Polymorphisms in DNA repair genes as risk factors for asbestos-related malignant mesothelioma in a general population study

Abstract

Differences in response to carcinogenic agents are due to the allelic variants of the genes that control it. Key genes are those involved in the repair of the DNA damage caused by such agents. This paper describes the results of a case-control epidemiological study designed to determine the genotypes of four of these genes in persons exposed to a single genotoxic factor, i.e. asbestos, who had or had not developed malignant mesothelioma (MM). Our working hypothesis was that an imperfect DNA repair, as revealed by subtle polymorphic variants, could reduce protection against the chronic DNA insult provoked by asbestos and eventually result in mutagenesis and cancer. Seven variants (i.e. XRCC1-R399Q-NCBI SNP, XRCC1-R194W, XRCC3-T241M, XRCC3-IVS6-14, XPD-K751Q, XPD-D312N, OGG1-S326C) were investigated in 81 patients and 110 age and sex-matched controls, all residents at Casale Monferrato, a Piedmontese town highly exposed to asbestos pollution. Unconditional multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). When considered as a categorical variable, XRCC1-399Q showed an increased OR both in heterozygotes (OR = 2.08; 95% CI = 1.00–4.33) and homozygotes (2.38; 95% CI = 0.82–6.94), although individual ORs were not significant. When it was considered as a continuous variable OR was significant (OR = 1.68; 95% CI: 1.02–2.75). When genotypes were divided into “non-risk” and “risk” genotypes, i.e. those thought to be associated with increased risk in the light of the functional significance of the variants, XRCC1-399Q (Q homozygotes + Q/R heterozygotes versus R homozygotes) had an OR = 2.147 (95% CI: 1.08–4.28), whereas that of XRCC3-241T (T homozygotes + M/T heterozygotes versus M homozygotes) was 4.09 (95% CI: 1.26–13.21) and that of OGG1-326C was increased, though not significantly. None of the haplotypes showed a significantly different frequency between patients and controls. This is the first report of an association between polymorphisms in DNA repair genes and asbestos-associated MM. Our data indicate that genetic factors are involved in MM development.