Abstract
BACKGROUND: Gastric cancer (GC) is one of the most common malignancies. Cuproptosis is a newly discovered type of cell death caused by protein toxicity stress, with copper having considerable importance in GC development. METHODS: First, differentially expressed (DE) cuproptosis-related genes (CRGs) were screened in GC. The tumor mutation burden (TMB) of CRGs was analyzed. We then performed enrichment analyses of DE-CRGs. Next, we constructed a GC cuproptosis-related (CR) signature (CRs) using Cox and least absolute shrinkage and selection operator (LASSO) regression analyses. The predictive efficacy was assessed using receiver operating characteristic (ROC) curves. Furthermore, we performed gene set enrichment analysis (GSEA). Different methods were used to assess tumor immunity of the CRs, and the Wilcoxon test was used to examine the expressions of m6A-, m7G-, and ferroptosis-related genes. The "pRRophetic" R package (The R Foundation for Statistical Computing) was used to predict the half maximal inhibitory concentration IC50 of common chemotherapeutic agents. Finally, the expression of CRGs in different clusters was analyzed using single-cell RNA sequencing (scRNA-seq). RESULTS: We identified 8 DE-CRGs in GC. There were 9 CRGs with TMB values >1%. We constructed gene expression networks and CRs for GC. The DE-CRGs were involved in important mitochondrial metabolic pathways, and the CRs was a valuable independent prognosis factor. The GSEA revealed that angiogenesis and metabolic-related pathways were enriched in the high-risk group, whereas the low-risk group showed enrichment in DNA replication mismatch and repair pathways. The expressions of immunological checkpoints, ferroptosis-, m6A-, and m7G-related genes, type II interferon (INF) response, major histocompatibility complex (MHC class-I), and the IC50 of the copper-based carrier drug elesclomol were significantly different between the 2 groups of the CRs. Furthermore, the scRNA-seq analysis showed that most CRGs were mainly upregulated in endothelial cells. CONCLUSIONS: The novel CRs could predict the prognosis of GC.