We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER+ or ER−) and human ERBB2 (HER2+ or HER2−) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER− tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
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We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. This study would not have been possible without the contributions of the following: A. Berchuck (OCAC), R.A. Eeles, A.A. Al Olama, Z. Kote-Jarai and S. Benlloch (PRACTICAL), C. Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, the staff of the CNIO genotyping unit, D.C. Tessier, F. Bacot, D. Vincent, S. LaBoissière, F. Robidoux and the staff of the McGill University and Génome Québec Innovation Centre, S.F. Nielsen, B.G. Nordestgaard and the staff of the Copenhagen DNA laboratory, and J.M. Cunningham, S.A. Windebank, C.A. Hilker, J. Meyer and the staff of the Mayo Clinic Genotyping Core Facility. Normal human tissues from the Susan G. Komen for the Cure Tissue Bank at the Indiana University Simon Cancer Center (Indianapolis) were used in this study. We thank the contributors, including Indiana University who collected samples used in this study, as well as the donors and their families, whose help and participation made this work possible. We also acknowledge National Institute for Health Research (NIHR) support to the Royal Marsden Biomedical Research Centre. Funding for the iCOGS infrastructure came from the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692 and C8197/A16565), the US National Institutes of Health (NIH; CA128978, CA192393, CA116167, CA176785 and an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201)) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112, the GAME-ON initiative), the US Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. Full acknowledgments are given in the Supplementary Note.
The authors declare no competing financial interests.
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Dunning, A., Michailidou, K., Kuchenbaecker, K. et al. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170. Nat Genet 48, 374–386 (2016). https://doi.org/10.1038/ng.3521
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