Glioma genetic profiles associated with electrophysiologic hyperexcitability

ABSTRACT Distinct genetic alterations determine glioma aggressiveness, however the diversity of somatic mutations contributing to peritumoral hyperexcitability and seizures is uncertain. In a large cohort of patients with sequenced gliomas (n=1716), we used discriminant analysis models to identify somatic mutation variants associated with electrographic hyperexcitability in a subset with continuous EEG recording (n=206). Overall tumor mutational burdens were similar between patients with and without hyperexcitability. A cross-validated model trained exclusively on somatic mutations classified the presence or absence of hyperexcitability with an overall accuracy of 70.9%, and improved estimates of hyperexcitability and anti-seizure medication failure in multivariate analysis incorporating traditional demographic factors and tumor molecular classifications. Somatic mutation variants of interest were also over-represented in patients with hyperexcitability compared to internal and external reference cohorts. These findings implicate diverse mutations in cancer genes associated with the development of hyperexcitability and response to treatment.