K-ras andp53 mutations and DNA repair genes polymorphisms as biomarkers for lung cancer

Lung cancer is currently the leading cause of cancer mortality in the United States. Cigarette smoking is acknowledged as the predominant cause of lung cancer and despite overwhelming efforts in public education to promote smoking cessation and abstinence, tobacco use continues. Patients with the best prognosis for long-term survival are those that are diagnosed and treated at a very early stage of disease. Therefore, identifying biomarkers for the early development of lung cancer would not only provide a means of identifying at high-risk population but may also shed light onto the mechanisms leading to the development of lung cancer.; Mutations in two cancer-related genes, the proto-oncogene K-ras and the tumor suppressor gene p53, are frequently identified in lung tumors and are implicated as being critical for lung cancer development. K-ras and p53 mutations may be induced by both polycyclic aromatic hydrocarbons (PAHs) and nitrosamines found in tobacco smoke. Certain types of K-ras and p53 mutations may be associated with geographic, ethnic and tumor histological differences. In this study, the K-ras and p53 mutational spectra was characterized for 296 resected tumors obtained from non-small cell lung cancer (NSCLC) patients with a history of smoking and who resided in the Western Pennsylvania region. The results indicate that K-ras and p53 mutations may arise from DNA adduction by both v PAHs and nitrosamines. These analyses also indicated K-ras mutations are more frequent in adenocarcinoma (AC) than that in squamous cell carcinoma (SCC) and that p53 mutations are less frequent in AC than that in SCC. A distinct but different spectrum in the p53 mutation pattern in both AC and SCC was observed. Finally, topographic analysis of K-ras and p53 mutations showed that mutations within those genes frequently occurred in histologically normal cells which may represent critical genetic alterations in the lung cancer development.; Since not everyone who smokes develops lung cancer, genetic susceptibility may play a role in lung carcinogenesis. Genetic differences resulting in interindividual variation in DNA repair capacity may, in part, account for the susceptibility of a cell to genotoxic agents that leads to somatic mutations, including K-ras and/or p53 mutations. The genotypes of DNA repair genes, including the nucleotide excision repair (NER) xeroderma pigmentosum group D (XPD) gene (codons 312 and 751) and the base excision repair (BER) X-ray repair cross-complementing group 1 (XRCC1) gene (codon 399) were analyzed. The results indicate that genetic polymorphisms in these DNA repair genes influenced the frequency of p53 mutations. Patients with the XPD codon 312 Asn allele were less likely to have p53 mutations than XPD 312 Asp/Asp [OR, 0.43, 95%CI 0.20–0.89, P = 0.023]. The p53 mutation frequency increased with the increased number of the combined genotypes among XPD 312WT (Asp/Asp), XPD 751VT (Lys/Gln or Gln/Gln) or XRCC1 399VT (Arg/Gln or Gln/Gln) (P = 0.01, trend test).; Taken together, the combination of K-ras and/or p53 mutations and susceptibility factors, such as polymorphisms in XPD and XRCC1 gene, might provide better biomarkers for lung cancer.