Abstract
A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r2=0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI =1.10-1.16 and, for ER-negative tumors, OR was 1.03, 95% CI =0.98-1.07, case-only P-heterogeneity =7.6 × 10-5]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P=6.7 × 10-3) and lobular histology (case-only P=0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer. Published by Oxford University Press 2011.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4693-4706 |
| Number of pages | 14 |
| Journal | Human molecular genetics |
| Volume | 20 |
| Issue number | 23 |
| DOIs | |
| State | Published - Dec 1 2011 |
Bibliographical note
Funding Information:The BBCC study was partly funded by the ELAN Funding of the University of Erlangen.
Funding Information:
The TBCS was funded by The National Cancer Institute Thailand.
Funding Information:
The GESBC study was supported by the Deutsche Kreb-shilfe e. V. [70492] and GESBC genotyping in part by the state of Baden-Württemberg through the Medical Faculty of the University of Ulm [P.685].
Funding Information:
The BSUCH study was supported by the Dietmar-Hopp Foundation and the Helmholtz Society.
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The UCIBCS study was supported by the National Institutes of Health, National Cancer Institute grants CA-58860 and the Lon V Smith Foundation grant LVS-39420.
Funding Information:
The LMBC Leuven Multidisciplinary Breast Center (LMBC) is supported by the ‘Stichting tegen Kanker’ (232–2008). B.T.Y is funded by FWO. We acknowledge Gilian Peuteman, Dominiek Smeets, Thomas Van Brussel for technical support.
Funding Information:
The ABCS study was supported by the Dutch Cancer Society [grants NKI 2001 – 2423; 2007 – 3839] and the Dutch National Genomics Initiative. ABCS acknowledges the Family Cancer Clinic at the NKI-AVL and Richard van Hien and Sten Cornelissen for DNA plating.
Funding Information:
The OFBCR 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 (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Northern California Cancer Center (U01 CA69417) and University of Melbourne (U01 CA69638) and by Cancer Care Ontario. 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:
KConFab/AOCS: kConFab (the Kathleen Cuningham Consortium for Research into Familial Breast Cancer) thanks Heather Thorne, Eveline 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 Australian Ovarian Cancer Study (AOCS) Management Group (D. Bowtell, G. Chenevix-Trench, A. deFazio, D. Gertig, A. Green and P.M. Webb) gratefully acknowledges the contribution of all the clinical and scientific collaborators (see http://www.a ocstudy.org/). The Australian Cancer Study Management Group (A. Green, P. Parsons, N. Hayward, P.M.Webb, and D. Whiteman) thank all of the project staff, collaborating institutions and study participants. A.B.S. is an NHMRC Senior Research Fellow, and G.C.T. is an NHMRC Senior Principal Research Fellow.
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The TWBCS study was supported by the Institute of Biomedical Sciences, Academia Sinica, National Sciences Council and Taiwan Biobank.
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HUBCS was supported by a grant from the German Federal Ministry of Research and Education (RUS08/017).
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The MSKCC study was supported by the Breast Cancer Research Foundation, the Normal and Carol Stone Genetics Research Fund, and the Robert, the Robert and Kate Niehaus Clinical Genetics Initiative and the Lymphoma Foundation.
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The KBCP was supported by Grants from the Finnish Cancer Society; the Academy of Finland (grant number 127220); EVO Research Fund (grant number 5654113 and 5501); EVO research funding of Vaasa Hospital District (grant number 100449); and the strategic funding of the University of Eastern Finland. We thank Mrs. Helena Kemiläinen, Mrs Aija Parkkinen and Mrs. Eija Myöhänen for their skillful technical assistance.
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The KARBAC study was supported by The Swedish Cancer Society, The Stockholm Cancer Society, The Gustav V Jubilee Foundation and The Bert von Kantzow Foundation.
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The HEBCS study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, and the Sigrid Juselius Foundation.
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The PBCS was supported by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA.
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The BBCS is funded by Cancer Research UK and Break-through Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN).
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The MCCS study was supported by Cancer Council Victoria and by NHMRC grants 209057, 251533, 396414, 504711 and 504715. The MEC study was supported by National Institutes of Health grants R01-CA63464 and R37-CA54281.
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The HABCS study was supported by an intramural grant from Hannover Medical School and by a grant from the German Research Foundation [DFG, Do761/2 – 1].
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SEARCH study was supported by Cancer Research UK grants: C490/A1102, C8197/A10123, C490/A10119, C490/ A11020, C1287/A10118 and A.M.D. was funded by CR-UK grant C8197/A10865. The pathology work in Cambridge was supported by the NIHR Cambridge Biomedical Research Centre and by the Cambridge Experimental Cancer Medicine Centre.
Funding Information:
The CGPS Funding: The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. Acknowledgements: 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.
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The MCBCS was supported by National Institutes of Health grant, R01 CA122340, and an NCI Specialized Program of Research Excellence (SPORE) in breast cancer, P50 CA116201.
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The Breast Cancer Association Consortium (BCAC) was supported by Cancer Research UK grant C1287/A12014. D.F.E. is a Principal Research Fellow of Cancer Research UK.
Funding Information:
FBCS Cancer Research UK (C8620/A83); US Military Acquisition (ACQ) Activity, Era of Hope Award (W81XWH-05–1–0204) The samples were collected and screened for BRCA mutations through funding from Cancer Research UK; US Military Acquisition (ACQ) Activity, Era of Hope Award (W81XWH-05–1–0204) and the Institute of Cancer Research (UK). This study makes use of data generated by the Wellcome Trust Case Control Consortium (WTCCC) 2. A full list of the investigators who contributed to the generation of the data is available from the WTCCC website. C.T. is funded by a Medical Research Council (UK) Clinical Research Fellowship.
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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.
Funding Information:
The NC-BCFR and OFBCR are funded 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 (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), the Cancer Prevention Institute of California (formerly the Northern California Cancer Center, U01 CA69417) and the 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 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 CNIO-BCS was supported by the Genome Spain Foundation, the Red Temática de Investigación Cooperativa en Cáncer and grants from the Asociación Española Contra Cáncer and the Fondo de Investigación Sanitario [PI081120 to J.B., PI081583 to R.L.M.]. We thank Charo Alonso, Tais Moreno, Guillermo Pita, Primitiva Menendez and Anna González-Neira.
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MBCSG is supported by grants from Ministero della Salute (Extraordinary National Cancer Program 2006 ‘Alleanza contro il Cancro’, and ‘Progetto Tumori Femminili’ to P.R.), Ministero dell’Universita’ e Ricerca (RBLAO3-BETH to P.R.), Fondazione Italiana per la Ricerca sul Cancro (Special Project ‘Hereditary tumors’), Associazione Italiana per la Ricerca sul Cancro (4017 and by funds from Italian citizens who allocated the 5 × 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘‘5 × 1000’).
Funding Information:
The ABCFS was supported by the National Health and Medical Research Council of Australia (NHMRC) [145604], the NIH [CA102740-01A2], and by the United States National Cancer Institute, NIH [CA-95-011] through cooperative agreements with members of the Breast Cancer Family Registry and principal investigators Cancer Care Ontario [CA69467], Columbia University [CA69398], Fox Chase Cancer Center [CA69631], Huntsman Cancer Institute [CA69446], Northern California Cancer Center [CA69417] and University of Melbourne [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. is an Australia Fellow of the NHMRC and Victorian Breast Cancer Research Consortium Group Leader. M.C.S. is a Senior Research Fellow of the NHMRC and Victorian Breast Cancer Research Consortium Group Leader. This research was supported by the Victorian Government through Victorian Cancer Agency funding of the Victorian Breast Cancer Research Consortium.
Funding Information:
The RBCS study was supported by Dutch Cancer Society: DDHK 2004-3124. RBCS would like to acknowledge Petra Bos, Jannet Blom, Ellen Crepin, Elisabeth Huijskens and Annette Heemskerk for their contribution in data management.
Funding Information:
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 analyses were supported by Robert Bosch Foundation of Medical Research, Stuttgart, Germany. The GENICA network would also like to acknowledge 1. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany; [C.J., H.B.]; Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany [Yon-Dschun Ko, Christian Baisch]; Institute of Pathology, University of Bonn, Bonn, Germany [Hand-Peter Fischer]. Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany [Ute Hamann]; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum, Germany [TB, Beate Pesch, Sylvia Rabstein, Volker Harth].
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OBCS was supported by research grants from the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the Academy of Finland, the University of Oulu, and the Oulu University Hospital.
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The US3SS study was supported by Massachusetts (K.M.E., R01CA47305), Wisconsin (P.A.N., R01 CA47147) and New Hampshire (L.T.-E., R01CA69664) centers, and Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA.
Funding Information:
The SZBCS was supported by Grant PBZ_KBN_122/P05/ 2004. K.J. is a fellow of International PhD program, Post-graduate School of Molecular Medicine, Warsaw Medical University, supported by the Polish Foundation of Science.
