Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

IDH-mutant glioma arises from glial progenitor cells harboring the initial driver mutation

ABSTRACT: Discovering the cell-of-origin with the initial driver mutation provides fundamental basis for understanding tumor evolution and developing new treatments. In isocitrate dehydrogenase (IDH)-mutant gliomas, the most common malignant primary brain tumors in young adult under 50, its cell-of-origin remains poorly understood. Here, we used patient brain tissues and genome edited mice to identify glial progenitor cells (GPCs) including oligodendrocyte progenitor cells (OPCs) as the cell-of-origin harboring the IDH mutation as the initial driver mutation. We conducted comprehensive deep sequencing, including droplet digital PCR and deep panel and amplicon sequencing on 128 tissues from 62 patient (29 IDH-mutant gliomas and 33 IDH-negative controls), comprising tumors, normal cortex, or normal subventricular zone (SVZ), and blood. Surprisingly, we found low-level IDH mutation in the normal cortex away from the tumor, in 38.5% (10 of 26) of IDH-mutant glioma patients, while no IDH mutation was detected in the normal SVZ. Furthermore, through the analysis of cell-type-specific mutations, the direction of clonal evolution, and the single-cell transcriptome from patient brains as well as novel mouse model of IDH-mutant glioma arising from mutation-carrying OPCs, we determined that GPCs including OPCs with the initial driver mutation are responsible for the development and evolution to IDH-mutant gliomas. In summary, our results demonstrate that GPCs containing the IDH mutation are the cells-of-origin harboring the initial driver mutation in IDH-mutant gliomas.

ORGANISM(S): Mus musculus

PROVIDER: GSE275791 | GEO | 2026/01/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

IDH-mutant gliomas arise from glial progenitor cells harboring the initial driver mutation (Related accession no. GSE275791) - Spatial transcriptomics dataset

Project description:Discovering the cell-of-origin harboring the initial driver mutation provides a fundamental basis for understanding tumor evolution and development of new treatments. For isocitrate dehydrogenase (IDH)-mutant gliomas–the most common malignant primary brain tumors in adults under 50–the cell-of-origin remains poorly understood. Here, using patient brain tissues and genome-edited mice, we identified glial progenitor cells (GPCs), including oligodendrocyte progenitor cells (OPCs), as the glioma-originating cell type harboring the IDH mutation as the initial driver mutation. We conducted comprehensive deep sequencing, including droplet digital PCR and deep panel and amplicon sequencing to 142 tissues from 70 patients (32 IDH-mutant gliomas and 38 IDH-negative controls) comprising tumors, histologically normal peritumoral regions or subventricular zones (SVZs), and blood. Surprisingly, low-level IDH mutation was found in the normal peritumor away from the tumor in 37.9% (11 of 29) of IDH-mutant glioma patients, whereas no IDH mutation was detected in the SVZ. Integrating cell-type–specific mutations analysis, the direction of clonal evolution, spatial transcriptomics from patient brains and a novel IDH-mutant glioma mouse model arising from mutant OPCs, we determined that GPCs, including OPCs, harboring the initial driver mutation are responsible for the development and evolution of IDH-mutant gliomas. In summary, our results demonstrate that GPCs containing the IDH mutation are the cells-of-origin harboring the initial driver mutation in IDH-mutant gliomas.

2026-01-13 | GSE302642 | GEO

Expression profiling of lower-grade diffuse astrocytic glioma

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

Genotyping by array of 297 adult-type diffuse gliomas comprise IDH-mutant astrocytomas, IDH-mutant 1p/19q codeleted oligodendrogliomas, and IDH-wildtype glioblastomas

Project description:Adult-type diffuse gliomas comprise IDH-mutant astrocytomas, IDH-mutant 1p/19q codeleted oligodendrogliomas (ODG), and IDH-wildtype glioblastomas (GBM). GBM display genome instability, which may result from two genetic events leading to massive chromosome alterations: chromothripsis (CT) and whole-genome duplication (WGD). The better prognosis of the latter may be related to their genome stability compared to GBM. Pangenomic profiles of 297 adult diffuse gliomas were analyzed at initial diagnosis using SNP arrays, including 192 GBM and 105 IDH-mutant gliomas (61 astrocytomas and 44 ODG). Tumor ploidy was assessed with Genome Alteration Print and CT events with CTLPScanner and through manual screening.

2024-12-24 | E-MTAB-13542 | biostudies-arrayexpress

Multi-omic analysis of cell-of-origin and epigenomic state in pediatric H3K27M gliomas (scRNA-Seq)

Project description:Canonical (H3.1/H3.2) and noncanonical (H3.3) histone 3 K27M-mutant gliomas have unique spatiotemporal distributions, partner alterations, and molecular profiles. The contribution of the cell-of-origin to these differences has been challenging to uncouple from the oncogenic reprogramming induced by the mutation. Here, we perform an integrated analysis of 116 tumors, including single-cell transcriptome and chromatin accessibility, 3D chromatin architecture and epigenomic profiles, and show that K27M-mutant gliomas faithfully maintain chromatin configuration at developmental genes consistent with anatomically distinct oligodendrocyte-precursor-like cells (OPC). H3.3K27M thalamic gliomas map to prosomere 2-derived lineages. In turn, H3.1K27M ACVR1-mutant pontine gliomas uniformly mirror early ventral NKX6-1+/SHH-dependent brainstem OPCs, while H3.3K27M gliomas frequently resemble dorsal PAX3+/BMP-dependent progenitors. Our data suggest a context-specific vulnerability in H3.1K27M-mutant SHH-dependent ventral OPCs, which rely on acquisition of ACVR1 mutations to drive aberrant BMP signaling required for oncogenesis. The unifying action of K27M mutations is to restrict H3K27me3 at PRC2 landing sites, while other epigenetic changes are mainly contingent on the cell-of-origin chromatin state and cycling rate.

2022-08-05 | GSE210567 | GEO

Multi-omic analysis of cell-of-origin and epigenomic state in pediatric H3K27M gliomas (multiome)

2022-08-05 | GSE210566 | GEO

Multi-omic analysis of cell-of-origin and epigenomic state in pediatric H3K27M gliomas (scATAC-Seq)

2022-08-05 | GSE210565 | GEO

DNA methylome evolution and reprogramming in recurrent glioblastoma

Project description:Recurrent glioblastoma (GBM) has a grim prognosis, though MGMT promoter methylation and IDH mutation provide a significant survival advantage. The product of IDH mutation, 2-hydroxyglutarate, increases global DNA methylation by inhibiting demethylases. While lower-grade IDH-mutant gliomas demonstrate increased methylation as a result of this process, DNA becomes relatively hypomethylated during progression from low-grade glioma to secondary (IDH-mutant) GBM. Here we show that global DNA hypomethylation also occurs during primary (IDH-wild type) GBM recurrence. Moreover, in a phase I trial of 14 patients with recurrent (IDH-wild type) GBM, we targeted DNA hypomethylation using a methyl donor treatment. In autopsied tumors from patients treated, we observed a global increase in DNA methylation compared to initial tumor. These results suggest that hypomethylation is a marker for recurrence, and its reprogramming represents a potential therapeutic vulnerability.

2021-12-31 | GSE111627 | GEO

Expression profiling of lower-grade diffuse astrocytic glioma

2012-02-24 | GSE35158 | GEO

Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas [CEL-Seq2]

Project description:Intratumoral microglia and MΦ constitute up to 70% of the tumor mass of high-grade gliomas (HGG) with profound impact on hallmarks of malignancy such as angiogenesis and immunosuppression. The dynamics and functional states of intratumoral myeloid cells during tumor progression and the molecular mechanisms controlling them are poorly understood. Here we define homeostatic and antigen-presenting myeloid cellular states in experimental and human HGG by longitudinal single-cell RNA-sequencing and combined transcriptome and proteome profiling, respectively. During glioma progression, myeloid cells gradually shift from a homeostatic to a tumor-associated effector state. We show that these dynamics are under strict control by early changes in resident microglia and the tumor genotype: In gliomas with mutations in isocitrate dehydrogenase (IDH), a disease-defining driver mutation, differentiation of invaded myeloid cells was blocked resulting in an immature, immunosuppressive phenotype. In late-stage IDH-mutant gliomas, monocyte-derived MΦ drive a tolerogenic remodeling of the glioma microenvironment thus preventing T-cell response. We define the molecular mechanism responsible for blocking functional differentiation in IDH-mutant gliomas to be causally related to enhanced metabolization of tryptophan to kynurenine, an endogenous ligand of the aryl hydrocarbon receptor (AHR), leading to a time-dependent uptake of extracellular tryptophan via LAT1-CD98 by intratumoral myeloid cells. Consequently, the immunosuppressive phenotype in IDH-mutant glioma models was reversed by pharmacologic inhibition of LAT1-CD98 or AHR. Thus, we provide evidence for a tumor genotype-dependent dynamic network of resident and recruited intratumoral myeloid cells shaping the immune microenvironment of IDH-mutant HGG and identify tryptophan metabolism as a viable therapeutic target for the immunotherapy of IDH-mutant tumors.

2021-03-04 | GSE166418 | GEO

Transformation of quiescent adult oligodendrocyte precursor cells into malignant glioma through a multi-step reactivation process

Project description:How malignant gliomas arise in a mature brain remains a mystery, hindering the development of preventive and therapeutic interventions. We previously showed that oligodendrocyte precursor cells (OPCs) can be transformed into glioma when mutations are introduced perinatally. However, adult OPCs rarely proliferate compared to their perinatal counterparts. Whether these relatively quiescent cells have the potential to transform is unknown, which is a critical question considering the late onset of human glioma. Additionally, the events taking place between initial mutation and a fully developed tumor mass (pre-malignant phase) are particularly poorly understood in glioma. Here we used a temporally controllable Cre transgene to delete p53 and NF1 specifically in adult OPCs, and demonstrated that these cells consistently give rise to malignant gliomas. To investigate the transforming process of quiescent adult OPCs, we then tracked these cells throughout the pre-malignant phase, which revealed a dynamic multi-step transformation, starting with rapid but transient hyper-proliferative reactivation, followed by a long period of dormancy, then final malignant transformation. Using pharmacological approaches, we discovered that mTOR signaling is critical for both the initial OPC reactivation step and late stage tumor cell proliferation, and thus might be a potential target for both glioma prevention and treatment. In summary, our results firmly establish the transforming potential of adult OPCs, and reveal an actionable multi-phasic reactivation process that turns slowly dividing OPCs into malignant gliomas. 44K Mouse Development Oligo Microarrays from Agilent Technologies were used for microarray analysis. For each experiment, total RNA was fluorescently labeled and hybridized directly against a common reference sample generated from the RNA pool of four WT P17 mouse brain neocortex.

2014-09-09 | E-GEOD-61282 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data