Integrated genomic analyses of de novo pathways underlying atypical meningiomas
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PRJNA356871PRJNA328491PRJNA360980PRJNA356864PRJNA356870PRJNA358043
ORGANISM(S): Homo sapiens
PROVIDER: GSE91376 | GEO | 2016/12/20
SECONDARY ACCESSION(S): PRJNA356864
REPOSITORIES: GEO
Similar Datasets
Project description:This corrects the article DOI: 10.1038/ncomms14433.
| S-EPMC5919704 | biostudies-literature
Project description: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.
| S-EPMC5316884 | biostudies-literature
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.
2016-12-20 | GSE91375 | GEO
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
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.
2017-01-12 | GSE93519 | GEO
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.
2016-12-20 | GSE92558 | GEO
Project description:Integrated genomic analyses of de novo pathways underlying atypical meningiomas
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Project description:A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs). To assess the contribution of noncoding DNVs to CHD, we compared genome sequences from 749 CHD probands and their parents with those from 1,611 unaffected trios. Neural network prediction of noncoding DNV transcriptional impact identified a burden of DNVs in individuals with CHD (n = 2,238 DNVs) compared to controls (n = 4,177; P = 8.7 × 10-4). Independent analyses of enhancers showed an excess of DNVs in associated genes (27 genes versus 3.7 expected, P = 1 × 10-5). We observed significant overlap between these transcription-based approaches (odds ratio (OR) = 2.5, 95% confidence interval (CI) 1.1-5.0, P = 5.4 × 10-3). CHD DNVs altered transcription levels in 5 of 31 enhancers assayed. Finally, we observed a DNV burden in RNA-binding-protein regulatory sites (OR = 1.13, 95% CI 1.1-1.2, P = 8.8 × 10-5). Our findings demonstrate an enrichment of potentially disruptive regulatory noncoding DNVs in a fraction of CHD at least as high as that observed for damaging coding DNVs.
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Project description:Most genetic studies consider autism spectrum disorder (ASD) and developmental disorder (DD) separately despite overwhelming comorbidity and shared genetic etiology. Here, we analyzed de novo variants (DNVs) from 15,560 ASD (6,557 from SPARK) and 31,052 DD trios independently and also combined as broader neurodevelopmental disorders (NDDs) using three models. We identify 615 NDD candidate genes (false discovery rate [FDR] < 0.05) supported by ≥1 models, including 138 reaching Bonferroni exome-wide significance (P < 3.64e-7) in all models. The genes group into five functional networks associating with different brain developmental lineages based on single-cell nuclei transcriptomic data. We find no evidence for ASD-specific genes in contrast to 18 genes significantly enriched for DD. There are 53 genes that show mutational bias, including enrichments for missense (n = 41) or truncating (n = 12) DNVs. We also find 10 genes with evidence of male- or female-bias enrichment, including 4 X chromosome genes with significant female burden (DDX3X, MECP2, WDR45, and HDAC8). This large-scale integrative analysis identifies candidates and functional subsets of NDD genes.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2010-12-01 | GSE16584 | GEO