title: Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations.
abstract: 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.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Priscilla K
authors: PK
authors: Brastianos
authors: Peleg M
authors: PM
authors: Horowitz
authors: Sandro
authors: S
authors: Santagata
authors: Robert T
authors: RT
authors: Jones
authors: Aaron
authors: A
authors: McKenna
authors: Gad
authors: G
authors: Getz
authors: Keith L
authors: KL
authors: Ligon
authors: Emanuele
authors: E
authors: Palescandolo
authors: Paul
authors: P
authors: Van Hummelen
authors: Matthew D
authors: MD
authors: Ducar
authors: Alina
authors: A
authors: Raza
authors: Ashwini
authors: A
authors: Sunkavalli
authors: Laura E
authors: LE
authors: Macconaill
authors: Anat O
authors: AO
authors: Stemmer-Rachamimov
authors: David N
authors: DN
authors: Louis
authors: William C
authors: WC
authors: Hahn
authors: Ian F
authors: IF
authors: Dunn
authors: Rameen
authors: R
authors: Beroukhim
mesh_terms: D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D023281:Genomics; D006801:Humans; D008579:Meningioma / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D000072086:Smoothened Receptor
chemical_list: D025581:Neurofibromin 2; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt