MUTATIONS IN THE P53 GENE IN LUNG-CANCER ARE ASSOCIATED WITH CIGARETTE-SMOKING AND ASBESTOS EXPOSURE

It has been proposed that the patterns of mutations in the p53 tumor s uppressor gene will provide clues to the mechanisms of cancer occurren ce, Cigarette smoking is known to be the greatest risk factor for lung cancer, Epidemiological evidence has also implicated radon and asbest os as exposures that significantly increase this disease risk; asbesto s exposure synergistically enhances the lung cancer risk of smokers, P revious studies of the mutational spectra of the p53 gene in lung canc er have shown cigarette smoke and radon exposure to be associated with the induction of particular lesions or classes of lesions, We have in vestigated the p53 gene in surgically resectable lung cancers in 85 pa tients from the Massachusetts General Hospital, We found 25 (29%) pati ents to have somatic p53 mutations in their tumors, The patients with p53 mutations who were current smokers were significantly older (75.1 versus 59.8 years; P < 0.01) and had smoked for significantly more yea rs (56.8 vel sus 41.2 years; P < 0.01) than had those without p53 chan ges, Consistent with other reports, we observed a large number (40%) o f G:C to T:A transversion mutations, noting that their occurrence incr eased with increasing cumulative exposure to cigarette smoke, Interest ingly, we also found that p53 mutations occurred significantly more fr equently in patients with a history of occupational exposure to asbest os [3 of 60 (5%) for patients without p53 mutations versus 5 of 25 (20 %) of those with p53 mutations; P < 0.05]. Additionally, 4 of the 5 pa tients with asbestos exposure and p53 alterations had G:C to T:A trans version mutations, and 3 of 3 double mutations that were seen in the p 53 gene occurred in patients who smoked and had a history of asbestos exposure, This suggests that asbestos exposure may increase the freque ncy of G:C to T:A transversion mutations in the p53 gene, Because thes e lesions can be induced by polyaromatic compounds found in cigarette smoke, our data also suggest that one possible important role of asbes tos may be to increase delivery of these substances to the respiratory epithelium. Asbestos might also act to alter clonal selection through other mechanisms, including apoptosis, oxyradical generation, or alte red proliferation.