Association between coffee drinking and K-ras mutations in exocrine pancreatic cancer. PANKRAS II Study Group.

Study objective—To analyse the relation between coVee consumption and mutations in the K-ras gene in exocrine pancreatic cancer. Design—Case-case study. Consumption of coVee among cases with the activating mutation in the K-ras gene was compared with that of cases without the mutation. Setting and patients—All cases of pancreatic cancer newly diagnosed at five hospitals in Spain during three years were included in the PANKRAS II Study (n=185, of whom 121 whose tissue was available for molecular analysis are the object of the present report). Over 88% were personally interviewed in hospital. DNA was amplified from paraYn wax embedded tissues, and mutations in codon 12 of K-ras were detected by the artificial RFLP technique. Main results—Mutations were found in tumours from 94 of 121 patients (77.7%). Mutations were more common among regular coVee drinkers than among nonregular coVee drinkers (82.0% v 55.6%, p=0.018, n=107). The odds ratio adjusted by age, sex, smoking and alcohol drinking was 5.41 (95% CI 1.64, 17.78). The weekly intake of coVee was significantly higher among patients with a mutated tumour (mean of 14.5 cups/week v 8.8 among patients with a wild type tumour, p<0.05). With respect to non-regular coVee drinkers, the odds ratio of a mutated tumour adjusted by age, sex, smoking and alcohol drinking was 3.26 for drinkers of 2–7 cups/ week, 5.77 for drinkers of 8–14 cups/week and 9.99 for drinkers of >15 cups/week (p<0.01, test for trend). Conclusions—Pancreatic cancer cases without activating mutations in the K-ras gene had drank significantly less coVee than cases with a mutation, with a significant dose response relation: the less they drank, the less likely their tumours were to harbour a mutation. In exocrine pancreatic cancer the K-ras gene may be activated less often among non-regular coVee drinkers than among regular drinkers. CaVeine, other coVee compounds or other factors with which coVee drinking is associated may modulate K-ras activation. (J Epidemiol Community Health 1999;53:702–709) Experimental studies in rodents and in vitro provide inadequate evidence that coVee is carcinogenic in the pancreas or in other tissues. CoVee and caVeine cannot be definitely categorised as mutagen or non-mutagen. The eVects of coVee intake on the activity of known mutagens and carcinogens vary from clear enhancement to clear inhibition of the occurrence of tumours. 2 CaVeine can aVect a wide variety of biological processes related to carcinogenesis, including multiple pathways involved in the cellular response to DNA damage. Epidemiological evidence does not indicate any significantly increased risk of pancreatic cancer with coVee intake, 6–17 although a weak association with higher levels of consumption remains a possibility. 10–17 None the less, from a mechanistic perspective it is important to note that coVee could play a modulating part in a subgroup of patients with pancreatic cancer, an eVect that would be diluted in the entire population of subjects with the disease. Progress in knowledge of the genetic mechanisms of human cancer provides a new basis for its molecular classification, and the integration of molecular and epidemiological approaches is helping to identify pathogenic clues. Exocrine pancreas cancer shows the highest frequency of K-ras gene mutations of any human neoplasm; the reasons are unknown. 17 23 24 In particular, no association between such mutations and lifestyle or environmental factors has been firmly established. Molecular pathology studies suggest that wild type K-ras carcinomas of the pancreas may arise through a genetic pathway distinct from carcinomas that harbour a K-ras mutation. There is a dearth of information on the relation between coVee consumption and K-ras mutations in human cancers. The aim of this study was to analyse whether a relation exists between coVee drinking and the presence of K-ras mutations in patients with exocrine pancreas cancer.