The epigenetic evolution of glioma is determined by the IDH1 mutation status and treatment regimen
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE248471 | GEO | 2023/12/13
REPOSITORIES: GEO
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Project description:Glial cell-derived brain tumors (gliomas) are devastating diseases without effective curative therapies. Gliomas are classified according to various schemes including the cancer-initiating cell type, World Health Organization tumor grades, and genetic markers such as Isocitrate dehydrogenase (IDH) mutations and chromosomal 1p/19q codeletion status. Genomics, transcriptomics and methylomics approaches are emerging as powerful means to refine classification. However, various aspects of cancer biology are solely reflected on the proteomelevel. Here, we employ mass spectrometry (MS) to characterize the proteomes and phospho-proteomes of IDHmut glioma entities with and without 1p/19q codeletion, IDHwt gliomas and control tissue from a total of 42 patients. Our data-dependent acquisition MS workflow on average quantifies more than 5000 proteins and 3000 phospho-sites per sample of formalin-fixed paraffin-embedded (FFPE) brain sections. The tumor proteomes reflected genetic alterations such as the loss of chromosome 1p/19q proteins, the loss of ATRX in non-codeletion IDHmut glioma, and the frequent loss and amplification of chromosomes 10 and 7, respectively,in IDH-wild type glioma. Nevertheless, 1p/19q codeletion status was not the major determinant of IDHmut glioma proteomes. Instead, the proteome profiles suggest an alternative classification of IDHmut gliomas that correlates with the loss of mitochondrial DNA-encoded proteins, the abundance of respiratory chain proteins, a distinct tumor suppressor and oncoprotein profile, an extracellular matrix signature, and alterations in the phospho-proteome. Moreover, the glioma association of numerous proteins implicated in other cancers by this dataset provides a resource for further mechanistic investigation of glioma genesis and progression.
2022-11-09 | PXD024427 | Pride
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
Project description:To investigate the peri-tumoral effect of IDHmut vs IDHwt glioma, we engrafted IDHmut or IDHwt mouse glioma intracranially in C57BL/6 mice.
2024-04-21 | GSE227995 | GEO
Project description:<p>Infiltrating gliomas are devastating and incurable tumors. Amongst all gliomas, those harboring an isocitrate dehydrogenase 1 mutation (IDHmut), acquire a different tumor biology and clinical manifestation than those that are IDHWT. Understanding the unique metabolic profile reprogrammed by IDH1 mutation has the potential to identify new molecular targets for glioma therapy. Herein, we discovered monounsaturated (MUFA) to polyunsaturated (PUFA) lipid imbalances in organelles, generated by IDH mutation in cells and patient tissue, that were responsible for Golgi and ER dilation. We demonstrated a direct link between the IDH mutation and these organelle morphology via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, the rate limiting enzyme in MUFA biosynthesis. Inhibition of IDH mutation or SCD silencing restored ER and Golgi morphology, while D-2HG and oleic acid induced morphological defects in these organelles. Moreover, addition of oleic acid, which tilted the balance towards elevated levels of MUFA, produced IDH1mut-specific cellular apoptosis. Collectively, these results suggest that IDH1mut-induced SCD overexpression can rearrange the biodistribution of lipids in the organelles of glioma, providing a new insight on the link between lipids metabolism and organelle morphology in these cells, with potential and unique therapeutic implications.</p><p><br></p><p>Linked studies;</p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1967' rel='noopener noreferrer' target='_blank'>MTBLS1967</a> FA_HILICZ</p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1974' rel='noopener noreferrer' target='_blank'>MTBLS1974</a> LCMS(CSHPos)</p>
2020-11-24 | MTBLS1973 | MetaboLights
Project description:<p>Infiltrating gliomas are devastating and incurable tumors. Amongst all gliomas, those harboring an isocitrate dehydrogenase 1 mutation (IDHmut), acquire a different tumor biology and clinical manifestation than those that are IDHWT. Understanding the unique metabolic profile reprogrammed by IDH1 mutation has the potential to identify new molecular targets for glioma therapy. Herein, we discovered monounsaturated (MUFA) to polyunsaturated (PUFA) lipid imbalances in organelles, generated by IDH mutation in cells and patient tissue, that were responsible for Golgi and ER dilation. We demonstrated a direct link between the IDH mutation and these organelle morphology via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, the rate limiting enzyme in MUFA biosynthesis. Inhibition of IDH mutation or SCD silencing restored ER and Golgi morphology, while D-2HG and oleic acid induced morphological defects in these organelles. Moreover, addition of oleic acid, which tilted the balance towards elevated levels of MUFA, produced IDH1mut-specific cellular apoptosis. Collectively, these results suggest that IDH1mut-induced SCD overexpression can rearrange the biodistribution of lipids in the organelles of glioma, providing a new insight on the link between lipids metabolism and organelle morphology in these cells, with potential and unique therapeutic implications.</p><p><br></p><p>Linked studies;</p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1967' rel='noopener noreferrer' target='_blank'>MTBLS1967</a> FA_HILICZ</p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1973' rel='noopener noreferrer' target='_blank'>MTBLS1973</a> LCMS(CSHNeg)</p>
2020-11-24 | MTBLS1974 | MetaboLights
Project description:<p>Infiltrating gliomas are devastating and incurable tumors. Amongst all gliomas, those harboring an isocitrate dehydrogenase 1 mutation (IDHmut), acquire a different tumor biology and clinical manifestation than those that are IDHWT. Understanding the unique metabolic profile reprogrammed by IDH1 mutation has the potential to identify new molecular targets for glioma therapy. Herein, we discovered monounsaturated (MUFA) to polyunsaturated (PUFA) lipid imbalances in organelles, generated by IDH mutation in cells and patient tissue, that were responsible for Golgi and ER dilation. We demonstrated a direct link between the IDH mutation and these organelle morphology via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, the rate limiting enzyme in MUFA biosynthesis. Inhibition of IDH mutation or SCD silencing restored ER and Golgi morphology, while D-2HG and oleic acid induced morphological defects in these organelles. Moreover, addition of oleic acid, which tilted the balance towards elevated levels of MUFA, produced IDH1mut-specific cellular apoptosis. Collectively, these results suggest that IDH1mut-induced SCD overexpression can rearrange the biodistribution of lipids in the organelles of glioma, providing a new insight on the link between lipids metabolism and organelle morphology in these cells, with potential and unique therapeutic implications.</p><p><br></p><p>Linked studies;</p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1973/' rel='noopener noreferrer' target='_blank'>MTBLS1973</a> LCMS(CSHNeg)</p><p><a href='https://www.ebi.ac.uk/metabolights/MTBLS1974' rel='noopener noreferrer' target='_blank'>MTBLS1974</a> LCMS(CSHPos)</p>
2020-11-24 | MTBLS1967 | MetaboLights
Project description:Diffuse gliomas represent the most prevalent class of primary brain tumor. Despite significant recent advances in the understanding of glioblastoma (WHO IV), its most malignant subtype, lower-grade (WHO II and III) glioma variants remain comparatively understudied, especially in light of their notably variable clinical behavior. To examine the foundations of this heterogeneity, we performed multidimensional molecular profiling, including global transcriptional analysis, on 101 lower-grade diffuse astrocytic gliomas collected at our own institution, and validated our findings using publically available gene expression and copy number data from large independent patient cohorts. We found that IDH mutational status delineated molecularly and clinically distinct glioma subsets, with IDH mutant (IDH mt) tumors exhibiting TP53 mutations, PDGFRA overexpression, and prolonged survival, and IDH wild-type (IDH wt) tumors exhibiting EGFR amplification, PTEN loss, and unfavorable disease outcome. Furthermore, global expression profiling revealed three robust molecular subclasses within lower-grade diffuse astrocytic gliomas, two of which were predominantly IDH mt and one almost entirely IDH wt. IDH mt subclasses were distinguished from each other on the basis of TP53 mutations, DNA copy number abnormalities, and links to distinct stages of neurogenesis in the subventricular zone (SVZ). This latter finding implicates discrete pools of neuroglial progenitors as cells of origin for the different subclasses of IDH mt tumors. In summary, we have elucidated molecularly distinct subclasses of lower-grade diffuse astrocytic glioma that dictate clinical behavior and demonstrate fundamental associations with both IDH mutational status and neuroglial developmental stage. 80 tumor samples, one normal tissue sample (brain)
2012-02-24 | E-GEOD-35158 | biostudies-arrayexpress
Project description:Background: Molecular profiling of diffuse gliomas has provided significant insights into the pathogenesis, classification and prognostication of these malignancies. However, previous molecular studies of glioma have largely focused on genomic readouts and targeted proteomic profiling technologies. Consequently, proteomic and downstream functional landscape of gliomas in general, and molecular subgroups in particular, remains largely unexplored. Here, we utilize liquid chromatography tandem mass spectrometry to profile genomically-defined cohorts of gliomas spanning the full range of World Health Organization (WHO) grades. Methods: Bulk frozen tissue and purified micro-dissected regions from formalin-fixed paraffin-embedded (FFPE) tissues were assembled and utilized to define robust proteomic signatures of both low grade, infiltrative and high-grade tumors. As a final analysis, primary tumor tissue was compared with both IDH-mutated and IDH-wildtype glioblastoma stem cell (GSC) lines to further overcome tissue heterogeneity and pinpoint proteins differences likely arising in the relevant glial cellular drivers of tumor development. Results: In aggregate, 5,496 unique proteins over 3 glioma cohorts were identified, and span common molecular subclasses based on IDH and 1p19q co-deletion status and all four WHO grades. Supervised clustering highlights substantial proteome and systems-level pathway differences between different genetically defined glioma subtypes and WHO grades. By using bulk tumor statistical analysis, 833 proteins distinguish different WHO grade tumors, while FFPE tumor dissection reveals 287 proteins in GBMs with abundance changes according to IDH mutation status. Using our integrative approach, calcium signaling, proteins of the endoplasmic reticulum and extracellular integrin proteins are most conserved proteomic markers that distinguish aggressive, IDH-wt, from IDH-mut GBM tumors in primary and tissue culture models gliomagenesis. Conclusions: This proteomic survey provides the largest and most diverse unbiased protein-based brain tumor resource to date. Current treatments for glial tumors are largely non-specific and overlap between genomic subtypes and WHO grades. Our analysis provides early insight into the vast downstream and epigenetic protein-level differences within this molecular framework. Given the central position proteins occupy in driving biology and phenotype, further characterization of the substantial proteomic diversity that exist between the molecular subtypes and grades of gliomas, proteomics may help define more personalized prognostic and predictive biomarkers for precision care.
2019-07-30 | PXD010099 | Pride
Project description:Background: Molecular profiling of diffuse gliomas has provided significant insights into the pathogenesis, classification and prognostication of these malignancies. However, previous molecular studies of glioma have largely focused on genomic readouts and targeted proteomic profiling technologies. Consequently, proteomic and downstream functional landscape of gliomas in general, and molecular subgroups in particular, remains largely unexplored. Here, we utilize liquid chromatography tandem mass spectrometry to profile genomically-defined cohorts of gliomas spanning the full range of World Health Organization (WHO) grades. Methods: Bulk frozen tissue and purified micro-dissected regions from formalin-fixed paraffin-embedded (FFPE) tissues were assembled and utilized to define robust proteomic signatures of both low grade, infiltrative and high-grade tumors. As a final analysis, primary tumor tissue was compared with both IDH-mutated and IDH-wildtype glioblastoma stem cell (GSC) lines to further overcome tissue heterogeneity and pinpoint proteins differences likely arising in the relevant glial cellular drivers of tumor development. Results: In aggregate, 5,496 unique proteins over 3 glioma cohorts were identified, and span common molecular subclasses based on IDH and 1p19q co-deletion status and all four WHO grades. Supervised clustering highlights substantial proteome and systems-level pathway differences between different genetically defined glioma subtypes and WHO grades. By using bulk tumor statistical analysis, 833 proteins distinguish different WHO grade tumors, while FFPE tumor dissection reveals 287 proteins in GBMs with abundance changes according to IDH mutation status. Using our integrative approach, calcium signaling, proteins of the endoplasmic reticulum and extracellular integrin proteins are most conserved proteomic markers that distinguish aggressive, IDH-wt, from IDH-mut GBM tumors in primary and tissue culture models gliomagenesis. Conclusions: This proteomic survey provides the largest and most diverse unbiased protein-based brain tumor resource to date. Current treatments for glial tumors are largely non-specific and overlap between genomic subtypes and WHO grades. Our analysis provides early insight into the vast downstream and epigenetic protein-level differences within this molecular framework. Given the central position proteins occupy in driving biology and phenotype, further characterization of the substantial proteomic diversity that exist between the molecular subtypes and grades of gliomas, proteomics may help define more personalized prognostic and predictive biomarkers for precision care.
2019-07-30 | PXD010098 | Pride
Project description:Background: Molecular profiling of diffuse gliomas has provided significant insights into the pathogenesis, classification and prognostication of these malignancies. However, previous molecular studies of glioma have largely focused on genomic readouts and targeted proteomic profiling technologies. Consequently, proteomic and downstream functional landscape of gliomas in general, and molecular subgroups in particular, remains largely unexplored. Here, we utilize liquid chromatography tandem mass spectrometry to profile genomically-defined cohorts of gliomas spanning the full range of World Health Organization (WHO) grades. Methods: Bulk frozen tissue and purified micro-dissected regions from formalin-fixed paraffin-embedded (FFPE) tissues were assembled and utilized to define robust proteomic signatures of both low grade, infiltrative and high-grade tumors. As a final analysis, primary tumor tissue was compared with both IDH-mutated and IDH-wildtype glioblastoma stem cell (GSC) lines to further overcome tissue heterogeneity and pinpoint proteins differences likely arising in the relevant glial cellular drivers of tumor development. Results: In aggregate, 5,496 unique proteins over 3 glioma cohorts were identified, and span common molecular subclasses based on IDH and 1p19q co-deletion status and all four WHO grades. Supervised clustering highlights substantial proteome and systems-level pathway differences between different genetically defined glioma subtypes and WHO grades. By using bulk tumor statistical analysis, 833 proteins distinguish different WHO grade tumors, while FFPE tumor dissection reveals 287 proteins in GBMs with abundance changes according to IDH mutation status. Using our integrative approach, calcium signaling, proteins of the endoplasmic reticulum and extracellular integrin proteins are most conserved proteomic markers that distinguish aggressive, IDH-wt, from IDH-mut GBM tumors in primary and tissue culture models gliomagenesis. Conclusions: This proteomic survey provides the largest and most diverse unbiased protein-based brain tumor resource to date. Current treatments for glial tumors are largely non-specific and overlap between genomic subtypes and WHO grades. Our analysis provides early insight into the vast downstream and epigenetic protein-level differences within this molecular framework. Given the central position proteins occupy in driving biology and phenotype, further characterization of the substantial proteomic diversity that exist between the molecular subtypes and grades of gliomas, proteomics may help define more personalized prognostic and predictive biomarkers for precision care.
2019-07-30 | PXD010133 | Pride