook, Jackie, Hodgson, Shirley, Brewer, Carole, Tischkowitz, Marc, Douglas, Fiona, Porteous, Mary, Side, Lucy, Walker, Lisa, Morrison, Patrick, Donaldson, Alan, Kennedy, John, Foo, Claire, Godwin, Andrew K, Schmutzler, Rita Katharina, Wappenschmidt, Barbara, Rhiem, Kerstin, Engel, Christoph, and Horwitz, Marshall S
Subjects: Risk, Adult, endocrine system diseases, DNA Repair, Genotype, Adolescent, Breast Neoplasms, and over, DNA Glycosylases, Rare Diseases, Breast Cancer, 80 and over, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Genetic Testing, Polymorphism, Aetiology, skin and connective tissue diseases, HEBON, Aged, Cancer, Ovarian Neoplasms, BRCA2 Protein, BRCA1 Protein, Prevention, Single Nucleotide, SWE-BRCA, Middle Aged, Ovarian Cancer, Female, KConFab Investigators, Developmental Biology
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
Published: 2014

48. Risk of ovarian cancer and the NF-κB pathway: genetic association with IL1A and TNFSF10

Author: Charbonneau, Bridget, Block, Matthew S, Bamlet, William R, Vierkant, Robert A, Kalli, Kimberly R, Fogarty, Zachary, Rider, David N, Sellers, Thomas A, Tworoger, Shelley S, Poole, Elizabeth, Risch, Harvey A, Salvesen, Helga B, Kiemeney, Lambertus A, Baglietto, Laura, Giles, Graham G, Severi, Gianluca, Trabert, Britton, Wentzensen, Nicolas, Chenevix-Trench, Georgia, for AOCS/ACS group, Whittemore, Alice S, Sieh, Weiva, Chang-Claude, Jenny, Bandera, Elisa V, Orlow, Irene, Terry, Kathryn, Goodman, Marc T, Thompson, Pamela J, Cook, Linda S, Rossing, Mary Anne, Ness, Roberta B, Narod, Steven A, Kupryjanczyk, Jolanta, Lu, Karen, Butzow, Ralf, Dörk, Thilo, Pejovic, Tanja, Campbell, Ian, Le, Nhu D, Bunker, Clareann H, Bogdanova, Natalia, Runnebaum, Ingo B, Eccles, Diana, Paul, James, Wu, Anna H, Gayther, Simon A, Hogdall, Estrid, Heitz, Florian, Kaye, Stanley B, Karlan, Beth Y, Anton-Culver, Hoda, Gronwald, Jacek, Hogdall, Claus K, Lambrechts, Diether, Fasching, Peter A, Menon, Usha, Schildkraut, Joellen, Pearce, Celeste Leigh, Levine, Douglas A, Kjaer, Susanne Kruger, Cramer, Daniel, Flanagan, James M, Phelan, Catherine M, Brown, Robert, Massuger, Leon FAG, Song, Honglin, Doherty, Jennifer A, Krakstad, Camilla, Liang, Dong, Odunsi, Kunle, Berchuck, Andrew, Jensen, Allan, Lubinski, Jan, Nevanlinna, Heli, Bean, Yukie T, Lurie, Galina, Ziogas, Argyrios, Walsh, Christine, Despierre, Evelyn, Brinton, Louise, Hein, Alexander, Rudolph, Anja, Dansonka-Mieszkowska, Agnieszka, Olson, Sara H, Harter, Philipp, Tyrer, Jonathan, Vitonis, Allison F, Brooks-Wilson, Angela, Aben, Katja K, Pike, Malcolm C, Ramus, Susan J, Wik, Elisabeth, Cybulski, Cezary, Lin, Jie, Sucheston, Lara, Edwards, Robert, McGuire, Valerie, Lester, Jenny, du Bois, Andreas, and Lundvall, Lene
Subjects: Ovarian Neoplasms, Risk, Prevention, Human Genome, Oncology and Carcinogenesis, NF-kappa B, Single Nucleotide, for AOCS/ACS group, Ovarian Cancer, TNF-Related Apoptosis-Inducing Ligand, Rare Diseases, Clinical Research, Case-Control Studies, Interleukin-1alpha, Genetics, Humans, 2.1 Biological and endogenous factors, Female, Oncology & Carcinogenesis, Polymorphism, Aetiology, Genetic Association Studies, Signal Transduction, Cancer
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.
Published: 2014

49. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

Author: Shen, Hui, Fridley, Brooke L, Song, Honglin, Lawrenson, Kate, Cunningham, Julie M, Ramus, Susan J, Cicek, Mine S, Tyrer, Jonathan, Stram, Douglas, Larson, Melissa C, Köbel, Martin, PRACTICAL Consortium, Ziogas, Argyrios, Zheng, Wei, Yang, Hannah P, Wu, Anna H, Wozniak, Eva L, Woo, Yin Ling, Winterhoff, Boris, Wik, Elisabeth, Whittemore, Alice S, Wentzensen, Nicolas, Weber, Rachel Palmieri, Vitonis, Allison F, Vincent, Daniel, Vierkant, Robert A, Vergote, Ignace, Van Den Berg, David, Van Altena, Anne M, Tworoger, Shelley S, Thompson, Pamela J, Tessier, Daniel C, Terry, Kathryn L, Teo, Soo-Hwang, Templeman, Claire, Stram, Daniel O, Southey, Melissa C, Sieh, Weiva, Siddiqui, Nadeem, Shvetsov, Yurii B, Shu, Xiao-Ou, Shridhar, Viji, Wang-Gohrke, Shan, Severi, Gianluca, Schwaab, Ira, Salvesen, Helga B, Rzepecka, Iwona K, Runnebaum, Ingo B, Rossing, Mary Anne, Rodriguez-Rodriguez, Lorna, Risch, Harvey A, Renner, Stefan P, Poole, Elizabeth M, Pike, Malcolm C, Phelan, Catherine M, Pelttari, Liisa M, Pejovic, Tanja, Paul, James, Orlow, Irene, Omar, Siti Zawiah, Olson, Sara H, Odunsi, Kunle, Nickels, Stefan, Nevanlinna, Heli, Ness, Roberta B, Narod, Steven A, Nakanishi, Toru, Moysich, Kirsten B, Monteiro, Alvaro NA, Moes-Sosnowska, Joanna, Modugno, Francesmary, Menon, Usha, McLaughlin, John R, McGuire, Valerie, Matsuo, Keitaro, Adenan, Noor Azmi Mat, Massuger, Leon FAG, Lurie, Galina, Lundvall, Lene, Lubiński, Jan, Lissowska, Jolanta, Levine, Douglas A, Leminen, Arto, Lee, Alice W, Le, Nhu D, Lambrechts, Sandrina, Lambrechts, Diether, Kupryjanczyk, Jolanta, Krakstad, Camilla, Konecny, Gottfried E, Kjaer, Susanne Krüger, Kiemeney, Lambertus A, Kelemen, Linda E, Keeney, Gary L, Karlan, Beth Y, Karevan, Rod, Kalli, Kimberly R, Kajiyama, Hiroaki, Ji, Bu-Tian, and Jensen, Allan
Subjects: Australian Ovarian Cancer Study Group, Ovarian Neoplasms, endocrine system diseases, Gene Expression Profiling, Prevention, Human Genome, Single Nucleotide, DNA Methylation, female genital diseases and pregnancy complications, Ovarian Cancer, Promoter Regions, Rare Diseases, Genetic, Australian Cancer Study, Genetics, PRACTICAL Consortium, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Female, Polymorphism, Aetiology, Epigenesis, Hepatocyte Nuclear Factor 1-beta, Cancer
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.
Published: 2013

50. Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families

Author: Bailey-Wilson, Joan E, Childs, Erica J, Cropp, Cheryl D, Schaid, Daniel J, Xu, Jianfeng, Camp, Nicola J, Cannon-Albright, Lisa A, Farnham, James M, George, Asha, Powell, Isaac, Carpten, John D, Giles, Graham G, Hopper, John L, Severi, Gianluca, English, Dallas R, Foulkes, William D, Mæhle, Lovise, Møller, Pål, Eeles, Rosalind, Easton, Douglas, Guy, Michelle, Edwards, Steve, Badzioch, Michael D, Whittemore, Alice S, Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Dimitrov, Latchezar, Stanford, Janet L, Karyadi, Danielle M, Deutsch, Kerry, McIntosh, Laura, Ostrander, Elaine A, Wiley, Kathleen E, Isaacs, Sarah D, Walsh, Patrick C, Thibodeau, Stephen N, McDonnell, Shannon K, Hebbring, Scott, Lange, Ethan M, Cooney, Kathleen A, Tammela, Teuvo LJ, Schleutker, Johanna, Maier, Christiane, Bochum, Sylvia, Hoegel, Josef, Grönberg, Henrik, Wiklund, Fredrik, Emanuelsson, Monica, Cancel-Tassin, Geraldine, Valeri, Antoine, Cussenot, Olivier, Isaacs, William B, International Consortium for Prostate Cancer Genetics, Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: Male, Chromosomes, Human, X, Genetic Linkage, Humans, Prostatic Neoplasms, Alleles, Genome-Wide Association Study, Microsatellite Repeats
Abstract: BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Published: 2012

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