Background & Aims: Approximately 10% of pancreatic cancers are inherited, but the factors that affect tumorigenesis in familial pancreatic cancer are unknown. We sought to determine whether smoking or other factors could predict cancer risk in familial pancreatic cancer kindreds. Methods: We conducted a nested case-control study including 251 members of 28 families. All families included 2 or more members with pancreatic cancer. We determined the effects of smoking, young age of onset within the family, diabetes mellitus, sex, and number/standing of affected relatives on the risk of pancreatic cancer. Results: Smoking was an independent risk factor for familial pancreatic cancer (odds ratio [OR], 3.7; 95% confidence interval [Cl], 1.8-7.6), and the risk was greatest in males and subjects younger than 50 (OR, 5.2 and OR, 7.6, respectively). Smokers developed cancer 1 decade earlier than nonsmokers (59.6 vs. 69.1 years; P = 0.01), and the number of affected first-degree relatives also increased risk (OR, 1.4; 95% Cl, 1.1-1.9 for each additional family member). Diabetes was not a risk factor for pancreatic cancer, although diabetes was associated with pancreatic dysplasia. One third of families demonstrated genetic anticipation, as the mean age of onset decreased by 2 decades between generations. Conclusions: Smoking is a strong risk factor in familial pancreatic cancer kindreds, particularly among males and those under age 50. Persons with multiple affected first-degree relatives are also at increased risk. These factors may be useful in selecting candidates for pancreatic cancer screening. Members of families with multiple pancreatic cancers should be counseled not to smoke.
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