Helicobacter pylori Infection and the Risk of Biliary Tract and Pancreatic Cancers: Subsite-Specific Associations in a Japanese Population

Abstract

Although Helicobacter pylori ( H. pylori ) infection, a well-established risk factor for gastric cancer, has been implicated as causative in biliary tract cancer (BTC) and pancreatic cancer (PC), the evidence remains inconclusive. Moreover, while germline pathogenic variants may modify the association between H. pylori infection and gastric cancer risk, their roles in BTC and PC are unclear. We examined these associations while accounting for genetic susceptibility and lifestyle factors. Two case–control studies were conducted, including 116 BTC cases, 417 PC cases, and 3086 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression adjusted for age, sex, study version, carrier status of pathogenic variants, smoking, and alcohol consumption. H. pylori infection was defined by antibody seropositivity, pepsinogen-based atrophic gastritis (AG), and their combination. Subsite-specific analyses were also performed. No significant association was observed between H. pylori infection and BTC risk. However, higher H. pylori antibody titers (per 10 U/mL increase) were positively associated with overall PC risk (OR 1.04, 95% CI: 1.01–1.07). In subsite analyses, AG without detectable antibodies was positively associated with pancreatic head cancer risk (OR 3.04, 95% CI: 1.23–7.54), whereas H. pylori seropositivity was positively associated with pancreatic body cancer risk (OR 1.75, 95% CI: 1.10–2.77). No interaction between H. pylori infection and pathogenic variants, smoking, or alcohol consumption was observed for either cancer. These findings suggest that H. pylori infection may be associated with pancreatic cancer risk in specific anatomical regions, with limited evidence for modification by genetic or lifestyle factors.