Abstract
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 inteNo 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.
Original language | English (US) |
---|---|
Pages (from-to) | 1356-1361 |
Number of pages | 6 |
Journal | British journal of cancer |
Volume | 104 |
Issue number | 8 |
DOIs | |
State | Published - Apr 12 2011 |
Keywords
- BRCA1
- BRCA2
- XRCC1
- breast cancer
ASJC Scopus subject areas
- Oncology
- Cancer Research
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In: British journal of cancer, Vol. 104, No. 8, 12.04.2011, p. 1356-1361.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - 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
AU - Osorio, A.
AU - Milne, R. L.
AU - Alonso, R.
AU - Pita, G.
AU - Peterlongo, P.
AU - Teulé, A.
AU - Nathanson, K. L.
AU - Domchek, S. M.
AU - Rebbeck, T.
AU - Lasa, A.
AU - Konstantopoulou, I.
AU - Hogervorst, F. B.
AU - Verhoef, S.
AU - Van Dooren, M. F.
AU - Jager, A.
AU - Ausems, M. G.E.M.
AU - Aalfs, C. M.
AU - Van Asperen, C. J.
AU - Vreeswijk, M.
AU - Waisfisz, Q.
AU - Van Roozendaal, C. E.
AU - Ligtenberg, M. J.
AU - Easton, D. F.
AU - Peock, S.
AU - Cook, M.
AU - Oliver, C. T.
AU - Frost, D.
AU - Curzon, B.
AU - Evans, D. G.
AU - Lalloo, F.
AU - Eeles, R.
AU - Izatt, L.
AU - Davidson, R.
AU - Adlard, J.
AU - Eccles, D.
AU - Ong, K. R.
AU - Douglas, F.
AU - Downing, S.
AU - Brewer, C.
AU - Walker, L.
AU - Nevanlinna, H.
AU - Aittomäki, K.
AU - Couch, F. J.
AU - Fredericksen, Z.
AU - Lindor, N. M.
AU - Godwin, A.
AU - Isaacs, C.
AU - Caligo, M. A.
AU - Loman, N.
AU - Jernström, H.
AU - Barbany-Bustinza, G.
AU - Liljegren, A.
AU - Ehrencrona, H.
AU - Stenmark-Askmalm, M.
AU - Feliubadaló, L.
AU - Manoukian, S.
AU - Peissel, B.
AU - Zaffaroni, D.
AU - Bonanni, B.
AU - Fortuzzi, S.
AU - Johannsson, O. T.
AU - Chenevix-Trench, G.
AU - Chen, X. C.
AU - Beesley, J.
AU - Spurdle, A. B.
AU - Sinilnikova, O. M.
AU - Healey, S.
AU - McGuffog, L.
AU - Antoniou, A. C.
AU - Brunet, J.
AU - Radice, P.
AU - Benítez, J.
N1 - Funding Information: Spanish National Cancer Centre (CNIO): We thank RM Alonso for her excellent technical assistance. The samples studied at CNIO were recruited by the Spanish Consortium for the Study of Genetic Modifiers of BRCA1 and BRCA2. This study was partially supported by Mutua Madrileña Foundations. The research leading to these results has received funding from the Ministry of Science (FIS08-1120) and European Community’s Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175). The Italian study (Milan Breast Cancer Study Group, MBCSG) is funded in part by grants from Fondazione Italiana per la Ricerca sul Cancro (Special Project ‘Hereditary tumors’), Associazione Italiana per la Ricerca sul Cancro (4017), Ministero della Salute (RFPS-2006-3-340203, Extraordinary National Cancer Program 2006 ‘Alleanza contro il Cancro’ and ‘Progetto Tumori Femminili’), Ministero dell’Universita’ e Ricerca (RBLAO3-BETH) and by funds from Italian citizens who allocated the 5 ⨯ 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5 ⨯ 1000’). The MBCSG acknowledges Marco Pierotti and Carla B Ripamonti of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Monica Barile and Loris Bernard of the Istituto Europeo di Oncologia, Milan, Italy. The Kathleen Cuningham Consortium for Research into Familial Breast Funding Information: Cancer (kConFab): We wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (funded by NHMRC grants 145684, 288704 and 454508) for their contributions to this resource, and the many families who contribute to kConFab. The kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. ABS is an NHMRC Senior Research Fellow, and GCT is an NHMRC Senior Principal Research Fellow. The MAYO study is supported in part by National Institute of Health Grants CA116167, CA122340, CA128978, a Specialized Program of Research Excellence grant in Breast Cancer P50 CA116201, a grant from the Breast Cancer Research Foundation, and a grant from the Komen Foundation for the Cure. The PBCS is supported by a grant of the Institute for Tumors of Tuscany. The Swedish BRCA1 and BRCA2 study collaborators (SWE-BRCA): SWE-BRCA collaborators: Per Karls-son, Margareta Nordling, Annika Bergman and Zakaria Einbeigi, Gothenburg, Sahlgrenska University Hospital; Marie Stenmark-Askmalm and Sigrun Liedgren, Linköping University Hospital; Åke Borg, Niklas Loman, Håkan Olsson, Ulf Kristoffersson, Helena Jernström, Katja Harbst and Karin Henriksson, Lund University Hospital; Annika Lindblom, Brita Arver, Anna von Wachenfeldt, Annelie Liljegren, Gisela Barbany-Bustinza and Johanna Rantala, Stockholm, Karolinska University Hospital; Beatrice Melin, Henrik Grönberg, Eva-Lena Stattin and Monica Emanuelsson, Umeå University Hospital; Hans Ehrencrona, Richard Rosenquist Brandell and Niklas Dahl, Uppsala University Hospital. The UPENN study is supported by the Breast Cancer Research Foundation and the MacDonald Family Foundation. The HEBON Collaborating Centres: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: FBL Hogervorst, S Verhoef, M Verheus, LJ van ‘t Veer, FE van Leeuwen, MA Rookus; Erasmus Medical Center, Rotterdam, NL: M Collée, AMW van den Ouweland, A Jager, MJ Hooning, MMA Tilanus-Linthorst, C Seynaeve; Leiden University Medical Center, NL, Leiden: CJ van Asperen, JT Wijnen, MP Vreeswijk, RA Tollenaar, P Devilee; Radboud University Nijmegen Medical Center, Nijmegen, NL: MJ Ligtenberg, N Hoogerbrugge; University Medical Center Utrecht, Utrecht, NL: MG Ausems, RB van der Luijt; Amsterdam Medical Center, NL: CM Aalfs, TA van Os; VU University Medical Center, Amsterdam, NL: JJP Gille, Q Waisfisz, HEJ Meijers-Heijboer; University Hospital Maastricht, Maastricht, NL: EB Gomez-Garcia, CE van Roozendaal, Marinus J Blok, B Caanen; University Medical Center Groningen University, NL: JC Oosterwijk, AH van der Hout, MJ Mourits; The Netherlands Foundation for the detection of hereditary tumours, Leiden, NL: HF Vasen. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088 and NKI2007-3756. Epidemiological study of BRCA1 and BRCA2 mutation carriers (EMBRACE): EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. Bridget Curzon is supported by Cancer Research UK Grant C8197/A10123. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeeles, Elizabeth Bancroft and Lucia D’Mello are also supported by Cancer Research UK Grant C5047/A8385. D Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. Douglas Easton is the PI of the study. EMBRACE Collaborating Centres are: Coordinating Centre, Cambridge: Susan Peock, Margaret Cook, Clare Oliver, Debra Frost. North of Scotland Regional Genetics Service, Aberdeen: Zosia Miedzybrodzka, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison, Lisa Jeffers. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Carole McKeown, Kai-ren Ong, Jonathan Hoffman. South West Regional Genetics Service, Bristol: Alan Donaldson. East Anglian Regional Genetics Service, Cambridge: Joan Paterson, Sarah Downing, Amy Taylor. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark T Rogers, Emma McCann. St James’s Hospital, Dublin and National Centre for Medical Genetics, Dublin: M John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous, Sarah Drummond. Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill. West of Scotland Regional Genetics Service, Glasgow:
PY - 2011/4/12
Y1 - 2011/4/12
N2 - 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 inteNo 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.
AB - 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 inteNo 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.
KW - BRCA1
KW - BRCA2
KW - XRCC1
KW - breast cancer
UR - http://www.scopus.com/inward/record.url?scp=79954440124&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79954440124&partnerID=8YFLogxK
U2 - 10.1038/bjc.2011.91
DO - 10.1038/bjc.2011.91
M3 - Article
C2 - 21427728
AN - SCOPUS:79954440124
SN - 0007-0920
VL - 104
SP - 1356
EP - 1361
JO - British journal of cancer
JF - British journal of cancer
IS - 8
ER -