Centers and Institutes
Published March 27, 2013 | Version v1
Journal article Open

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

Creators

  • 1. Mayo Clinic
  • 2. University of Cambridge
  • 3. Universitaire de Québec
  • 4. American Cancer Society
  • 5. Queensland Institute of Medical Research
  • 6. Université Lyon
  • 7. Université McGill
  • 8. University of Chicago

Description

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.

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Additional details

Identifiers

DOI
10.1371/journal.pgen.1003212
Other
oai:uchicago.tind.io:7972

Funding

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
Breast Cancer Research Foundation
Komen Foundation for the Cure
Cancer Research UK
C12292/A11174
Cancer Research UK
C1287/A10118
European Commission
Seventh Framework Programme
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
Unknown funder
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
Unknown funder
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
Unknown funder
Chancellors Distinguished Chair in Biomedical Sciences Professorship
Unknown funder
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
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
U.S. Department of Defence
Ovarian Cancer Idea award
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
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

UChicago Information

Division(s)
Biological Sciences Division, Institutes & Centers, Pritzker School of Medicine
Center(s) or Institute(s)
Center for Clinical Cancer Genetics and Global Health