Serum concentrations of organochlorine compounds and K-ras mutations in exocrine pancreatic cancer

Background Organochlorine compounds such as 1,1,1-trichloro-2,2-bis(p-chlorophenyl)-ethane (p,pʹ -DDT), 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (p,pʹ -DDE), and some polychlorinated biphenyls (PCBs) are carcinogenic to animals and possibly also to human beings. Occupational exposure to DDT may increase the risk of pancreas cancer. The high frequency of K-ras mutations in pancreatic cancer remains unexplained. We analysed the relation between serum concentrations of selected organochlorine compounds and mutations in codon 12 of the K-ras gene in patients with exocrine pancreatic cancer. Methods Cases were prospectively identified in five hospitals. Mutations in K-ras were analysed by PCR and artificial restriction fragment length polymorphism. Cases of pancreatic cancer with wild-type K-ras (n=17) were frequency matched for age and sex to cases of pancreatic cancer with a K-ras mutation (n=34, case-case study). These 51 cases were further compared with 26 hospital controls (case-control comparison). Serum organochlorine concentrations were measured by high-resolution gas chromatography with electron-capture detection and negative ion chemical ionisation mass spectrometry. Findings Serum concentrations of p,pʹ-DDT were significantly higher in pancreatic cancer cases with a K-ras mutation than in cases without a mutation (odds ratio for upper tertile 8•7 [95% CI 1•6–48•5], p for trend=0•005). For p,pʹ-DDE the corresponding figures were 5•3 (1•1–25•2, p for trend=0•031). These estimates held after adjusting for total lipids, other covariates, and total PCBs. A specific association was observed between a glycine to valine substitution at codon 12 and both p,pʹ-DDT and p,pʹ-DDE concentrations (odds ratio 15•9, p=0•044 and odds ratio 24•1, p=0•028; respectively). A similar pattern was shown for the major di-ortho-chlorinated PCBs (congeners 138, 153, and 180), even after adjustment for p,pʹ-DDE, but without a specific association with spectrum. Concentrations of p,pʹ-DDT and p,pʹ-DDE were similar among wild-type cases and controls, but significantly higher for K-ras mutated cases than for controls (p<0•01). Interpretation Organochlorine compounds such as p,pʹ-DDT, p,pʹ-DDE, and some PCBs could play a part in the pathogenesis of exocrine pancreatic cancer through modulation of K-ras activation. The results require replication, but they suggest new roles for organochlorines in the development of several cancers in human beings.