Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7×10-3) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8×10-3). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
Funding Information
Mutua Madrileña Foundation
Spanish Association against Cancer
RTICC, 06/0020/1060
RTICC, FISPI12/00070
European Community, Seventh Framework Programme, HEALTH-F2-2009-223175
Cancer Research UK, C1287/A10118
Cancer Research UK, C1287/A 10710
Cancer Research UK, C12292/A11174
Cancer Research UK, C5047/A8384
Cancer Research UK, C5047/A15007
Cancer Research UK, C5047/A10692
National Institutes of Health, CA128978
Post-Cancer GWAS initiative, 1 U19 CA 148537
Department of Defence, W81XWH-10-1-0341
Canadian Institutes of Health Research
Komen Foundation for the Cure
Breast Cancer Research Foundation
Ovarian Cancer Research Fund
Swedish Cancer Society
Cancer Association of South Africa
National Cancer Institute, Specialized Program of Research Excellence in Breast Cancer, CA125183
National Cancer Institute, R01 CA142996
National Cancer Institute, 1U01CA161032
Ralph and Marion Falk Medical Research Trust
Entertainment Industry Fund National Women's Cancer Research Alliance
Basser Research Center
American Cancer Society, Early Detection Professorship, SIOP-06-258-01-COUN
National Cancer Institute, UM1 CA164920
Research Council of Lithuania, LIG-07/2012
Hereditary Cancer Association
LSC, 10.0010.08
ESF, Nr.2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016
National Institutes of Health, R01CA74415
National Institutes of Health, P30 CA033752
Morris and Horowitz Families, Professorship
NEYE Foundation
National Cancer Institute, RC4A153828
Italian Association for Cancer Research
FiorGen Foundation for Pharmacogenomics
Associazione CAOS Varese
Italian citizens
European Union, European Social Fund
Greek national funds, Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework
Hellenic Cooperative Oncology Group
Hellenic Foundation for Cancer Research
Cancer Research UK, C1287/A11990
National Institute for Health and Care Research
Cancer Research UK, C5047/A8385
University of Kansas, Cancer Center, P30 CA168524
Kansas Bioscience Authority, Eminent Scholar Program
5U01CA113916
R01CA140323
Chancellors Distinguished Chair in Biomedical Sciences Professorship
German Cancer Aid, 109076
Center for Molecular Medicine Cologne
Ligue National Contre le Cancer
Association “Le cancer du sein, parlons-en!”
Canadian Institutes of Health Research, "CIHR Team in Familial Risks of Breast Cancer” program
National Cancer Institute, CA 27469
GOG, Statistical and Data Center, CA 37517
GOG, Cancer Prevention and Control Committee, CA 101165
National Cancer Institute, Intramural Research Program
National Cancer Institute, CA 37517
National Cancer Institute, CA 101165
RTICC, RD06/0020/0021
Helsinki University, Hospital Research Fund
Academy of Finland, 132473
Finnish Cancer Society
Sigrid Juselius Foundation
Dutch Cancer Society, NKI1998-1854
Dutch Cancer Society, NKI2004-3088
Dutch Cancer Society, NKI2007-3756
Netherlands Organization of Scientific Research, NWO 91109024
Pink Ribbon, 110005
BBMRI, NWO 184.021.007/CP46
Hungarian Research Grant, KTIA-OTKA CK-80745
Polish Foundation of Science
Nordic Cancer Union
Icelandic Association, "Walking for Breast Cancer Research"
Landspitali University Hospital, Research Fund
Canadian Institutes of Health, "CIHR Team in Familial Risks of Breast Cancer" program
Canadian Breast Cancer Research Alliance, 019511
Ministry of Economic Development, Innovation and Export Trade, PSR-SIIRI-701
Ministero dell'Istruzione
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
National Cancer Institute, Specialized Program of Research Excellence in Breast Cancer, CA116201
U.S. Department of Defence, Ovarian Cancer Idea award, W81XWH-10-1-0341
Sharon Levine Corzine
Niehaus Clinical Cancer Genetics Initiative
Andrew Sabin Family Foundation
Lymphoma Foundation
Westat, Inc., NO2-CP-11019-50
Westat, Inc., N02-CP-65504
Clalit Health Services
Israel Cancer Association
Ohio State University
