Transcriptomic and Metabolomic Profiling in Helicobacter pylori-Induced Gastric Cancer Identified Prognosis- and Immunotherapy-Relevant Gene Signatures

Background: Chronic Helicobacter pylori (HP) infection is considered the major cause of non-cardia gastric cancer (GC). However, how HP infection influences the metabolism and further regulates the progression of GC remains unknown.Methods: We comprehensively evaluated the metabolic pattern of HP-positive (HP+) GC samples using transcriptomic data and correlated these patterns with tumor microenvironment (TME)-infiltrating characteristics. The metabolic score was constructed to quantify metabolic patterns of individual tumors using principal component analysis (PCA) algorithms. The expression alterations of key metabolism-related genes (MRGs) and downstream metabolites were validated by PCR and untargeted metabolomics analysis.Results: Two distinct metabolic patterns and differential metabolic scores were identified in HP+ GC, which had various biological pathways in common and were associated with clinical outcomes. TME-infiltrating profiles under both patterns were highly consistent with the immunophenotype. Furthermore, the analysis indicated that a low metabolic score was correlated with an increased EMT subtype, immunosuppression status, and worse survival. Importantly, we identified that the expression of five MRGs, GSS, GMPPA, OGDH, SGPP2, and PIK3CA, was remarkably correlated with HP infection, patient survival, and therapy response. Furthermore, the carbohydrate metabolism and citric acid may be downstream regulators of the function of metabolic genes in HP-induced GC.Conclusion: Our findings suggest that there is cross talk between metabolism and immune promotion during HP infection. MRG-specific transcriptional alterations may serve as predictive biomarkers of survival outcomes and potential targets for treatment of patients with HP-induced GC.