29948e84-4604-4bf0-a480-6b84d4270120
title
A single-nucleotide polymorphism in the  RAD51  gene modifies breast cancer risk in  BRCA2  carriers, but not in  BRCA1  carriers or noncarriers.
09c97269-a8d5-4c7e-847a-7569a9a0e97a
abstract
Variation in the penetrance estimates for  BRCA1  and  BRCA2  mutation carriers suggests that other genetic polymorphisms may modify the cancer risk in carriers. The  RAD51  gene, which participates in homologous recombination double-strand breaks (DSB) repair in the same pathway as the  BRCA1  and  BRCA2  gene products, is a candidate for such an effect. A single-nucleotide polymorphism (SNP),  RAD51-135g-->c , in the 5' untranslated region of the gene has been found to elevate breast cancer (BC) risk among  BRCA2  carriers. We genotyped 309  BRCA1 /2 mutation carriers, of which 280 were of Ashkenazi origin, 166 noncarrier BC patients and 152 women unaffected with BC (a control group), for the  RAD51-135g-->c  SNP. Risk analyses were conducted using COX proportional hazard models for the  BRCA1 /2 carriers and simple logistic regression analysis for the noncarrier case-control population.  BRCA2  carriers were also studied using logistic regression and Kaplan-Meier survival analyses. The estimated BC hazard ratio (HR) for  RAD51-135c  carriers adjusted for origin (Ashkenazi vs non-Ashkenazi) was 1.28 (95% CI 0.85-1.90, P=0.23) for  BRCA1 /2 carriers, and 2.09 (95% CI 1.04-4.18, P=0.04) when the analysis was restricted to  BRCA2  carriers. The median BC age was younger in  BRCA2 - RAD51-135c  carriers (45 (95% CI 36-54) vs 52 years (95% CI 48-56), P=0.05). In a logistic regression analysis, the odds ratio (OR) was 5.49 (95% CI 0.5-58.8, P=0.163). In noncarrier BC cases, carrying  RAD51-135c  was not associated with BC risk (0.97; 95% CI 0.47-2.00). These results indicate significantly elevated risk for BC in carriers of  BRCA2  mutations who also carry a  RAD51-135c  allele. In  BRCA1  carriers and noncarriers, no effect for this SNP was found.