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

Abstract

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWASs) 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<5x108^{-8} with 10 variants at nine novel loci. At P< 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative or BRCA1 mutation carrier GWASs, and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other breast cancer GWASs. 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 carriers. These findings will likely lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.Genotyping for the OncoArray was funded by the government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-129344), the Ministère de l'Économie, de la Science et de l'Innovation du Québec through Génome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (NIH) (1 U19 CA 148065 for the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract HHSN268201200008I), Cancer Research UK (C1287/A16563), the Odense University Hospital Research Foundation (Denmark), the National R&D Program for Cancer Control–Ministry of Health and Welfare (Republic of Korea) (1420190), the Italian Association for Cancer Research (AIRC; IG16933), the Breast Cancer Research Foundation, the National Health and Medical Research Council (Australia) and German Cancer Aid (110837). Genotyping for the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710, C1287/A10118 and C12292/A11174]), NIH grants (CA128978, CA116167 and CA176785) and the Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 (GAME-ON initiative)), an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Ministère de l'Économie, Innovation et Exportation du Québec (PSR-SIIRI-701), the Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. Combination of the GWAS data was supported in part by the NIH Cancer Post-Cancer GWAS initiative (1 U19 CA 148065) (DRIVE, part of the GAME-ON initiative). LD score regression analysis was supported by grant CA194393. BCAC is funded by Cancer Research UK (C1287/A16563) and by the European Union via its Seventh Framework Programme (HEALTH-F2-2009-223175, COGS) and the Horizon 2020 Research and Innovation Programme (633784, B-CAST; 634935, BRIDGES). CIMBA is funded by Cancer Research UK (C12292/A20861 and C12292/A11174)

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