K-ras and p53 genes mutations and polymorphisms of the DNA repair XPD and XRCC1 genes in lung cancer among smokers and nonsmokers
Authors: Phouthone Keohavong, Wei-Min Gao, Jill M. Siegfried, James D. Luketich, Marjorie Romkes
Journal: Cancer Research (2004)

2907   Lung cancer is associated with a high frequency of mutations in both the p53 tumor suppressor gene and K-ras oncogene. In smokers, these mutations are believed to be a consequence of DNA damage caused by tobacco smoke carcinogens, while, in nonsmokers, the origin(s) of these mutations remains elusive. Genetic differences resulting in interindividual variation in DNA repair capacity may in part account for susceptibility to p53 and/or K-ras mutations. The repair of DNA damage is critically important since reduced DNA repair capacity increases the sensitivity of a cell to genotoxic environmental agents, leading to a somatic mutation and eventual transformation of a normal cell into a malignant phenotype. We have previously studied the relationship between the polymorphisms of two DNA repair genes, the nucleotide excision repair XPD (codons 312 and 751) gene and the base excision repair XRCC1 (codon 399) gene, and p53 mutations among patients with non-small cell lung cancer (NSCLC). We have demonstrated a significant association between smoking NSCLC patients who carried a variant polymorphism of the XPD 312 Asp/Asp and an increased p53 mutation frequency in their lung tumor, suggesting individuals who smoke and have the XPD codon 312 Asp/Asp polymorphism may be at a greater risk of p53 mutations. Here, we have extended this study by investigating the relationship between these DNA repair gene polymorphisms and K-ras mutations in the same patients. In addition, 33 nonsmoking NSCLC patients were analyzed for both p53 and K-ras mutations and DNA repair enzyme genotype. The results showed that the K-ras mutations, mostly G to T transversions, occurred in 31% of the smokers (64/204), and in 9% (3/33) of the nonsmokers, suggesting these mutations were primarily associated with tobacco smoke carcinogens. In nonsmokers, seven p53 mutations (21%, 7/33), mostly G to A or C to T transitions, were found at sites different from those found in smokers. Comparison of the K-ras mutation frequency with the DNA repair gene polymorphisms in smokers showed no significant association between the presence of these mutations in lung tumors and any of the XPD 312, XPD 751 or XRCC1 399 genotypes, alone or combined (P=0.43, trend test). In nonsmokers, comparison of the p53 mutations with DNA repair gene polymorphisms showed patients with the XRCC1 399 Gln were more likely to have p53 mutations than those with the XRCC1 399 Arg/Arg (P=0.073, trend test). No association was found between these mutations and either XPD Asp312Asn or XPD Lys751Gln allele alone. However, the p53 mutation frequency increased with the increased number of the combined genotypes among XPD 312 Asp/Asp, XPD 751 Lys/Gln or Gln/Gln, or XRCC1 399 Arg/Gln or Gln/Gln (P=0.05). Taken together, these results suggest a difference in the types and/or repair pathways of DNA damage for the p53 and K-ras genes in smokers and for the p53 gene between smokers and nonsmokers.