To characterize WHO grade 4 gliomas and associated epilepsy via whole-exome sequencing.

Over half of patients with gliomas experience seizures, but the pathogenesis of glioma-associated epilepsy remains unclear. Recent studies suggest that tumor molecular characteristics may differ between patients with and without seizures, and for patients with seizures, molecular characteristics may differ depending on seizure incidence (before or after glioma diagnosis). Tumor mutational burden (TMB) is a biomarker associated with worse prognosis in patients with gliomas but has not yet been characterized with seizure activity.

83 patients diagnosed with grade 4 gliomas from 2015 to 2023 who underwent whole exome sequencing (WES) were identified retrospectively. Seizure activity was obtained through review of patient records. Patients were stratified by time of seizure incidence: none, early (preceding diagnosis via surgery), or late (after diagnosis). Spearman’s rank correlation and multivariable regression were used for analysis.

There were 514 observed exome variants, and no specific exome variants were significantly associated with seizure incidence (none, early, late) via Pearson’s Chi-squared test (p = 0.2). TMB also did not differ depending on seizure incidence via Kruskal-Wallis rank sum test (p = 0.5). Exome variants and TMB were then compared to patient characteristics via Spearman’s rank correlation. Higher TMB was significantly associated with lower KPS at diagnosis (r = -0.24, p < 0.05); this finding was stronger among patients with early seizures (r = -0.5, p < 0.01). Higher TMB was significantly associated with older age among patients without seizures (r = 0.44, p < 0.01) but not among patients with seizures.

Among patients with early seizures related to gliomas, lower KPS at diagnosis was associated with higher TMB. This suggests a role for TMB in seizure occurrence and outcomes in grade 4 glioma that warrants further investigation.