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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 (<jats:italic>de novo<\/jats:italic>) atypical meningiomas display loss of <jats:italic>NF2<\/jats:italic>, which co-occurs either with genomic instability or recurrent <jats:italic>SMARCB1<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/ncomms14433","type":"journal-article","created":{"date-parts":[[2017,2,14]],"date-time":"2017-02-14T10:36:36Z","timestamp":1487068596000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":179,"title":["Integrated genomic analyses of de novo pathways underlying atypical meningiomas"],"prefix":"10.1038","volume":"8","author":[{"given":"Akdes Serin","family":"Harmanc\u0131","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark W.","family":"Youngblood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria E.","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00fcleyman","family":"Co\u015fkun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Octavian","family":"Henegariu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6888-252X","authenticated-orcid":false,"given":"Daniel","family":"Duran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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