Helicobacter pylori Treatment and Gastric Cancer Risk Among Individuals With High Genetic Risk for Gastric Cancer

Abstract

Importance: Helicobacter pylori treatment and nutrition supplementation may protect against gastric cancer (GC), but whether the beneficial effects only apply to potential genetic subgroups and whether high genetic risk may be counteracted by these chemoprevention strategies remains unknown.

Objective: To examine genetic variants associated with the progression of gastric lesions and GC risk and to assess the benefits of H pylori treatment and nutrition supplementation by levels of genetic risk.

Design, setting, and participants: This cohort study used follow-up data of the Shandong Intervention Trial (SIT, 1989-2022) and China Kadoorie Biobank (CKB, 2004-2018) in China. Based on the SIT, a longitudinal genome-wide association study was conducted to identify genetic variants for gastric lesion progression. Significant variants were examined for incident GC in a randomly sampled set of CKB participants (set 1). Polygenic risk scores (PRSs) combining independent variants were assessed for GC risk in the remaining CKB participants (set 2) and in an independent case-control study in Linqu.

Exposures: H pylori treatment and nutrition supplementation.

Main outcomes and measures: Primary outcomes were the progression of gastric lesions (in SIT only) and the risk of GC. The associations of H pylori treatment and nutrition supplementation with GC were evaluated among SIT participants with different levels of genetic risk.

Results: Our analyses included 2816 participants (mean [SD] age, 46.95 [9.12] years; 1429 [50.75%] women) in SIT and 100 228 participants (mean [SD] age, 53.69 [11.00] years; 57 357 [57.23%] women) in CKB, with 147 GC cases in SIT and 825 GC cases in CKB identified during follow-up. A PRS integrating 12 genomic loci associated with gastric lesion progression and incident GC risk was derived, which was associated with GC risk in CKB (highest vs lowest decile of PRS: hazard ratio [HR], 2.54; 95% CI, 1.80-3.57) and further validated in the analysis of 702 case participants and 692 control participants (mean [SD] age, 54.54 [7.66] years; 527 [37.80%] women; odds ratio, 1.83; 95% CI, 1.11-3.05). H pylori treatment was associated with reduced GC risk only for individuals with high genetic risk (top 25% of PRS: HR, 0.45; 95% CI, 0.25-0.82) but not for those with low genetic risk (HR, 0.81; 95% CI, 0.50-1.34; P for interaction = .03). Such effect modification was not found for vitamin (P for interaction = .93) or garlic (P for interaction = .41) supplementation.

Conclusions and relevance: The findings of this cohort study indicate that a high genetic risk of GC may be counteracted by H pylori treatment, suggesting primary prevention could be tailored to genetic risk for more effective prevention.

Figure 1.. Manhattan Plot for Longitudinal Genome-Wide Association Analysis

Each point on the graph represents a variant. The dashed horizontal line indicates the suggestive significance threshold (P = .0005) in the Shandong Intervention Trial cohort. The triangles highlight 51 single-nucleotide variants (SNVs) in set 1 of the China Kadoorie Biobank that were further associated with gastric cancer risk (P < .05). Overall, 12 genomic loci within gastric cancer–associated SNVs are noted, referred by Annotate Variation cytoband database.

Figure 2.. Cumulative Risk of Incident Gastric Cancer Associated With Helicobacter pylori Treatment and Nutrition Supplementation by Different Levels of Genetic Risk

The Gray test was performed to compare the overall difference in cumulative gastric cancer incidence between individuals with high or low genetic risk receiving active treatment or placebo in each intervention arm.

Figure 3.. Functional Annotation of 22q13.1

A, A regional plot was used to display positional annotation of gastric cancer–associated variants and BAIAP2L2 genes. Each point on the graph represents a variant. Colored points represent single-nucleotide variants in different linkage disequilibrium correlation with the lead variant, rs5995654, of 22q13.1. B, Expression of the BAIAP2L2 gene in different stomach histopathological groups. The boxplot shows a higher expression of BAIAP2L2 gene in gastric cancer tissue (The Cancer Genome Atlas-Stomach Adenocarcinoma [TCGA-STAD]; n = 413), compared with adjacent nontumor tissue (TCGA-STAD; n = 36) or independent nontumor tissue (Genotype-Tissue Expression; n = 174). The expression of the BAIAP2L2 gene was higher in advanced gastric lesions (n = 34) than mild gastric lesions (n = 54) in the analysis only among individuals in Linqu without tumors (n = 88). Each box represents the IQR, with the bottom and top edges of the boxes indicating the 25th and 75th percentiles, respectively. The center line denotes the median value. Whiskers show the range, typically 1.5 times the IQR from the quartile edges, highlighting outliers as dots beyond the whiskers. CAG indicates chronic atrophic gastritis; DYS, dysplasia; IM, intestinal metaplasia; SG, superficial gastritis.