Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Victoria Clark
PROVIDER: E-GEOD-85135 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations in this enzyme have not been previously linked to any pathology in humans, a testament to its indispensable role in cell biology. Based on a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II, are sufficient to hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors reveal dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC4. In addition to POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA and SMO, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features. RNAseq data from 19 meningioma tumors representing major mutation groups (NF2/chr22 loss, POLR2A, KLF4/TRAF7, PI3K mutant)
2016-08-21 | E-GEOD-85133 | biostudies-arrayexpress
Project description:Purpose: In this study, we try to investigate the possible signaling pathways involved in the tumorigenesis of fibroblastic and anaplastic meningiomas. We also attempt to investigate EGFL6 gene expression in brain arachnoidal tissues and various tumors and to measure EGFL6 levels in serum samples from healthy people and patients with various tumors by using ELISA. Experimental Design: Differential gene expression profiles between meningiomas and brain arachnoidal tissues were established by using Affymetrix GeneChip Human U133 Plus 2.0 Array. KEGG pathway analysis was performed to identify potential gene pathways that may be involved in the pathogenesis of meningiomas. Quantitative real-time PCR (qRT-PCR) was performed to validate the differentially expressed genes in the KEGG pathways. EGFL6 mRNA levels were also determined in brain arachnoidal tissues, meningiomas, and other tumors by qRT-PCR. EGFL6 levels were measured in serum samples from healthy people and patients with various tumors by using ELISA. Results: Fibroblastic meningioma exhibited upregulated PI3K/Akt and TGFβ signaling pathways, and accelerated G1/S progression cell cycle. KEGG analysis also demonstrated that focal adhesion and ECM-receptor interaction pathways were activated in anaplastic meningioma. Benign meningiomas had significantly higher levels of EGFL6 mRNA than brain arachnoidal tissues and atypical and anaplastic meningiomas (P<0.001). EGFL6 gene was also highly expressed in ovarian cancer, but expressed lowly in all other investigated tumors. EGFL6 was hardly detectable in serum samples of healthy people. The mean serum EGFL6 concentration was 675, 118, and 126 pg/ml in patients with benign, atypical, and anaplastic meningiomas respectively. Patients with ovarian cancers also had high serum EGFL6 levels (mean concentration: 617 pg/ml). Patients with all other investigated tumors, however, had low levels of serum EGFL6 with mean concentration less than 240 pg/ml. Conclusion: We proposed that deregulation of cell cycle and PI3K/Akt pathways might play important roles in the tumorigenesis of fibroblastic meningioma. It was also suggested that the activated integrin-mediated signaling pathways were involved in the pathogenesis of anaplastic meningioma. We presented evidence that EGFL6 might serve as a novel serum biomarker for benign meningioma and ovarian cancer. It was also suggested that EGFL6 could help discriminate benignancy or malignancy of meningiomas before surgery or at early time points. Differential gene expression profiles between meningiomas and brain arachnoidal tissues were established by using Affymetrix GeneChip Human U133 Plus 2.0 Array. KEGG pathway analysis was performed to identify potential gene pathways that may be involved in the pathogenesis of meningiomas. Quantitative real-time PCR (qRT-PCR) was performed to validate the differentially expressed genes in the KEGG pathways. EGFL6 mRNA levels were also determined in brain arachnoidal tissues, meningiomas, and other tumors by qRT-PCR. EGFL6 levels were measured in serum samples from healthy people and patients with various tumors by using ELISA.
2013-01-01 | E-GEOD-32197 | biostudies-arrayexpress
Project description:The aim of this study was to determine the relationship between gene expression profiles and new metabolic subgroups of benign meningioma with potential clinical relevance. 19 human meningiomas biopsies were obtained at the Department of Neurosurgery of the Clinical University Hospital of Valencia. This study was reviewed and approved by the local ethics committee. During surgery, most of the resected tissue was sent for routine histological analysis and the remainder was immediately put in cryogenic vials and snap-frozen in liquid nitrogen. All snap-frozen samples were stored in a freezer at -80 C until further analysis. Tumors were classified according to the 2007 WHO Histological Classification 1. Grade II meningioma were classified according to previously published criteria, including high mitotic index and three out of five markers of atypia.In summary, this work demonstrates gene expression differences in a new subgroup of histological benign meningiomas that exhibit aggressive metabolism and tumor recurrence.
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Project description:Comparative genomics studies in primates are extremely restricted due to our limited access to samples from non-human apes. In order to gain better insight into the genetic processes that underlie variation in complex phenotypes in primates, we must have access to faithful model systems for a wide range of cell types. To facilitate this, we have generated a panel of 7 fully characterized chimpanzee induced pluripotent stem cell (iPSC) lines derived from healthy donors. To begin demonstrating the utility of comparative iPSC panels, we collected RNA-sequencing and DNA methylation data from the chimpanzee iPSCs and the corresponding fibroblast lines, as well as from 7 human iPSCs and their source lines, which encompass multiple populations and cell types. We observe much less within-species variation in iPSCs than in somatic cells, indicating that the reprogramming process erases many inter-individual differences. The low within-species regulatory variation in iPSCs allowed us to identify many novel inter-species regulatory differences of small magnitude. We used ChIP-seq to characterize the genome-wide distribution of two types of histone modifications (H3K27me3 and H3K27ac) in three of our chimpanzee iPSCs and compared them to histone modification data from three human iPSC lines from the Roadmap Epigenomics project:
2015-06-17 | E-GEOD-69919 | biostudies-arrayexpress
Project description:We report the enhancer landscape in primary human macrophages and foam cells using ChIP-seq for the H3K27ac histone mark CD14+ monocytes were isolated from the blood of 2 healthy male volunteers. Monocytes were differentiated into macrophages by culture for 7 days with 50ng/ml macrophage colony stimulating factor and then treated for 48 hours with either oxidized low density lipoprotein (oxLDL) to induce foam cell formation or with a control buffer that lacked oxLDL. The resulting 4 samples were then subjected to ChIP-seq for H3K27ac.
2015-04-08 | E-GEOD-54972 | biostudies-arrayexpress
Project description:We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics. Analysis of meningioma gene expression data for each mutation subtype. Includes gene expression data from 75 unique meningiomas and 39 replicates.
2014-05-29 | E-GEOD-58037 | biostudies-arrayexpress
Project description:We performed ChIP-seq in the GR18 cell line (derived from U2OS ATTC:HTB-96, stably transfected with an expression construct for GR), upon glucocorticoid (dexamethasone)treatment for 90 minutes. Cells were cross-linked with 1% formaldehyde for 3 minutes.
2019-03-11 | E-MTAB-7747 | biostudies-arrayexpress
Project description:We determined genome-wide nucleosome occupancy in mouse embryonic stem cells and their neural progenitor and embryonic fibroblast counterparts to assess features associated with nucleosome positioning during lineage commitment. Cell type and protein specific binding preferences of transcription factors to sites with either low (e.g. Myc, Klf4, Zfx) or high (e.g. Nanog, Oct4 and Sox2) nucleosome occupancy as well as complex patterns for CTCF were identified. Nucleosome depleted regions around transcription start and termination sites were broad and more pronounced for active genes, with distinct patterns for promoters classified according to their CpG-content or histone methylation marks. Throughout the genome nucleosome occupancy was dependent on the presence of certain histone methylation or acetylation modifications. In addition, the average nucleosome-repeat length increased during differentiation by 5-7 base pairs, with local variations for specific genomic regions. Our results reveal regulatory mechanisms of cell differentiation acting through nucleosome repositioning. For chromatin immunoprecipitation, for each sample, 1 x 106 cells were cross-linked with 1% PFA and cell nuclei were prepared using a swelling buffer (25 mM Hepes pH 7.8, 1 mM MgCl2, 10 mM KCl, 0.1% NP-40, 1 mM DTT). Chromatin was sheared to mononucleosomal fragments. After IgG preclearance the sheared chromatin was incubated with 4 µg of either a H3K9ac (Abcam, ab4441), a H3K27ac (Abcam, ab4729), or a H3K9me3 (Abcam ab8898) antibody over night. After washes with sonication (10 mM Tris-HCl, pH 8.0, 200 mM NaCl, 1 mM EDTA, 0.5% N-lauroylsarcosine, 0.1% Na-deoxycholate), high-salt- (50 mM Hepes pH 7.9, 500 mM NaCl, 1mM EDTA, 1% Triton X-100, 0.1% Na-deoxycholate, 0.1% SDS), lithium- (20 mM Tris-HCl pH 8.0, 1mM EDTA, 250 mM LiCl, 0.5% NP-40, 0.5% Na-deoxycholate) and 10 mM Tris-HCl, chromatin was eluted from the protein G magnetic beads and the crosslink was reversed over night. After RNase A and proteinase K digestion, the DNA was purified and subsequently cloned into a multiplexed Illumina library according to standard protocols. Sequenced 50 bp reads were mapped with bowtie and subsequently clustered with MACS 55 implemented in the Genomatix software suite (Genomatix, Munich, Germany) using a p-value of 10-5.
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