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Background Helicobacter pylori (H. pylori) infection is the dominant risk factor for gastric cancer (GC), yet GC also occurs among individuals without infection or after eradication. Whether genetic susceptibility and environmental risk factors differ by H. pylori infection status remains unclear. We aimed to investigate clinicopathologic characteristics and genetic susceptibility of incident GC according to baseline H. pylori infection status in a population-based cohort.Methods This case-cohort study was conducted within the Mass Intervention Trial in Linqu, China (IDDF2026-ABS-0377 Figure 1(A)). Baseline H. pylori infection was determined using concordant results from the 13C-urea breath test and immunoblot assays. Genetic susceptibility was assessed using variant-level analyses and polygenic risk scores (PRS) derived from large East Asian genome-wide association studies (GWAS). Environmental risk scores (ERS) were constructed based on dietary and lifestyle factors. Associations with GC risk were estimated using weighted Cox proportional hazards models stratified by baseline H. pylori status.Results Among 1733 participants, 420 were H. pylori-negative and 1313 were H. pylori-positive at baseline. During follow-up, 621 incident GC cases were identified (102 in negatives and 519 in positives). H. pylori-negative GC more frequently exhibited well-differentiated histology and a less advanced stage. Fourteen genetic variants showed heterogeneity in their associations with GC by infection status (IDDF2026-ABS-0377 Figure 1(B)). For example, rs10074991 in PRKAA1 showed a stronger association among H. pylori-negative individuals, whereas the ABO locus (rs7849280) was associated with GC risk primarily among H. pylori-positive individuals. Higher PRS was associated with increased GC risk overall and showed stronger effects among H. pylori-negative individuals (per SD: hazard ratio[HR]=2.03, 95% confidence interval[CI]:1.52-2.71) than positives (HR=1.23,95%CI:1.13-1.35; P-for-heterogeneity=0.0012; IDDF2026-ABS-0377 Figure 1(C,D)). Combined analyses demonstrated significant joint effects of PRS and ERS on GC risk, particularly in the H. pylori-negative group. Among H. pylori-positive individuals, healthy lifestyle and successful eradication attenuated genetic risk, with the strongest reduction observed in high-PRS individuals adhering to a healthy lifestyle after eradication (HR=0.30, 95% CI:0.16-0.58; IDDF2026-ABS-0377 Figure 1(E)).Conclusions Clinicopathologic and germline susceptibility profiles of GC differed by baseline H. pylori infection status, with inherited risk exerting a stronger effect among H. pylori-negatives. Lifestyle modification and eradication may offset inherited risk, supporting precision prevention.