Occupational exposure to organic solvents and K-ras mutations in exocrine pancreatic cancer

Abstract

Occupational exposure to hydrocarbon solvents has been found to be associated with an increased risk of exocrine pancreatic cancer (EPC), the human tumor with the highest prevalence of K-ras mutations. Ras genes are critical DNA targets for chemical carcinogens. We analysed the relationship between past occupational exposure to hydrocarbon solvents and mutations in codon 12 of the K-ras gene in 107 incident cases of EPC. Information on occupational factors and life-style was obtained from personal interviews conducted during hospital stay. Occupational exposure to hydrocarbon solvents (aliphatic, aromatic, chlorinated, benzene, other organic solvents) was examined using two methods: expert assessment and the Finnish job-exposure matrix (Finjem). Exposure among K-ras mutated EPC cases (n = 83) was compared with that of K-ras wild-type EPC cases (n = 24). An association between K-ras mutations and solvent exposure was observed with Finjem but barely so with the expert assessment. Over 7-fold increased odds ratios (OR) were found for every group of solvents evaluated with Finjem (all P < 0.05). On the basis of the expert assessment, K-ras mutations were significantly associated only with exposure to benzene in men (OR = 7.07, P < 0.05). When requiring exposure to have occurred according to both the experts and Finjem, over 4-fold risks were obtained for aromatic, aliphatic, and for "any hydrocarbon solvent". A significantly higher proportion of cases with a mutation from glycine to valine (GGT-->GTT) or to aspartic acid (GGT-->GAT) were exposed to a hydrocarbon solvent. The results raise the possibility that hydrocarbon solvents might be involved in the pathogenesis of EPC, possibly through indirect modulation of K-ras activation. Since this is only the first study on occupational exposures and K-ras mutations in EPC, studies able to refute or to confirm the findings are required before public health implications, if any, are assessed.