Cnsc-11. seizure presentation in idh wt glioma is related to upregulated synaptic signaling and ionic transport genes

Abstract Isocitrate dehydrogenase wildtype (IDH WT) glioblastoma (GBM) is the most common malignant brain tumor in adults and is universally lethal. Seizures often occur as a presenting sign of tumor. Recent studies have implicated tumor-neuron communication facilitating synaptic remodeling and peritumoral circuit hyperactivity influencing tumor growth. We assessed the clinical and transcriptional effect of seizure presentation on GBM biology. 63 tumor samples were analyzed for clinical characteristics. Bulk RNA sequencing data was used to identify differentially expressed genes (DEGs), gene sets enrichment analysis (GSEA), and gene ontologies (GO). 24 IDH WT GBM patients presented with seizures compared to 39 patients presenting with other symptoms. There were no significant differences between age at presentation, sex, tumor lobe, tumor location, or grade of tumor. GSEA of gene ontologies revealed upregulated genes in the seizure cohort were largely related to synaptic signaling, ionic transport, and receptor signaling (p-val< 0.05). Alternatively downregulated gene sets were related to extracellular matrix organization, and inflammatory and immune response (p-val< 0.05). Focusing on significantly upregulated DEGs (padj< 0.05,) biological processes related to glutamatergic synaptic transmission and cellular components related to synaptic structures were upregulated. Alternatively, significantly downregulated DEGs (padj< 0.05) were related to biological processes of immunity and extracellular matrix organization and cellular components related to the extracellular matrix. Upregulated genes include IGFN1 and THBS4, both involved in synapse assembly, and SLC17A3, involved in presynaptic glutamate sorting (Log2FC >1,padj <0.05). The downregulated genes include numerous collagen related genes and immune related genes and KCNJ15, an inward rectifying potassium channel and GABRR1, a GABA-rho subunit. Using bulk RNA sequencing in a clinically similar set of IDH WT tumors, we found gene sets and gene ontologies related to synaptic signaling and glutamatergic signaling upregulated in patients with seizures while genes related to both extracellular matrix and immune inflammation were downregulated.