Serum concentrations of organochlorine compounds and K-ras mutations in exocrine pancreatic cancer. PANKRAS II Study Group.
BACKGROUND
Organochlorine compounds such as 1,1,1-trichloro-2,2-bis(p-chlorophenyl)-ethane (p,p'-DDT), 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (p,p'-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.


RESULTS
Serum concentrations of p,p'-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,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 valine 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 similar 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 specific association with spectrum. Concentrations of p,p'-DDT and p,p'-DDE were similar among wild-type cases and controls, but significantly higher for K-ras mutated cases than for controls (p<0.01).


CONCLUSIONS
Organochlorine compounds such as p,p'-DDT, p,p'-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.
Porta
M
M
Institut Municipal d'Investigació Mèdica, Universitat Autònoma de Barcelona, Spain. mporta@imim.es
Malats
N
N
Jariod
M
M
Grimalt
J O
JO
Rifà
J
J
Carrato
A
A
Guarner
L
L
Salas
A
A
Santiago-Silva
M
M
Corominas
J M
JM
Andreu
M
M
Real
F X
FX
D000368:Aged; D016022:Case-Control Studies; D003062:Codon / Q000187:drug effects; D005260:Female; D011905:Genes, ras / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007306:Insecticides / Q000009:adverse effects* / Q000097:blood*; D016015:Logistic Models; D008297:Male; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000097:blood* / Q000209:etiology / Q000235:genetics*; D011078:Polychlorinated Biphenyls / Q000009:adverse effects / Q000097:blood; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011446:Prospective Studies; D013030:Spain
D003062:Codon; D007306:Insecticides; D011078:Polychlorinated Biphenyls