16IN - Meningioma: what Can we Learn from the Biology for Precision Medicine?

Abstract

ABSTRACT Meningiomas differ considerably by their histological appearance, location, biological behavior, recurrence rate, and overall survival. The most frequent alteration found in sporadic meningioma corresponds to biallelic NF2 inactivation. Besides the central role of NF2, other alternative genetic alterations have been recently identified in meningioma initiation. The AKT1E17K mutation was found in 12%, predominantly in benign skull base meningiomas, occurring frequently together with mutations in the TRAF7 gene. TRAF7 mutations are exclusively of NF2 mutations and occur in about 24% of meningiomas. In addition, meningiomas with TRAF7 mutations are almost always characterized by recurrent mutation in the KLF4 gene (co-regulator of the bradykinin B2 receptor). Another non-NF2-associated mutation of meningiomas affects the SMO (Smoothened) gene which is a member of the hedgehog pathway. SMO mutations occur in 5% of grade I meningiomas and are restricted to the midline skull base. Meningioma progression and recurrence are linked to chromosome instability, CDKN2AB genes on chromosome 9p being suspected to be important. Mouse models that reproduce human meningioma tumorigenesis have been developed. Two conditional Nf2 knockout models have shown that Nf2 inactivation in leptomeningeal cells of mice is sufficient to induce meningiomas. Additional deletion of Cdkn2ab, together with Nf2 inactivation, results in increased meningioma frequency, as well as development of grade II or grade III meningiomas. All relevant growth factor receptors/kinases have been described to be expressed in meningiomas, including epidermal growth factor receptor (EGFR), platelet-derived growth factor beta receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), and insulin-like growth factor receptor (IGFR). A new mouse model surexpressing PDGF-beta has been recently developed showing an increase in frequency and malignancy in association with Nf2 and Cdkn2ab inactivation. In conclusion, increasing knowledge on the molecular mechanisms of meningioma initiation and development provides target that could be relevant to develop new therapeutic approaches, particularly in surgery and radiotherapy-refractory meningiomas. Disclosure: All authors have declared no conflicts of interest.