Epidemiology and potential mechanisms of tobacco smoking and heavy alcohol consumption in pancreatic cancer.

Tobacco smoking represents an important known cause of ductal pancreatic adenocarcinoma. Recent data from pooled analyses in consortia involving multiple case-control and cohort studies suggest that heavy (but not moderate or light) alcohol consumption also may increase pancreatic cancer risk. Animal and human evidence indicate that tobacco carcinogens and metabolites may act in concert and have both genetic and epigenetic effects at early and later stages in pancreatic tumorigenesis. One of the more important tobacco-related carcinogens, NNK, probably acts via multiple pathways. Heavy alcohol consumption may increase pancreatic cancer risk by potentiating the effects of other risk factors such as tobacco smoking, poor nutrition, and inflammatory pathways related to chronic pancreatitis, but also may have independent genetic and epigenetic effects. Animal and human studies of tobacco- and alcohol-related pancreatic carcinogenesis suggest multi-modal, overlapping mechanistic pathways. Tobacco smoking and heavy alcohol consumption are preventable exposures, and their avoidance would substantially decrease the burden of pancreatic cancer worldwide.