Abstract

Abstract Recent literature has highlighted neural signaling markers (SM) as drivers for synaptogenesis, invasion, and proliferation in gliomas. Further work on elucidating key mutations can provide improved prognostication and potential treatment targets. Our objective is to identify correlates of neural signaling in relation to glioma histopathology and patient outcomes. We used a combination of bulk RNA sequencing (RNA-seq) and a DNA gene panel (DPG) by Tempus next-generation sequencing. Differential gene expression (DGE) was performed using DESeq2 after subsetting genes for neural SM. Dimensionality reduction was applied through t-SNE projections. Variant calls were analyzed using EnsemblVEP and maftools. Survival analysis was determined through log-rank tests. All analyses were conducted with R. 176 and 184 patient samples were analyzed for RNA-seq and DPG, respectively. t-SNE of DGE highlights two distinct functional clusters with no correlation to WHO classification status (Chi-squared p = 0.39) The median survival for the big cluster was observed at 957 days, while no median survival was reached even after 4,420 days of follow-up in the small cluster (p = 0.01). This contrast remains consistent when examining subsets of gliomas with unmethylated MGMT promoter (p = 0.02) and glioblastomas (p = 0.02), but not others such as IDH mutation status and low-grade gliomas (p > 0.1). Genes upregulated in the small cluster had equal representation of synaptic and paracrine SM (45% and 55%), while the big cluster had a greater representation of paracrine SM (69% and 31%). DPG of low-grade gliomas highlighted 3 somatic signaling mutations (FGFR1, PTPRD, and SLIT2) that are more prevalent in the big cluster. Functional classification based on neural signaling markers can elucidate a novel set of biomarkers that may impact survival in glioma patients. Further studies are required to validate such findings and develop therapeutic targets.