Differential Gene Expression Underlying Epileptogenicity in Patients with Gliomas

Background: Seizures are a common sequela for patients suffering from gliomas. Molecular properties are known to influence the initiation of seizures that may influence tumor growth. Different levels of gene expression with seizures related to gliomas remain unclear. We analyzed RNA sequencing of gliomas to further probe these differences.

Methods: Total RNA sequencing was obtained from The Cancer Genome Atlas-Lower-Grade Glioma project, comprised of 2021 World Health Organization classification low-grade gliomas, including IDH-mutant and IDH-wild type, to distinguish differential expression in patients who did and did not experience seizures. Utilizing QIAGEN Ingenuity Pathways Analysis, we identified canonical and functional pathways to characterize differential expression.

Results: Of 289 patients with gliomas, 83 (28.7%) had available information regarding seizure occurrence prior to intervention and other pertinent variables of interest. Of these, 50 (60.2%) were allocated to the seizure group. When comparing the level of RNA expression from these tumors between the seizure and non-seizure groups, 52 genes that were significantly differentially regulated were identified. We found canonical pathways that were altered, most significantly RhoGDI and semaphorin neuronal repulsive signaling. Functional gene analysis revealed tumors that promoted seizures had significantly increased functional gene sets involving neuronal differentiation and synaptogenesis.

Conclusions: In the setting of gliomas, differences in tumor gene expression exist between individuals with and without seizures, despite similarities in patient demographics and other tumor characteristics. There are significant differences in gene expression associated with neuron development and synaptogenesis, ultimately suggesting a mechanistic role of a tumor-neuron synapse in seizure initiation.