Genetic polymorphisms in double-strand break DNA repair genes associated with risk of oral premalignant lesions.

Oral premalignant lesions (OPLs) are early genetic events en route to oral cancer. To identify individuals susceptible to OPL is critical to the prevention of oral cancer. In a case-control study consisting of 147 patients with histologically confirmed OPL and 147 matched controls, we evaluated the associations of 10 genetic variants in nine genes of the double-strand break (DSB) DNA repair pathway with OPL risk. The most notable finding was an intronic polymorphism (A17893G) of the XRCC3 gene. Compared with the homozygous wild-type AA genotype, the odds ratio (OR) (95% confidence interval [CI]) for the heterozygous AG and homozygous variant GG genotype was 0.85 (0.49-1.48) and 0.18 (0.07-0.47), respectively (P for trend=0.002). In addition, compared with the most common A-C haplotypes of XRCC3 (in the order of A17893G-T241M), the G-C haplotypes were associated with a significantly decreased risk of OPL (OR=0.40, 95% CI 0.23-0.68). Moreover, compared with individuals without the G-C haplotype, the OR was 1.04 (0.56-1.95) and 0.20 (0.08-0.51) for subjects with one copy and two copies of the G-C haplotypes, respectively (P for trend=0.005). Classification and regression tree (CART) analysis further revealed potential high-order gene-gene and gene-environmental interactions and categorised subjects into different risk groups according to their specific polymorphic signatures. Overall, our study provides the first epidemiological evidence supporting a connection between DSB gene variants and OPL development. Our data also suggest that the effects of high-order interactions should be taken into consideration when evaluating OPL predisposition.