The XRCC1 -77T->C variant: haplotypes, breast cancer risk, response to radiotherapy and the cellular response to DNA damage

Abstract

X-ray repair cross-complementing 1 ( XRCC1 ) is required for single-strand break repair in human cells and several polymorphisms in this gene have been implicated in cancer risk and clinical prognostic factors. We examined the frequency of the 5′-untranslated region (5′–UTR) variant −77T→C (rs 3213235) in 247 French breast cancer (BC) patients, 66 of whom were adverse radiotherapy responders, and 380 controls and determined the haplotypes based on this and the previously genotyped variants Arg194Trp, Arg280His and Arg399Gln. The −77T→C variant alone showed no significant association with BC risk or therapeutic radiation sensitivity. The H5 haplotype (variant allele codon 280, wild-type allele other positions) was associated with increased BC risk [odds ratio (OR), 1.90; 95% confidence interval (CI), 1.12–3.23] and the H3 haplotype (wild-type allele all four positions) was inversely associated with therapeutic radiation sensitivity compared with the reference group (H1 haplotype, −77C , wild-type allele codons 194, 280, 399) (OR, 0.39; 95% CI, 0.16–0.92). However given that the global tests for association were not significant these results should be interpreted carefully. Lymphoblastoid cell lines heterozygous for the H1/H3 haplotypes had a significantly higher cell survival ( P = 0.04) after exposure to ionising radiation (IR) than those with the H1/H1 haplotypes, in agreement with the association study. However no haplotype-specific differences in XRCC1 expression or cell cycle progression were noted in the 24 h following IR exposure. These results suggest that the −77T→C genotype or another variant in linkage disequilibrium influences the cellular response to DNA damage, although the underlying molecular mechanisms remain to be established.