Targeted anticonvulsive treatment of IDH-wildtype glioblastoma based on DNA methylation subclasses.

Abstract

Seizures occur in one-third of glioblastoma patients, and in another third, seizures develop during the course of the disease.1 Nevertheless, the choice of antiseizure medication (ASM) remains challenging, and many patients need an increase in dosage or a polytherapy to achieve seizure control.2 We recently demonstrated that the DNA methylation subclass RTK II has a strong epileptogenic potential, as a high frequency of preoperative and follow-up seizures was observed.1 Here, we investigated the efficacy of levetiracetam to achieve seizure control and define therapeutic targets in RTK I, RTK II, and mesenchymal (MES) glioblastoma. We studied 201 patients with IDH-wildtype glioblastoma from 2 neurooncological centers (Hamburg and Bonn) and DNA methylation was analyzed using the Illumina EPIC array. Differential methylation analysis was performed, examining differentially methylated CpG sites of genes that are therapeutic targets of the most clinically relevant ASM. To further identify RNA expression of these genes, we queried the TCGA database to vertically integrate DNA methylation and RNA expression (n = 68). This study was approved by the medical ethics committee of the Hamburg chamber of physicians (PV4904). Informed written consent was obtained from all patients.