A Prognostic Neuromodulation-Related Gene Signature Identifies Immunomodulation and Tumour-Associated Hallmarks in Glioblastoma

<b>Background and Objective</b>: Neuromodulators such as neuropeptide, neurotrophic factors and neurotransmitters are increasingly reported to be involved in glioblastoma (GBM) progression. Nonetheless, the association between neuromodulation-related genes (NMRGs) and GBM prognosis remains elusive. Hence, this study aims to identify clinically significant NMRGs that can form a prognostic gene signature for GBM patients. <b>Methods and Results</b>: Differential expression analysis of transcriptomic profiles extracted from GSE147352, GSE165595, TCGA and CGGA determined 272 differentially expressed NMRGs (deNMRGs) in GBM compared to normal brain tissue. The subsequent Kaplan-Meier survival analysis and Cox proportional hazard model further identified ten common deNMRGs (<i>IGF2</i>, <i>RETN</i>, <i>EDNRB</i>, <i>C3AR1</i>, <i>CLCF1</i>, <i>NTRK1</i>, <i>OSMR</i>, <i>KCNN4</i>, <i>SLC18A3</i> and <i>HTR7</i>), forming a 10-NMRG signature. This signature stratifies GBM patients and consistently predicts poorer survival outcomes for the high-risk score group compared to the low-risk score group in the TCGA and CGGA cohorts. The gene set enrichment analysis and active-subnetwork-oriented enrichment analysis identified a connection between immunomodulation and tumour-associated hallmarks with the high-risk GBM patient group. Next, the correlation proportionality analysis identified a positive association between the signature genes with immune activators, immune suppressors and pro-motility genes. Additionally, high expressions of the 10-NMRGs were noted in the mesenchymal GBM subtype. <b>Conclusions</b>: Collectively, our analysis highlights the potential use of the 10-NMRG signature to stratify the high-risk GBM group with a strong association of immunomodulation and tumour-associated hallmarks that can contribute to the poor survival outcomes.