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RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies.

  • 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

17999359

Am. J. Hum. Genet.. 2007 Dec 81 (6).

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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