Abstract
OBJECTIVE: The key molecular events signifying the Helicobacter pylori-induced gastric carcinogenesis process are largely unknown. METHODS: Bulk tissue-proteomics profiling were leveraged across multi-stage gastric lesions from Linqu (n = 166) and Beijing sets (n = 99) and single-cell transcriptomic profiling (n = 18) to decipher key molecular signatures of H. pylori-related gastric lesion progression and gastric cancer (GC) development. The association of key proteins association with gastric lesion progression and GC development were prospectively studied building on follow-up of the Linqu set and UK Biobank (n = 48,529). RESULTS: Concordant proteomics signatures associated with H. pylori infection and gastric carcinogenesis (ρ = 0.784, correlation P = 1.80 × 10(-36)) were identified. RNA expression of genes encoding 13 up- and 15 down-regulated key proteins displayed trending alterations in the transition from normal gastric epithelium to intestinal metaplasia, then to malignant cells. A 15-tissue protein panel integrating these signatures demonstrated potential for targeting individuals at high risk for progressing to gastric neoplasia (OR = 7.22, 95% CI: 1.31-39.72 for the high-score group). A 4-circulating protein panel may be used as non-invasive markers predicting the risk of GC development (hazard ratio = 3.73, 95% confidence interval: 1.63-8.54, high-risk vs. low-risk populations, area under the curve = 0.75). CONCLUSIONS: Concordant proteomics signatures associated with H. pylori infection and gastric carcinogenesis were unveiled with potential as biomarkers for targeted prevention strategies.