Elsevier

The Lancet

Volume 354, Issue 9196, 18–25 December 1999, Pages 2125-2129
The Lancet

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

https://doi.org/10.1016/S0140-6736(99)04232-4Get rights and content

Summary

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.

Findings

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).

Interpretation

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.

Introduction

The relation between exposure to organochlorine compounds and the risk of several major cancers is receiving abundant attention,1, 2 but there are no data for pancreatic cancer. 1,1,1-trichloro-2,2-bis(p-chlorophenyl)-ethane (p,p'-DDT), its main metabolite and environmental degradation product 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p'-DDE), and some polychlorinated biphenyls (PCBs) are ubiquitous in the environment, lipophilic, resistance to excretion, and stored in many human tissues.3, 4, 5

DDT and PCBs have been judged as “possibly” and “probably” carcinogenic to human beings, respectively,4, 6 and as “reasonably anticipated to be human carcinogens”.7 Several organochlorine compounds can act as carcinogens and tumour promoters.3, 4, 5, 6, 7, 8 Some modulate the expression of oncogenes, including ras genes.9, 10 DDT and some PBCs have endocrine effects.1, 2, 11, 12 Although presumably weak, such effects may be enhanced by environmental biodegradation, the long half-lives of the compounds (about 10 years for DDE, 30 years or more for some PCBs), and their concentrations in target tissues (100-fold to 350-fold higher in adipose tissue than in blood).1, 5, 6

The aetiology of exocrine pancreatic cancer remains poorly understood. Smoking is the only firmly established environmental risk factor.8, 13 Some epidemiological studies showed that exposure to DDT, PCBs, and other organochlorine compounds increased the risk of pancreatic cancer.1, 4, 8, 13, 14 In a study of chemical workers in Philadelphia, USA, relative risks of pancreatic cancer of 15 and higher were associated with exposure to DDT and related compounds.14 However, epidemiological studies have generally found weak or no association.1, 4, 6, 8, 13

Pancreatic cancer has a high prevalence of K-ras mutations in codon 12, but whether this is partly due to environmental or other factors is not known. Carcinomas of the pancreas with wild-type (non-mutated) K-ras may arise through a genetic pathway distinct from carcinomas with K-ras mutations.15 The ras genes are critical DNA targets for chemical carcinogens.16, 17, 18

In 1991, we designed a multicentre prospective study, one of whose primary aims was to assess interactions between specific genetic alterations (notably K-ras mutations) and environmental, occupational, and lifestyle factors. In this report we analyse the relation between serum concentrations of organochlorine compounds and mutations in codon 12 of the K-ras gene in patients with exocrine pancreatic cancer. We also compare serum organochlorine concentrations in patients with pancreatic cancer with concentrations in a hospital control group.

Section snippets

Selection of patients

The PANKRAS II study took place in 1992–95 at five general hospitals in eastern Spain.19 The longest distance between any two of the hospitals is 420 km. Incident cases of exocrine pancreatic cancer were prospectively identified and patients were interviewed during their hospital stay on preceding symptoms, and on tobacco, coffee, and alcohol consumption for each period of life.

Blood and other biological samples were collected before any treatment was given. We took blood from cubital veins and

Results

All 51 cases of exocrine pancreatic cancer had detectable concentrations of p,p'-DDE, and 36 (71%) cases had detectable concentrations of p,p'-DDT. Cases of pancreatic cancer with a K-ras mutation had significantly higher concentrations of p,p'-DDT and p,p'-DDE than cases with wild-type K-ras (table 1). Tumours of patients in the mid and upper p,p'-DDT tertiles were more than five times more likely and more than eight times more likely to have a mutation, respectively, than tumours of cases in

Discussion

We have shown that patients with exocrine pancreatic cancer whose tumours had a K-ras mutation had significantly higher concentrations of p,p'-DDT, p,p'-DDE, and PCB congeners 138, 153, and 180 than patients without a mutation. The results do not necessarily imply that organochlorines play a direct part in activation of K-ras. Rather, the compounds might enhance the effects of K-ras mutagens or might provide a growth advantage to the mutated cells.

Several observations suggest that our findings

References (29)

  • 8th Report on Carcinogens. Summary, US Department of Health and Human Services, 1998

  • KE Anderson et al.

    Pancreatic cancer

  • L Gribaldo et al.

    Modulation of proto-oncogene expression by polychlorinated biphenyls in 3T3-L1 cell line

    J Toxicol Environ Health A

    (1998)
  • Cited by (0)

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