RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies.
Abstact
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.
Authors
- Andrulis IL
- Antoniou AC
- Arason A
- Arnold N
- Barjhoux L
- Baynes C
- Belotti M
- Benitez J
- Bignon YJ
- Bonadona V
- Byrski T
- Chen X
- Chenevix-Trench G
- Cloonan N
- Cook M
- Couch FJ
- Coupier I
- Daly PA
- Deissler H
- Devilee P
- Domchek SM
- Dorkins H
- Dumont M
- Durocher F
- Easton DF
- Engel C
- Friedman E
- Galore G
- Garber JE
- Godwin A
- Greene MH
- Gronwald J
- Górski B
- Hamann U
- Hughes DJ
- Huzarski T
- Ilyushik E
- Isaacs C
- Jakubowska A
- Kaufmann B
- Kilpivaara O
- Kirchhoff T
- Laitman Y
- Lasset C
- Lejbkowicz F
- Lubinski J
- Lynch HT
- Léoné M
- Meindl A
- Murray A
- Narod SA
- Nathanson KL
- Neuhausen SL
- Nevanlinna H
- Niederacher D
- Offit K
- Olopade OI
- Osorio A
- Ozcelik H
- Peock S
- Prindiville SA
- Raskin L
- Rebbeck TR
- Rennert G
- Rogers M
- Schmutzler RK
- Simard J
- Sinilnikova OM
- Spurdle AB
- Stoppa-Lyonnet D
- Struewing JP
- Szabo CI
- Tomlinson G
- Versmold B
- Vreeswijk MP
- Waddell N
- Wagner T
- Weitzel J
- Zikan M