Recurrent mutations in SMO and AKT1 are mutually exclusive with NF2 loss in meningioma.

  • Major finding: Recurrent mutations in SMO and AKT1 are mutually exclusive with NF2 loss in meningioma.

  • Clinical relevance: Non-NF2 meningiomas have distinct anatomic distribution and gene expression signatures.

  • Impact: Some therapeutically challenging meningiomas may respond to Hedgehog or PI3K inhibition.

Meningiomas arise from the meninges and are the most common tumors of the central nervous system. Although meningiomas are generally benign, tumors in locations like the skull base are challenging to resect safely and often recur. Loss of the NF2 tumor suppressor gene occurs in approximately half of meningiomas, but the genetic basis for non-NF2 meningiomas remains unclear. Brastianos and colleagues performed whole-genome or whole-exome sequencing on 17 meningiomas and targeted sequencing of cancer-associated genes in 48 additional meningiomas. Although the most commonly mutated gene was NF2, recurrent mutations were identified in SMO, encoding a negative regulator of the Hedgehog pathway, and AKT1, encoding a key effector of phosphoinositide 3-kinase (PI3K) signaling, in 5% and 8% of tumors, respectively. Of note, these mutations were mutually exclusive with NF2 mutations and predominantly occurred in skull base tumors. Importantly, immunohistochemical staining showed evidence of Hedgehog pathway activation in SMO-mutant tumors and PI3K pathway activation in AKT1-mutant tumors, suggesting that these mutations are functionally relevant. Clark and colleagues analyzed a larger set of 50 meningiomas by genome-wide genotyping and exome sequencing followed by targeted resequencing of an independent cohort of 250 meningiomas. They identified mutations in TRAF7, encoding a proapoptotic E3 ubiquitin ligase not previously implicated in cancer, in half of non-NF2 mutant meningiomas. TRAF7 mutations mainly coexisted with recurrent mutations either in KLF4, another newly identified cancer gene, or AKT1, which was mutated in 13% of tumors. Mutually exclusive SMO mutations that activated Hedgehog signaling were identified in approximately 5% of tumors. NF2 and non-NF2 meningiomas had different gene expression signatures and anatomical distributions, with NF2-mutant meningiomas originating from hemispheric regions and SMO and AKT1 mutations enriched in medial anterior skull base tumors. Together, these 2 studies identify a clinically distinctive subset of meningiomas driven by SMO and AKT1 mutations that may respond to Hedgehog or PI3K inhibitor therapy.

Brastianos PK, Horowitz PM, Santagata S, Jones RT, McKenna A, Getz G, et al. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet 2013 Jan 20 [Epub ahead of print].

Clark VE, Erson-Omay EZ, Serin A, Yin J, Cotney J, Ozduman K, et al. Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science 2013 Jan 24 [Epub ahead of print].