It has been proposed that the patterns of mutations in the p53 tumor suppressor gene will provide clues to the mechanisms of cancer occurrence. Cigarette smoking is known to be the greatest risk factor for lung cancer. Epidemiological evidence has also implicated radon and asbestos as exposures that significantly increase this disease risk; asbestos exposure synergistically enhances the lung cancer risk of smokers. Previous studies of the mutational spectra of the p53 gene in lung cancer have shown cigarette smoke and radon exposure to be associated with the induction of particular lesions or classes of lesions. We have investigated the p53 gene in surgically resectable lung cancers in 85 patients from the Massachusetts General Hospital. We found 25 (29%) patients 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 years (56.8 versus 41.2 years; P < 0.01) than had those without p53 changes. Consistent with other reports, we observed a large number (40%) of G:C to T:A transversion mutations, noting that their occurrence increased with increasing cumulative exposure to cigarette smoke. Interestingly, we also found that p53 mutations occurred significantly more frequently in patients with a history of occupational exposure to asbestos [3 of 60 (5%) for patients without p53 mutations versus 5 of 25 (20%) of those with p53 mutations; P < 0.05].(ABSTRACT TRUNCATED AT 250 WORDS)