Oligosarcomas, IDH-mutant are distinct and aggressive [Methylation]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA786873 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Oligosarcomas, IDH-mutant are distinct and aggressive
| PRJNA786871 | ENA
Project description:Oligosarcomas, IDH-mutant are distinct and aggressive [SNP]
| PRJNA786877 | ENA
Project description:Oligodendrogliomas are defined by IDH-mutations and codeletions of chromosomal arms 1p and 19q. In the past, case reports and small studies described gliomas with sarcomatous features arising from oligodendrogliomas, so called oligosarcomas. Here, we report a series of 23 IDH-mutant oligosarcomas forming a distinct methylation class. The tumors were recurrences from prior oligodendrogliomas or developed de novo. Precursor tumors of 11 oligosarcomas were histologically and molecularly indistinguishable from conventional oligodendrogliomas. Oligosarcoma tumor cells were embedded in a dens network of reticulin fibers, frequently showing p53 accumulation, positivity for SMA, and gain of H3K27 trimethylation (H3K27me3) as compared to primary lesions. In 5 oligosarcomas no 1p/19q codeletion was detectable, although it was present in the primary lesions. Oligosarcomas harbored an increased chromosomal copy number variation load with frequent CDKN2A/B deletions. Proteomic profiling demonstrated oligosarcomas to be highly distinct from conventional grade 3 oligodendrogliomas with consistent evidence for a smooth muscle differentiation. Expression of several tumor suppressors was reduced with NF1 being lost frequently. In contrast, oncogenic YAP1 was aberrantly overexpressed in oligosarcomas. Panel sequencing revealed mutations in NF1 and TP53 along with IDH1/2 and TERT promoter mutations. Survival of patients was significantly poorer for oligosarcomas than for grade 3 oligodendrogliomas and comparable to that of grade 4 IDH-mutant astrocytomas. These results establish oligosarcoma as a distinct type of IDH-mutant glioma differing from conventional oligodendrogliomas on the histologic, epigenetic, proteomic, molecular and clinical level. Diagnosis can be based on the characteristic DNA methylation profile or the combined evidence of sarcomatous histology, IDH-mutation and an oligodendroglioma-typical molecular alteration as TERT promoter mutation and/or 1p/19q codeletion.
2021-12-16 | MSV000088571 | MassIVE
Project description:Oligodendrogliomas are defined by IDH-mutations and codeletions of chromosomal arms 1p and 19q. In the past, case reports and small studies described gliomas with sarcomatous features arising from oligodendrogliomas, so called oligosarcomas. Here, we report a series of 23 IDH-mutant oligosarcomas forming a distinct methylation class. The tumors were recurrences from prior oligodendrogliomas or developed de novo. Precursor tumors of 11 oligosarcomas were histologically and molecularly indistinguishable from conventional oligodendrogliomas. Oligosarcoma tumor cells were embedded in a dens network of reticulin fibers, frequently showing p53 accumulation, positivity for SMA, and gain of H3K27 trimethylation (H3K27me3) as compared to primary lesions. In 5 oligosarcomas no 1p/19q codeletion was detectable, although it was present in the primary lesions. Oligosarcomas harbored an increased chromosomal copy number variation load with frequent CDKN2A/B deletions. Proteomic profiling demonstrated oligosarcomas to be highly distinct from conventional grade 3 oligodendrogliomas with consistent evidence for a smooth muscle differentiation. Expression of several tumor suppressors was reduced with NF1 being lost frequently. In contrast, oncogenic YAP1 was aberrantly overexpressed in oligosarcomas. Panel sequencing revealed mutations in NF1 and TP53 along with IDH1/2 and TERT promoter mutations. Survival of patients was significantly poorer for oligosarcomas than for grade 3 oligodendrogliomas and comparable to that of grade 4 IDH-mutant astrocytomas. These results establish oligosarcoma as a distinct type of IDH-mutant glioma differing from conventional oligodendrogliomas on the histologic, epigenetic, proteomic, molecular and clinical level. Diagnosis can be based on the characteristic DNA methylation profile or the combined evidence of sarcomatous histology, IDH-mutation and an oligodendroglioma-typical molecular alteration as TERT promoter mutation and/or 1p/19q codeletion.
2022-01-01 | GSE190362 | GEO
Project description:Oligodendrogliomas are defined by IDH-mutations and codeletions of chromosomal arms 1p and 19q. In the past, case reports and small studies described gliomas with sarcomatous features arising from oligodendrogliomas, so called oligosarcomas. Here, we report a series of 23 IDH-mutant oligosarcomas forming a distinct methylation class. The tumors were recurrences from prior oligodendrogliomas or developed de novo. Precursor tumors of 11 oligosarcomas were histologically and molecularly indistinguishable from conventional oligodendrogliomas. Oligosarcoma tumor cells were embedded in a dens network of reticulin fibers, frequently showing p53 accumulation, positivity for SMA, and gain of H3K27 trimethylation (H3K27me3) as compared to primary lesions. In 5 oligosarcomas no 1p/19q codeletion was detectable, although it was present in the primary lesions. Oligosarcomas harbored an increased chromosomal copy number variation load with frequent CDKN2A/B deletions. Proteomic profiling demonstrated oligosarcomas to be highly distinct from conventional grade 3 oligodendrogliomas with consistent evidence for a smooth muscle differentiation. Expression of several tumor suppressors was reduced with NF1 being lost frequently. In contrast, oncogenic YAP1 was aberrantly overexpressed in oligosarcomas. Panel sequencing revealed mutations in NF1 and TP53 along with IDH1/2 and TERT promoter mutations. Survival of patients was significantly poorer for oligosarcomas than for grade 3 oligodendrogliomas and comparable to that of grade 4 IDH-mutant astrocytomas. These results establish oligosarcoma as a distinct type of IDH-mutant glioma differing from conventional oligodendrogliomas on the histologic, epigenetic, proteomic, molecular and clinical level. Diagnosis can be based on the characteristic DNA methylation profile or the combined evidence of sarcomatous histology, IDH-mutation and an oligodendroglioma-typical molecular alteration as TERT promoter mutation and/or 1p/19q codeletion.
2022-01-01 | GSE190364 | GEO
Project description:The progression of IDH-mutant gliomas (IDH-G) from slow-growing tumors to fatal disease is associated with transcriptional and DNA methylation changes that remain poorly understood. Here, we profiled a longitudinal cohort of 36 IDH-G samples from 19 patients by joint-capture multi-omic single-nucleus (sn) DNA methylation and snRNA-seq. We show that IDH-G progression is associated with increase in malignant stem-like states, decreased differentiation and with methylation loss, which marks tumors with worse clinical outcome. Methylation loss was uniformly observed across malignant cells within individual tumors, suggesting that it may underlie rather than result from the increase in stem-like states. Analysis of cell state heritability and plasticity based on high-resolution phylogenetic trees connects DNA methylation loss to alterations in glioma cell states encoding and heritability. Our study offers insights on how DNA methylation loss reshapes cellular transitions and how it may mark clinically more aggressive tumors across IDH-G subsets.
2026-04-27 | GSE292025 | GEO
Project description:The progression of IDH-mutant gliomas (IDH-G) from slow-growing tumors to fatal disease is associated with transcriptional and DNA methylation changes that remain poorly understood. Here, we profiled a longitudinal cohort of 36 IDH-G samples from 19 patients by joint-capture multi-omic single-nucleus (sn) DNA methylation and snRNA-seq. We show that IDH-G progression is associated with increase in malignant stem-like states, decreased differentiation and with methylation loss, which marks tumors with worse clinical outcome. Methylation loss was uniformly observed across malignant cells within individual tumors, suggesting that it may underlie rather than result from the increase in stem-like states. Analysis of cell state heritability and plasticity based on high-resolution phylogenetic trees connects DNA methylation loss to alterations in glioma cell states encoding and heritability. Our study offers insights on how DNA methylation loss reshapes cellular transitions and how it may mark clinically more aggressive tumors across IDH-G subsets.
2026-04-27 | GSE291885 | GEO
Project description:Background: Aggressiveness guides treatment in IDH-mutant gliomas. Objective grading of oligodendrogliomas is therefore urgently needed. Material and Methods: 211 primary and recurrent resections from 111 oligodendroglioma patients were collected, complemented with 91 samples for validation. Samples were subjected to Ki-67 staining, proteomics and DNA-methylation profiling. Data were analyzed using various multivariate differential models and algorithms. Results & conclusion: We developed CGCψ, a continuous grading coefficient independent of tumor typing, and demonstrate its prognostic value in oligodendrogliomas. Its prognostic value outperformed WHO grade at tumor recurrence. CGCψ is linked to large scale DNA de-methylation, but increased DNA methylation of polycomb transcription factors, aging, Ki-67, and losses on chr4 and chr9p. DNA de-methylation at tumor recurrence/higher grade is sequence context specific and associated with TET recognition sites. Both oligodendrogliomas and astrocytomas progress along this shared epi-genetic axis. Oligosarcomas are characterized by a high CGCψ and low tumor purity.
2026-01-19 | PXD070222 | Pride
Project description:Oncogenic mutations in isocitrate dehydrogenase (IDH)-1 and -2 occur in a wide range of cancers, including acute myeloid leukemias (AMLs) and gliomas1-3. Mutant IDH enzymes convert 2-oxoglutarate (2OG) to (R)-2-hydroxyglutarate [(R)-2HG]4,5, an oncometabolite that induces cellular transformation by dysregulating 2OG-dependent enzymes. The only direct target of (R)-2HG known to contribute to transformation is the 5-methylcytosine hydroxylase TET2, and there is ample evidence to suggest that (R)-2HG drives leukemogenesis at least in part by inhibiting TET26,7. However, IDH mutations, but not TET2 mutations, are specifically associated with aggressive hematologic diseases, suggesting that (R)-2HG has targets other than TET2 that contribute to mutant IDH-mediated transformation. Here, we report that (R)-2HG directly inhibits KDM5 histone lysine demethylases in IDH-mutant AMLs and gliomas to induce cellular transformation. These studies provide a functional link between dysregulation of histone lysine methylation and tumorigenesis in IDH-mutant cancers.
2023-03-01 | GSE184611 | GEO
Project description:Gain-of-function IDH mutations define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylase enzymes, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes are critical for the dynamic regulation of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), though the functional significance of this altered epigenetic state remains unclear. Here we show that IDH1 mutant gliomas exhibit hyper-methylation at CTCF binding sites, leading to reduced binding of this methylation-sensitive insulator protein. Loss of CTCF binding is associated with a loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to aberrantly interact with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with demethylating agent partially restores insulator function and reduces PDGFRA expression. Conversely, CRISPR-mediated disruption of the CTCF binding sequence in IDH wildtype gliomaspheres induces PDGFRA expression and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression. CTCF occupancy characterization and histone H3K27 acetylation profiling in IDH1 mutant and wild-type glioma patient specimens and culture models. ChIP-seq raw data is to be made available through dbGaP (controlled access) due to patient privacy concerns.
2015-12-23 | E-GEOD-70991 | biostudies-arrayexpress