Gene mutations linked to drug-resistant epilepsy in astrocytoma

Abstract

Introduction: Epilepsy is common in gliomas, particularly astrocytomas, even in patients who have undergone total tumor resection. Resistance to antiseizure drugs presents a significant challenge in managing epilepsy. Seizure outcomes after brain surgery for drug-resistant epilepsy (DRE) are heterogeneous and difficult to predict using models that evaluate current clinical, imaging, and electrophysiological variables. This study aimed to investigate possible correlations between genetic mutations and antiseizure resistance using whole-exome sequencing.

Methods: Tumor samples from a medical biobank were subjected to whole-exome sequencing, and the contribution of 64 genes from a previous report was analyzed.

Results: Fifteen patients had DRE. Compared to the patients who showed drug responsiveness, patients in the DRE group exhibited mutations in glutamate receptor genes (GRIA1, GRIK5, GRIN2B, or GRIN2C), ATRX, and the glutamate-S-transferase gene. No significant differences were found between the groups in terms of mutations in BRAF, Olig2, Ki-67, IDH, PIK3CA, p53, GRM, or BCL2A.

Discussion: These findings suggest that somatic gene mutations are closely linked to DRE. Identifying the molecular basis of antiseizure drug resistance is crucial for improving the management of DRE.

Keywords: astrocytoma; drug resistance; drug-resistant epilepsy; exome sequencing; receptors.

Figure 1

Cohort of 25 paired cases for genetic analysis. AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.

Figure 2

Magnetic resonance images of a patient (N11) with drug-resistant epilepsy and GRIK2, GRIN3B, GRM3, GRM5, and GRM6 mutations (A). The axial 5-mm thick T1-weighted image shows an intra-axial mass at the left frontoparietal operculum with surrounding vasogenic edema (arrow) with heterogeneous enhancement (B).