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

Clinical and molecular correlates of seizures in meningioma remain unexplored. Previously, we identified MenG molecular grouping, wherein MenG C meningiomas recur more than MenG A or B. We sought to identify molecular and clinical drivers of seizures in meningioma. We identified 144 primary supratentorial meningiomas, excluding those with pre-existing epilepsy. Whole exome sequencing assessed somatic mutation burden. Bulk RNA-sequencing identified differentially expressed genes and gene ontologies (GO). Immunohistochemistry confirmed protein levels. No differences in canonical gene mutations (NF2, TRAF7, AKT1, KLF4, SMO, and SMARC) were found between seizure and nonseizure groups ([Fig. 1]). Seizure-presenting groups had higher rates of chr.14q deletion (p = 0.004, [Table 1]). MenG C tumors had higher seizure incidence compared to MenG A or B (p = 0.023, [Table 1]). Seizure causing meningiomas, though extra-axial, exhibited dysregulated neuronal signaling genes ([Fig. 2]). GABAA receptor subunit genes GABRA3 and GABRG1 were downregulated in tumors causing seizure (Log2FC = −1.67, padj = 0.014; Log2FC = −2.24, padj = 0.009). Immunohistochemistry confirmed expression of GABRB2 subunit, the first documentation of GABA receptor expression in meningiomas ([Fig. 2]). Neuropeptide Y Receptor Y1 (NPY1R) is downregulated in seizure causing meningiomas (Log2FC = −1.64, padj = 0.002). NPY1R loss correlate is observed in mesial temporal lobe epilepsy and post-electroconvulsive shock mouse brains ([Fig. 2]). In GO analysis, the terms “GABA signaling pathway,” “neuropeptide signaling,” “excitatory postsynaptic membrane potential,” and “ionotropic glutamate pathway” were downregulated in meningiomas with seizure (padj < 0.05, [Fig. 2]). We assessed which alterations within MenG C caused seizures by identifying genes associated with both seizure and MenG C classification. Glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) is downregulated in MenG C tumors (Log2FC = −2.29, padj = 6.02E-07) and seizure causing tumors (Log2FC = −1.75, padj = 0.03). Clinically, patients experiencing preoperative seizures had more severe other presenting factors such as higher rates of reduced GCS and ER presentation and were less likely to have incidental or headache presentation (p< 0.05 for all, [Table 2]). On MRI, meningiomas presenting with seizures had higher rates of cerebral edema, nonhomogenous enhancement, and intratumoral calcification (p< 0.05 for all, [Table 2]) Seizure patients had tumors with higher mean MIB-1 and higher rates of atypical grade 1 on histopathology (p < 0.05 for all, [Table 2]). MenG classification predicts seizure presentation whereas somatic mutation status does not. Meningiomas causing seizures show pathologic neurotransmitter receptor dysregulation.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
07 February 2025