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

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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1356-1361
Number of pages6
JournalBritish Journal of Cancer
Volume104
Issue number8
DOIs
StatePublished - Apr 12 2011

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Research Personnel
Mutation
DNA Repair
Single Nucleotide Polymorphism
Genes
Homozygote
BRCA2 Gene
Breast Neoplasms
BRCA1 Gene
Confidence Intervals

Keywords

  • BRCA1
  • BRCA2
  • breast cancer
  • XRCC1

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / 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, Fergus J; Fredericksen, Z.; Lindor, Noralane Morey; 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.; Benítez, J.

In: British Journal of Cancer, Vol. 104, No. 8, 12.04.2011, p. 1356-1361.

Research output: Contribution to journalArticle

Osorio, A, Milne, RL, Alonso, R, Pita, G, Peterlongo, P, Teulé, 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, Aittomäki, K, Couch, FJ, Fredericksen, Z, Lindor, NM, Godwin, A, Isaacs, C, Caligo, MA, 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, OT, Chenevix-Trench, G, Chen, XC, Beesley, J, Spurdle, AB, Sinilnikova, OM, Healey, S, McGuffog, L, Antoniou, AC, Brunet, J, Radice, P & 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, vol. 104, no. 8, pp. 1356-1361. https://doi.org/10.1038/bjc.2011.91
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, Fergus J ; Fredericksen, Z. ; Lindor, Noralane Morey ; 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. ; Benítez, J. / 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. In: British Journal of Cancer. 2011 ; Vol. 104, No. 8. pp. 1356-1361.
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title = "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",
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.",
keywords = "BRCA1, BRCA2, breast cancer, XRCC1",
author = "A. Osorio and Milne, {R. L.} and R. Alonso and G. Pita and P. Peterlongo and A. Teul{\'e} and Nathanson, {K. L.} and Domchek, {S. M.} and T. Rebbeck and A. Lasa and I. Konstantopoulou and Hogervorst, {F. B.} and S. Verhoef and {Van Dooren}, {M. F.} and A. Jager and Ausems, {M. G E M} and Aalfs, {C. M.} and {Van Asperen}, {C. J.} and M. Vreeswijk and Q. Waisfisz and {Van Roozendaal}, {C. E.} and Ligtenberg, {M. J.} and Easton, {D. F.} and S. Peock and M. Cook and Oliver, {C. T.} and D. Frost and B. Curzon and Evans, {D. G.} and F. Lalloo and R. Eeles and L. Izatt and R. Davidson and J. Adlard and D. Eccles and Ong, {K. R.} and F. Douglas and S. Downing and C. Brewer and L. Walker and H. Nevanlinna and K. Aittom{\"a}ki and Couch, {Fergus J} and Z. Fredericksen and Lindor, {Noralane Morey} and A. Godwin and C. Isaacs and Caligo, {M. A.} and N. Loman and H. Jernstr{\"o}m and G. Barbany-Bustinza and A. Liljegren and H. Ehrencrona and M. Stenmark-Askmalm and L. Feliubadal{\'o} and S. Manoukian and B. Peissel and D. Zaffaroni and B. Bonanni and S. Fortuzzi and Johannsson, {O. T.} and G. Chenevix-Trench and Chen, {X. C.} and J. Beesley and Spurdle, {A. B.} and Sinilnikova, {O. M.} and S. Healey and L. McGuffog and Antoniou, {A. C.} and J. Brunet and P. Radice and J. Ben{\'i}tez",
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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, Fergus J

AU - Fredericksen, Z.

AU - Lindor, Noralane Morey

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.

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 - breast cancer

KW - XRCC1

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