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INTERNATIONAL CONGRESS OF

CancerGenetics

• Comparative Transcriptomic and Network-Based Analysis of the Tumor Core and Peritumoral Margin in Glioma

• Arada Sarkisian,¹ Soroush Jadidi,² Hamed Shafaroodi,^3,*
  1. Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
  2. School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  3. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  
  
  
• Introduction: Gliomas exhibit marked spatial heterogeneity, with molecular and cellular differences between the contrast-enhancing tumor core and the surrounding non-enhancing FLAIR-positive margin. Characterizing these differences may provide insight into the distinct biological processes associated with the tumor core and its infiltrative peripheral region. This study aimed to identify differentially expressed genes and enriched biological pathways distinguishing the glioma tumor core from the peritumoral margin, followed by protein–protein interaction and network analysis to identify candidate hub genes.
• Methods: Gene expression data were obtained from the Gene Expression Omnibus (GEO) dataset GS59612, comprising 40 glioma tissue samples, including 20 contrast-enhancing tumor core samples and 20 non-enhancing FLAIR-positive margin samples. Differential expression analysis was performed using GEO2R, with the comparison defined as margin versus core. Genes were considered differentially expressed based on an adjusted P value <0.05 and an absolute log2 fold-change (|logFC|) >2.5. Differentially expressed genes were separated into upregulated and downregulated groups and analyzed independently using Enrichr. Gene Ontology (GO) biological process, cellular component, and molecular function categories, together with Reactome and KEGG pathway enrichment, were evaluated. Subsequently, separate gene lists were submitted to STRING to construct protein–protein interaction networks. Network files were imported into Cytoscape, and hub genes were ranked primarily according to degree centrality, with betweenness centrality used as a secondary criterion.
• Results: A total of 300 genes met the predefined differential expression criteria, including 220 upregulated and 80 downregulated genes in the margin relative to the core. Upregulated genes were predominantly enriched in neuronal and synaptic processes, including extrasynaptic GABA signaling, synaptic vesicle exocytosis, neurotransmitter secretion, inhibitory synapse assembly, and GABAergic synaptic transmission. GO cellular component and molecular function analyses further highlighted neuronal projections, dendrites, axons, synaptic vesicle membranes, GABA-A receptor complexes, GABA receptor activity, ligand-gated ion channel activity, and calcium-dependent functions. Reactome analysis demonstrated enrichment of the neuronal system, chemical synaptic transmission, neurotransmitter release cycles, GABA, glutamate, and dopamine neurotransmitter pathways, while KEGG analysis highlighted neuroactive ligand–receptor interaction, GABAergic and cholinergic synapses, synaptic vesicle cycling, calcium signaling, and retrograde endocannabinoid signaling. In contrast, downregulated genes were mainly associated with extracellular matrix (ECM) organization, collagen fibril organization, regulation of MAPK signaling, leukocyte chemotaxis, and receptor-mediated signaling. Cellular component enrichment included elastic fibers, microfibrils, extracellular exosomes, and secretory vesicles, while molecular function analysis emphasized cytokine and growth factor activity, receptor ligand activity, protease binding, and transforming growth factor-β binding. Reactome and KEGG analyses consistently identified ECM organization, collagen formation and degradation, integrin-mediated interactions, focal adhesion, and PI3K-AKT-related signaling. Network analysis identified distinct hub-gene signatures for the two expression patterns. The top upregulated hub genes were SNAP25, SLC17A7, SYT1, SYN1, GRIN1, CAMK2A, SYN2, GAD2, SYP, and GABRG2, whereas the principal downregulated hub genes were IL6, COL1A1, CXCL8, LOX, TIMP1, COL1A2, THBS1, POSTN, CD36, and CA9.
• Conclusion: The transcriptional landscape of the glioma margin differed substantially from that of the contrast-enhancing core. Margin-associated upregulation was characterized predominantly by neuronal, synaptic, GABAergic, and neurotransmitter-related programs, whereas genes reduced in the margin were strongly linked to extracellular matrix organization, collagen biology, inflammatory signaling, and cell–matrix interactions. The identified hub genes provide candidate molecular markers for further investigation of the distinct biological characteristics of the glioma core and peripheral margin. These findings may help generate hypotheses regarding the spatial molecular heterogeneity of glioma and warrant validation in independent datasets and experimental models.
• Keywords: Glioma, Tumor heterogeneity, Transcriptomic analysis, Differential gene expression, PPIN