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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

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
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
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: 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.
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Osorio, A.
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Healey, S.
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Osorio, A.
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Alonso, R.
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Jager, A.
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Cook, M.
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Oliver, C.T.
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Frost, D.
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Eccles, D.
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Osorio, A., Milne, R.L., Alonso, R., Pita, G., Peterlongo, P., Teulé, A., Nathanson, K.L., Domchek, S.M., Rebbeck, T., Lasa, A., Konstantopoulou, I., Hogervorst, F.B., Verhoef, S., van Dooren, M.F., Jager, A., Ausems, M.G.E.M., Aalfs, C.M., van Asperen, C.J., Vreeswijk, M., Waisfisz, Q., Van Roozendaal, C.E., Ligtenberg, M.J., Easton, D.F., Peock, S., Cook, M., Oliver, C.T., Frost, D., Curzon, B., Evans, D.G., Lalloo, F., Eeles, R., Izatt, L., Davidson, R., Adlard, J., Eccles, D., Ong, K.-r., Douglas, F., Downing, S., Brewer, C., Walker, L., Nevanlinna, H., Aittomäki, K., Couch, F.J., Fredericksen, Z., Lindor, N.M., Godwin, A., Isaacs, C., Caligo, M.A., Loman, N., Jernström, H., Barbany-Bustinza, G., Liljegren, A., Ehrencrona, H., Stenmark-Askmalm, M., Feliubadaló, L., Manoukian, S., Peissel, B., Zaffaroni, D., Bonanni, B., Fortuzzi, S., Johannsson, O.T., Chenevix-Trench, G., Chen, X.-C., Beesley, J., Spurdle, A.B., Sinilnikova, O.M., Healey, S., McGuffog, L., Antoniou, A.C., Brunet, J., Radice, P. and Benítez, J. (2011) 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. British Journal of Cancer, 104 (8), 1356-1361. (doi:10.1038/bjc.2011.91).

Record type: Article

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: 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.

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More information

Published date: 22 March 2011
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 352339
URI: http://eprints.soton.ac.uk/id/eprint/352339
ISSN: 0007-0920
PURE UUID: 1ff8237c-2c94-4fa1-b813-42e03328687d
ORCID for D. Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 14 May 2013 14:55
Last modified: 15 Mar 2024 02:40

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Contributors

Author: A. Osorio
Author: R.L. Milne
Author: R. Alonso
Author: G. Pita
Author: P. Peterlongo
Author: A. Teulé
Author: K.L. Nathanson
Author: S.M. Domchek
Author: T. Rebbeck
Author: A. Lasa
Author: I. Konstantopoulou
Author: F.B. Hogervorst
Author: S. Verhoef
Author: M.F. van Dooren
Author: A. Jager
Author: M.G.E.M. Ausems
Author: C.M. Aalfs
Author: C.J. van Asperen
Author: M. Vreeswijk
Author: Q. Waisfisz
Author: C.E. Van Roozendaal
Author: M.J. Ligtenberg
Author: D.F. Easton
Author: S. Peock
Author: M. Cook
Author: C.T. Oliver
Author: D. Frost
Author: B. Curzon
Author: D.G. Evans
Author: F. Lalloo
Author: R. Eeles
Author: L. Izatt
Author: R. Davidson
Author: J. Adlard
Author: D. Eccles ORCID iD
Author: K.-r. Ong
Author: F. Douglas
Author: S. Downing
Author: C. Brewer
Author: L. Walker
Author: H. Nevanlinna
Author: K. Aittomäki
Author: F.J. Couch
Author: Z. Fredericksen
Author: N.M. Lindor
Author: A. Godwin
Author: C. Isaacs
Author: M.A. Caligo
Author: N. Loman
Author: H. Jernström
Author: G. Barbany-Bustinza
Author: A. Liljegren
Author: H. Ehrencrona
Author: M. Stenmark-Askmalm
Author: L. Feliubadaló
Author: S. Manoukian
Author: B. Peissel
Author: D. Zaffaroni
Author: B. Bonanni
Author: S. Fortuzzi
Author: O.T. Johannsson
Author: G. Chenevix-Trench
Author: X.-C. Chen
Author: J. Beesley
Author: A.B. Spurdle
Author: O.M. Sinilnikova
Author: S. Healey
Author: L. McGuffog
Author: A.C. Antoniou
Author: J. Brunet
Author: P. Radice
Author: J. Benítez

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