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Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2

Lookup NU author(s): Dr Fiona Douglas


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BACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers. British Journal of Cancer (2011) 104, 1356-1361. doi:10.1038/bjc.2011.91 Published online 22 March 2011 (C) 2011 Cancer Research UK

Publication metadata

Author(s): Osorio A, Milne RL, Alonso R, Pita G, Peterlongo P, Teule A, Nathanson KL, Domchek SM, Rebbeck T, Lasa A, Konstantopoulou I, Hogervorst FB, Verhoef S, van Dooren MF, Jager A, Ausems MGEM, Aalfs CM, van Asperen CJ, Vreeswijk M, Waisfisz Q, Van Roozendaal CE, Ligtenberg MJ, Easton DF, Peock S, Cook M, Oliver CT, Frost D, Curzon B, Evans DG, Lalloo F, Eeles R, Izatt L, Davidson R, Adlard J, Eccles D, Ong KR, Douglas F, Downing S, Brewer C, Walker L, Nevanlinna H, Aittomaki K, Couch FJ, Fredericksen Z, Lindor NM, Godwin A, Isaacs C, Caligo MA, Loman N, Jernstrom H, Barbany-Bustinza G, Liljegren A, Ehrencrona H, Stenmark-Askmalm M, Feliubadalo L, Manoukian S, Peissel B, Zaffaroni D, Bonanni B, Fortuzzi S, Johannsson OT, Chenevix-Trench G, Chen XC, Beesley J, Spurdle AB, Sinilnikova OM, Healey S, McGuffog L, Antoniou AC, Brunet J, Radice P, Benitez J, HEBON, EMBRACE, SWE-BRCA, kConFab, CIMBA

Publication type: Article

Publication status: Published

Journal: British Journal of Cancer

Year: 2011

Volume: 104

Issue: 8

Pages: 1356-1361

Print publication date: 22/03/2011

ISSN (print): 0007-0920

ISSN (electronic): 1532-1827

Publisher: Nature Publishing Group


DOI: 10.1038/bjc.2011.91


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Funder referenceFunder name
Breast Cancer Research Foundation
Cancer Councils of New South Wales, Victoria, Tasmania and South Australia
Cancer Foundation of Western Australia
Institute for Tumors of Tuscany
National Breast Cancer Foundation
National Health and Medical Research Council
Queensland Cancer Fund
Fondazione IRCCS Istituto Nazionale Tumori
Fondazione Italiana per la Ricerca sul Cancro
Komen Foundation for the Cure
MacDonald Family Foundation
Mutua Madrilena Foundations
Royal Marsden NHS Foundation Trust
223175 (HEALTH-F2-2009-223175)European Community
4017Associazione Italiana per la Ricerca sul Cancro
CA122340National Institute of Health
CA128978National Institute of Health
C1287/A10118Cancer Research UK
C1287/A11990Cancer Research UK
C5047/A8385Cancer Research UK
C8197/A10123Cancer Research UK
CA116167National Institute of Health
FIS08-1120Ministry of Science
NKI1998-1854Dutch Cancer Society
NKI2004-3088Dutch Cancer Society
NKI2007-3756Dutch Cancer Society
P50 CA116201Breast Cancer Research Foundation
RFPS-2006-3-340203Ministero della Salute
RBLAO3-BETHMinistero dell'Universitae Ricerca