k-ras mutation and occupational asbestos exposure in lung adenocarcinoma: Asbestos-related cancer without asbestosis

Environmental carcinogen exposure is requisite for the development of nearl y all lung cancer, and it is well known that asbestos exposure interacts sy nergistically with tobacco smoke to induce lung cancer. However, the precis e molecular lesions induced by asbestos are unknown, Furthermore, it is als o unknown whether asbestos carcinogenesis proceeds in a fashion independent of or dependent upon the induction of fibrosis in workers with high asbest os exposures. Previous studies have suggested that asbestos is associated w ith the presence of a k-ras mutation in adenocarcinoma of the lung. We aime d to test whether occupational asbestos exposure was associated with k-ras codon 12 mutations in lung adenocarcinoma tumors and to determine whether t his was conditional on the presence of asbestosis. All newly diagnosed, res ectable lung cancer patients receiving treatment at the Massachusetts Gener al Hospital between November 1992 and December 1996 were eligible to partic ipate, Because k-ras mutation is very strongly associated with adenocarcino ma, and men were more likely to be occupationally exposed to asbestos, the study was restricted to males with this histological diagnosis, There were 84 male patients with available questionnaire-derived work history data and paraffin-embedded tumor tissue for determination of k-ras mutation status. Chest radiographic evaluation was done for all of the patients who reporte d occupational exposure to asbestos. The prevalence of k-ras mutation was h igher among those with a history of occupational asbestos exposure (crude o dds ratio, 4.8; 95% confidence interval, 1.5-15.4) compared to those withou t asbestos exposure, and this association remained after adjustment for age and pack-years smoked (adjusted odds ratio, 6.9; 95% confidence interval, 1.7-28.6), An index score that weights both the dates of exposure and the e stimated intensity of exposure indicated that those with k-ras mutations ha d significantly greater asbestos exposures than those without mutations (P < 0.01). Analysis of the descriptive components of exposure indicated that the duration of exposure was not associated with k-ras mutation, but that t he time since initial exposure was significantly associated with mutation s tatus. The association of k-ras mutation and reported asbestos exposure was not dependent on the presence of radiographic evidence of asbestos-related disease. These data suggest that asbestos exposure increases the likelihoo d of mutation at k-ras codon 12 and that this process occurs independently of the induction of interstitial fibrosis.