Synaptic-related Gene Dysregulation Reveals Novel Prognostic Biomarkers in Glioblastoma: An Integrated Bioinformatics Study

Introduction: Glioblastoma (GBM) is the most common primary intrinsic brain tumor in adults and represents the most aggressive diffuse astrocytic glioma. This study aimed to identify Differentially Expressed Genes (DEGs) in GBM, elucidate their functional roles, and validate potential hub genes as independent prognostic biomarkers through integrated bioinformatics analysis. Methods: We conducted an integrated bioinformatics analysis using publicly available datasets from the Gene Expression Omnibus (GEO). The GSE4290 and GSE50161 datasets were analyzed to identify DEGs between GBM and normal brain tissue. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to explore the biological functions of DEGs. Protein-Protein Interaction (PPI) networks were constructed using the STRING database and Cytoscape to identify hub genes. Genetic alterations of hub genes were examined through cBioPortal. Prognostic relevance was assessed using Cox regression analysis in the Chinese Glioma Genome Atlas (CGGA), and expression levels were validated in UALCAN. Results: A total of 467 overlapping DEGs were identified, including 94 upregulated and 373 downregulated genes in GBM. GO and KEGG analyses revealed enrichment mainly in synaptic signaling and neurotransmitter release. PPI network analysis identified 10 downregulated hub genes: SNAP25, SYN2, SYN1, RAB3A, SYT1, SLC17A7, CPLX1, RIMS1, STX1A, and STXBP1. Genetic alterations in these genes were observed in 73 (12%) of 585 GBM patients. Higher expression of SYN2 and CPLX1 correlated with improved overall survival, and UALCAN confirmed their reduced expression in GBM compared with normal brain. Discussion: SYN2, encoding a neuronal phosphoprotein critical for synaptic plasticity and vesicle trafficking, and CPLX1, encoding complexin-1, which regulates neurotransmitter release via SNARE complex interaction, emerged as key modulators of neuron-glioma interaction. Their downregulation in GBM and association with improved survival when expressed suggest that dysregulation of the synaptic communication may drive tumor progression. These findings align with mounting evidence that GBM exploits neural signaling circuits, including synaptic and neurotransmitter pathways, to sustain growth and invasion. Conclusion: This study highlights synaptic-related genes as key contributors to GBM pathology and suggests that synaptic dysregulation may present novel prognostic markers. Further experimental validation is required to confirm their clinical utility.