AUTHOR=Wang Ke , Qi Lina , Sun Hua , Diao Min , Yang Lin 

TITLE=Integrative Analysis Identifies a TNFα-Derived Gene Signature for Predicting Prognosis, Tumor Immunity, and Treatment Sensitivity in Gastric Cancer

JOURNAL=Frontiers in Genetics

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.882519

DOI=10.3389/fgene.2022.882519

ISSN=1664-8021

ABSTRACT=Objective: TNF-α is an essential pro-inflammatory cytokine in the tumor microenvironment of gastric cancer (GC), possessing the key biological and clinical impact. Here, we conducted an integrative analysis of the role of TNFα-derived genes in GC prognosis and precision medicine.
Methods: We pooled transcriptome and clinical features of GC patients from TCGA and GSE15459 projects. TNFα signaling was quantified through ssGSEA algorithm and TNFα-derived genes were screened with WGCNA. Thereafter, a LASSO model was established. Somatic mutation was analyzed across GC specimens. Immune cell infiltrations were inferred through ESTIMATE and ssGSEA algorithms, followed by measuring immune checkpoint expression. AKR1B1, CPVL and CTSL expressions were measured in gastric mucosal cells GES-1 and GC cells (HGC-27, MKN-28 and AGS) through RT-qPCR and western blotting.
Results: TNFα-derived gene signature (containing AKR1B1, CPVL and CTSL) was developed for GC. High risk score indicated more undesirable OS, DFS, DSS and PFS outcomes. Time-independent ROC curves and multivariate cox regression models confirmed that the signature reliably and independently predicted GC prognosis. Additionally, risk score displayed significant correlations to more severe histological grade and pathological stage. Low risk score was characterized by increased somatic mutation, while high risk score was characterized by immune and stromal activation, enhanced immune cell infiltrations, and increased expression of immune checkpoint molecules. Experimental results confirmed the significant up-regulations of AKR1B1, CPVL and CTSL in GC cells.
Conclusion: Collectively, stratification based on TNFα-derived gene signature might enable GC patients to predict prognosis, benefit from immunotherapy as well as assist formulate novel therapeutic regimens.