Integrated genomic analyses of de novo pathways underlying atypical meningiomas

• DOI: 10.1038/ncomms14433
• Publication Date: 2017-02-14T10:36:36Z
• Authors: Akdes Serin Harmancı; Mark W. Youngblood; Victoria E. Clark; Süleyman Coşkun; Octavian Henegariu; Daniel Duran; E. Zeynep Erson-Omay; Leon D. Kaulen; Tong Ihn Lee; Brian J. Abraham; Matthias Simon; Boris Krischek; Marco Timmer; Roland Goldbrunner; S. Bülent Omay; Jacob Baranoski; Burçin Baran; Geneive Carrión-G...; Hanwen Bai; Ketu Mishra-Gorur; Johannes Schramm; Jennifer Moliterno; Alexander O. Vort...; Kaya Bilgüvar; Katsuhito Yasuno; Richard A. Young; Murat Günel
• Keywords: Epigenomics; Binding Sites; Genome; Genotyping Techniques; Brain Neoplasms; Science; Gene Expression Profiling; Q; Forkhead Box Protein M1; Human Embryonic Stem Cells; Genomics; DNA Methylation; Article; 3. Good health; Gene Expression Regulation, Neoplastic; Cell Transformation, Neoplastic; E2F2 Transcription Factor; Chromosomal Instability; Genes, Neurofibromatosis 2; Cluster Analysis; Enhancer of Zeste Homolog 2 Protein; Exome; Gene Regulatory Networks; Gene Silencing

AbstractMeningiomas 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.