title: Integrated genomic analyses of de novo pathways underlying atypical meningiomas.
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.
authors.affiliation: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Akdes Serin
authors.initials: AS
authors.lastname: Harmancı
authors.affiliation: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Youngblood
authors.affiliation: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Clark
authors.affiliation: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Süleyman
authors.initials: S
authors.lastname: Coşkun
authors.affiliation: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Yale Program on Neurogenetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Octavian
authors.initials: O
authors.lastname: Henegariu
authors.affiliation: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Daniel
authors.identifier: 0000-0001-6888-252X
authors.initials: D
authors.lastname: Duran
authors.affiliation: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: E Zeynep
authors.initials: EZ
authors.lastname: Erson-Omay
authors.affiliation: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Leon D
authors.initials: LD
authors.lastname: Kaulen
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Tong Ihn
authors.initials: TI
authors.lastname: Lee
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Abraham
authors.affiliation: Department of Neurosurgery, University of Bonn Medical School, Bonn 53105, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Simon
authors.affiliation: Department of General Neurosurgery, University Hospital of Cologne, Cologne 50937, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Krischek
authors.affiliation: Department of General Neurosurgery, University Hospital of Cologne, Cologne 50937, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Timmer
authors.affiliation: Department of General Neurosurgery, University Hospital of Cologne, Cologne 50937, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Goldbrunner
authors.affiliation: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: S Bülent
authors.initials: SB
authors.lastname: Omay
authors.affiliation: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Baranoski
authors.affiliation: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Burçin
authors.initials: B
authors.lastname: Baran
authors.affiliation: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Geneive
authors.initials: G
authors.lastname: Carrión-Grant
authors.affiliation: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Hanwen
authors.identifier: 0000-0002-8473-5279
authors.initials: H
authors.lastname: Bai
authors.affiliation: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Yale Program on Neurogenetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Ketu
authors.initials: K
authors.lastname: Mishra-Gorur
authors.affiliation: Department of Neurosurgery, University of Bonn Medical School, Bonn 53105, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schramm
authors.affiliation: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Moliterno
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Vortmeyer
authors.affiliation: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Yale Center for Genome Analysis, Yale School of Medicine, Orange, Connecticut 06477, USA.
authors.forename: Kaya
authors.initials: K
authors.lastname: Bilgüvar
authors.affiliation: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Katsuhito
authors.identifier: 0000-0002-3606-532X
authors.initials: K
authors.lastname: Yasuno
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Richard A
authors.identifier: 0000-0001-8855-8647
authors.initials: RA
authors.lastname: Young
authors.affiliation: Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Genetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Yale Program on Neurogenetics, Yale School of Medicine, New Haven, Connecticut 06510, USA.|Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Murat
authors.initials: M
authors.lastname: Günel
mesh_terms: D001665:Binding Sites; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D043171:Chromosomal Instability; D016000:Cluster Analysis; D019175:DNA Methylation; D050703:E2F2 Transcription Factor / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism; D057890:Epigenomics / Q000379:methods; D059472:Exome / Q000235:genetics; D000072278:Forkhead Box Protein M1 / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics* / Q000502:physiology*; D020868:Gene Silencing; D016515:Genes, Neurofibromatosis 2; D016678:Genome; D023281:Genomics / Q000379:methods*; D060005:Genotyping Techniques; D000066449:Human Embryonic Stem Cells / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics; D008577:Meningeal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D008579:Meningioma / Q000235:genetics* / Q000378:metabolism*; D015336:Molecular Probe Techniques; D009154:Mutation; D010641:Phenotype; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D000071796:SMARCB1 Protein / Q000235:genetics; D017421:Sequence Analysis; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome
chemical_list: D050703:E2F2 Transcription Factor; C493761:E2F2 protein, human; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D012333:RNA, Messenger; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2