Abstract
Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10-5in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10-8) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10-6) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10-9), and with both ER-positive (OR = 1.09; P = 1.5 × 10-5) and ER-negative (OR = 1.16, P = 2.5 × 10-7) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5373-5384 |
| Number of pages | 12 |
| Journal | Human molecular genetics |
| Volume | 21 |
| Issue number | 24 |
| DOIs | |
| State | Published - Dec 15 2012 |
Bibliographical note
Funding Information:The breast cancer GWAS in Japanese and Latinos in the MEC (MEC-LAT and MEC-JPT) were supported by NIH grants CA132839, CA54281 and CA63464. Genotyping of the Latino breast cancer cases and controls from SFBCS and NC-BCFR was supported by NIH grant CA120120.
Funding Information:
The TNBCC studies were supported by the following grants: MCBCS (National Institutes of Health Grants CA122340 and a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201) and the Breast Cancer Research Foundation (BCRF); MARIE (Deutsche Krebshilfe e.V., grant number 70-2892-BR I, the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany grant 01KH0402); GENICA (Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114, and the Robert Bosch Foundation Stuttgart, Germany; MCCS (Australian NHMRC grants 209057, 251553 and 504711 and infrastructure provided by the Cancer Council Victoria); SBCS [Breast Cancer Campaign (grant 2004Nov49 to A.C.), and by Yorkshire Cancer Research core funding]; DFCI (DFCI Breast Cancer SPORE NIH P50 CA089393); POSH (Cancer Research UK); DEMOKRITOS [Hellenic Cooperative Oncology Group research grant (HR R_BG/04) and the Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II, funded at 75% by the European Union]; BBCC (Dr Mildred Scheel Stiftung of the Deutsche Krebshilfe e.V.); BBCS (Cancer Research UK and Breakthrough Breast Cancer and NHS funding to the NIHR biomedical Research Centre and the National Cancer Research Network (NCRN); LMBC (European Union Frame-work Programme 6 Project LSHC-CT-2003-503297 (the Can-cerdegradome) and by the ‘Stichting tegen Kanker’ (232-2008); OBCS (Finnish Cancer Foundation, the Sigrid Juselius Foundation, the Academy of Finland, the University of Finland, and Oulu University Hospital); HEBCS (Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation); FCCC (U01CA69631, 5U01CA113916, the University of Kansas Cancer Center and the Kansas Bioscience Authority Eminent Scholar Program); RPCI (RPCI DataBank and BioRepository (DBBR), a Cancer Center Support Grant Shared Resource (P30 CA016056-32)); SKKDKFZS (Deutsches Krebs-forschungszentrum); BIGGS (National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust); ABCTB (National Health and Medical Research Council of Australia, The Cancer Institute NSW and the National Breast Cancer Foundation); ABCS (Dutch Cancer Society grant number 2009-4363); KARBAC (The Stockholm Cancer Society).
Funding Information:
AABC was supported by a Department of Defense Breast Cancer Research Program Era of Hope Scholar Award to C.A.H. (W81XWH-08-1-0383) and the Norris Foundation. Each of the participating AABC studies was supported by the following grants: MEC (National Institutes of Health grants R01-CA63464 and R37-CA54281); CARE (National Institute for Child Health and Development grant NO1-HD-3-3175), WCHS (U.S. Army Medical Research and Material Command (USAMRMC) grant DAMD-17-01-0-0334, the National Institutes of Health grant R01-CA100598 and the Breast Cancer Research Foundation, SFBCS (National Institutes of Health grant R01-CA77305 and United States Army Medical Research Program grant DAMD17-96-6071), NC-BCFR (National Institutes of Health grant U01-CA69417), CBCS (National Institutes of Health Specialized Program of Research Excellence in Breast Cancer, grant number P50-CA58223, and Center for Environmental Health and Susceptibility, National Institute of Environmental Health Sciences, National Institutes of Health, grant number P30-ES10126), PLCO (Intramural Research Program, National Cancer Institute, National Institutes of Health) and NBHS (National Institutes of Health grant R01-CA100374),WFBC (National Institutes of Health grant R01-CA73629). The NC-BCFR is one of six sites participating in The Breast Cancer Family Registry (BCFR) which was supported by the National Cancer Institute, National Institutes of Health under RFA CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry and Principal Investigators. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the BCFR.
Funding Information:
The biofeature analysis was supported by NIH grant CA109147.
Funding Information:
BPC3 is supported by the US National Institutes of Health, National Cancer Institute under cooperative agreements U01-CA98233 (NHS, NHSII, WHS), U01-CA98710 (CPS2), U01-CA98216 (EPIC), U01-CA98758 (MEC) and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics (PLCO). The authors thank Drs Christine Berg and Philip Prorok, Division of Cancer Prevention, NCI, the screening center investigators and staff of the PLCO Cancer Screening Trial, Mr Thomas Riley and staff at Information Management Services, Inc., and Ms Barbara O’Brien and staff at Westat, Inc. for their contributions to the PLCO Cancer Screening Trial.
Funding Information:
The UK2 GWAS was funded by Wellcome Trust and Cancer Research UK. The WTCCC was funded by the Wellcome Trust. BCAC is funded by CR-UK (C1287/A10118, C1287/A12014) and by the European Community’s Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). The ABCFS study was supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and the Principle Investigators. The University of Melbourne (U01 CA69638) contributed data to this study. The content of this manuscript does not necessarily reflect the views or the policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the BCFR. We extend our thanks to the many women and their families that generously participated in the Australian Breast Cancer Family Study and consented to us accessing their pathology material. J.L.H. is a National Health and Medical Research Council Australia Fellow. M.C.S. is a National Health and Medical Research Council Senior Research Fellow. J.L.H. and M.C.S. are both group leaders of the Victoria Breast Cancer Research Consortium. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). The BBCS GWAS received funding from The Institut National de Cancer. The DFBBCS GWAS was funded by The Netherlands Organisation for Scientific Research (NWO) as part of a ZonMw/VIDI grant number 91756341. We thank Muriel Adank for selecting the samples and Margreet Ausems, Christi van Asperen, Senno Verhoef and Rogier van Oldenburg for providing samples from their Clinical Genetic centers. The GC-HBOC was supported by Deutsche Krebshilfe (107054), the Dietmar-Hopp Foundation, the Helmholtz society and the German Cancer Research Centre (DKFZ). The GC-HBOC GWAS was supported by the German Cancer Aid (grant no. 107352). The MARIE study was supported by the Deutsche Krebshilfe e.V. (70-2892-BR I), the Hamburg Cancer Society, the German Cancer Research Center and the genotype work in part by the Federal Ministry of Education and Research (BMBF) Germany (01KH0402). MARIE would like to thank Tracy Slanger and Elke Mutschelknauss for their valuable contributions, and S. Behrens, R. Birr, M.Celik, U. Eilber, B. Kaspereit, N. Knese and K. Smit for their excellent technical assistance. The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A∗STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. CGEMS. The Nurses’ Health Studies are supported by NIH grants CA 65725, CA87969, CA49449, CA67262, CA50385 and 5UO1CA098233. The HEBCS study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation. The population allele and genotype frequencies were obtained from the data source funded by the Nordic Center of Excellence in Disease Genetics based on samples regionally selected from Finland, Sweden and Denmark. We thank Drs Kirsimari Aaltonen, Päivi Heik-kilä and Tuomas Heikkinen and RN Hanna Jäntti and Irja Erkkilä for their help with the HEBCS data and samples.
Funding Information:
The WHS is supported by HL043851 and HL080467 from the National Heart, Lung, and Blood Institute and CA 047988 from the National Cancer Institute, the Donald W. Reynolds Foundation and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen.
