Identification of LGR5 and TFF2 as Biomarkers in High-Risk Chronic Atrophic Gastritis: From Multi-Omics Mining to Clinical Validation

Background: High-risk chronic atrophic gastritis (CAG; OLGA/OLGIM III-IV) carries significant gastric cancer (GC) risk, yet lacks reliable gastric stem cell (GSC)-based biomarkers. We evaluated GSC markers LGR5 (proliferative) and TFF2 (protective) for risk stratification and their Wnt/β-catenin-mediated mechanisms. Methods: TCGA/GEO bioinformatics analysis preceded immunohistochemical validation in 60 clinical samples. Protein co-expression (Wnt/β-catenin, Ki67, Bax) was assessed. Diagnostic/prognostic power was tested via ROC and Kaplan-Meier analyses. Functional networks were deciphered through GO/KEGG enrichment. Results: High-risk CAG and GC tissues showed LGR5 upregulation and TFF2 downregulation (P<0.001). IHC confirmed these patterns, with concurrent Wnt activation (β-catenin↑, Cyclin D1↑) and proliferation-apoptosis imbalance (Ki67↑, Bax↓). TFF2 outperformed LGR5 in diagnosing high-risk CAG (AUC: 0.89 vs. 0.76). Poor GC prognosis correlated with high LGR5/low TFF2 (P<0.05). Co-expression networks linked LGR5 to metabolic genes (CPS1, ADH6) and TFF2 to mucosal defense (GKN1, PGC). Conclusion: LGR5 and TFF2 are promising biomarkers for high-risk CAG identification. Their inverse expression reflects GSC dysregulation via Wnt/β-catenin signaling, offering mechanistic insights for early intervention.