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Integrated genomic analyses of de novo pathways underlying atypical meningiomas [H3k27me3 ChIP-Seq]

ABSTRACT: Meningiomas are mostly benign brain tumors, with a potential for becoming atypical or malignant. Based on comprehensive genomic, transcriptomic and epigenomic analyses of meningiomas, we compared benign tumors to atypical ones. We show that the vast majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent mutations in SMARCB1. These tumors harbor increased H3K27me3 repressive signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells (hESCs), thereby phenocopying a more primitive cellular state. Consistent with this observation, and based on differential gene expression analysis as well as correlation of mRNA:miRNA regulatory networks, atypical meningiomas exhibit up-regulation of EZH2, the catalytic subunit of the PRC2 complex, well as the E2F2 and FOXM1 transcriptional networks that promote proliferation through activation of the cell cycle pathways. In addition, based on H3K27ac ChIP-seq analysis, we show atypical tumors to display an activated super-enhancer near the meningeal identity transcription factor ZIC1, leading to its transcriptional upregulation. Importantly, these primary atypical meningiomas do not harbor activating TERT promoter mutations, which have been reported in atypical tumors that progressed from benign ones. Our results establish the genomic landscape of primary atypical meningiomas, differentiating their profile from benign and progressed tumors and establishing novel therapeutic targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE92558 | GEO | 2016/12/20

SECONDARY ACCESSION(S): PRJNA358043

REPOSITORIES: GEO

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Integrated genomic analyses of de novo pathways underlying atypical meningiomas [miRNA-seq]

Project description:Meningiomas are mostly benign brain tumors, with a potential for becoming atypical or malignant. Based on comprehensive genomic, transcriptomic and epigenomic analyses of meningiomas, we compared benign tumors to atypical ones. We show that the vast majority of primary (de novo atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent mutations in SMARCB1. These tumors harbor increased H3K27me3 repressive signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2 binding sites in human embryonic stem cells (hESCs, thereby phenocopying a more primitive cellular state. Consistent with this observation, and based on differential gene expression analysis as well as correlation of mRNA:miRNA regulatory networks, atypical meningiomas exhibit up-regulation of EZH2, the catalytic subunit of the PRC2 complex, well as the E2F2 and FOXM1 transcriptional networks that promote proliferation through activation of the cell cycle pathways. In addition, based on H3K27ac ChIP-seq analysis, we show atypical tumors to display an activated super-enhancer near the meningeal identity transcription factor ZIC1, leading to its transcriptional upregulation. Importantly, these primary atypical meningiomas do not harbor activating TERT promoter mutations, which have been reported in atypical tumors that progressed from benign ones. Our results establish the genomic landscape of primary atypical meningiomas, differentiating their profile from benign and progressed tumors and establishing novel therapeutic targets.

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Integrated genomic analyses of de novo pathways underlying atypical meningiomas [methylation]

Project description:Meningiomas are mostly benign brain tumors, with a potential for becoming atypical or malignant. Based on comprehensive genomic, transcriptomic and epigenomic analyses of meningiomas, we compared benign tumors to atypical ones. We show that the vast majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent mutations in SMARCB1. These tumors harbor increased H3K27me3 repressive signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells (hESCs), thereby phenocopying a more primitive cellular state. Consistent with this observation, and based on differential gene expression analysis as well as correlation of mRNA:miRNA regulatory networks, atypical meningiomas exhibit up-regulation of EZH2, the catalytic subunit of the PRC2 complex, well as the E2F2 and FOXM1 transcriptional networks that promote proliferation through activation of the cell cycle pathways. In addition, based on H3K27ac ChIP-seq analysis, we show atypical tumors to display an activated super-enhancer near the meningeal identity transcription factor ZIC1, leading to its transcriptional upregulation. Importantly, these primary atypical meningiomas do not harbor activating TERT promoter mutations, which have been reported in atypical tumors that progressed from benign ones. Our results establish the genomic landscape of primary atypical meningiomas, differentiating their profile from benign and progressed tumors and establishing novel therapeutic targets.

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Integrated genomic analyses of de novo pathways underlying atypical meningiomas [ChIP-Seq]

Project description:Meningiomas are mostly benign brain tumors, with a potential for becoming atypical or malignant. Based on comprehensive genomic, transcriptomic and epigenomic analyses of meningiomas, we compared benign tumors to atypical ones. We show that the vast majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent mutations in SMARCB1. These tumors harbor increased H3K27me3 repressive signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells (hESCs), thereby phenocopying a more primitive cellular state. Consistent with this observation, and based on differential gene expression analysis as well as correlation of mRNA:miRNA regulatory networks, atypical meningiomas exhibit up-regulation of EZH2, the catalytic subunit of the PRC2 complex, well as the E2F2 and FOXM1 transcriptional networks that promote proliferation through activation of the cell cycle pathways. In addition, based on H3K27ac ChIP-seq analysis, we show atypical tumors to display an activated super-enhancer near the meningeal identity transcription factor ZIC1, leading to its transcriptional upregulation. The H3k27ac ChIP-seq data for 15 benign meningiomas and 2 dura samples listed below were created by Dr. Justin Cotney in Dr. James Noonan’s lab at Yale and previously published in a paper by our group with Drs. Cotney and Noonan as co-authors (Clark et al. Science, 2013). Sample IDs: MN-297, MN-288, MN-292, MN-163, MN-1037, MN-105, MN-201, MN-249, MN-191, MN-1066, MN-169, MN-291, MN-24, MN-79, MN-1044, CONTROL1, CONTROL2. In this study, we used these benign meningioma H3k27ac ChIP-seq data as controls and compared them to the newly created ChIP-seq data. Sample IDs: MN-54, MN-97 and MN-171. This GEO entry contains ChIP-seq results for both data sets.

2016-12-20 | GSE91372 | GEO

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Project description:Meningiomas are common brain tumors that are classified into three World Health Organization grades (Grade I: benign, Grade II: atypical and Grade III: malignant) and are molecularly ill-defined tumors. The purpose of this study was identify microRNA (miRNA) molecular signatures unique to the different grades of meningiomas correlating them to prognosis. We have used a miRNA expression microarray to show that meningiomas of all three grades fall into two main molecular groups designated “benign” and “malignant” meningiomas. While all typical meningiomas fall into the benign group and all anaplastic meningiomas fall into the malignant group, atypical meningiomas distribute into either one of these groups. We have identified a miRNA signature that distinguishes benign meningiomas from malignant meningiomas. We studied the gene expression profiles of 340 mammalian miRNAs in 37 primary meningioma tumors by means of DNA microarrays.

2011-01-02 | E-GEOD-19720 | biostudies-arrayexpress

Human primary meningioma vs. non-neoplastic adult meningeal tissue

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Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.

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2014-05-29 | E-GEOD-58037 | biostudies-arrayexpress

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2023-03-10 | GSE221429 | GEO

Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.

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High-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling.

Project description:Meningiomas are the most common primary brain tumors in adults. Although generally benign, a subset is of higher grade, recurs even after multiple surgeries, and frequently fatal. Around half of meningiomas harbor inactivating mutations in NF2. While low-grade NF2 mutant meningiomas harbor few additional mutations in addition to NF2 inactivation, high-grade NF2 mutant tumors frequently harbor a highly aberrant genome. We and others have previously shown that NF2 inactivation leads to YAP1 activation and that YAP1 acts as an oncogene in NF2 mutant meningiomas. Here, we show that high-grade NF2 mutant meningiomas downregulate YAP1 signaling, in part through upregulating the expression of the YAP1 competitor VGLL4 and the YAP1 upstream regulators FAT3/4. Overexpression of VGLL4 resulted in the downregulation of YAP activity and the growth inhibition of low-grade NF2 mutant meningioma cells. Our results have important implications for the efficacy of therapies targeting oncogenic YAP1 in high-grade NF2 mutant meningiomas.

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