Seizure-presenting IDH-wildtype glioblastoma and the upregulation of a synaptic signature

OBJECTIVE: Epileptic activity is common throughout the glioma disease course and causes significant morbidity for patients. While its clinical impact on glioma has been analyzed, the underlying biological mechanisms of hyperactivity remain uncharacterized. Herein, the authors characterized the differences in epileptic activity across the disease course of various glioma subtypes based on tumor grade and histopathology. To gain further understanding of potential transcriptional differences between tumor cases presenting with seizures and those with other presentation signs, they analyzed a subset of patients with bulk RNA-sequenced tumors. METHODS: The authors assessed clinical factors associated with glioma-related epilepsy across gliomas: IDH-wildtype glioblastoma (GBM), IDH-mutant astrocytoma, and IDH-mutant oligodendroglioma. They conducted multivariate Cox regression for survival analysis, incorporating variables known to influence glioma patient survival and seizure status. They also utilized bulk RNA sequencing to assess transcriptional correlates of hyperactivity in a subset of the cohort and conducted multivariate logistic regression for seizure presentation using this subgroup's transcriptional and clinical data. RESULTS: Among 363 gliomas-190 IDH-wildtype GBMs, 113 IDH-mutant astrocytomas, and 60 IDH-mutant oligodendrogliomas-the frequency of seizure as a presenting symptom was assessed. The rate of seizure presentation was significantly lower in IDH-wildtype GBM (30.5%) than in IDH-mutant astrocytoma (56.6%) and IDH-mutant oligodendroglioma (66.7%; p < 0.001) with no difference in seizure at recurrence among the groups. Seizure presentation was associated with smaller-volume tumors and less peritumoral edema in IDH-wildtype GBM (both p < 0.001) and with smaller-volume tumors in IDH-mutant astrocytoma (p = 0.0289). Seizure presentation had lower-grade tumors in IDH-mutant astrocytoma (p = 0.026). When accounting for relevant clinical factors, there was no survival difference between seizure at presentation and seizure at recurrence for any glioma subtype. Transcriptional analysis demonstrated upregulation of pathways related to ion transport and synaptic function in seizure-presenting IDH-wildtype tumors, including specifically IGFN1, RELN, and SLC17A8 (VGLUT3). VGLUT3, a vesicular glutamate transporter, was elevated at a protein level for IDH-wildtype GBM presenting with seizures. A multivariate logistic regression for seizure presentation combining clinical and transcriptional variables demonstrated that temporal location (p = 0.032, OR 3.25), parietal location (p = 0.023, OR 5.44), and SLC17A8 levels (p = 0.019, OR 3.44) were positively predictive of seizure, whereas the presence of edema (p = 0.004, OR -7.57) and ADAMTS2 expression (p = 0.015, OR -3.46) were both negative predictors. CONCLUSIONS: In IDH-wildtype GBM, tumors presenting with seizures had smaller volumes than those presenting with other signs. Transcriptionally, seizure presentation in IDH-wildtype GBM correlated with the upregulation of synaptic and ionic pathways, with SLC17A8 holding independent predictive value for seizure presentation.