Abstract
Objective: This study aimed to investigate the molecular mechanism of tumor necrosis factor (TNF) superfamily-related genes and potential therapeutic drugs for glioblastoma multiforme (GBM) patients based on transcriptome and epigenome.Methods: Gene expression data, corresponding clinical data, and methylation data of GBM samples and normal samples in the TCGA-GBM and GTEx datasets were downloaded. The TNF-related genes were obtained, respectively, from two groups in the TCGA dataset. Then, the TNF-related differentially expressed genes (DEGs) were investigated between two groups, followed by enrichment analysis. Moreover, TNF superfamily-related gene expression and upstream methylation regulation were investigated to explore candidate genes and the prognostic model. Finally, the protein expression level of candidate genes was performed, followed by drug prediction analysis.Results: A total of 41 DEGs including 4 ligands, 18 receptors, and 19 downstream signaling molecules were revealed between two groups. These DEGs were mainly enriched in pathways like TNF signaling and functions like response to TNF. A total of 5 methylation site-regulated prognosis-related genes including TNF Receptor Superfamily Member (TNFRSF) 12A, TNFRSF11B, and CD40 were explored. The prognosis model constructed by 5 genes showed a well-prediction effect on the current dataset and verification dataset. Finally, drug prediction analysis showed that zoledronic acid (ZA)-TNFRSF11B was the unique drug–gene relation in both two databases.Conclusion: Methylation-driven gene TNFRSF12A might participate in the development of GBM via response to the TNF biological process and TNF signaling pathway and significantly associated with prognosis. ZA that targets TNFRSF11B expression might be a potential effective drug for clinical treatment of GBM.
Highlights
Glioblastoma multiforme (GBM) is the most aggressive cancer that represents 15% of all brain tumors [1]
A total of 41 tumor necrosis factor (TNF)-related differentially expressed genes (DEGs) including 4 TNF superfamily (TNFSF), TNF receptor superfamily (TNFRSF), and downstream signal molecules were identified between the tumor and normal groups
The obtained DEGs were significantly enriched in 103 GOBP, 1 GO-cellular component (GO-CC), 19 GO-molecular function (GO-MF), and 32 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in the current functional enrichment analysis
Summary
Glioblastoma multiforme (GBM) is the most aggressive cancer that represents 15% of all brain tumors [1]. A previous study shows that tumor necrosis factor (TNF) and the associated receptor superfamily play important roles in the development of GBM [8]. Some TNFs such as TNF-α are upregulated in GBM cells, which further play an important role in GBM progression [9]. DNA methylation plays an important role in gene expression regulation during the development of tumor [11]. A previous study shows that epigenetic therapy with inhibitors of histone methylation suppresses DNA damage signaling and increases glioma cell radiosensitivity [13]. Due to the lack of integrated analysis of epigenomic and transcriptome data, the specific role of DNA methylation sites and TNF-related gene expression changes in GBM progress, as well as potential effective drugs associated with these genes, are still unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
