DLG2–DLG4 Expression Is Associated with Improved Survival and a Synaptic Gene Signature in Lower-Grade Glioma

Background/Objectives: Increasing evidence indicates that gliomas co-opt mechanisms of excitatory synaptic transmission and plasticity to support tumor progression, yet these processes remain poorly characterized in lower-grade gliomas (LGGs). Here, we investigated whether genes associated with excitatory synaptic function are linked to patient prognosis in LGG. Methods: A curated panel of 36 synaptic genes was analyzed in LGG using RNA-sequencing and clinical data from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) datasets. Results: Among the genes investigated, DLG2, DLG3, and DLG4, which encode the postsynaptic scaffolding proteins PSD-93, SAP-102, and PSD-95, respectively, showed strong associations with patient overall survival (OS). Higher expression of each gene was consistently associated with longer OS across both datasets. Expression of DLG2–DLG4 was higher in oligodendroglioma and IDH-mutant, 1p/19q co-deleted tumors, and lower in astrocytoma and IDH-wild-type tumors. Furthermore, expression of all three genes positively correlated with a broad gene signature associated with a synaptic gene program, including multiple components of glutamatergic signaling and postsynaptic organization. Conclusions: These findings suggest that elevated expression of DLG2–DLG4 is associated with a transcriptional program resembling differentiated neuron-like features and favorable clinical outcome in LGG.