Revealing Hidden Drivers: ARMC5 Intronic Variant Coexists with NF2, TRAF7 and AKT1 Mutations in Sporadic Meningiomas

Abstract Background: Sporadic intracranial meningiomas exhibit a diverse molecular landscape. While ARMC5 mutations are recognized in bilateral macronodular adrenal disease (BMAD)-associated meningiomas, their role in sporadic cases is uncertain. Objective: To determine the frequency and implications of ARMC5 variants, particularly intronic alterations, alongside canonical driver mutations in surgically treated sporadic meningiomas. Methods: Forty-one patients undergoing surgical resection for sporadic meningiomas were analyzed. Tumor DNA was screened using targeted next-generation sequencing (NGS) for variants in ARMC5, NF2, TRAF7, AKT1, KLF4, and SMO. Patients were clinically and biochemically evaluated to exclude BMAD. Results: No pathogenic coding variants in ARMC5 were found. However, 58.5% of cases harbored the intronic variant c.1864+250C>T. This variant frequently co-occurred with driver mutations, notably in NF2 (34.1%), TRAF7, AKT1, KLF4, and SMO. Most tumors were WHO grade I and predominantly meningothelial in subtype. Conclusion: Our findings identify a high prevalence of a specific ARMC5 intronic variant in sporadic meningiomas, co-occurring with key oncogenic mutations. These results suggest a potential modifying or synergistic role for this variant, warranting further functional investigation.