Age at Diagnosis (years) Assessment of “Gene-Environment” Interaction in Cases of Familial & Sporadic Pancreatic Cancer Theresa Yeo*, Ralph Hruban**, Kieran Brune**, Alison Klein** , Sheila Fitzgerald*** & Charles Yeo* * Department of Surgery and School of Nursing, Thomas Jefferson University, Philadelphia, PA, & **Department of Pathology & ***Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD Insert Jefferson Logo Here Background: Pancreatic cancer (PC) is the fourth leading cause of cancer death in the United States. Reported risk factors for PC include: advancing age, a family history of PC, high-risk inherited syndromes, cigarette smoking, exposure to occupational and environmental carcinogens, African-American race, high fat/high cholesterol diet, obesity, chronic pancreatitis, and diabetes mellitus. Purpose: The purpose of this study was to characterize 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. Methods: Retrospective cross-sectional, case-only analysis of FPC cases (n = 569) and SPC cases (n = 689) from the Johns Hopkins National Familial Pancreas Tumor Registry (NFPTR) enrolled between 1994 and 2005. Exposure Variable Odds Ratio Confidence Intervals (95%) p- value Multiplicative Interaction Ever Smoker 0.86 0.68 – 1.09 0.20 None Welding 1.16 0.75 – 1.80 0.48 ETS exposure, bt age 41- 60 years 1.31 1.04 – 1.65 0.02* Mild Asbestos 1.83 1.31 – 2.56 <0.002* Residential Radon 2.39 1.39 – 4.30 <0.0008* Moderate Variable Mean Age at Diagnosis (yrs)a p – valuea Smokers with no reported ETS exposure (reference group) (n = 81) 63.8 p = 0.82 Smokers with any reported ETS exposure (n = 629) 63.5 All non-smokers with no reported ETS exposure (reference group) (n = 140) 66.5 p = 0.05* All non-smokers with any reported ETS exposure (n = 364) 64.0 FPC Non-smokers with no reported ETS exposure (reference group) (n = 62) 66.6 FPC Smokers with any reported ETS exposure (n = 296) 63.7 Table 3: Unadjusted Multiplicative Interaction between Familial History of PC Compared to Sporadic PC group and Smoking, ETS, Asbestos, and Radon Exposure Variable Mean Age at Diagnosis (years) p- value Ashkenazi Heritage in sample (n = 169) 65.1 Ashkenazi FPC Group (n = 75) Ashkenazi SPC Group (n = 94) 66.4 64.3 0.05 Ashkenazi FPC Group: Smokers Non- smokers 64.4 70.3 Ashkenazi SPC Group: Smokers Non-smokers 63.8 65.2 0.53 Table 1: Mean Age at Diagnosis of PC if Combined Cigarette Smoking and ETS Exposure Variable FPC Cases: Mean Age Diagnosis p- value SPC Cases: Mean Age Diagnosis No Reported ETS Exposure 65.3 (reference) 65.8 (reference) 0.75 ETS exposure,< age 21 59.6 0.001* 56.7 <0.0004a ETS exposure, age 21-40 61.2 0.01* 59.5 ETS exposure, age 41-60 65.7 0.73 66.9 0.38a Table 4: Mean Age at Diagnosis- Ashkenazi Jews Conclusions Occupational and environmental exposures may act synergistically with inherited or acquired genetic alterations, resulting in earlier occurrence of PC. Exposure to cigarette smoking and ETS is associated with a younger mean age of diagnosis in FPC and SPC cases and those with an Ashkenazi Jewish heritage, compared to non-exposed cases. Unaffected individuals from families with history of PC who smoke, have had early life ETS exposure, or have certain occupational and environmental exposures may benefit from screening and early identification of pre-malignant lesions. Preliminary evidence for an acquired alteration in a genome maintenance or repair gene as the inherited culprit. Table 2: Mean Age at PC Diagnosis Within the FPC and SPC Groups of ETS-Exposed to Non-ETS Exposed Cases