title: 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.
authors.affiliation: Institut Municipal d'Investigació Mèdica, Universitat Autònoma de Barcelona, Carrer del Doctor Aiguader 80, E-08003 Barcelona, Catalonia, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Alguacil
authors.forename: Miquel
authors.initials: M
authors.lastname: Porta
authors.forename: Núria
authors.initials: N
authors.lastname: Malats
authors.forename: Timo
authors.initials: T
authors.lastname: Kauppinen
authors.forename: Manolis
authors.initials: M
authors.lastname: Kogevinas
authors.forename: Fernando G
authors.initials: FG
authors.lastname: Benavides
authors.forename: Timo
authors.initials: T
authors.lastname: Partanen
authors.forename: Alfredo
authors.initials: A
authors.lastname: Carrato
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007407:Interviews as Topic; D008297:Male; D008875:Middle Aged; D016296:Mutagenesis / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000187:drug effects* / Q000235:genetics; D016273:Occupational Exposure / Q000009:adverse effects*; D016272:Occupational Health; D009930:Organic Chemicals / Q000009:adverse effects*; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012997:Solvents / Q000009:adverse effects*
chemical_list: D004273:DNA, Neoplasm; D009930:Organic Chemicals; D012997:Solvents