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

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.

[1]  N. Malats,et al.  Validity of the hospital discharge diagnosis in epidemiologic studies of biliopancreatic pathology , 2000, European Journal of Epidemiology.

[2]  K. Hemminki,et al.  Organic solvents and cancer , 1997, Cancer Causes & Control.

[3]  Cancer Epidemiol Biomarkers Prev , 2004 .

[4]  R. Hruban,et al.  Molecular pathogenesis of pancreatic cancer. , 2006, Annual review of genomics and human genetics.

[5]  C. Rosty,et al.  Molecular pathogenesis of pancreatic cancer. , 2002, Hematology/oncology clinics of North America.

[6]  N. Malats,et al.  Occupation and pancreatic cancer in Spain: a case-control study based on job titles. PANKRAS II Study Group. , 2000, International journal of epidemiology.

[7]  S. Morisawa,et al.  Comparison of the mutations induced by p-benzoquinone, a benzene metabolite, in human and mouse cells. , 2000, Mutation research.

[8]  S. Pavanello,et al.  Biological indicators of genotoxic risk and metabolic polymorphisms. , 2000, Mutation research.

[9]  J. Wiencke,et al.  NAD(P)H:quinone oxidoreductase-dependent risk for colorectal cancer and its association with the presence of K-ras mutations in tumors. , 2000, Carcinogenesis.

[10]  N. Malats,et al.  Coffee, pancreatic cancer, and K-rasmutations: updating the research agenda , 2000, Journal of epidemiology and community health.

[11]  Ivar Heuch,et al.  Coffee, K-ras mutations and pancreatic cancer: A heterogeneous aetiology or an artefact? , 2000, Journal of epidemiology and community health.

[12]  N. Malats,et al.  Risk of pancreatic cancer and occupational exposures in Spain , 2000 .

[13]  M. Kogevinas,et al.  Occupational exposures and pancreatic cancer: a meta-analysis , 2000, Occupational and environmental medicine.

[14]  A. Barbin.  Etheno-adduct-forming chemicals: from mutagenicity testing to tumor mutation spectra. , 2000, Mutation research.

[15]  P A Stewart,et al.  Comparison of industrial hygienists' exposure evaluations for an epidemiologic study. , 2000, Scandinavian journal of work, environment & health.

[16]  Michael E. McManus,et al.  Some industrial chemicals , 2000 .

[17]  N. Malats,et al.  Serum concentrations of organochlorine compounds and K-ras mutations in exocrine pancreatic cancer , 1999, The Lancet.

[18]  N. Malats,et al.  Association between coffee drinking and K-ras mutations in exocrine pancreatic cancer. PANKRAS II Study Group. , 1999, Journal of epidemiology and community health.

[19]  A. Cebulska-Wasilewska,et al.  Examination of ras oncoproteins in human plasma from healthy controls and workers exposed to petroleum emissions, including benzene-related compounds. , 1999, Mutation research.

[20]  K. Hemminki,et al.  An evaluation of styrene genotoxicity using several biomarkers in a 3-year follow-up study of hand-lamination workers. , 1999, Mutation research.

[21]  E. Mark,et al.  k-ras mutation and occupational asbestos exposure in lung adenocarcinoma: asbestos-related cancer without asbestosis. , 1999, Cancer research.

[22]  N. Matton,et al.  Inefficient in vivo repair of mismatches at an oncogenic hotspot correlated with lack of binding by mismatch repair proteins and with phase of the cell cycle. , 1999, Carcinogenesis.

[23]  R. Barale,et al.  Genetic polymorphisms influence variability in benzene metabolism in humans. , 1999, Pharmacogenetics.

[24]  D. Jerina,et al.  Stereospecific differences in repair by human cell extracts of synthesized oligonucleotides containing trans-opened 7,8,9, 10-tetrahydrobenzo[a]pyrene 7,8-diol 9,10-epoxide N2-dG adduct stereoisomers located within the human K-ras codon 12 sequence. , 1999, Biochemistry.

[25]  T. Devereux,et al.  Mutations in ras genes in experimental tumours of rodents. , 1999, IARC scientific publications.

[26]  N. Malats,et al.  Association between coffee drinking and K-ras mutations in exocrine pancreatic cancer. PANKRAS II Study Group. , 1999, Journal of epidemiology and community health.

[27]  T. Cheng,et al.  Plasma Asp13-Ki-ras oncoprotein expression in vinyl chloride monomer workers in Taiwan. , 1998, Journal of occupational and environmental medicine.

[28]  L. Hagmar,et al.  K-ras mutations in sinonasal adenocarcinomas in patients occupationally exposed to wood or leather dust. , 1998, Cancer letters.

[29]  T Kauppinen,et al.  From cross-tabulations to multipurpose exposure information systems: a new job-exposure matrix. , 1998, American journal of industrial medicine.

[30]  Y. Konishi,et al.  Mechanistic analysis of pancreatic ductal carcinogenesis in hamsters. , 1998, Pancreas.

[31]  L. Anderson,et al.  Levels and membrane localization of the c-K-ras p21 protein in lungs of mice of different genetic strains and effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and Aroclor 1254. , 1998, Carcinogenesis.

[32]  K. Peltonen,et al.  Examination of ras (P21) proteins in plasma from workers exposed to benzene emissions from petrochemical plants and healthy controls. , 1997, Mutation research.

[33]  P. Söderkvist,et al.  Genetic alterations of p53 and ras genes in 1,3-butadiene- and 2',3'-dideoxycytidine-induced lymphomas. , 1997, Cancer research.

[34]  N. Malats,et al.  Ki‐ras mutations in exocrine pancreatic cancer: Association with clinico‐pathological characteristics and with tobacco and alcohol consumption , 1997, International journal of cancer.

[35]  R. Coda,et al.  Exposure to aromatic amines and ras and c-erbB-2 overexpression in bladder cancer. , 1996, Journal of occupational and environmental medicine.

[36]  K. Peltonen,et al.  Levels of ras oncoproteins in human plasma from 1,3-butadiene-exposed workers and controls. , 1996, Mutation research.

[37]  Jack A. Taylor,et al.  p53 and K-ras in radon-associated lung adenocarcinoma. , 1995, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[38]  M. Hegi,et al.  Hepatic and pulmonary carcinogenicity of methylene chloride in mice: a search for mechanisms. , 1995, Toxicology.

[39]  E. Zappone,et al.  A screen for RAS mutations in individuals at risk of secondary leukaemia due to occupational exposure to petrochemicals. , 1995, Leukemia research.

[40]  A. Tates,et al.  Marked differences in the role of O6-alkylguanine in hprt mutagenesis in T-lymphocytes of rats exposed in vivo to ethylmethanesulfonate, N-(2-hydroxyethyl)-N-nitrosourea, or N-ethyl-N-nitrosourea. , 1995, Cancer research.

[41]  R. Hayes,et al.  Benzene induces gene-duplicating but not gene-inactivating mutations at the glycophorin A locus in exposed humans. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[42]  P. Stewart,et al.  Effects of three features of a job-exposure matrix on risk estimates. , 1994, Epidemiology.

[43]  R. Maronpot,et al.  Ras proto-oncogene activation in liver and lung tumors from B6C3F1 mice exposed chronically to methylene chloride. , 1993, Carcinogenesis.

[44]  M. Ridanpää,et al.  K‐ras mutations in human adenocarcinoma of the lung: Association with smoking and occupational exposure to asbestos , 1993, International journal of cancer.

[45]  F Berrino,et al.  Retrospective evaluation of occupational exposure to organic solvents: questionnaire and job exposure matrix. , 1993, International journal of epidemiology.

[46]  C. Bloomfield,et al.  ras oncogene activation and occupational exposures in acute myeloid leukemia. , 1992, Journal of the National Cancer Institute.

[47]  Andrew G Smith,et al.  Search for Ha-ras codon 61 mutations in liver tumours caused by hexachlorobenzene and Aroclor 1254 in C57BL/10ScSn mice with iron overload. , 1992, Carcinogenesis.

[48]  B. Diwan,et al.  GGT to GTT transversions in codon 12 of the K-ras oncogene in rat renal sarcomas induced with nickel subsulfide or nickel subsulfide/iron are consistent with oxidative damage to DNA. , 1992, Cancer research.

[49]  M. Marion,et al.  Activation of Ki‐ras gene by point mutation in human liver angiosarcoma associated with vinyl chloride exposure , 1991, Molecular carcinogenesis.

[50]  F. Perera,et al.  Serum oncogene proteins in foundry workers. , 1990, The Journal of the Society of Occupational Medicine.

[51]  D. Wynford‐Thomas,et al.  Agent-specific ras oncogene activation in rat thyroid tumours. , 1988, Oncogene.

[52]  P. Brandt-Rauf,et al.  Serum screening for oncogene proteins in workers exposed to PCBs. , 1988, British journal of industrial medicine.

[53]  A. Leonard,et al.  Lack of mutagenic activity of white spirit , 1984, International archives of occupational and environmental health.

[54]  J. Schlesselman,et al.  Case-Control Studies: Design, Conduct, Analysis , 1982 .

[55]  R. L. Carter,et al.  IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans , 1980, IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans.

[56]  R. Pollack,et al.  Cancer biology. , 1978, Science.