Integrated Clinical Genetic Analysis Reveals Transcriptional Neurotransmitter Receptor Dysregulation in Meningiomas Causing Seizure.

Abstract

Clinical risk factors for seizure presentation in meningioma patients have been reported, but molecular correlates of seizures in meningioma remain unexplored. We assessed a total of 144 primary meningiomas for clinical data and performed bulk RNA sequencing (n = 141), whole-exome sequencing (n = 35), targeted DNA sequencing (n = 67), and DNA methylation analysis (n = 62). Clinically, seizure presentation was associated with higher rates of emergency room presentation (P = .005), altered consciousness (P = .014), and fewer headaches (P = .015). Radiographically, seizure presentation correlated with higher rates of cerebral edema (P = .005), nonhomogenous enhancement (P = .001), and intratumoral calcification (P = .034). Pathologically, seizure presenting tumors had higher molecular immunology borstel 1 index (P = .001) and cellular atypia in World Health Organization grade 1 tumors (P = .023) but were not associated with World Health Organization grade 2 status (P = .059). There was no difference in rates of canonical mutations between groups. Chromosome 14q loss was enriched in the seizure group (P = .004). Seizure presentation was associated with the Molecular Group C (MenG C) (P = .023). Transcriptomic analysis revealed downregulation of GABAergic signaling, synaptic pathways, and neurotransmitter receptors in meningiomas causing seizure. Dysregulated genes included both MenG C-specific (GABRG1, GRIA1, DKK2) and seizure-specific/MenG-independent (GABRA3, GABRQ, GRIK3, NPY1R) genes. Here, we show that seizure causing meningiomas demonstrate distinct clinical, radiographic, chromosomal, and transcriptional features. Novel associations with seizure presentation in meningioma include MenG C status, chromosome 14q loss, and seizure-specific dysregulation of neurotransmitter receptor genes.