Elevated expression of TNFRSF4 impacts immune cell infiltration and gene mutation in hepatocellular carcinoma

Article type: Research Article

Authors: Wang, Di^a | Hu, Huan^a | Ding, Huan^a | Zhao, Han^c | Tian, Feifei^{a; *} | Chi, Qingjia^{b; *}

Affiliations: [a] School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China | [b] Department of Engineering Structure and Mechanics, School of Science, Wuhan University of Technology, Wuhan, Hubei, China | [c] School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, China

Correspondence: [*] Corresponding authors: Feifei Tian, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan, China. E-mail: [email protected]. Qingjia Chi, Department of Engineering Structure and Mechanics, School of Science, Wuhan University of Technology, Wuhan, Hubei, China. E-mail: [email protected].

Abstract: BACKGROUND: Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, which makes prognostic prediction challenging.We aimed to investigate association of TNFRSF4 expression with the immune infiltration and gene mutation in HCC. METHODS: In this study, the expression profiles and corresponding clinical data of HCC patients were downloaded from the Cancer Genome Atlas (TCGA) database.Kaplan-Meier and Cox regression were used to evaluate the clinical value of TNFRSF4. ESTIMATE and CIBERSORT algorithms were applied to investigate the infiltration ratio of 22 immune cells. The WGCNA and LASSO COX algorithms were performed, establishing a prognostic risk model that was then validated by HCC samples from GEO. Finally, the effects on gene mutation occurring in HCC patients of TNFRSF4 expression and risk score were appraised. RESULTS: In HCC tissues, it was found the TNFRSF4 expression profile was significantly different with age, gender, tumor grade, disease stage, prominently affecting the survival outcome and prognosis of patients. Univariate and multivariate COX regression analysis suggested that TNFRSF4 was an independent prognostic marker. Samples of high/low expression of TNFRSF4 were screened for differential genes, and then the WGCNA and LASSO COX constructed a 13-gene signature, excellently dividing samples into hign/low risk groups. Compared with the low-risk group, the overall survival (OS) of high-risk group was markedly lower, with P< 0.0001. By ROC curve analysis, the predictive ability of the 13-gene signature was further confirmed. Both the high/low TNFRSF4 expression and the high/low risk score were demonstrated to exert effects on the frequency of gene mutation in HCC. CONCLUSIONS: As an independent prognostic marker of HCC, TNFRSF4 was found simultaneously to affect the immune infiltration of cells and the frequency of gene mutations.

Keywords: TNFRSF4, hepatocellular carcinoma, prognosis, immune infiltration, mutation

DOI: 10.3233/CBM-210538

Journal: Cancer Biomarkers, vol. 36, no. 2, pp. 147-159, 2023