期刊
PLOS GENETICS
卷 9, 期 3, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1003173
关键词
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资金
- University of Eastern Finland
- Cancer Fund of North Savo
- National Breast Cancer Foundation
- National Health and Medical Research Council (NHMRC)
- Queensland Cancer Fund
- Cancer Councils of New South Wales, Victoria
- Cancer Councils of New South Wales, Tasmania
- Cancer Councils of New South Wales, South Australia
- Cancer Foundation of Western Australia
- United States Army Medical Research and Materiel Command [DAMD17-01-1-0729]
- Cancer Council of Tasmania
- NHMRC [199600]
- NHMRC
- Cancer Australia [628333]
- National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea [1020350]
- Stichting tegen Kanker [232-2008, 196-2010]
- FWO
- KULPFV/10/016-SymBioSysII
- Deutsche Krebshilfe e.V. [70-2892-BR I]
- Hamburg Cancer Society
- German Cancer Research Center
- Federal Ministry of Education and Research (BMBF) [01KH0402]
- NIH [CA128978, CA63464, CA54281, CA098758, CA132839]
- NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]
- U.S. Department of Defence Ovarian Cancer Idea award [W81XWH-10-1-0341]
- Breast Cancer Research Foundation
- Komen Foundation for the Cure
- Fondazione Italiana per la Ricerca sul Cancro
- Italian Association for Cancer Research (AIRC) [IG 8713]
- Italian Ministry of Health (Progetto Tumori Femminili)
- Italian citizens
- Fondazione IRCCS Istituto Nazionale Tumori
- VicHealth and Cancer Council Victoria
- Australian NHMRC [209057, 251553, 504711]
- Jewish General Hospital
- Niehaus Clinical Cancer Genetics Initiative
- Andrew Sabin Family Foundation
- Lymphoma Foundation
- Quebec Breast Cancer Foundation
- Canadian Institutes of Health Research [CRN-87521]
- Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]
- Intramural Research Program of the US National Cancer Institute, NIH
- Westat, Rockville, MD [NO2-CP-11019-50, N02-CP-65504]
- Clalit Health Services in Israel
- Israel Cancer Association
- Breast Cancer Research Foundation (BCRF)
- Russian Federation for Basic Research [11-04-00227, 12-04-00928, 12-04-01490]
- Federal Agency for Science and Innovations, Russia [02.740.11.0780]
- Finnish Cancer Foundation
- Academy of Finland
- University of Oulu
- Oulu University Hospital
- Dutch Cancer Society [RUL 1997-1505, DDHK 2004-3124, DDHK 2009-4318]
- Biobanking and Biomolecular Resources Research Infrastructure [BBMRI-NL CP16]
- Ohio State University Comprehensive Cancer Center
- Ministry of Science, Technology and Innovation, Ministry of Higher Education [UM.C/HlR/MOHE/06]
- Cancer Research Initiatives Foundation
- National Cancer Institute, Department of Health and Human Services, USA
- Marit and Hans Rausings Initiative Against Breast Cancer
- Agency for Science, Technology and Research of Singapore (A*STAR)
- U.S. National Institute of Health (NIH)
- Susan G. Komen Breast Cancer Foundation
- Yorkshire Cancer Research [S295, S299, S305PA]
- Malaysian Ministry of Science, Technology and Innovation
- Ministry of Higher Education [UM.C/HIR/MOHE/06]
- Cancer Research UK [[C490/A10124][C8197/A10123]
- Swedish Cancer Society
- U.S. National Cancer Institute (NIH/NCI)
- Ralph and Marion Falk Medical Research Trust
- Entertainment Industry Fund National Women's Cancer Research Alliance,
- Jonsson Comprehensive Cancer Center Foundation
- UCSF Cancer Risk Program
- Helen Diller Family Comprehensive Cancer Center
- Breakthrough Breast Cancer
- Institute of Cancer Research (ICR)
- NHS
- CRUK
- National Institutes of Health (NIH) [R01-CA102776, R01-CA083855]
- Rooney Family Foundation
- Susan G. Komen Foundation for the Cure
- Facdonald Family Foundation
- Victorian Cancer Agency
- Cancer Australia
- American Cancer Society [SIOP-06-258-01-COUN]
- Ligue National Contre le Cancer
- Association Le cancer du sein, parlons-en! Award
- Canadian Institutes of Health Research for the CIHR Team in Familial Risks of Breast Cancer program
- [C8197/A10865]
- [PBZ_KBN_122/P05/2004]
- Cancer Foundation Finland sr [110135] Funding Source: researchfish
- Cancer Research UK [16561, 16565, 11174, 11022, 10118] Funding Source: researchfish
- National Breast Cancer Foundation [IF-12-06] Funding Source: researchfish
- National Institute for Health Research [03/DHCS/03/G121/51] Funding Source: researchfish
- The Francis Crick Institute
- Cancer Research UK [10124] Funding Source: researchfish
Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 x 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
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