Comparison of mutations in the p53 and K-ras genes in lung carcinomas fromsmoking and nonsmoking women

Lung cancer incidence is increasing in women with Little or no tobacco expo sure, and the cause of this trend is not known, One possibility is increase d sensitivity to environmental tobacco smoke in women nonsmokers diagnosed with lung cancer. To determine whether mutations associated with tobacco ex posure are found in the lung tumors of women who are lifetime nonsmokers or occasional smokers, we compared the p53 and K-ras mutational spectra in lu ng carcinomas from 23 female nonsmokers, 2 female occasional smokers (<10 p ack-years), and 30 female long-term smokers (20-100 pack-years). We also lo oked for p53 and K-ras mutations in three carcinoid lung tumors, two from f emale nonsmokers and one from a female occasional smoker. For the p53 gene, exons 4-8 were examined for mutations; for the K-ras gene, exon 1 was exam ined. No mutations were found in the carcinoid tumors. In lung carcinomas, p53 mutations were identified in six (26.1%) of the cases from lifetime non smokers and consisted of five transitions (including three C to T, one G to A, and one T to C) and one T to A transversion. In comparison, p53 mutatio ns were identified in 10 (31.3%) of the 32 lung carcinomas from short-term and long-term smokers and consisted of six transversions (four G to T, one A to T, and one G to C), one A to G transition, one C to T transition, and two deletions of one to four bp, Mutations in the p53 gene found in nonsmok ers also occurred in either different codons or different positions within a codon compared with those seen in long-term smokers. K-ras mutations in c odon 12 were identified in two lung carcinomas (8.7%) from lifetime nonsmok ers, The K-ras mutations found were a G to T transversion and a G to A tran sition. Eight (25%) of the 32 lung carcinomas from smokers contained K-ras mutations in codons 12 and 23 (four G to T transversions and four G to A tr ansitions). In addition, six silent mutations that are most likely polymorp hisms mere found in both smokers and nonsmokers. These results confirm that K-ras mutations are more frequent in smokers than in nonsmokers, but that the same type of mutation in the K-ras gene is found in both groups. In con trast, although the frequency of mutation in the p53 gene was similar in li fetime nonsmokers compared with long-term smokers, the types and spectra of mutation are significantly different. Two of the C to T transitions found in nonsmokers, but none of those found in smokers, occur at the C of a CpG site. These results suggest the mutagen(s) and/or mechanisms of p53 mutatio ns in women nonsmokers are different from those responsible for p53 mutatio ns in women smokers, which are probably largely induced by tobacco mutagens .