August 9, 2016


Meningiomas are the most common primary nervous system tumor, with no effective systemic therapy. The tumor suppressor NF2 was reported to be disrupted in approximately half of meningiomas but the complete spectrum of genetic changes remained undefined. We recently comprehensively characterized meningiomas (Brastianos et al. Nature Genetics 2013). Through whole-genome, whole-exome and targeted sequencing, we demonstrated that most meningiomas exhibited simple genomes, with fewer mutations, rearrangements, and copy-number alterations than reported in other adult tumors. We confirmed NF2 inactivation in 43% of tumors. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (E17K) and SMO (W535L). These are known drivers in other cancer types. We also demonstrated that these tumors exhibited evidence of activation of their pathways. Notably, these mutations were present in therapeutically challenging tumors of the skull base and higher grade tumors. Because therapeutic targets for SMO and AKT1 mutations are currently in clinical use in other cancers, we will be conducting a prospective Phase 2 study of an AKT1 or SMO inhibitor in patients with recurrent or progressive meningiomas harboring AKT1 or SMO mutations, respectively.