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Nat Commun. 2017 Feb 14;8:14433. doi: 10.1038/ncomms14433.

Integrated genomic analyses of de novo pathways underlying atypical meningiomas.

Author information

1
Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.
2
Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut 06510, USA.
3
Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.
4
Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut 06510, USA.
5
Yale Program on Neurogenetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.
6
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
7
Department of Neurosurgery, University of Bonn Medical School, Bonn 53105, Germany.
8
Department of General Neurosurgery, University Hospital of Cologne, Cologne 50937, Germany.
9
Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06510, USA.
10
Yale Center for Genome Analysis, Yale School of Medicine, Orange, Connecticut 06477, USA.
11
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
12
Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, Connecticut 06510, USA.

Abstract

Meningiomas are mostly benign brain tumours, with a potential for becoming atypical or malignant. On the basis of comprehensive genomic, transcriptomic and epigenomic analyses, we compared benign meningiomas to atypical ones. Here, we show that the majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent SMARCB1 mutations. These tumours harbour increased H3K27me3 signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells, thereby phenocopying a more primitive cellular state. Consistent with this observation, atypical meningiomas exhibit upregulation of EZH2, the catalytic subunit of the PRC2 complex, as well as the E2F2 and FOXM1 transcriptional networks. Importantly, these primary atypical meningiomas do not harbour TERT promoter mutations, which have been reported in atypical tumours that progressed from benign ones. Our results establish the genomic landscape of primary atypical meningiomas and potential therapeutic targets.

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