Plasma proteomic signatures improve risk stratification and personalized screening for gastric cancer

Abstract Background Accurate identification of individuals at high risk of gastric cancer (GC) remains a major challenge for effective screening. We aimed to identify plasma proteomic signatures and develop a risk prediction model for GC risk stratification. Methods Plasma proteomic profiling was performed using liquid chromatography–tandem mass spectrometry in a case–control discovery set (100 GC cases and 94 controls). Candidate proteins were evaluated in 52,552 UK Biobank participants with a median follow-up of 13.63 years, during which 92 incident GC cases were identified. Risk models integrating clinical, genetic, and proteomic factors were developed using LASSO-penalized Cox regression with stability selection and internally validated using bootstrap resampling. Results Among 2306 differentially expressed proteins in discovery, 25 were replicated in validation at nominal significance ( P < 0.05) with consistent directions. Two proteins (CTSD and GGH) remained significant after false discovery rate correction. A primary proteomic model (clinical factors plus five proteins) improved discrimination versus clinical model (optimism-corrected C-index: 0.745 vs. 0.732, P = 0.046). Risk stratification revealed a clear GC risk gradient: hazard ratios were 6.08 (95% CI 2.15–17.20) for moderate-risk and 23.88 (95% CI 8.66–65.87) for high-risk groups. The risk score was also associated with GC risk as continuous variable (HR per standard deviation: 1.09, 95% CI 1.08–1.11). The 15-year cumulative incidence ranged from 0.02 to 0.56% across risk groups. Decision curve analysis indicated improved clinical utility. Conclusions Plasma proteomic signatures may improve GC risk stratification beyond traditional clinical factors and could support more targeted screening strategies. Further validation is warranted.