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RAD51 135G-->C Modifies Breast Cancer Risk among BRCA2 Mutation Carriers: Results from a Combined Analysis of 19 Studies

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Antoniou, A.C. | Sinilnikova, O.M. | Simard, J. | Leone, M. | Dumont, M. | Neuhausen, S.L. | Struewing, J.P. | Stoppa-Lyonnet, Dominique | Barjhoux, L. | Hughes, D.J. | Coupier, I. | Belotti, M. | Lasset, Christine | Bonadona, Valérie | Bignon, Y.J. | Rebbeck, T.R. | Wagner, T. | Lynch, H.T. | Domchek, S.M. | Nathanson, K.L. | Garber, J.E. | Weitzel, J. | Narod, S.A. | Tomlinson, G. | Olopade, O.I. | Godwin, A. | Isaacs, C. | Jakubowska, A. | Lubinski, J. | Gronwald, J. | Gorski, B. | Byrski, T. | Huzarski, T. | Peock, S. | Cook, M. | Baynes, C. | Murray, A. | Rogers, M. | Daly, P.A. | Dorkins, H. | Schmutzler, R.K. | Versmold, B. | Engel, C. | Meindl, A. | Arnold, N. | Niederacher, D. | Deissler, H. | Spurdle, A.B. | Chen, X. | Waddell, N. | Cloonan, N. | Kirchhoff, T. | Offit, K. | Friedman, E. | Kaufmann, B. | Laitman, Y. | Galore, G. | Rennert, G. | Lejbkowicz, F. | Raskin, L. | Andrulis, I.L. | Ilyushik, E. | Ozcelik, H. | Devilee, P. | Vreeswijk, M.P. | Greene, M.H. | Prindiville, S.A. | Osorio, A. | Benitez, J. | Zikan, M. | Szabo, C.I. | Kilpivaara, O. | Nevanlinna, H. | Hamann, U. | Durocher, F. | Arason, A. | Couch, F.J. | Easton, D.F. | Chenevix-Trench, G.

Edité par CCSD ; Elsevier (Cell Press) -

International audience. RAD51 is an important component of double-stranded DNA-repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5' untranslated region (UTR) of RAD51, 135G-->C, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G-->C SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval {CI} 1.25-2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83-1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91-1.51) among heterozygotes and 3.18 (95% CI 1.39-7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G-->C variant affects RAD51 splicing within the 5' UTR. Thus, 135G-->C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers.

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