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

BACKGROUND AND OBJECTIVES: – Clinical risk factors for seizure presentation in meningioma patients have been reported, but molecular correlates of seizures in meningioma remain unexplored.METHODS: – 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).RESULTS: – 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.CONCLUSION: – 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.