Assessment of Gene-Environment Interaction in Cases of Familial and Sporadic Pancreatic Cancer

Pancreatic cancer (PC) is the fourth leading cause of cancer death in the United States. This study characterizes one of the largest national registries of familial PC (FPC) and sporadic PC (SPC), focusing on demographics, clinical factors, self-reported environmental and occupational lifetime exposures, and survival status. Reported risk factors for PC include advancing age, a family history of PC, high-risk inherited syndromes, cigarette, cigar, and pipe smoking, exposure to occupational and environmental carcinogens, African-American race, high fat/high cholesterol diet, obesity, chronic pancreatitis, and diabetes mellitus. This retrospective cross-sectional, case-only analysis includes cases of FPC (n = 569) and SPC (n = 689) from the Johns Hopkins National Familial Pancreas Tumor Registry (NFPTR) enrolled between 1994 and 2005. FPC smokers with environmental tobacco smoke (ETS) exposure were diagnosed at a significantly younger mean age (63.7 years) as compared to FPC non-smokers without ETS exposure (66.6 years; p = 0.05). Non-smoker ETS-exposed cases were diagnosed with PC at a significantly younger mean age (64.0 years) compared to non-smoker non-ETS-exposed cases (66.5 years) (p < 0.0004). The mean age at diagnosis for Ashkenazi Jewish SPC subjects was significantly younger (by 2.1 years) than Ashkenazi Jewish FPC cases (p = 0.05). In addition, Ashkenazi Jewish FPC subjects who smoked were diagnosed 5.9 years earlier than Ashkenazi Jewish FPC non-smokers (p = 0.05). The median length of survival for unresected FPC cases was significantly shorter (168 days) as compared to unresected SPC cases (200 days) (p = 0.04). Survival was improved in resected cases, 713 days for FPC cases and 727 days for SPC cases, but was not significantly different between the groups (p = 0.4). Mild to moderate multiplicative interaction was found between a family history of PC and exposure to asbestos, environmental radon, and environmental tobacco smoke (ETS), as evidenced by odds ratios > 1.0. These are the first data to show that occupational and environmental exposures may act synergistically with inherited or acquired genetic polymorphisms, resulting in earlier occurrence of PC. Exposure to cigarette smoking and ETS exposure in non-smokers when younger than 21 years of age are associated with a younger mean age of diagnosis in FPC and SPC cases and Ashkenazi Jewish smokers, when compared to non-exposed cases. Risk prediction models which take into account environmental exposures as well as family history may more accurately predict the risk of PC. High-risk individuals will likely benefit from early identification of pre-malignant lesions and molecular profiling, as methods of early detection, prevention, and personalized therapy.