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DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Lookup NU author(s): Dr Fiona Douglas

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Abstract

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 = 2.7x10(-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 = 4.8x10(-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.


Publication metadata

Author(s): Osorio A, Milne RL, Kuchenbaecker K, Vaclova T, Pita G, Alonso R, Peterlongo P, Blanco I, de la Hoya M, Duran M, Diez O, Cajal TRY, Konstantopoulou I, Martinez-Bouzas C, Conejero RA, Soucy P, McGuffog L, Barrowdale D, Lee A, Arver B, Rantala J, Loman N, Ehrencrona H, Olopade OI, Beattie MS, Domchek SM, Nathanson K, Rebbeck TR, Arun BK, Karlan BY, Walsh C, Lester J, John EM, Whittemore AS, Daly MB, Southey M, Hopper J, Terry MB, Buys SS, Janavicius R, Dorfling CM, van Rensburg EJ, Steele L, Neuhausen SL, Ding YC, Hansen TVO, Jonson L, Ejlertsen B, Gerdes AM, Infante M, Herraez B, Moreno LT, Weitzel JN, Herzog J, Weeman K, Manoukian S, Peissel B, Zaffaroni D, Scuvera G, Bonanni B, Mariette F, Volorio S, Viel A, Varesco L, Papi L, Ottini L, Tibiletti MG, Radice P, Yannoukakos D, Garber J, Ellis S, Frost D, Platte R, Fineberg E, Evans G, Lalloo F, Izatt L, Eeles R, Adlard J, Davidson R, Cole T, Eccles D, Cook J, Hodgson S, Brewer C, Tischkowitz M, Douglas F, Porteous M, Side L, Walker L, Morrison P, Donaldson A, Kennedy J, Foo C, Godwin AK, Schmutzler RK, Wappenschmidt B, Rhiem K, Engel C, Meindl A, Ditsch N, Arnold N, Plendl HJ, Niederacher D, Sutter C, Wang-Gohrke S, Steinemann D, Preisler-Adams S, Kast K, Varon-Mateeva R, Gehrig A, Stoppa-Lyonnet D, Sinilnikova OM, Mazoyer S, Damiola F, Poppe B, Claes K, Piedmonte M, Tucker K, Backes F, Rodriguez G, Brewster W, Wakeley K, Rutherford T, Caldes T, Nevanlinna H, Aittomaki K, Rookus MA, van Os TAM, van der Kolk L, de Lange JL, Meijers-Heijboer HEJ, van der Hout AH, van Asperen CJ, Garcia EBG, Hoogerbrugge N, Collee JM, van Deurzen CHM, van der Luijt RB, Devilee P, Olah E, Lazaro C, Teule A, Menendez M, Jakubowska A, Cybulski C, Gronwald J, Lubinski J, Durda K, Jaworska-Bieniek K, Johannsson OT, Maugard C, Montagna M, Tognazzo S, Teixeira MR, Healey S, Olswold C, Guidugli L, Lindor N, Slager S, Szabo CI, Vijai J, Robson M, Kauff N, Zhang LY, Rau-Murthy R, Fink-Retter A, Singer CF, Rappaport C, Kaulich DG, Pfeiler G, Tea MK, Berger A, Phelan CM, Greene MH, Mai PL, Lejbkowicz F, Andrulis I, Mulligan AM, Glendon G, Toland AE, Bojesen A, Pedersen IS, Sunde L, Thomassen M, Kruse TA, Jensen UB, Friedman E, Laitman Y, Shimon SP, Simard J, Easton DF, Offit K, Couch FJ, Chenevix-Trench G, Antoniou AC, Benitez J, SWE-BRCA, HEBON, KConFab Investigators

Publication type: Article

Publication status: Published

Journal: PLoS Genetics

Year: 2014

Volume: 10

Issue: 4

Print publication date: 03/04/2014

Date deposited: 22/08/2014

ISSN (print): 1553-7390

ISSN (electronic): 1553-7404

Publisher: Public Library of Science

URL: http://dx.doi.org/10.1371/journal.pgen.1004256

DOI: 10.1371/journal.pgen.1004256


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Funding

Funder referenceFunder name
Andrew Sabin Family Foundation
Breast Cancer Research Foundation (BCRF), NY
Canadian Institutes of Health Research
Canadian Institutes of Health Research (CIHR)
Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program
Clalit Health Services in Israel
European Union (European Social Fund - ESF)
Finnish Cancer Society
Hereditary Cancer Association (Paveldimo vezio asociacija)
Kansas Bioscience Authority Eminent Scholar Program
Landspitali University Hospital Research Fund
Liepaja's municipal council
Ligue National Contre le Cancer
Lymphoma Foundation
Ministero dell'Istruzione, dell'Universitae della Ricerca and Ministero della Salute
Morris and Horowitz Families Professorship
NEYE Foundation
Ohio State University Comprehensive Cancer Center
Ovarian Cancer Research Fund
Polish Foundation of Science
Ralph and Marion Falk Medical Research Trust
Sigrid Juselius Foundation
Association "Le cancer du sein, parlons-en!" Award
Associazione CAOS Varese
Basser Research Center
Breast Cancer Research Foundation
Cancer Association of South Africa (CANSA)
Cancer Councils of New South Wales, Victoria
Center for Molecular Medicine Cologne (CMMC)
Chancellors Distinguished Chair in Biomedical Sciences Professorship
Entertainment Industry Fund National Women's Cancer Research Alliance
FiorGen Foundation for Pharmacogenomics
Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: ARISTEIA
Helsinki University Central Hospital Research Fund
Intramural Research Program, NCI
Israel Cancer Association
Italian Association for Cancer Research (AIRC)
Komen Foundation for the Cure
Mutua Madrilena Foundation (FMMA)
National Breast Cancer Foundation
National Health and Medical Research Council (NHMRC)
Niehaus Clinical Cancer Genetics Initiative
NIHR
Nordic Cancer Union, Icelandic Association "Walking for Breast Cancer Research"
Office of the Director, National Institutes of Health
Queensland Cancer Fund
Sharon Levine Corzine Fund
Swedish Cancer Society
US National Cancer Institute, NIH
019511Canadian Breast Cancer Research Alliance-grant
06/0020/1060RTICC
1 U19 CA 148537Post-Cancer GWAS initiative
10.0010.08LSC
109076German Cancer Aid
2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016ESF
110005Pink Ribbon grant
132473Academy of Finland
1U01CA161032NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer
5U01CA113916
223175 (HEALTH-F2-2009-223175)European Community
C1287/A 10710Cancer Research UK
CA 101165National Cancer Institute
CA128978National Institutes of Health
AECC08Spanish Association against Cancer
CA128978NIH
C12292/A11174Cancer Research UK
C1287/A10118Cancer Research UK
C1287/A11990Cancer Research UK
C5047/A10692Cancer Research UK
C5047/A15007Cancer Research UK
C5047/A8384Cancer Research UK
C5047/A8385Cancer Research UK
CA 27469National Cancer Institute
CA 37517National Cancer Institute
CA116201NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer
CA125183NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer
FISPI12/00070
CK-80745Hungarian Research Grant KTIA-OTKA
LIG-07/2012Lithuania (BFBOCC-LT): Research Council of Lithuania
N02-CP-65504Westat, Inc, Rockville, MD
NKI1998-1854Dutch Cancer Society
NKI2004-3088Dutch Cancer Society
NWO 184.021.007/CP46BBMRI
NWO 91109024Netherlands Organization of Scientific Research
P30 CA168524University of Kansas Cancer Center
PSR-SIIRI-701Ministry of Economic Development, Innovation and Export Trade
R01 CA142996NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer
R01CA140323
NKI2007-3756Dutch Cancer Society
NO2-CP-11019-50Westat, Inc, Rockville, MD
RC4A153828City of Hope Clinical Cancer Genetics Community Research Network, National Cancer Institute
RD06/0020/0021RTICC (ISCIII), Spanish Ministry of Economy and Competitivity
SIOP-06-258-01-COUNAmerican Cancer Society Early Detection Professorship
UM1 CA164920National Cancer Institute
W81XWH-10-1-0341U.S. Department of Defence Ovarian Cancer Idea award
W81XWH-10-1-0341Department of Defence

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