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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Binding Sites
-
Brain Neoplasms / genetics
-
Brain Neoplasms / metabolism
-
Cell Transformation, Neoplastic / genetics
-
Chromosomal Instability
-
Cluster Analysis
-
DNA Methylation
-
E2F2 Transcription Factor / metabolism
-
Enhancer of Zeste Homolog 2 Protein / metabolism
-
Epigenomics / methods
-
Exome / genetics
-
Forkhead Box Protein M1 / metabolism
-
Gene Expression Profiling
-
Gene Expression Regulation, Neoplastic
-
Gene Regulatory Networks / genetics*
-
Gene Regulatory Networks / physiology*
-
Gene Silencing
-
Genes, Neurofibromatosis 2
-
Genome*
-
Genomics / methods*
-
Genotyping Techniques
-
Human Embryonic Stem Cells / metabolism
-
Humans
-
Jumonji Domain-Containing Histone Demethylases / genetics
-
Meningeal Neoplasms / genetics*
-
Meningeal Neoplasms / metabolism*
-
Meningioma / genetics*
-
Meningioma / metabolism*
-
Molecular Probe Techniques
-
Mutation
-
Phenotype
-
Polycomb Repressive Complex 2 / genetics
-
Polycomb Repressive Complex 2 / metabolism
-
Promoter Regions, Genetic
-
RNA, Messenger / metabolism
-
SMARCB1 Protein / genetics
-
Sequence Analysis
-
Signal Transduction / genetics
-
Transcriptome
Substances
-
E2F2 Transcription Factor
-
E2F2 protein, human
-
FOXM1 protein, human
-
Forkhead Box Protein M1
-
RNA, Messenger
-
SMARCB1 Protein
-
SMARCB1 protein, human
-
Jumonji Domain-Containing Histone Demethylases
-
EZH2 protein, human
-
Enhancer of Zeste Homolog 2 Protein
-
Polycomb Repressive Complex 2