Background: Smoking is a recognised risk factor for pancreatic cancer and has been associated with chronic pancreatitis and also with type II diabetes. Aims: The aim of this study was to investigate the effect of tobacco on the age of diagnosis of pancreatitis and progression of disease, as measured by the appearance of calcification and diabetes. Patients: We used data from a retrospective cohort of 934 patients with chronic alcoholic pancreatitis where information on smoking was available, who were diagnosed and followed in clinical centres in five countries. Methods: We compared age at diagnosis of pancreatitis in smokers versus non-smokers, and used the Cox proportional hazards model to evaluate the effects of tobacco on the development of calcification and diabetes, after adjustment for age, sex, centre, and alcohol consumption. Results: The diagnosis of pancreatitis was made, on average, 4.7 years earlier in smokers than in non-smokers (p = 0.001). Tobacco smoking increased significantly the risk of pancreatic calcifications (hazard ratio (HR) 4.9 (95% confidence interval (CI) 2.3–10.5) for smokers v non-smokers) and to a lesser extent the risk of diabetes (HR 2.3 (95% CI 1.2–4.2)) during the course of pancreatitis. Conclusions: In this study, tobacco smoking was associated with earlier diagnosis of chronic alcoholic pancreatitis and with the appearance of calcifications and diabetes, independent of alcohol consumption.

https://gut.bmj.com/content/gutjnl/54/4/510.full.pdf

Cigarette smoking accelerates progression of alcoholic chronic pancreatitis

Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta-analysis.

Pancreatic cancer is a deadly disease and the fourth most common cause of cancer death in the United States. Since chemotherapy and radiotherapy have thus far largely failed to significantly improve the survival of patients with pancreatic ductal adenocarcinoma, there is considerable interest in identifying better diagnostic markers of pancreatic neoplasia. Not only could better markers improve the early diagnosis of pancreatic cancer and allow more patients to undergo curative surgical resection, but also could potentially be used for patients at high risk of developing pancreatic cancer to identify precancerous lesions while they are amenable to cure. A wealth of information has recently become available about gene expression, DNA methylation, and proteomics alterations that occur in pancreatic cancers creating hope that better diagnostic markers of pancreatic cancer will be soon forthcoming.

Molecular Markers of Early Pancreatic Cancer

Adenocarcinoma of the lungs and pancreas are among the most common and most deadly smoking-associated cancers. Cigarette smoke contains various toxic chemicals, including a carcinogenic nitrosamine, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). One of the most well-known features of NNK is the ability of its metabolites to bind to DNA and induce activating point mutations in the RAS gene. But NNK is also a β-adrenergic-receptor agonist that stimulates arachidonic acid release, leading to the formation of mitogenic metabolites that stimulate DNA synthesis and cell proliferation. NNK therefore contributes to tobacco-induced carcinogenesis by several mechanisms.

Mechanisms of smoking-related lung and pancreatic adenocarcinoma development

https://www.gynecologiconcology-online.net/article/S0090-8258(04)00880-7/pdf

Histologic types of epithelial ovarian cancer: have they different risk factors?

BACKGROUND

Cigarette smoking is among the few unequivocal risk factors for the development of pancreatic ductal adenocarcinoma (PDAC). Activating mutations in codon 12 of the K-ras protooncogene is a frequent and early molecular event in the pathogenesis of PDAC and a variety of nonmalignant ductal pancreatic lesions. The molecular epidemiologic relation between heavy cigarette smoking and mutational activation of K-ras in PDAC has been examined to a limited extent. The authors have examined the mutational status of K-ras in nonneoplastic pancreata in relation to cigarette smoking status.



METHODS

Archival formalin fixed paraffin embedded specimens of nonneoplastic pancreata (n = 39) were obtained from the American Cancer Society and evaluated histopathologically. Specimens from age- and gender-matched individuals were stratified into three groups: 1) those who never smoked cigarettes (n = 16), 2) those who smoked 1–2 packs/day for more than 20 years (n = 10 cases), and 3) those who smoked more than 2 packs/day for 20 or more years (n = 13). Cases were preselected from 77 specimens based on the quality, suitability, and cellularity of the archival tissues for analyses. Furthermore, none of the patients died of primary PDAC or had evidence of pancreatic metastases from an extrapancreatic primary tumor. Tissue sections were microdissected and deparaffinized, and genomic DNA was purified by standard proteinase K-phenol-chloroform extraction techniques. Genomic DNA was analyzed for mutations in codon 12 of the K-ras protooncogene by two mutant-allele-enriched polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assays and by multiplex PCR-based ligase chain reaction (LCR) analyses.



RESULTS

Analyses of multiple microdissected pancreata specimens from 39 cases revealed wild-type K-ras codon 12 sequences in both nonsmoking individuals and those who smoked 1–2 packs/day for 20 or more years. K-ras codon 12 mutations were confirmed by PCR-RFLP and PCR-LCR assays in 5 of 13 pancreata cases (39%) obtained from individuals who smoked more than 2 packs of cigarettes/day for 20 years or more (P < 0.005). The K-ras mutation spectra revealed two GT transversions, one GC transversion and two GA transitions. There was no clear relation between the incidence or spectra of mutations and pancreatic histopathology, as overtly normal pancreata as well as pancreata with squamous metaplasia, periductal fibrosis, and ductal atypia revealed reproducible K-ras alterations. Similarly, among those 34 cases in which a wild-type K-ras sequence was revealed by both approaches, a similar histopathologic profile was evident.



CONCLUSIONS

Mutational activation of codon 12 of the K-ras protooncogene was confirmed reproducibly by mutant allele-enriched PCR-RFLP and multiplex PCR-LCR analyses in 39% (5 of 13) of archival nonneoplastic pancreata from age- and gender-matched individuals who smoked more than 2 packs of cigarettes/day for 20 or more years. The presence of a mutated or wild-type or K-ras was independent of the histopathologic profile of the 39 cases examined. The data provide further suggestive molecular epidemiologic evidence of an association between a major and unequivocal risk factor for PDAC (heavy cigarette smoking) and mutations in a molecular target (K-ras), the activation of which is an important and early event Cancer 1999;85:326–32. © 1999 American Cancer Society.

David H. Berger

Papers

Mutational activation of K-ras in nonneoplastic exocrine pancreatic lesions in relation to cigarette smoking status.