Molecular subtype construction and prognosis model for stomach adenocarcinoma characterized by metabolism-related genes.

BACKGROUND: Metabolic reprogramming is implicated in cancer progression. However, the impact of metabolism-associated genes in stomach adenocarcinomas (STAD) has not been thoroughly reviewed. Herein, we characterized metabolic transcription-correlated STAD subtypes and evaluated a metabolic RiskScore for evaluation survival.

METHOD: Genes related to metabolism were gathered from previous study and metabolic subtypes were screened using ConsensusClusterPlus in TCGA-STAD and GSE66229 dataset. The ssGSEA, MCP-Count, ESTIMATE and CIBERSORT determined the immune infiltration. A RiskScore model was established using the WGCNA and LASSO Cox regression in the TCGA-STAD queue and verified in the GSE66229 datasets. RT-qPCR was employed to measure the mRNA expressions of genes in the model.

RESULT: Two metabolism-related subtypes (C1 and C2) of STAD were constructed on account of the expression profiles of 113 prognostic metabolism genes with different immune outcomes and apparently distinct metabolic characteristic. The overall survival (OS) of C2 subtype was shorter than that of C1 subtype. Four metabolism-associated genes in turquoise model, which closely associated with C2 subtype, were employed to build the RiskScore (MATN3, OSBPL1A, SERPINE1, CPNE8) in TCGA-train dataset. Patients developed a poorer prognosis if they had a high RiskScore than having a low RiskScore. The promising effect of RiskScore was verified in the TCGA-test, TCGA-STAD and GSE66229 datasets. The prediction reliability of the RiskScore was validated by time-dependent receiver operating characteristic curve (ROC) and nomogram. Moreover, samples with high RiskScore had an enhanced immune status and TIDE score. Moreover, MATN3, OSBPL1A, SERPINE1 and CPNE8 mRNA levels were all elevated in SGC7901 cells. Inhibition of OSBPL1A decreased SGC7901 cells invasion numbers.

CONCLUSION: This work provided a new perspective into heterogeneity in metabolism and its association with immune escape in STAD. RiskScore was considered to be a strong prognostic label that could help individualize the treatment of STAD patients.