Construction and Validation of a Novel Pyroptosis-Related Four-lncRNA Prognostic Signature Related to Gastric Cancer and Immune Infiltration

Abstract

Increasing evidence has demonstrated that pyroptosis, a type of inflammatory programmed cell death, plays an important role in the pathogenesis and progression of gastric cancer. However, it remains unclear whether pyroptosis-related long non-coding RNAs (lncRNAs) can be used to predict the diagnosis and prognosis of gastric adenocarcinoma. This study aimed to evaluate and test the role of the lncRNA signature associated with pyroptosis as a prognostic tool for stomach adenocarcinoma (STAD) and to ascertain their immune value. Relative RNA-sequencing data were extracted from The Cancer Genome Atlas database (TCGA), and data preprocessing was performed for STAD. Pearson correlation analysis was used to determine whether lncRNAs were significantly correlated with pyroptosis based on 23 genes related to pyroptosis. Univariate Cox regression and least absolute shrinkage and selection operator(LASSO) analyses were both adopted to select features and establish the pyroptosis-related lncRNA (PRL) prognostic signature. Kaplan-Meier(KM) survival analysis of the different risk groups was conducted according to the risk scores. We further examined the functional enrichment, tumor microenvironment, and landscape of mutation status among the different risk groups, and these analyses further explained the reasons for the differences in the prediction as well as survival value of the different risk groups. Four lncRNAs, including HAND2-AS1, LINC01354, RP11-276H19.1, and PGM5-AS1, were involved in the PRL signature and used to split STAD patients into two risk groups. Overall survival time(OS) was significantly higher in the low-risk group than in the high-risk group in both the training and validation groups. Functional enrichment analysis was further employed to analyze differentially expressed genes in high- and low-risk groups to identify potential molecular functions and pathways associated with pyroptosis in the gastric cancer microenvironment. Protein-protein interaction (PPI) and Friends analysis identified hub genes that may play a key role in differentially expressed genes in high- and low-risk groups. In addition, there were remarkable discrepancies between the different risk groups in the tumor stage (P < 0.01) and histologic grade (P < 0.05). Furthermore, drug-susceptibility testing indicated potential sensitive chemotherapeutic drugs for each risk group. This study is the first to establish and validate STAD-associated PRLs that can effectively guide the prognosis and the immune microenvironment in STAD patients and provide evidence for the development of molecularly targeted therapies related to pyroptosis.

Keywords: immune infiltration; prognostic signature; pyroptosis; stomach adenocarcinoma; tumor microenvironment.