gms | German Medical Science

Objective: Extracranial metastases of intracranial meningiomas are rare. Little is known about the mutational pattern of these tumors and their metastatic seeding. Here we retrospectively explored the molecular alterations of these metastatic lesions and their respective intracranial tumor manifestation.

Methods: Histology and genome sequencing was performed in intracranial meningiomas (WHO grade I-III) and their extracranial metastatic lesions operated upon between 2002 and 2021. Next-generation DNA/RNA sequencing (NGS) and methylome analysis were performed to determine molecular alterations.

Results: We identified four patients with available tissue samples of both intracranial meningioma and the respective distant metastatic lesions. Three intraspinal - including one intraosseus - and one pulmonary meningioma metastases as well as the primary intracranial meningioma manifestation were further characterized. Aberrations within the BAP1 gene in both intracranial and distant tumor manifestation were detected in three patients. Two patients with meningioma WHO III had a BAP 1 mutation with an additional PIK3CA mutation in one patient and FANCC mutations in the other, in all cases the intracranial and the distant lesion displayed the identical molecular pattern. One patient with WHO I meningioma harbored copy-number variations in the BAP1-gene and mutation in FLT4 gene in both intra- and extracranial manifestations, however an additional ERBB3 and FANCC mutation were detected solely in the extracranial lesion, suggesting a secondary acquisition of mutational aberrations in the metastasis. Another patient displayed an identical NF2 and PTEN mutation in both manifestations. No patient had a TERT-mutation.

Conclusion: Our results reveal an identical molecular signature in both primary and metastatic extracranial meningioma in 3/4 patients and an additional mutational acquisition in the fourth patient. Bap-1 gene alterations were the most frequent one and might indicate patients at risk for metastatic spread. Further explorations within larger cohorts are necessary to validate these findings which might influence the clinical management in the future.