Meningiomas are the most common primary nervous system tumor. The tumor 
suppressor NF2 is disrupted in approximately half of all meningiomas, but the 
complete spectrum of genetic changes remains undefined. We performed 
whole-genome or whole-exome sequencing on 17 meningiomas and focused sequencing 
on an additional 48 tumors to identify and validate somatic genetic alterations. 
Most meningiomas had simple genomes, with fewer mutations, rearrangements and 
copy-number alterations than reported in other tumors in adults. However, 
several meningiomas harbored more complex patterns of copy-number changes and 
rearrangements, including one tumor with chromothripsis. We confirmed focal NF2 
inactivation in 43% of tumors and found alterations in epigenetic modifiers in 
an additional 8% of tumors. A subset of meningiomas lacking NF2 alterations 
harbored recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO 
(p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these 
pathways. These mutations were present in therapeutically challenging tumors of 
the skull base and higher grade. These results begin to define the spectrum of 
genetic alterations in meningiomas and identify potential therapeutic targets.