A Subset of G Protein-Coupled Serotonin Receptor Genes is Linked to a Neuronal Gene Expression Signature and Clinically Favorable Biology in IDH-Mutant Gliomas

Increasing evidence indicates that neurotransmitter signaling and neuronal interactions are important determinants of glioma biology. However, the clinical and biological significance of serotonin (5-hydroxytryptamine; 5-HT) receptor expression in lower-grade glioma (LGG) remains poorly understood. Here, we investigated G protein-coupled 5-HT receptor genes in LGG using transcriptomic and clinical data from The Cancer Genome Atlas (TCGA-LGG) and Chinese Glioma Genome Atlas (CGGA) cohorts. Initial survival screening identified HTR1A, HTR2A, HTR2C, and HTR6 as the genes most consistently associated with longer overall survival (OS). Multivariable Cox regression further identified HTR2A and HTR6 as independently associated with longer OS after adjustment for age, sex, tumor grade, and IDH/1p19q molecular subtype. Expression of the four genes was preferentially associated with molecular features of less aggressive gliomas, particularly IDH-mutant tumors. Single-cell RNA-sequencing (scRNA-seq) data supported malignant glioma cells as a major source of their expression, while cell-type deconvolution revealed strong positive associations with neuronal enrichment and inverse associations with stromal and immune signatures. Transcriptome-wide co-expression and Gene Ontology analyses showed that all four receptor genes were associated with neuronal and synaptic programs involving neurotransmitter release, synaptic vesicle function, ion channels, and synaptic signaling. These transcriptional programs were particularly coherent in IDH-mutant gliomas and more heterogeneous in IDH-wildtype tumors. Together, these findings identify a subset of 5-HT receptor genes associated with favorable clinical and molecular features in LGG and suggest that their expression may mark a neuronal/synaptic differentiation state, particularly within IDH-mutant gliomas.