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-chlor ophenyl)-ethane (p,p'-DDT), 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene ( p,p'-DDE), and same polychlorinated biphenyls (PCBs) are carcinogenic to an imals and possibly also to human beings. Occupational exposure to DDT may i ncrease 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 poly morphism. Cases of pancreatic cancer with wild-type K-ras (n=17) were frequ ency matched for age and sex to cases of pancreatic cancer with a K-ras mut ation (n=34, case-case study). These 51 cases were further compared with 26 hospital controls (case-control comparison). Serum organochlorine concentr ations measured by high-resolution gas chromatography with electron-capture detection and negative ion chemical ionisation mass spectrometry. Findings Serum concentrations of p,p'-DDT were significantly higher in panc reatic 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). Fo r p,p'-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 va line substitution at codon 12 and both p,p'-DDT and p,p'-DDE concentrations (odds ratio 15.9, p=0.044 and odds ratio 24.1, p=0.028; respectively). A s imilar pattern was shown for the major di-ortho-chlorinated PCBs (congeners 138, 153, and 180), even after adjustment for p,p'-DDE, but without a spec ific association with spectrum, Concentrations of p,p'-DDT and p,p'-DDE wer e 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,p'-DDT, p,p'-DDE, and som e PCBs could play a part in the pathogenesis of exocrine pancreatic cancer through modulation of K-ras activation. The results require replication, bu t they suggest new roles for organochlorines in the development of several cancers in human beings.