High density foci in IDH1-mutated diffuse low-grade gliomas in adults
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ABSTRACT:
PROVIDER: PRJNA534092 | ENA |
REPOSITORIES: ENA
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Project description:20% of patients affected with diffuse low-grade brain tumors have high cell density foci harboring higher KI67 index and DNA alterations. These foci may represent tumor progression towards high-grade gliomas. Here we performed transcriptome analysis of those foci vs adjacent tumoral tissues dissected from formalin fixed and paraffin embedded blocks.
2020-03-17 | GSE130149 | GEO
Project description:The discovery of the IDH1 R132H (IDH1 mut) mutation in low-grade glioma and the associated change in function of the IDH1 enzyme has increased the interest in glioma metabolism. In an earlier study, we found that changes in expression of genes involved in the aerobic glycolysis and the TCA-cycle are associated with IDH1 mut. Here we apply proteomics to FFPE samples of diffuse gliomas with or without IDH1 mutations, in order to map changes in protein levels associated with this mutation. We observed significant changes in the enzyme abundance associated with aerobic glycolysis, glutamate metabolism and the TCA-cycle in IDH1 mut gliomas. Specifically, the enzymes involved in the metabolism of glutamate, lactate and enzymes involved in the conversion of α-ketoglutarate were increased in IDH1 mut gliomas. In addition, the bicarbonate transporter (SLC4A4) was increased in IDH1 mut gliomas, supporting the idea that a mechanism preventing intracellular acidification is active. We also found that enzymes that convert proline, valine, leucine and isoleucine into glutamate were increased in IDH1 mut glioma. We conclude that in IDH1 mut glioma metabolism is rewired (increased input of lactate and glutamate) to preserve TCA cycle activity in IDH1 mut gliomas.
2020-03-09 | PXD016697 | Pride
Project description:The discovery of the IDH1 R132H (IDH1 mut) mutation in low-grade glioma and the associated change in function of the IDH1 enzyme has increased the interest in glioma metabolism. In an earlier study, we found that changes in expression of genes involved in the aerobic glycolysis and the TCA-cycle are associated with IDH1 mut. Here we apply proteomics to FFPE samples of diffuse gliomas with or without IDH1 mutations, in order to map changes in protein levels associated with this mutation. We observed significant changes in the enzyme abundance associated with aerobic glycolysis, glutamate metabolism and the TCA-cycle in IDH1 mut gliomas. Specifically, the enzymes involved in the metabolism of glutamate, lactate and enzymes involved in the conversion of α-ketoglutarate were increased in IDH1 mut gliomas. In addition, the bicarbonate transporter (SLC4A4) was increased in IDH1 mut gliomas, supporting the idea that a mechanism preventing intracellular acidification is active. We also found that enzymes that convert proline, valine, leucine and isoleucine into glutamate were increased in IDH1 mut glioma. We conclude that in IDH1 mut glioma metabolism is rewired (increased input of lactate and glutamate) to preserve TCA cycle activity in IDH1 mut gliomas.
2020-03-09 | PXD016698 | Pride
Project description:Gene expression data generated for the purpose of correlating differentially-expressed genes between IDH1 mutant and IDH1 wild-type high grade gliomas with differential hydroxymethylcytosine profiles as determined using Illumina EPIC BeadChip platform.
2020-10-06 | GSE104722 | GEO
Project description:Gliomas harboring mutations in isocitrate dehydrogenase 1/2 (IDH1/2) have the CpG island methylator phenotype (CIMP) and significantly longer patient survival time than wild-type IDH1/2 tumors. Although there are many factors underlying the differences in survival between these two tumor types, immune-related differences in cell content are potentially important contributors. In order to investigate the role of IDH mutations in immune response, we created a syngeneic pair mouse model for mutated IDH1 (mutIDH1) and wild-type IDH1 (wtIDH1) gliomas and demonstrated that muIDH1 mice showed many molecular and clinical similarities to muIDH1 human gliomas, including a 100-fold higher concentration of 2-hydroxygluratate (2-HG), longer survival time, and higher CpG methylation compared to wtIDH1. Also, we showed that IDH1 mutations caused downregulation of leukocyte chemotaxis, resulting in repression of the tumor-associated immune system. Given that significant infiltration of immune cells such as macrophages, microglia, monocytes, and neutrophils is linked to poor prognosis in many cancer types, these reduced immune infiltrates in muIDH1 glioma tumors may contribute in part to the differences in aggressiveness of the two glioma types.
2017-05-21 | GSE96979 | GEO
Project description:To examine the NRF2 activity in anaplastic glioma with mutated IDH1/2, we conducted the microarray analysis to measure the expression levels of representative NRF2 target genes, including NQO1, HMOX1, GCLM, TXNRD1, and PRDX1. 12 anaplastic gliomas with or without mutated IDH1/2.
2013-12-04 | E-GEOD-52942 | biostudies-arrayexpress
Project description:Diffuse low-grade gliomas are incurable brain tumours that often carry a mutation in the IDH1 gene. These tumours are heterogeneous and have different types of tumour cells. They can progress toward high grade gliomas. To understand the diversity of tumour cells and how they arise, we have performed single RNA seq of 8 cell lines derived from IDH1 mutant patients. Some cell lines maintained the IDH1 mutation while others lost it. We analysed these cultures when growth factors are present or absent for 4 days to promote differentiation.
2024-05-17 | GSE263796 | GEO
Project description:B7H3 (also known as CD276) is a co-stimulator checkpoint protein of the cell surface B7 superfamily. Recently, the function beyond immune regulation of B7H3 has been widely studied. However, the expression preference and the regulation mechanism underlying B7H3 in different subtypes of gliomas is rarely understood. We show here that B7H3 expression is significantly decreased in IDH-mutated gliomas and in cultured IDH1-R132H glioma cells. Accumulation of 2-HG leads to a remarkable downregulation of B7H3 protein and the activity of IDH1-R132H mutant is responsible for B7H3 reduction in glioma cells. Inhibition of autophagy by inhibitors like leupeptin, chloroquine (CQ), and Bafilomycin A1 (Baf-A1) blocks the degradation of B7H3 in glioma cells. In the meantime, the autophagy flux is more active with higher LC3B-II and lower p62 in IDH1-R132H glioma cells than in IDH1-WT cells. Furthermore, sequence alignment analysis reveals potential LC3-interacting region (LIR) motifs 'F-V-S/N-I/V' in B7H3. Moreover, B7H3 interacts with p62 and CQ treatment significantly enhances this interaction. Additionally, we find that <i>B7H3</i> is positively correlated with <i>VEGFA</i> and <i>MMP2</i> by bioinformatics analysis in gliomas. B7H3 and VEGFA are decreased in IDH-mutated gliomas and further reduced in 2-HG<sup>high</sup> gliomas compared to 2-HG<sup>low</sup> glioma sections by IHC staining. Our study demonstrates that B7H3 is preferentially overexpressed in IDH wild-type gliomas and could serve as a potential theranostic target for the precise treatment of glioma patients with wild-type IDH.
2021-05-26 | MTBLS2692 | MetaboLights
Project description:Single-nucleus RNA and ATAC sequencing of IDH1 mutant gliomas
| PRJNA847562 | ENA
Project description:High-grade gliomas are malignant neuroepithelial tumors. The current WHO classification for adult-type diffuse gliomas is based on IDH1/2 mutational and 1p/19q-codeletion status, which can be refined by emerging genomics, transcriptomics, and methylomics approaches. Nevertheless, therapy has been dominated by radiochemotherapy for about 15 years and progressed little in efficacy or precision through advanced molecular patient stratification. Glioma proteome alterations remain undercharacterized despite their promise for a better stratification and, in particular, the identification of therapeutic targets. Here, we used mass spectrometry (MS) to characterize 42 formalin-fixed, paraffin-embedded (FFPE) samples from IDH-wildtype (IDHwt), IDH-mutant (IDHmut) gliomas with and without 1p/19q-codeletion, and non-neoplastic brain tissue controls. Based on more than 5500 quantified proteins and 5000 phospho-sites, gliomas separated according to IDH1/2 mutational status and reflected loss of proteins encoded on 1p/19q in IDHmut, gains on chromosome 7 and losses on chromosome 10 in IDHwt. Unexpectedly, the 1p/19q-codeletion resulted in minor proteome changes. Instead, two proteomic subtypes of IDHmut gliomas showed major perturbations of mitochondrial DNA-encoded proteins, aerobic/anaerobic energy metabolism, RNA metabolism, chromatin dynamics, the extracellular matrix as well as tumor suppressor and oncoproteins. Reanalysis of three glioma proteomics studies independently validate the observed hallmarks and associate these proteomic subtypes with the well-established proneural and classic/mesenchymal IDHwt glioma subtypes. These results suggest an alternative stratification of IDHmut gliomas as part of common phenotypic subtypes independent of the IDH status, with broad therapeutic implications for patients with IDHmut gliomas in the future. Altogether, our study provides a rich protein and phospho-site resource restratifying glioma subtypes and supporting future mechanism of action and target discovery investigations.
2023-02-07 | GSE212838 | GEO