Analysis of exposome and genetic variability suggests stress as a major contributor for development of pancreatic ductal adenocarcinoma

Background: The current knowledge on pancreatic ductal adenocarcinoma (PDAC) risk factors is limited and no study has comprehensively tested the exposome in combination with the genetic variability in relation to the disease susceptibility. Aim: The aim of this study was to analyze the exposome and its interaction with known genetic susceptibility loci, in relation to PDAC risk. Methods: A case-control study nested in UK Biobank cohort was conducted on 816 PDAC cases and 302,645 controls. A total of 347 exposure variables, and a polygenic risk score (PRS) were analyzed through logistic regression. Gene-environment interaction analyses were conducted. Results: A total of 52 associations under the Bonferroni corrected threshold of p < 1.46 × 10−4 were observed. Known risk factors such as smoking, pancreatitis, diabetes, PRS, heavy alcohol drinking and overweight were replicated in this study. As for novel associations, a clear indication for length and intensity of mobile phone use and the stress-related factors and stressful events with increase of PDAC risk was observed. Although the PRS was associated with PDAC risk (P = 2.09 × 10−9), statistically significant gene-exposome interactions were not identified. Conclusion: In conclusion, our results suggest that a stressful lifestyle and sedentary behaviors may play a major role in PDAC susceptibility independently from the genetic background.