Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.
Roger L Milne, Karoline B Kuchenbaecker, Kyriaki Michailidou, Jonathan Beesley, Siddhartha Kar, Sara Lindström, Shirley Hui, Audrey Lemaçon, Penny Soucy, Joe Dennis, Xia Jiang, Asha Rostamianfar, Hilary Finucane, Manjeet K Bolla, Lesley McGuffog, Qin Wang, Cora M Aalfs, Marcia Adams, Julian Adlard, Simona Agata, Shahana Ahmed, Habibul Ahsan, Kristiina Aittomäki, Fares Al-Ejeh, Jamie Allen, Christine B Ambrosone, Christopher I Amos, Irene L Andrulis, Hoda Anton-Culver, Natalia N Antonenkova, Volker Arndt, Norbert Arnold, Kristan J Aronson, Bernd Auber, Paul L Auer, Margreet G E M Ausems, Jacopo Azzollini, François Bacot, Judith Balmaña, Monica Barile, Laure Barjhoux, Rosa B Barkardottir, Myrto Barrdahl, Daniel Barnes, Daniel Barrowdale, Caroline Baynes, Matthias W Beckmann, Javier Benitez, Marina Bermisheva, Leslie Bernstein, Yves-Jean Bignon, Kathleen R Blazer, Marinus J Blok, Carl Blomqvist, William Blot, Kristie Bobolis, Bram Boeckx, Natalia V Bogdanova, Anders Bojesen, Stig E 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Asperen, David Van Den Berg, Ans M W van den Ouweland, Elizabeth J van Rensburg, Liliana Varesco, Raymonda Varon-Mateeva, Ana Vega, Alessandra Viel, Joseph Vijai, Daniel Vincent, Jason Vollenweider, Lisa Walker, Zhaoming Wang, Shan Wang-Gohrke, Barbara Wappenschmidt, Clarice R Weinberg, Jeffrey N Weitzel, Camilla Wendt, Jelle Wesseling, Alice S Whittemore, Juul T Wijnen, Walter Willett, Robert Winqvist, Alicja Wolk, Anna H Wu, Lucy Xia, Xiaohong R Yang, Drakoulis Yannoukakos, Daniela Zaffaroni, Wei Zheng, Bin Zhu, Argyrios Ziogas, Elad Ziv, Kristin K Zorn, Manuela Gago-Dominguez, Arto Mannermaa, Håkan Olsson, Manuel R Teixeira, Jennifer Stone, Kenneth Offit, Laura Ottini, Sue K Park, Mads Thomassen, Per Hall, Alfons Meindl, Rita K Schmutzler, Arnaud Droit, Gary D Bader, Paul D P Pharoah, Fergus J Couch, Douglas F Easton, Peter Kraft, Georgia Chenevix-Trench, Montserrat García-Closas, Marjanka K Schmidt, Antonis C Antoniou, Jacques SimardMost common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10-8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
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