Do Glioma Cells Rewire Neural Circuits through Epigenetic Changes? DNA Methylation Analysis of Genes Involved in Neuron-Glioma Communication in the Human Frontal Cortex.

Gliomas are known to form connections with nearby neurons, which help drive their own growth. What is less clear is how these tumor cells adapt at the molecular level to join neural circuits. We investigated whether changes in DNA methylation might play a role, focusing on genes that support communication between neurons and glial cells. We analyzed DNA methylation in 302 glioma samples from the frontal lobe and compared them to 261 control brain samples, via the Illumina 450K array. From these data, we focused on 70 genes involved in astrocyte-neuron signaling. Our analysis was adjusted for age, sex, race, and cell-type composition. We applied multiple testing correction (FDR < 0.01) and performed enrichment analysis on significant sites. We identified 528 CpG sites with significant differences in methylation. Approximately 77% of these genes were hypomethylated in glioma. Several of the most affected genes, CACNA1C, KCNMA1, SYT7, and GABBR2, are important for ion flow, neurotransmission, and synaptic structure. Interestingly, several of these genes show reduced expression in previous studies despite being hypomethylated, indicating the involvement of additional regulatory mechanisms. Functional analysis revealed links to apoptosis, synaptic signaling, and remodeling of the extracellular matrix. Glioma cells appear to shift their epigenetic landscape in ways that support a more neuron-like identity. This may help them integrate into brain circuits. These findings highlight genes and pathways that could serve as potential biomarkers or treatment targets at the interface between tumors and the nervous system.