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Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations

2013; Nature Portfolio; Volume: 45; Issue: 3 Linguagem: Inglês

10.1038/ng.2526

1546-1718

Priscilla K. Brastianos, Peleg Horowitz, Sandro Santagata, Robert T. Jones, Aaron McKenna, Gad Getz, Keith L. Ligon, Emanuele Palescandolo, Paul Van Hummelen, Matthew D. Ducar, Alina Raza, Ashwini Sunkavalli, Laura E. MacConaill, Anat Stemmer‐Rachamimov, David N. Louis, William C. Hahn, Ian F. Dunn, Rameen Beroukhim,

Bone Tumor Diagnosis and Treatments

Rameen Beroukhim, Ian Dunn, William Hahn and colleagues report genome and exome sequencing of meningiomas. They identified recurrent somatic mutations in AKT1 and SMO. Meningiomas are the most common primary nervous system tumor. The tumor suppressor NF2 is disrupted in approximately half of all meningiomas1, 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.