MOLECULAR EPIDEMIOLOGY OF HUMAN CANCER

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Environmental Tobacco Smoke and Radon Produce Molecular Signatures in Lung Cancers from Nonsmokers. Increasing evidence shows that environmental carcinogens can leave "fingerprints" of genetic damage in the p53 tumor suppressor gene within human tumors. These data suggest that specific carcinogens may be linked directly to individual tumors by telltale mutation profiles. Passive smoking has been linked to lung cancer development by several epidemiologic studies, and the Environmental Protection Agency classified secondhand smoke as a Class A carcinogen in December 1992. This project examines human lung tumor tissues from nonsmokers for genetic evidence linking secondhand smoke exposure to mutations in the p53 tumor suppressor gene. Specific hypotheses include: (i) Frequency of G:C to T:A transversions with a coding strand bias will correlate with passive smoke exposure. (ii) Susceptibility factors including GSTM1 and CYP1A1 genotypes will modulate the frequency of G:C to T:A transversions. Radon Produces 249met p53 Mutation in Lung Cancers from Uranium. In contrast to our initial report of the p53 mutation spectrum in lung cancer from uranium miners in New Mexico and that of Bartsch et al., Taylor and coworkers observed a mutation hotspot 249met, in lung squamous cell carcinoma but not adenocarcinoma from uranium miners in Colorado. Therefore, we have initiated a study to directly test the above hypothesis by chronically exposing normal human bronchial epithelial cells to a total of 4 Gy dose (equivalent to 1460 working level months) of high linear energy transfer alpha radiation and then using the genotypic mutation assay to determine the p53 mutation frequency. The exposure phase of this study has been completed. Our data indicate that 249met p53 mutations are not induced and that the p53 mutation spectrum is consistent with the spectrum observed by us in the uranium miners from New Mexico.