Mutagenesis Advance Access originally published online on October 1, 2009
Mutagenesis 2009 24(6):513-521; doi:10.1093/mutage/gep037
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In pancreatic ductal adenocarcinoma blood concentrations of some organochlorine compounds and coffee intake are independently associated with KRAS mutations
1Institut Municipal d'Investigació Mèdica—Hospital del Mar, Barcelona, Spain 2School of Medicine, Universitat Autònoma de Barcelona, Spain 3CIBER en Epidemiología y Salud Pública (CIBERESP), Spain 4Universitat Rovira i Virgili, Tarragona, Reus, Spain 5Department of Environmental Chemistry, Institute of Chemical and Environmental Research (IIQAB-CSIC), Barcelona, Spain 6Hospital Son Dureta, Palma de Mallorca, Spain 7Centro Nacional de Investigaciones Oncológicas, Madrid, Spain 8Universitat Pompeu Fabra, Barcelona, Spain
While KRAS activation is a fundamental initiating event in the aetiopathogenesis of pancreatic ductal adenocarcinoma (PDA), environmental factors influencing the occurrence and persistence of KRAS mutations remain largely unknown. The objective was to test the hypothesis that in PDA there are aetiopathogenic relationships among concentrations of some organochlorine compounds (OCs) and the mutational status of the KRAS oncogene, as well as among the latter and coffee intake. Incident cases of PDA were interviewed and had blood drawn at hospital admission (N = 103). OCs were measured by high-resolution gas chromatography with electron capture detection. Cases whose tumours harboured a KRAS mutation had higher concentrations of p,p'-dichlorodiphenyltrichloroethane (DDT), p,p'-dichlorodiphenyldichloroethene (DDE) and polychlorinated biphenyls (PCBs) 138, 153 and 180 than cases with wild-type KRAS, but differences were statistically significant only for p,p'-DDT and PCBs 138 and 153. The association between coffee intake and KRAS mutations remained significant (P-trend < 0.015) when most OCs where accounted for. When p,p'-DDT, PCB 153, coffee and alcohol intake were included in the same model, all were associated with KRAS (P = 0.042, 0.007, 0.016 and 0.025, respectively). p,p'-DDT, p,p'-DDE and PCB 138 were significantly associated with the two most prevalent KRAS mutations (Val and Asp). OCs and coffee may have independent roles in the aetiopathogenesis of PDA through modulation of KRAS activation, acquisition or persistence, plausibly through non-genotoxic or epigenetic mechanisms. Given that KRAS mutations are the most frequent abnormality of oncogenes in human cancers, and the lifelong accumulation of OCs in humans, refutation or replication of the findings is required before any implications are assessed.
* To whom correspondence should be addressed. Institut Municipal d'Investigació Mèdica (IMIM), Universitat Autònoma de Barcelona, Carrer del Dr Aiguader 88, E-08003 Barcelona, Catalonia, Spain. Tel: +34 93 316 0700; Fax: +34 93 316 0410; Email: mporta{at}imim.es
Received on August 11, 2009; revised on September 2, 2009; accepted on September 7, 2009.