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

Am J Hum Genet. 2007 Dec;81(6):1186-200. doi: 10.1086/522611. Epub 2007 Oct 16.

Abstract

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.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alternative Splicing
  • BRCA1 Protein / genetics
  • BRCA2 Protein / genetics*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / prevention & control
  • DNA Primers
  • DNA Repair / genetics
  • Family
  • Female
  • Genetic Variation
  • Heterozygote
  • Homozygote
  • Humans
  • Middle Aged
  • Mutation
  • Polymorphism, Single Nucleotide*
  • Rad51 Recombinase / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • BRCA1 Protein
  • BRCA2 Protein
  • DNA Primers
  • RAD51 protein, human
  • Rad51 Recombinase