Early ReportSerum concentrations of organochlorine compounds and K-ras mutations in exocrine pancreatic cancer
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)
- et al.
The effect of heptachlor on ras proto-oncogene expression in human myeloblastic leukemia (ML-1) cells
Toxicology
(1991) - et al.
An updated review of environmental estrogen and androgen mimics and antagonists
J Steroid Biochem Mol Biol
(1998) - et al.
Hexachlorocyclohexanes in human blood serum
J Chromatogr A
(1997) - et al.
Estrogen, DNA damage and mutations
Mut Res
(1999) - et al.
Levels of selected polychlorinated biphenyl congeners in total diet samples from Aragón, Spain
J Food Protect
(1999) - et al.
The human health effects of DDT (dichlorodiphenyl-trichloroethane) and PCBs (polychlorinated biphenyls) and an overview of organochlorines in public health
Annu Rev Public Health
(1997) - et al.
Rethinking breast cancer and the environment: the case for the precautionary principle
Environ Health Perspect
(1998) Chlorinated hydrocarbon insecticides
IARC Monographs on the evaluation of carcinogenic risks to humans, vol 53: occupational exposures in insecticide application, and some pesticides
(1991)Assessing the cancer risk from environmental PCBs
Environ Health Perspect
(1998)
8th Report on Carcinogens. Summary, US Department of Health and Human Services, 1998
Pancreatic cancer
Modulation of proto-oncogene expression by polychlorinated biphenyls in 3T3-L1 cell line
J Toxicol Environ Health A
Cited by (0)
Members listed at end of paper