Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

Fergus J. Couch, Xianshu Wang, Lesley McGuffog, Andrew Lee, Curtis Olswold, Karoline B. Kuchenbaecker, Penny Soucy, Zachary Fredericksen, Daniel Barrowdale, Joe Dennis, Mia M. Gaudet, Ed Dicks, Matthew Kosel, Sue Healey, Olga M. Sinilnikova, Adam Lee, François Bacot, Daniel Vincent, Frans B L Hogervorst, Susan PeockDominique Stoppa-Lyonnet, Anna Jakubowska, Paolo Radice, Rita Katharina Schmutzler, Susan M. Domchek, Marion Piedmonte, Christian F. Singer, Eitan Friedman, Mads Thomassen, Thomas V O Hansen, Susan L. Neuhausen, Csilla I. Szabo, Ignacio Blanco, Mark H. Greene, Beth Y. Karlan, Judy Garber, Catherine M. Phelan, Jeffrey N. Weitzel, Marco Montagna, Edith Olah, Irene L. Andrulis, Andrew K. Godwin, Drakoulis Yannoukakos, David E. Goldgar, Trinidad Caldes, Heli Nevanlinna, Ana Osorio, Mary Beth Terry, Mary B. Daly, Elizabeth J. van Rensburg, Ute Hamann, Susan J. Ramus, Amanda Ewart Toland, Maria A. Caligo, Olufunmilayo I. Olopade, Nadine Tung, Kathleen Claes, Mary S. Beattie, Melissa C. Southey, Evgeny N. Imyanitov, Marc Tischkowitz, Ramunas Janavicius, Esther M. John, Ava Kwong, Orland Diez, Judith Balmaña, Rosa B. Barkardottir, Banu K. Arun, Gad Rennert, Soo Hwang Teo, Patricia A. Ganz, Ian Campbell, Annemarie H. van der Hout, Carolien H M van Deurzen, Caroline Seynaeve, Encarna B. Gómez Garcia, Flora E. van Leeuwen, Hanne E J Meijers-Heijboer, Johannes J P Gille, Margreet G E M Ausems, Marinus J. Blok, Marjolijn J L Ligtenberg, Matti A. Rookus, Peter Devilee, Senno Verhoef, Theo A M van Os, Juul T. Wijnen, Debra Frost, Steve Ellis, Elena Fineberg, Radka Platte, D. Gareth Evans, Louise Izatt, Rosalind A. Eeles, Julian Adlard, Diana M. Eccles, Jackie Cook, Carole Brewer, Fiona Douglas, Shirley Hodgson, Patrick J. Morrison, Lucy E. Side, Alan Donaldson, Catherine Houghton, Mark T. Rogers, Huw Dorkins, Jacqueline Eason, Helen Gregory, Emma McCann, Alex Murray, Alain Calender, Agnès Hardouin, Pascaline Berthet, Capucine Delnatte, Catherine Nogues, Christine Lasset, Claude Houdayer, Dominique Leroux, Etienne Rouleau, Fabienne Prieur, Francesca Damiola, Hagay Sobol, Isabelle Coupier, Laurence Venat-Bouvet, Laurent Castera, Marion Gauthier-Villars, Mélanie Léoné, Pascal Pujol, Sylvie Mazoyer, Yves Jean Bignon, Elzbieta Złowocka-Perłowska, Jacek Gronwald, Jan Lubinski, Katarzyna Durda, Katarzyna Jaworska, Tomasz Huzarski, Amanda B. Spurdle, Alessandra Viel, Bernard Peissel, Bernardo Bonanni, Giulia Melloni, Laura Ottini, Laura Papi, Liliana Varesco, Maria Grazia Tibiletti, Paolo Peterlongo, Sara Volorio, Siranoush Manoukian, Valeria Pensotti, Norbert Arnold, Christoph Engel, Helmut Deissler, Dorothea Gadzicki, Andrea Gehrig, Karin Kast, Kerstin Rhiem, Alfons Meindl, Dieter Niederacher, Nina Ditsch, Hansjoerg Plendl, Sabine Preisler-Adams, Stefanie Engert, Christian Sutter, Raymonda Varon-Mateeva, Barbara Wappenschmidt, Bernhard H F Weber, Brita Arver, Marie Stenmark-Askmalm, Niklas Loman, Richard Rosenquist, Zakaria Einbeigi, Katherine L. Nathanson, Timothy R. Rebbeck, Stephanie V. Blank, David E. Cohn, Gustavo C. Rodriguez, Laurie Small, Michael Friedlander, Victoria L. Bae-Jump, Anneliese Fink-Retter, Christine Rappaport, Daphne Gschwantler-Kaulich, Georg Pfeiler, Muy Kheng Tea, Noralane M. Lindor, Bella Kaufman, Shani Shimon Paluch, Yael Laitman, Anne Bine Skytte, Anne Marie Gerdes, Inge Sokilde Pedersen, Sanne Traasdahl Moeller, Torben A. Kruse, Uffe Birk Jensen, Joseph Vijai, Kara Sarrel, Mark Robson, Noah Kauff, Anna Marie Mulligan, Gord Glendon, Hilmi Ozcelik, Bent Ejlertsen, Finn C. Nielsen, Lars Jønson, Mette K. Andersen, Yuan Chun Ding, Linda Steele, Lenka Foretova, Alex Teulé, Conxi Lazaro, Joan Brunet, Miquel Angel Pujana, Phuong L. Mai, Jennifer T. Loud, Christine Walsh, Jenny Lester, Sandra Orsulic, Steven A. Narod, Josef Herzog, Sharon R. Sand, Silvia Tognazzo, Simona Agata, Tibor Vaszko, Joellen Weaver, Alexandra V. Stavropoulou, Saundra S. Buys, Atocha Romero, Miguel de la Hoya, Kristiina Aittomäki, Taru A. Muranen, Mercedes Duran, Wendy K. Chung, Adriana Lasa, Cecilia M. Dorfling, Alexander Miron, Javier Benitez, Leigha Senter, Dezheng Huo, Salina B. Chan, Anna P. Sokolenko, Jocelyne Chiquette, Laima Tihomirova, Tara M. Friebel, Bjarni A. Agnarsson, Karen H. Lu, Flavio Lejbkowicz, Paul A. James, Per Hall, Alison M. Dunning, Daniel Tessier, Julie Cunningham, Susan L. Slager, Chen Wang, Steven Hart, Kristen Stevens, Jacques Simard, Tomi Pastinen, Vernon S. Pankratz, Kenneth Offit, Douglas F. Easton, Georgia Chenevix-Trench, Antonis C. Antoniou, Heather Thorne, Eveline Niedermayr, Åke Borg, Håkan Olsson, Helena Jernström, Karin Henriksson, Katja Harbst, Maria Soller, Niklas Loman, Ulf Kristoffersson, Anna Öfverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi, Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza, Johanna Rantala, Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson, Hans Ehrencrona, Maritta Hellström Pigg, Richard Rosenquist, Marie Stenmark-Askmalm, Sigrun Liedgren, M. A. Rookus, F. B L Hogervorst, S. Verhoef, F. E. van Leeuwen, M. K. Schmidt, J. de Lange, J. M. Collée, A. M W van den Ouweland, M. J. Hooning, C. Seynaeve, C. J. van Asperen, J. T. Wijnen, R. A. Tollenaar, P. Devilee, T. C T E F van Cronenburg, C. M. Kets, A. R. Mensenkamp, M. G E M Ausems, R. B. van der Luijt, C. M. Aalfs, T. A M van Os, J. J P Gille, Q. Waisfisz, H. E J Meijers-Heijboer, E. B. Gómez-Garcia, M. J. Blok, J. C. Oosterwijk, H. van der Hout, M. J. Mourits, G. H. de Bock, Susan Peock, Debra Frost, Steve Ellis, Elena Fineberg, Radka Platte, Zosia Miedzybrodzka, Helen Gregory, Patrick Morrison, Lisa Jeffers, Trevor Cole, Kai Ren Ong, Jonathan Hoffman, Alan Donaldson, Margaret James, Marc Tischkowitz, Joan Paterson, Amy Taylor, Alexandra Murray, Mark T. Rogers, Emma McCann, M. John Kennedy, David Barton, Mary Porteous, Sarah Drummond, Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill, Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan, Louise Izatt, Chris Jacobs, Caroline Langman, Huw Dorkins, Angela Brady, Athalie Melville, Kashmir Randhawa, Julian Barwell, Julian Adlard, Gemma Serra-Feliu, Ian Ellis, Catherine Houghton, Fiona Lalloo, Jane Taylor, Lucy Side, Alison Male, Cheryl Berlin, Jacqueline Eason, Rebecca Collier, Fiona Douglas, Oonagh Claber, Irene Jobson, Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah Durell, Barbara Stayner, Rosalind A. Eeles, Susan Shanley, Nazneen Rahman, Richard Houlston, Astrid Stormorken, Elizabeth Bancroft, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Elena Castro, Emma Killick, Sue Martin, Gillian Rea, Anjana Kulkarni, Jackie Cook, Oliver Quarrell, Cathryn Bardsley, Shirley Hodgson, Sheila Goff, Glen Brice, Lizzie Winchester, Charlotte Eddy, Vishakha Tripathi, Virginia Attard, Anna Lehmann, Diana Eccles, Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley, Olga Sinilnikova, Sylvie Mazoyer, Francesca Damiola, Laure Barjhoux, Carole Verny-Pierre, Sophie Giraud, Mélanie Léone, Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Virginie Moncoutier, Muriel Belotti, Carole Tirapo, Antoine de Pauw, Brigitte Bressac-de-Paillerets, Olivier Caron, Yves Jean Bignon, Nancy Uhrhammer, Christine Lasset, Valérie Bonadona, Sandrine Handallou, Agnès Hardouin, Pascaline Berthet, Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, François Eisinger, Isabelle Coupier, Pascal Pujol, Jean Philippe Peyrat, Joëlle Fournier, Françoise Révillion, Philippe Vennin, Claude Adenis, Etienne Rouleau, Rosette Lidereau, Liliane Demange, Catherine Nogues, Danièle Muller, Jean Pierre Fricker, Emmanuelle Barouk-Simonet, Françoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy, Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel, Dominique Leroux, Hélène Dreyfus, Christine Rebischung, Magalie Peysselon, Fanny Coron, Laurence Faivre, Fabienne Prieur, Marine Lebrun, Caroline Kientz, Sandra Fert Ferrer, Marc Frénay, Laurence Vénat-Bouvet, Capucine Delnatte, Isabelle Mortemousque, Florence Coulet, Chrystelle Colas, Florent Soubrier, Johanna Sokolowska, Myriam Bronner, Henry T. Lynch, Carrie L. Snyder, Maggie Angelakos, Judi Maskiell, Gillian Dite

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218 Scopus citations

Abstract

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10-4). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

Original languageEnglish (US)
Article numbere1003212
JournalPLoS genetics
Volume9
Issue number3
DOIs
StatePublished - 2013

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