Antoniou, AC; Sinilnikova, OM; Simard, J; Léoné, M; Dumont, M; Neuhausen, SL; Struewing, JP; Stoppa-Lyonnet, D; Barjhoux, L; Hughes, DJ; Coupier, I; Belotti, M; Lasset, C; Bonadona, V; Bignon, YJ; Rebbeck, TR; Wagner, T; Lynch, HT; Domchek, SM; Nathanson, KL; Garber, JE; Weitzel, J; Narod, SA; Tomlinson, G; Olopade, OI; Godwin, A; Isaacs, C; Jakubowska, A; Lubinski, J; Gronwald, J; Górski, B; Byrski, T; Huzarski, T; Peock, S; Cook, M; Baynes, C; Murray, A; Rogers, M; Daly, PA; Dorkins, H; Schmutzler, RK; Versmold, B; Engel, C; Meindl, A; Arnold, N; Niederacher, D; Deissler, H; Spurdle, AB; 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, IL; Ilyushik, E; Ozcelik, H; Devilee, P; Vreeswijk, MP; Greene, MH; Prindiville, SA; Osorio, A; Benitez, J; Zikan, M; Szabo, CI; Kilpivaara, O; Nevanlinna, H; Hamann, U; Durocher, F; Arason, A; Couch, FJ; Easton, DF; Chenevix-Trench, G    «

Antoniou, AC; Sinilnikova, OM; Simard, J; Léoné, M; Dumont, M; Neuhausen, SL; Struewing, JP; Stoppa-Lyonnet, D; Barjhoux, L; Hughes, DJ; Coupier, I; Belotti, M; Lasset, C; Bonadona, V; Bignon, YJ; Rebbeck, TR; Wagner, T; Lynch, HT; Domchek, SM; Nathanson, KL; Garber, JE; Weitzel, J; Narod, SA; Tomlinson, G; Olopade, OI; Godwin, A; Isaacs, C; Jakubowska, A; Lubinski, J; Gronwald, J; Górski, B; Byrski, T; Huzarski, T; Peock, S; Cook, M; Baynes, C; Murray, A; Rogers, M; Daly, PA; Dorkins, H; Schmut...    »

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.    «

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...    »