We report genomic analysis of 300 meningiomas, the most common primary brain 
tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 
ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 
commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription 
factor known for its role in inducing pluripotency, or with AKT1(E17K), a 
mutation known to activate the PI3K pathway. SMO mutations, which activate 
Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These 
non-NF2 meningiomas were clinically distinctive-nearly always benign, with 
chromosomal stability, and originating from the medial skull base. In contrast, 
meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be 
atypical, showing genomic instability, and localizing to the cerebral and 
cerebellar hemispheres. Collectively, these findings identify distinct 
meningioma subtypes, suggesting avenues for targeted therapeutics.