Influence of common XPD and XRCC1 variant alleles on p53 mutations in lung tumors

Abstract

The DNA repair proteins XPD and XRCC1 are involved in the nucleotide and base excision repair of DNA lesions induced by many tobacco and environmental carcinogens. Common variant alleles at the XPD (312Asn, 751Gln) and XRCC1 (399Gln) loci have been identified and associated with increased risk for lung cancer. We therefore investigated a possible effect of these variant alleles on the frequency and spectrum of p53 mutations in the tumors of 97 Swedish lung cancer patients (56 never-smokers and 41 age-, gender-, and hospital-matched ever-smokers). The p53 gene was mutated in 4 never-smokers (7%) and 11 ever-smokers (27%). Smoking-related transversion-type mutations predominated over transitions among smokers (8:3), but not among never-smokers (1:3). None of the variant alleles altered the overall frequency of p53 mutation. Transversions, however, were marginally increased among patients with at least one XPD variant allele compared with patients who were wild-type homozygotes (73% vs. 25% for the Asp312Asn polymorphism, P = 0.095; 78% vs. 33% for Lys751Gln, P = 0.085). Five of six women or six of seven smokers who carried at least one XPD 751Gln allele had p53 transversion. The XRCC1 variant allele did not show any effect on the p53 mutation. We conclude that the XPD variant alleles may be associated with an increased frequency of smoking-related p53 mutations in lung tumors, presumably due to reduced DNA repair proficiency.