期刊
PLOS GENETICS
卷 9, 期 3, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1003212
关键词
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资金
- NIH [CA128978, P30 CA033752, R01CA74415, 1R01 CA149429-01]
- NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]
- U.S. Department of Defense Ovarian Cancer Idea award [W81XWH-10-1-0341]
- Breast Cancer Research Foundation
- Komen Foundation for the Cure
- Cancer Research UK [C12292/A11174, C1287/A10118, C1287/A11990, C5047/A8385]
- European Commission [223175 (HEALTH-F2-2009-223175)]
- National Cancer Institute, National Institutes of Health under RFA [CA-06-503]
- Breast Cancer Family Registry (BCFR)
- Cancer Care Ontario [U01 CA69467]
- Cancer Prevention Institute of California [U01 CA69417]
- Columbia University [U01 CA69398]
- Fox Chase Cancer Center [U01 CA69631]
- Huntsman Cancer Institute [U01 CA69446]
- University of Melbourne [U01 CA69638]
- National Health and Medical Research Council of Australia
- New South Wales Cancer Council
- Victorian Health Promotion Foundation (Australia)
- Victorian Breast Cancer Research Consortium
- National Institutes of Health [P01 CA16094, R01 CA22435]
- National Center for Research Resources
- National Center for Advancing Translational Sciences, NIH [UL1 RR025764]
- National Cancer Institute [P30 CA042014, RC4A153828, CA 27469, CA 37517, CA 101165]
- Research Council of Lithuania [LIG-19/2010]
- Lithuania (BFBOCC-LT)
- Hereditary Cancer Association (Paveldimo vezio asociacija)
- LSC [10.0010.08]
- ESF [2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016]
- Cancer Association of South Africa (CANSA)
- Morris and Horowitz Families Endowed Professorship
- NEYE Foundation
- Spanish Association against Cancer [AECC08, RTICC 06/0020/1060, FISPI08/1120]
- Mutua Madrilena Foundation (FMMA)
- Office of the Director, National Institutes of Health
- Fondazione Italiana per la Ricerca sul Cancro (Special Project Hereditary tumors)
- Italian Association for Cancer Research (AIRC) [IG 8713]
- Italian Minitry of Health
- Italian Ministry of Education, University and Research, Centro di Ascolto Donne Operate al Seno (CAOS) association
- DKFZ
- Dutch Cancer Society [NKI1998-1854, NKI2004-3088, NKI2007-3756]
- NWO [91109024]
- Pink Ribbon grant [110005]
- BBMRI [CP46/NWO]
- NIHR
- Royal Marsden NHS Foundation Trust
- University of Kansas Cancer Center
- Kansas Bioscience Authority Eminent Scholar Program
- Chancellors Distinguished Chair in Biomedical Sciences Professorship
- German Cancer Aid [109076]
- Center for Molecular Medicine Cologne (CMMC)
- Ligue National Contre le Cancer
- Association Le cancer du sein, parlons-en!
- Canadian Institutes of Health Research for the CIHR Team in Familial Risks of Breast Cancer program
- Intramural Research Program, NCI, NIH
- RETICC [06/0020/0021]
- FIS [09/00859]
- Instituto de Salud Carlos III
- Spanish Ministry of Economy and Competitivity
- European Regional Development Fund (ERDF)
- Helsinki University Central Hospital Research Fund
- Academy of Finland [132473]
- Finnish Cancer Society
- Nordic Cancer Union
- Sigrid Juselius Foundation
- Hong Kong Hereditary Breast Cancer Family Registry
- Dr. Ellen Li Charitable Foundation, Hong Kong
- Hungarian Research [HU0115/NA/2008-3/OP-9]
- Asociacion Espanola Contra el Cancer
- Spanish Health Research Foundation
- Ramon Areces Foundation
- Carlos III Health Institute
- Catalan Health Institute
- Autonomous Government of Catalonia [ISCIIIRETIC RD06/0020/1051, PI09/02483, PI10/01422, PI10/00748, 2009SGR290, 2009SGR283]
- Polish Foundation of Science
- Icelandic Association Walking for Breast Cancer Research
- Landspitali University Hospital Research Fund
- Canadian Institutes of Health Research
- Canadian Breast Cancer Research Alliance [019511]
- Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-701]
- Ministero dell'Istruzione, dell'Universitae della Ricerca
- Ministero della Salute [RFPS 2006-5-341353, ACC2/R6.9]
- 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
- NHMRC
- Cancer Australia [628333]
- Jewish General Hospital
- Quebec Ministry of Economic Development, Innovation, and Export Trade
- Niehaus Clinical Cancer Genetics Initiative
- Andrew Sabin Family Foundation
- Lymphoma Foundation
- European Regional Development Fund
- State Budget of the Czech Republic (RECAMO) [CZ.1.05/2.1.00/03.0101]
- 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), NY
- Russian Foundation for Basic Research [11-04-00227, 12-04-00928, 12-04-01490]
- Federal Agency for Science and Innovations, Russia [02.740.11.0780]
- Royal Society [JP090615]
- Ohio State University Comprehensive Cancer Center
- Swedish Cancer Society
- US 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
- CRUK
- National Institutes of Health (NIH) [R01-CA102776, R01-CA083855]
- Rooney Family Foundation
- Susan G. Komen Foundation for the Cure
- Macdonald Family Foundation
- Victorian Cancer Agency
- Cancer Australia
- American Cancer Society Early Detection Professorship [SIOP-06-258-01-COUN]
- [SAF2010-20493]
- [5U01CA113916]
- [R01CA140323]
- Cancer Research UK [10118, 16565, 11174, 15007, 11022] Funding Source: researchfish
- National Breast Cancer Foundation [IF-12-06] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10096] Funding Source: researchfish
BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
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