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Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk
PLoS Genet. 2013 ;9(3) :e1003212
PMID: 23544013    PMCID: PMC3609646   
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Abstract
BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2x10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
Notes
Couch, Fergus J Wang, Xianshu McGuffog, Lesley Lee, Andrew Olswold, Curtis Kuchenbaecker, Karoline B Soucy, Penny Fredericksen, Zachary Barrowdale, Daniel Dennis, Joe Gaudet, Mia M Dicks, Ed Kosel, Matthew Healey, Sue Sinilnikova, Olga M Lee, Adam Bacot, Francois Vincent, Daniel Hogervorst, Frans B L Peock, Susan Stoppa-Lyonnet, Dominique Jakubowska, Anna kConFab Investigators Radice, Paolo Schmutzler, Rita Katharina SWE-BRCA Domchek, Susan M Piedmonte, Marion Singer, Christian F Friedman, Eitan Thomassen, Mads Ontario Cancer Genetics Network Hansen, Thomas V O Neuhausen, Susan L Szabo, Csilla I Blanco, Ignacio Greene, Mark H Karlan, Beth Y Garber, Judy Phelan, Catherine M Weitzel, Jeffrey N Montagna, Marco Olah, Edith Andrulis, Irene L Godwin, Andrew K Yannoukakos, Drakoulis Goldgar, David E Caldes, Trinidad Nevanlinna, Heli Osorio, Ana Terry, Mary Beth Daly, Mary B van Rensburg, Elizabeth J Hamann, Ute Ramus, Susan J Toland, Amanda Ewart Caligo, Maria A Olopade, Olufunmilayo I Tung, Nadine Claes, Kathleen Beattie, Mary S Southey, Melissa C Imyanitov, Evgeny N Tischkowitz, Marc Janavicius, Ramunas John, Esther M Kwong, Ava Diez, Orland Balmana, Judith Barkardottir, Rosa B Arun, Banu K Rennert, Gad Teo, Soo-Hwang Ganz, Patricia A Campbell, Ian van der Hout, Annemarie H van Deurzen, Carolien H M Seynaeve, Caroline Gomez Garcia, Encarna B van Leeuwen, Flora E Meijers-Heijboer, Hanne E J Gille, Johannes J P Ausems, Margreet G E M Blok, Marinus J Ligtenberg, Marjolijn J L Rookus, Matti A Devilee, Peter Verhoef, Senno van Os, Theo A M Wijnen, Juul T HEBON EMBRACE Frost, Debra Ellis, Steve Fineberg, Elena Platte, Radka Evans, D Gareth Izatt, Louise Eeles, Rosalind A Adlard, Julian Eccles, Diana M Cook, Jackie Brewer, Carole Douglas, Fiona Hodgson, Shirley Morrison, Patrick J Side, Lucy E Donaldson, Alan Houghton, Catherine Rogers, Mark T Dorkins, Huw Eason, Jacqueline Gregory, Helen McCann, Emma Murray, Alex Calender, Alain Hardouin, Agnes Berthet, Pascaline Delnatte, Capucine Nogues, Catherine Lasset, Christine Houdayer, Claude Leroux, Dominique Rouleau, Etienne Prieur, Fabienne Damiola, Francesca Sobol, Hagay Coupier, Isabelle Venat-Bouvet, Laurence Castera, Laurent Gauthier-Villars, Marion Leone, Melanie Pujol, Pascal Mazoyer, Sylvie Bignon, Yves-Jean GEMO Study Collaborators Zlowocka-Perlowska, Elzbieta Gronwald, Jacek Lubinski, Jan Durda, Katarzyna Jaworska, Katarzyna Huzarski, Tomasz Spurdle, Amanda B Viel, Alessandra Peissel, Bernard Bonanni, Bernardo Melloni, Giulia Ottini, Laura Papi, Laura Varesco, Liliana Tibiletti, Maria Grazia Peterlongo, Paolo Volorio, Sara Manoukian, Siranoush Pensotti, Valeria Arnold, Norbert Engel, Christoph Deissler, Helmut Gadzicki, Dorothea Gehrig, Andrea Kast, Karin Rhiem, Kerstin Meindl, Alfons Niederacher, Dieter Ditsch, Nina Plendl, Hansjoerg Preisler-Adams, Sabine Engert, Stefanie Sutter, Christian Varon-Mateeva, Raymonda Wappenschmidt, Barbara Weber, Bernhard H F Arver, Brita Stenmark-Askmalm, Marie Loman, Niklas Rosenquist, Richard Einbeigi, Zakaria Nathanson, Katherine L Rebbeck, Timothy R Blank, Stephanie V Cohn, David E Rodriguez, Gustavo C Small, Laurie Friedlander, Michael Bae-Jump, Victoria L Fink-Retter, Anneliese Rappaport, Christine Gschwantler-Kaulich, Daphne Pfeiler, Georg Tea, Muy-Kheng Lindor, Noralane M Kaufman, Bella Shimon Paluch, Shani Laitman, Yael Skytte, Anne-Bine Gerdes, Anne-Marie Pedersen, Inge Sokilde Moeller, Sanne Traasdahl Kruse, Torben A Jensen, Uffe Birk Vijai, Joseph Sarrel, Kara Robson, Mark Kauff, Noah Mulligan, Anna Marie Glendon, Gord Ozcelik, Hilmi Ejlertsen, Bent Nielsen, Finn C Jonson, Lars Andersen, Mette K Ding, Yuan Chun Steele, Linda Foretova, Lenka Teule, Alex Lazaro, Conxi Brunet, Joan Pujana, Miquel Angel Mai, Phuong L Loud, Jennifer T Walsh, Christine Lester, Jenny Orsulic, Sandra Narod, Steven A Herzog, Josef Sand, Sharon R Tognazzo, Silvia Agata, Simona Vaszko, Tibor Weaver, Joellen Stavropoulou, Alexandra V Buys, Saundra S Romero, Atocha de la Hoya, Miguel Aittomaki, Kristiina Muranen, Taru A Duran, Mercedes Chung, Wendy K Lasa, Adriana Dorfling, Cecilia M Miron, Alexander BCFR Benitez, Javier Senter, Leigha Huo, Dezheng Chan, Salina B Sokolenko, Anna P Chiquette, Jocelyne Tihomirova, Laima Friebel, Tara M Agnarsson, Bjarni A Lu, Karen H Lejbkowicz, Flavio James, Paul A Hall, Per Dunning, Alison M Tessier, Daniel Cunningham, Julie Slager, Susan L Wang, Chen Hart, Steven Stevens, Kristen Simard, Jacques Pastinen, Tomi Pankratz, Vernon S Offit, Kenneth Easton, Douglas F Chenevix-Trench, Georgia Antoniou, Antonis C CIMBA 5U01CA113916/CA/NCI NIH HHS/United States C12292/A11174/Cancer Research UK/United Kingdom C1287/A10118/Cancer Research UK/United Kingdom C1287/A11990/Cancer Research UK/United Kingdom C5047/A8385/Cancer Research UK/United Kingdom CA 101165/CA/NCI NIH HHS/United States CA 27469/CA/NCI NIH HHS/United States CA 37517/CA/NCI NIH HHS/United States CA-06-503/CA/NCI NIH HHS/United States CA116201/CA/NCI NIH 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HHS/United States U01 CA69638/CA/NCI NIH HHS/United States UL1 RR025764/RR/NCRR NIH HHS/United States Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. United States PLoS Genet. 2013;9(3):e1003212. doi: 10.1371/journal.pgen.1003212. Epub 2013 Mar 27.