Genetic Polymorphisms in RAD23B and XPC Modulate DNA Repair Capacity and Breast Cancer Risk in Puerto Rican Women

摘要

Studies have shown that DNA repair capacity is significantly decreased in breast cancer patients, but the molecular causes of inter-individual variations in DNA repair capacity are unknown. We hypothesized that genetic variations in the nucleotide excision repair pathway genes can modulate DNA repair capacity (DRC) and breast cancer risk in Puerto Rican women. A total of 228 breast cancer cases and 418 controls were recruited throughout Puerto Rico. For all study participants, eight SNPs in the genes XPC, XPD and RAD23B were genotyped using a TaqMan PCR, and the DRC levels of UV induced-DNA damage was measured in peripheral lymphocytes using a host cell reactivation assay. After adjustment for confounders, RAD23B rs1805329 (Ala249Val) was found to be significantly associated with breast cancer risk under all models tested (P<0.001). There was also a significant association between breast cancer risk and RAD23B rs10739234 (intronic) under the recessive model (P=0.003, OR: 2.72, 95% CI: 1.40–5.30). In cases, there was a statistically significant difference in mean DRC per genotype for RAD23B rs1805329 (P<0.001) and XPC rs2607775 (P=0.002). When we modeled the combined effect of multiple SNPs that each independently affected DRC on cancer risk, we observed incremental augmentations in risk with increasing number of risk genotypes at those loci (P overall model < 0.001). The increase in adverse genotypes was also correlated with a progressive decrease in DRC values. Our data indicate an additive effect of the NER SNPS on DRC and breast cancer risk in Puerto Rican women.