DNA repair gene genotypes and associated phenotypes in breast cancer

Genetic susceptibilities for breast cancer can be elucidated by studying genotype-phenotype correlates. This study investigated women from high risk breast cancer families, a sporadic breast cancer case-control study and associations for specific BRCA1 SNPs and haplotypes, Rad51 SNPs, and deficient DNA repair. EBV-immortalized lymphocytes from 138 affected and unaffected BRCA1+ women were available for study. The mutagen sensitivity assay (MSA), used to measure DNA repair capacity, was used to test associations with genotypes and haplotypes. Positive associations were then tested as predictors of breast cancer risk in a population-based case control study (n=1165 cases and 2170 controls). BRCA1 carriers with breast cancer had more mean breaks per cell (MBPC) than BRCA1 carriers without breast cancer. An association was found for the Rad51 5'UTR 135C allele and MBPC (OR=3.40 95% CI: 1.20-9.90). There also was an increased risk for MBPC with the BRCA1 D693N allele (OR=6.03 95% CT: 0.69-52.02), but this was not statistically significant (p=0.10). There was no association with for the BRCA1 Q356R and E1038G genotypes or haplotypes. The Rad51 5'UTR 135C allele was examined in a population-based case-control study of breast cancer, but no association was found in premenopausal (OR=0.83 95% CI: 0.56-1.23) or postmenopausal women (OR=1.19 95% CI: 0.93-1.51). This study provides data to justify a well-designed epidemiology study of the MSA as a predictive phenotype in BRCA1 mutation carriers and breast cancer risk. The results indicated that the Rad51 5'U7'R 135C allele and maybe the D693N allele are modifying genotypes for the penetrance of BRCA1 mutation carriers and so might only be risk factor for high risk families.