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

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Bibtex

@article{e372e4b36cbb42d6b4d886c1642e36e1,
title = "Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk",
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 = 2 x 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.",
author = "Couch, {Fergus J.} and Xianshu Wang and Lesley McGuffog and Andrew Lee and Curtis Olswold and Kuchenbaecker, {Karoline B.} and Penny Soucy and Zachary Fredericksen and Daniel Barrowdale and Joe Dennis and Gaudet, {Mia M.} and Ed Dicks and Matthew Kosel and Sue Healey and Sinilnikova, {Olga M.} and Adam Lee and Francois Bacot and Daniel Vincent and Hogervorst, {Frans B. L.} and Susan Peock and Dominique Stoppa-Lyonnet and Anna Jakubowska and Paolo Radice and Schmutzler, {Rita Katharina} and Domchek, {Susan M.} and Marion Piedmonte and Singer, {Christian F.} and Eitan Friedman and Mads Thomassen and Hansen, {Thomas V. O.} and Neuhausen, {Susan L.} and Szabo, {Csilla I.} and Ignacio Blanco and Greene, {Mark H.} and Karlan, {Beth Y.} and Judy Garber and Phelan, {Catherine M.} and Weitzel, {Jeffrey N.} and Marco Montagna and Edith Olah and Andrulis, {Irene L.} and Godwin, {Andrew K.} and Drakoulis Yannoukakos and Goldgar, {David E.} and Trinidad Caldes and Heli Nevanlinna and Ana Osorio and Terry, {Mary Beth} and Daly, {Mary B.} and {van Rensburg}, {Elizabeth J.} and Ute Hamann and Ramus, {Susan J.} and Toland, {Amanda Ewart} and Caligo, {Maria A.} and Olopade, {Olufunmilayo I.} and Nadine Tung and Kathleen Claes and Beattie, {Mary S.} and Southey, {Melissa C.} and Imyanitov, {Evgeny N.} and Marc Tischkowitz and Ramunas Janavicius and John, {Esther M.} and Ava Kwong and Orland Diez and Judith Balmana and Barkardottir, {Rosa B.} and Arun, {Banu K.} and Gad Rennert and Soo-Hwang Teo and Ganz, {Patricia A.} and Ian Campbell and {van der Hout}, {Annemarie H.} and {van Deurzen}, {Carolien H. M.} and Caroline Seynaeve and Garcia, {Encarna B. Gomez} and {van Leeuwen}, {Flora E.} and Meijers-Heijboer, {Hanne E. J.} and Gille, {Johannes J. P.} and Ausems, {Margreet G. E. M.} and Blok, {Marinus J.} and Ligtenberg, {Marjolijn J. L.} and Rookus, {Matti A.} and Peter Devilee and Senno Verhoef and {van Os}, {Theo A. M.} and Wijnen, {Juul T.} and Debra Frost and Steve Ellis and Elena Fineberg and Radka Platte and Evans, {D. Gareth} and Louise Izatt and Eeles, {Rosalind A.} and Julian Adlard and Eccles, {Diana M.} and Jackie Cook and Carole Brewer and Fiona Douglas and Shirley Hodgson and Morrison, {Patrick J.} and Side, {Lucy E.} and Alan Donaldson and Catherine Houghton and Rogers, {Mark T.} and Huw Dorkins and Jacqueline Eason and Helen Gregory and Emma McCann and Alex Murray and Alain Calender and Agnes Hardouin and Pascaline Berthet and Capucine Delnatte and Catherine Nogues and Christine Lasset and Claude Houdayer and Dominique Leroux and Etienne Rouleau and Fabienne Prieur and Francesca Damiola and Hagay Sobol and Isabelle Coupier and Laurence Venat-Bouvet and Laurent Castera and Marion Gauthier-Villars and Melanie Leone and Pascal Pujol and Sylvie Mazoyer and Yves-Jean Bignon and Elzbieta Zlowocka-Perlowska and Jacek Gronwald and Jan Lubinski and Katarzyna Durda and Katarzyna Jaworska and Tomasz Huzarski and Spurdle, {Amanda B.} and Alessandra Viel and Bernard Peissel and Bernardo Bonanni and Giulia Melloni and Laura Ottini and Laura Papi and Liliana Varesco and Tibiletti, {Maria Grazia} and Paolo Peterlongo and Sara Volorio and Siranoush Manoukian and Valeria Pensotti and Norbert Arnold and Christoph Engel and Helmut Deissler and Dorothea Gadzicki and Andrea Gehrig and Karin Kast and Kerstin Rhiem and Alfons Meindl and Dieter Niederacher and Nina Ditsch and Hansjoerg Plendl and Sabine Preisler-Adams and Stefanie Engert and Christian Sutter and Raymonda Varon-Mateeva and Barbara Wappenschmidt and Weber, {Bernhard H. F.} and Brita Arver and Marie Stenmark-Askmalm and Niklas Loman and Richard Rosenquist and Zakaria Einbeigi and Nathanson, {Katherine L.} and Rebbeck, {Timothy R.} and Blank, {Stephanie V.} and Cohn, {David E.} and Rodriguez, {Gustavo C.} and Laurie Small and Michael Friedlander and Bae-Jump, {Victoria L.} and Anneliese Fink-Retter and Christine Rappaport and Daphne Gschwantler-Kaulich and Georg Pfeiler and Muy-Kheng Tea and Lindor, {Noralane M.} and Bella Kaufman and Paluch, {Shani Shimon} and Yael Laitman and Anne-Bine Skytte and Anne-Marie Gerdes and Pedersen, {Inge Sokilde} and Moeller, {Sanne Traasdahl} and Kruse, {Torben A.} and Jensen, {Uffe Birk} and Joseph Vijai and Kara Sarrel and Mark Robson and Noah Kauff and Mulligan, {Anna Marie} and Gord Glendon and Hilmi Ozcelik and Bent Ejlertsen and Nielsen, {Finn C.} and Lars Jonson and Andersen, {Mette K.} and Ding, {Yuan Chun} and Linda Steele and Lenka Foretova and Alex Teule and Conxi Lazaro and Joan Brunet and {Angel Pujana}, Miquel and Mai, {Phuong L.} and Loud, {Jennifer T.} and Christine Walsh and Jenny Lester and Sandra Orsulic and Narod, {Steven A.} and Josef Herzog and Sand, {Sharon R.} and Silvia Tognazzo and Simona Agata and Tibor Vaszko and Joellen Weaver and Stavropoulou, {Alexandra V.} and Buys, {Saundra S.} and Atocha Romero and {de la Hoya}, Miguel and Kristiina Aittomaki and Muranen, {Taru A.} and Mercedes Duran and Chung, {Wendy K.} and Adriana Lasa and Dorfling, {Cecilia M.} and Alexander Miron and Javier Benitez and Leigha Senter and Dezheng Huo and Chan, {Salina B.} and Sokolenko, {Anna P.} and Jocelyne Chiquette and Laima Tihomirova and Friebel, {Tara M.} and Agnarsson, {Bjarni A.} and Lu, {Karen H.} and Flavio Lejbkowicz and James, {Paul A.} and Per Hall and Dunning, {Alison M.} and Daniel Tessier and Julie Cunningham and Slager, {Susan L.} and Chen Wang and Steven Hart and Kristen Stevens and Jacques Simard and Tomi Pastinen and Pankratz, {Vernon S.} and Kenneth Offit and Easton, {Douglas F.} and Georgia Chenevix-Trench and Antoniou, {Antonis C.}",
year = "2013",
doi = "10.1371/journal.pgen.1003212",
language = "English",
volume = "9",
journal = "PLoS Genetics",
issn = "1553-7404",
publisher = "Public Library of Science",
number = "3",

}