Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk
Couch, Fergus J.; Wang, Xianshu; McGuffog, Lesley; Lee, Andrew; Olswold, Curtis; Kuchenbaecker, Karoline B.; Soucy, Penny; Fredericksen, Zachary; Barrowdale, Daniel; Dennis, Joe; Gaudet, Mia M.; Dicks, Ed; Kosel, Matthew; Healey, Sue; Sinilnikova, Olga M.; Lee, Adam; Bacot, François; Olopade, Olufunmilayo I.; Rodriguez, Gustavo C.; Huo, Dezheng
2013
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Abstract

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 = 2.7×10−8, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10−8, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10−8, 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 = 2×10−4). 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.

Details

Title
Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk
Author
Couch, Fergus J. : Mayo Clinic
Wang, Xianshu : Mayo Clinic
McGuffog, Lesley : University of Cambridge
Lee, Andrew : University of Cambridge
Olswold, Curtis : Mayo Clinic
Kuchenbaecker, Karoline B. : University of Cambridge
Soucy, Penny : Universitaire de Québec
Fredericksen, Zachary : Mayo Clinic
Barrowdale, Daniel : University of Cambridge
Dennis, Joe : University of Cambridge
Gaudet, Mia M. : American Cancer Society
Dicks, Ed : University of Cambridge
Kosel, Matthew : Mayo Clinic
Healey, Sue : Queensland Institute of Medical Research
Sinilnikova, Olga M. : Université Lyon
Lee, Adam : Mayo Clinic
Bacot, François : Université McGill
Olopade, Olufunmilayo I. : University of Chicago
Rodriguez, Gustavo C. : University of Chicago
Huo, Dezheng : University of Chicago
Content Type
Article
Published in
PLOS Genetics
Identifier(s)
DOI: https://doi.org/10.1371/journal.pgen.1003212
Funding Information
National Institutes of Health, CA128978
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
Cancer Research UK, C1287/A10118
European Commission, Seventh Framework Programme, 223175
National Cancer Institute, CA-06-503
Breast Cancer Family Registry
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
Victorian Breast Cancer Research Consortium
National Institutes of Health, P01 CA16094
NHMRC
National Institutes of Health, R01 CA22435
National Institutes of Health, P30 CA13696
National Institutes of Health, P30 ES009089
National Institutes of Health, UL1 RR025764
National Cancer Institute, P30 CA042014
Research Council of Lithuania, LIG-19/2010
Hereditary Cancer Association, 10.0010.08
LSC
ESF, Nr.2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016
Cancer Association of South Africa
Beckman Research Institute of the City of Hope
Morris and Horowitz Families Endowed Professorship
National Institutes of Health, R01CA74415
National Institutes of Health, P30 CA033752
NEYE Foundation
Spanish Association against Cancer, AECC08
Spanish Association against Cancer, RTICC 06/0020/1060
Spanish Association against Cancer, FISPI08/1120
Mutua Madrileña Foundation
SAF2010-20493
National Cancer Institute, RC4A153828
Fondazione Italiana per la Ricerca sul Cancro, Hereditary tumors
Italian Association for Cancer Research, IG 8713
Italian Ministry of Health, Extraordinary National Cancer Program 2006
Italian Ministry of Education, University and Research, Prin 2008
Centro di Ascolto Donne Operate al Seno
Italian citizens, INT-Institutional strategic projects ‘5×1000’
Dutch Cancer Society, NKI1998-1854
Dutch Cancer Society, NKI2004-3088
Dutch Cancer Society, NKI2007-3756
NWO, 91109024
Pink Ribbon, 110005
BBMRI, CP46/NWO
Cancer Research UK, C1287/A11990
Cancer Research UK, C1287/A10118
NIHR
Cancer Research UK Grant, C5047/A8385
University of Kansas, Cancer Center
Kansas Bioscience Authority, Eminent Scholar Program
Chancellors Distinguished Chair in Biomedical Sciences Professorship, 5U01CA113916
R01CA140323
German Cancer Aid, 109076
Center for Molecular Medicine Cologne
Ligue National Contre le Cancer, Association “Le cancer du sein, parlons-en!” Award
Canadian Institutes of Health Research, CIHR Team in Familial Risks of Breast Cancer
National Cancer Institute, CA 27469
National Cancer Institute, CA 37517
National Cancer Institute, CA 101165
National Cancer Institute, Intramural Research Program
RETICC, 06/0020/0021
FIS, research grant, 09/00859
Instituto de Salud Carlos III
Spanish Ministry of Economy and Competitivity
European Regional Development Fund
Helsinki University Central Hospital, Research Fund
Academy of Finland, 132473
Finnish Cancer Society
Nordic Cancer Union
Sigrid Juselius Foundation
The Hong Kong Hereditary Breast Cancer Family Registry
Dr. Ellen Li Charitable Foundation
Hungarian Research Grant, KTIA-OTKA CK-80745
Norwegian EEA Financial Mechanism, HU0115/NA/2008-3/ÖP-9
Asociación Española Contra el Cáncer
Spanish Health Research Foundation
Ramón Areces Foundation
Carlos III Health Institute
Catalan Health Institute
Autonomous Government of Catalonia
ISCIIIRETIC, RD06/0020/1051
ISCIIIRETIC, PI09/02483
ISCIIIRETIC, PI10/01422
ISCIIIRETIC, PI10/00748
ISCIIIRETIC, 2009SGR290
ISCIIIRETIC, 2009SGR283
Polish Foundation of Science
Warsaw Medical University, fellowship
Icelandic Association, Walking for Breast Cancer Research
Landspitali University Hospital, Research Fund
Canadian Institutes of Health Research, CIHR Team in Familial Risks of Breast Cancer
Canadian Breast Cancer Research Alliance, 019511
Ministry of Economic Development, Innovation and Export Trade, PSR-SIIRI-701
Ministero dell'Istruzione, dell'Università e della Ricerca and Ministero della Salute, Progetto Tumori Femminili
Ministero dell'Istruzione, dell'Università e della Ricerca and Ministero della Salute, RFPS 2006-5-341353,ACC2/R6.9
National Breast Cancer Foundation
National Health and Medical Research Council
Queensland Cancer Fund
Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia
Cancer Foundation of Western Australia
NHMRC, Senior Research Fellowship
NHMRC
National Breast Cancer Foundation and Cancer Australia, 628333
NIH, CA128978
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
Jewish General Hospital, Weekend to End Breast Cancer
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
National Institutes of Health, 1R01 CA149429-01
US National Cancer Institute, Intramural Research Program
Westat, Rockville, MD, NO2-CP-11019-50
Westat, Rockville, MD, N02-CP-65504
Clalit Health Services
Israel Cancer Association
Russian Foundation for Basic Research, 11-04-00227
Russian Foundation for Basic Research, 12-04-00928
Russian Foundation for Basic Research, 12-04-01490
Federal Agency for Science and Innovations, 02.740.11.0780
Royal Society, International Joint grant, JP090615
Ohio State University Comprehensive Cancer Center
Ministry of Science, Technology and Innovation
Ministry of Higher Education
Cancer Research Initiatives Foundation
Israel Cancer Association
Israeli Inherited Breast Cancer Consortium
Swedish Cancer Society
National Cancer Institute
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, project grant
National Institutes of Health, R01-CA102776
National Institutes of Health, R01-CA083855
Rooney Family Foundation
Susan G. Komen Foundation for the Cure
Macdonald Family Foundation
Victorian Cancer Agency
Cancer Australia
National Breast Cancer Foundation
American Cancer Society, Early Detection Professorship, SIOP-06-258-01-COUN
Publication Date
2013-03-27
Language
English
Copyright Statement

© 2013 Couch et al.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Record Appears in
Centers and Institutes > Center for Clinical Cancer Genetics and Global Health
Pritzker School of Medicine
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Record Created
2023-09-12

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