IDDF2023-ABS-0124 Leveraging Genetic Predisposition to Gastric Lesion Progression for Risk Assessment of Gastric Cancer and Its Precision Primary Prevention: a Longitudinal Genome-Wide Association Study

Background Gastric cancer (GC) develops through a cascade progression of gastric lesions involving multiple genetic alterations. Whether the beneficial effect of Helicobacter pylori (H.pylori) treatment and nutrition supplementation may only apply to potential genetic subgroups remains unknown. We examined genetic variants associated with the progression of gastric lesions and incident GC risk and assessed the effect of primary prevention on GC in individuals with different genetic risks. Methods Our study leveraged two population-based prospective studies in China, including the Shandong Intervention Trial (SIT) and China Kadoorie Biobank (CKB). Based on SIT (discovery set, n=2816), a longitudinal genome-wide association study was conducted to identify genetic variants associated with gastric lesion progression, integrating multiple-time histopathological diagnoses of gastric lesions. Significant genetic variants were examined for GC risk in a randomly sampled validation set (n=50110) of CKB. Independent variants were combined to construct polygenic risk scores (PRSs), further assessed for GC risk in the remaining participants of CKB as a test set (n=50529). The effect of H. pylori treatment and nutrition supplementation was evaluated among SIT attendants with different genetic risks (IDDF2023-ABS-0124 Figure 1. Study design). Results We newly identified 12 genomic loci associated with gastric lesion progression and incident GC risk and derived a PRS prospectively predicting GC risk (HR=1.34, 95%CI:1.27-1.43, per SD increase). Applying the PRS to SIT, a favorable effect of H.pylori treatment on GC was observed among those with high genetic risk (top 25% of PRS, HR=0.47 (0.26-0.87)), but not for the low genetic risk group (HR=0.83 (0.51-1.37), p-interaction=0.03) (IDDF2023-ABS-0124 Figure 2. The effect of H.pylori treatment, vitamin supplementation and garlic supplementation on the risk of incident gastric cancer for individuals with low or high genetic risk in the Shandong intervention trial). For those without H.pylori treatment, vitamin supplementation only benefitted high genetic-risk individuals (IDDF2023-ABS-0124 Figure 3. The effect of vitamin supplementation and garlic supplementation on the risk of incident gastric cancer for individuals with low or high genetic risk who did not accept H.pylori treatment in the Shandong intervention trial). Further functional annotation implied potential biological importance for GC development. Conclusions We found novel genetic variants for GC development, corroborating genetic predisposition underlying GC cascade evolution. H.pylori treatment and vitamin supplementation particularly benefited individuals with the top 25% of PRS, demonstrating that a high genetic risk may be offset by appropriate primary GC prevention. Our results suggest that chemoprevention strategies be tailored to genetic risk for efficient precision GC prevention.