Identification of Novel Prognostic Biomarkers That are Associated with Immune Microenvironment Based on GABA-Related Molecular Subtypes in Gastric Cancer.

Background: Gamma-aminobutyric acid (GABA) plays an important role in tumorigenesis and progression. Despite this, the role of Reactome GABA receptor activation (RGRA) on gastric cancer (GC) remains unclear. This study was intended to screen RGRA-related genes in GC and investigate their prognostic value.

Methods: GSVA algorithm was used to assess the score of RGRA. GC patients were divided into two subtypes based on the median score of RGRA. GSEA, functional enrichment analysis, and immune infiltration analysis were performed between the two subgroups. Then, differentially expressed analysis, and weighted gene co-expression network analysis (WGCNA) were used to identify RGRA-related genes. The prognosis and expression of core genes were analyzed and validated in the TCGA database, GEO database, and clinical samples. ssGSEA and ESTIMATE algorithms were used to assess the immune cell infiltration in the low- and high-core genes subgroups.

Results: High-RGRA subtype had a poor prognosis and activated immune-related pathways, as well as an activated immune microenvironment. ATP1A2 was identified to be the core gene. The expression of ATP1A2 was associated with the overall survival rate and tumor stage, and its expression was down-regulated in GC patients. Furthermore, ATP1A2 expression was positively correlated with the level of immune cells, including B cells, CD8 T cells, cytotoxic cells, DC, eosinophils, macrophages, mast cells, NK cells, and T cells.

Conclusion: Two RGRA-related molecular subtypes were identified that could predict the outcome in GC patients. ATP1A2 was a core immunoregulatory gene and was associated with prognosis and immune cell infiltration in GC.