Akt1 e17k and nf2 mutations dominate spinal meningiomas who grade 1 and present distinct tumor features

Abstract INTRODUCTION While the mutational landscape of intracranial meningiomas has been extensively studied, our understanding of the molecular profile of spinal meningiomas (SM) remains incomplete. In this study, we correlate the molecular status with tumor features in a clinically well-characterized cohort. METHODS Samples from 50 patients (38 females and 12 males) with WHO grade 1 SM were collected. We performed next-generation sequencing (NGS) using an assay covering frequently mutated genes in meningiomas including AKT1, KLF4, NF2, PIK3CA, POLR2A, SMARCB1, SMARCE1, SMO, SUFU, and TRAF7. We correlated clinical and imaging data with the molecular tumor status. RESULTS AKT1 E17K mutations were detected in 15 (30%) and NF2 mutations in 32 (64%) patients. Both mutations were mutually exclusive. In contrast to AKT1-mutant intracranial meningiomas, AKT1-mutant SM only harbored a TRAF7 co-mutation in a single case. NF2-mutant meningiomas had a significant female predominance (n= 30/32, 94%) when compared to the balanced incidence of AKT1-mutant tumors (n= 7/15, 46.7%, p= 0.0006). The two groups demonstrated stark differences in the location: a thoracic localization was significantly more common in NF2-mutant meningiomas (n= 25/32, 78.1%, p= 0.0012), while meningiomas harboring an AKT1 mutation were predominantly located in the cervical spine (n= 11/15, 73.3%). Moreover, while a substantial proportion of NF2-mutant meningiomas developed in the dorsal location (n= 19/32, 59.3%), the vast majority of AKT1-mutant meningiomas (n= 13/15, 87%) arose ventral to the spinal cord. The histologic subtype of NF2-mutant meningiomas was variable, while all but one AKT1-mutant meningioma showed meningothelial histology (93.3%, p= 0.0001). All calcified meningiomas (n= 17) were NF2-mutant (p= 0.0002), whereas none of the AKT1-mutant meningiomas showed intratumoral calcifications. CONCLUSIONS Our findings support the central role of AKT1 and NF2 mutations in the molecular pathogenesis of WHO grade 1 SM. These mutations are mutually exclusive and are associated with distinct tumor and clinical features.