Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08-1.13, P = 4.1 × 10-23) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92-0.97, P = 1.4 × 10 -8). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q.
Bibliographical noteFunding Information:
The initial GWAS, SEARCH, the replication genotyping through BCAC and the main analysis of this study were supported by Cancer Research UK grants C1287/ A7497, C490/A11021, C1287/A10118 and C1287/A5260. D.F.E. and P.D.P.P. are supported by Cancer Research UK. Meetings of BCAC have been supported in part by ESF COST action BM0606. The Nurses’ Health Studies are supported by US National Institutes of Health grants CA65725, CA87969, CA49449, CA67262, CA50385 and 5UO1CA098233. The WHI program is supported by contracts from the National Heart, Lung, and Blood Institute, NIH. We thank the WHI investigators and staff for their dedication and the study participants for making the program possible. A full listing of WHI investigators can be found at http://www.whiscience.org/ publications/WHI_investigators_shortlist.pdf. The ACS study is supported by UO1 CA098710. We thank C. Lichtman for data management and the participants on the CPS-II. The PLCO study is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and contracts from the Division of Cancer Prevention, National Cancer Institute, NIH and DHHS. We thank P. Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Center investigators and staff of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) and T. Sheehy and staff at SAIC-Frederick. We acknowledge the study participants for their contributions to making this study possible. The ABCFS was supported by the National Health and Medical Research Council (NHMRC) of Australia (#145604), the US NIH (RO1 CA102740-01A2) and by the National Cancer Institute, NIH under RFA #CA-95-011 through cooperative agreements with members of the Breast Cancer Family Registry (Breast CFR) and principal investigators from Cancer Care Ontario (UO1 CA69467), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), Northern California Cancer Center (U01 CA69417) and University of Melbourne (U01 CA69638). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of collaborating centers in the Breast CFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US government or the Breast CFR. The ABCFS was initially supported by the NHMRC, the New South Wales Cancer Council and the Victorian Health Promotion Foundation. J.L.H. and M.C.S. are supported by NHMRC. We thank M. Angelakos, J. Maskiell and G. Dite. We thank X. Chen for genotyping the ABCFS, kConFab and AOCS samples, and H. Thorne, E. Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics and the Clinical Follow Up Study (funded by NHMRC grants 145684, 288704 and 454508) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. The AOCS Management Group (D. Bowtell, G.C.-T., A. deFazio, D. Gertig, A. Green and P. Webb) gratefully acknowledges the contribution of all the clinical and scientific collaborators (see http://www.aocstudy.org/). The ACS Management Group (A. Green, P. Parsons, N. Hayward, P .Webb, D. Whiteman) thank all of the project staff, collaborating institutions and study participants. Financial support was provided by US Army Medical Research and Materiel Command under DAMD17-01-1-0729, the Cancer Council Tasmania and Cancer Foundation of Western Australia (AOCS study) and The National Health and Medical Research Council of Australia (199600) (ACS study). G.C.-T. is supported by NHMRC. Funding of the ABCS study was provided by the Dutch Cancer Society (grants NKI 2001-2423; 2007-3839) and the Dutch National Genomics Initiative. ABCS acknowledges L. Braaf, L. Van’t Veer, F. Van Leeuwen, R. Tollenaar and other contributors to the ‘BOSOM’ study and the support of H.B. Bueno-de-Mesquita for organizing the release of control DNA. The British Breast Cancer Study is funded by Cancer Research UK and Breakthrough Breast Cancer. We acknowledge NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). The CGPS was supported by the Danish Medical Research Council and Copenhagen County. The CNIO-BCS was supported by the Genome Spain Foundation and grants from the Asociación Española Contra Cáncer and the Fondo de Investigación Sanitario (PI081120 and PI081583). We thank J.I. Arias from the Hospital Monte Naranco, P. Zamora from the Hospital La Paz and C. Alonso and T. Moreno from the CNIO. The GENICA study was supported by the German Human Genome Project and funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114. Genotyping analysis was supported by the Robert Bosch Foundation of Medical Research. B. Pesch, V. Harth and T. Brüning were involved in the recruitment of study subjects and responsible for the collection of epidemiological data. The Genetic Epidemiology Study of Breast Cancer by Age 50 (GESBC) was supported by the Deutsche Krebshilfe e.V. (project number 70492) and the genotyping in part by the state of Baden-Württemberg through Medical Faculty of the University of Ulm (P.685). We thank U. Eilber and T. Koehler for their technical support. We cordially thank M. Bremer, A. Scharf and C. Sohn for their support of the breast cancer studies in Hannover. HABCS and HMBCS received funding through a Hannelore-Munke stipend to N.V.B. HUBCS was supported by a grant from the German Federal Ministry of Education and Research (RUS 08/017). HEBCS wishes to thank H. Jäntti and K. Aaltonen for help with the subject data. The Finnish Cancer registry is gratefully acknowledged for the cancer data. The HEBCS study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (110663), Finnish Cancer Society and the Sigrid Juselius Foundation. KARBAC was supported by The Swedish Cancer Foundation, The Gustav V Jubilee Foundation and the Bert von Kantzow Foundation. KBCP is grateful to E. Myöhänen for her assistance. KBCP was supported by special Government Funding (EVO) of Kuopio University Hospital, The Finnish Cancer Society, University of Kuopio and by the Northern Savo Cancer Society. MCBCS was supported by grants from the NIH (P50 CA116201 and R01 CA122340). We thank all the participants in the MCCS and the team of investigators, project and data managers and project assistants. The MCCS is supported by the Australian National Health and Medical Research Council (grants 209057, 251533, 396414 and 504711). Cohort recruitment and follow up is funded by The Cancer Council Victoria. The OFBCR was supported by the National Cancer Institute, NIH under RFA #CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry and Cancer Care Ontario (U01 CA69467). We thank N. Weerasooriya, M. Gill, L. Collins and N. Gokgoz for their assistance. The ORIGO study was supported by the Dutch Cancer Society; we thank P.E.A. Huijts, E. Krol-Warmerdam and J. Blom for recruiting subjects, administering questionnaires and managing clinical information. RBCS was supported by the Dutch Cancer Society. SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US NIH and the Susan G. Komen Breast Cancer Foundation. The SBCS was supported by Yorkshire Cancer Research and the Breast Cancer Campaign. We thank S. Higham, H. Cramp, D. Connley and S. Balasubramanian for their contribution to the SBCS. The PBCS was funded by Intramural Research Funds of the US National Cancer Institute, DHHS. The PBCS thanks N. Szeszenia-Dabrowska, B. Peplonska, W. Zatonski, M. Sherman and P. Chao for their valuable contributions to the study. SEBCS was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare (R.O.K.) (AO30001) and by a grant from the National R&D program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (0620410-1). The UCIBCS component of this research was supported by the US NIH, National Cancer Institute grants CA-58860 and CA-92044 and the Lon V. Smith Foundation grant LVS-39420.