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PFA ependymoma primary and recurring tumors show differences in cellularity, DNA methylation and relevant copy number variations.

ABSTRACT: PFA ependymoma primary and recurring tumors show differences in cellularity, DNA methylation and relevant copy number variations.

PROVIDER: PRJNA1045253 | ENA |

REPOSITORIES: ENA

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PFA ependymoma primary and recurring tumors show differences in cellularity, DNA methylation and relevant copy number variations.

Project description:Posterior fossa type A (PF-EPN-A, PFA) ependymoma are aggressive tumors that mainly affect children and have a poor prognosis. Histopathology shows significant intratumoral heterogeneity, ranging from loose tissue to often sharply demarcated, extremely cell dense tumor areas. To determine molecular differences in morphologically different areas and to understand their clinical significance, we analyzed 113 PF-EPN-A samples, including 40 corresponding relapse samples. Relapsing tumors displayed a higher proportion of cell dense areas (p=0.036), a change in PF-EPN-A methylation subtypes (13/32 patients), and novel chromosome 1q gains and 6q losses (12/32 cases) compared to corresponding primary tumors.

2024-01-31 | GSE248617 | GEO

Spatial transcriptomics reveal unnresolved wound repair as potential driver of PFA Ependymoma progression

Project description:Childhood brain tumor ependymoma remains incurable in approximately 50 percent of cases. No oncogenic mechanism has been firmly established for the commonest ependymoma variant posterior fossa subgroup A (PFA), impeding clinical advances. Uncovering how heterogeneous cell types within the tumor microenvironment interact is crucial to a complete understanding of PFA disease progression. The underlying cellular components of the PFA tumor microenvironment have been revealed by single cell transcriptomics, identifying divergent epithelial differentiation and EMT lineages. Here we utilize spatial transcriptomics (Visium) of 14 PFA samples to chart neoplastic and immune cell architecture and identify novel biological processes.

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TULIPs decorate the three-dimensional genome of PFA ependymoma

Project description:Hi-C and RNA-seq for a large cohort of pediatric brain tumors including ependymoma (PFA, PFB, Ste, spinal), medulloblastoma (G3, G4, SHH), high grade glioma (H3K27 and H3-WT), pilocytic astrocytoma, and more.

2024-07-05 | GSE186599 | GEO

EZHIP / CXorf67 mimics oncohistones to inhibit PRC2 in PFA ependymoma

Project description:Expression of CXorf67 is an oncogenic mechanism that drives H3K27 hypomethylation in PFA ependymomas by mimicking K27M mutated oncohistones. Background: Posterior fossa A (PFA) ependymomas comprise one out of nine molecular groups of ependymoma. PFA tumors are mainly diagnosed in infants and young children, show a poor prognosis and are characterized by a lack of the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark. Recently, we reported CXorf67 overexpression as hallmark of PFA ependymoma and showed that CXorf67 can interact with EZH2 thereby inhibiting polycomb repressive complex 2 (PRC2), but the mechanism of action remained unclear. Methods: We performed mass spectrometry (MS) and peptide modelling analyses to identify the functional domain of CXorf67 responsible for binding and inhibition of EZH2. Our findings were validated by immunocytochemistry, western blot and methyltransferase assays. Results: We find that the inhibitory mechanism of CXorf67 is similar as in diffuse midline gliomas harboring H3K27M mutations. A small, highly conserved peptide sequence located in the C-terminal region of CXorf67 mimics the sequence of K27M mutated histones and binds to the SET domain of EZH2. This interaction blocks EZH2 methyltransferase activity and inhibits PRC2 function causing de-repression of PRC2 target genes including genes involved in neurodevelopment. Conclusions: Expression of CXorf67 is an oncogenic mechanism that drives H3K27 hypomethylation in PFA tumors by mimicking K27M mutated histones. Disrupting the interaction between CXorf67 and EZH2 may serve as a novel targeted therapy for PFA tumors but also for other tumors that overexpress CXorf67. Based on its function, we have renamed CXorf67 into EZH Inhibitory Protein (EZHIP).

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Epigenetic methylation chip analysis of childhood PFA ependymoma patient samples [EPIC Methylation]

Project description:DNA methylation analysis was perfomed using Infinium EPIC Methylation BeadChip platform on 65 PFA ependymoma patient samples. Resulting .idat files were then uploaded to the molecularneuropathology.org classifier to obtain molecular subgroup and copy number variance. Idat files were batch normalized and background corrected using default settings of the R package ChAMP to obtain GpG methylation beta values for analysis of differentially methylated GpG regions.

2023-06-01 | GSE226895 | GEO

Epigenetic methylation chip analysis of childhood ependymoma PFA subgroup patient samples [Infinium 450K Methylation Beadchip]

Project description:DNA methylation analysis was perfomed using Infinium 450K Methylation BeadChip platform on 140 PFA ependymoma patient samples. Resulting .idat files were then uploaded to the molecularneuropathology.org classifier to obtain molecular subgroup and copy number variance. Idat files were batch normalized and background corrected using default settings of the R package ChAMP to obtain GpG methylation beta values for analysis of differentially methylated GpG regions.

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Project description:Sequencing data related the PFA ependymoma study (Michealraj et al., Cell 2020), a lethal glial malignancy of the hindbrain found in babies and toddlers.

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TULIPs decorate the three-dimensional genome of PFA ependymoma

Project description:TULIPs decorate the three-dimensional genome of PFA ependymoma

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Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma

Project description:PFA ependymomas are a lethal glial malignancy of the hindbrain found in babies and toddlers. Lacking any highly recurrent somatic mutations, PFAs have been proposed as a largely epigenetically driven tumor type. An almost complete lack of model systems has inhibited discovery of novel PFA therapies. Both in vitro and in vivo, the PFA hypoxic microenvironment controls the availability of specific metabolites to diminish histone methylation, and to increase both histone demethylation and acetylation at H3K27. PFA ependymoma initiates from a cell lineage in the first trimester of human development where there is a known hypoxic microenvironment. Unique to PFA cells, transient exposure to ambient oxygen results in irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and paradoxically inhibition of H3K27 methylation shows significant and specific activity against PFA. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.

2020-08-13 | PXD018191 | Pride

EZHIP / CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma

Project description:Posterior fossa A (PFA) ependymomas comprise one out of nine molecular groups of ependymoma. PFA tumors are mainly diagnosed in infants and young children, show a poor prognosis and are characterized by a lack of the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark. Recently, we reported CXorf67 overexpression as hallmark of PFA ependymoma and showed that CXorf67 can interact with EZH2 thereby inhibiting polycomb repressive complex 2 (PRC2). Here, we report that the inhibitory mechanism of this interaction is similar as in diffuse midline gliomas harboring H3K27M mutations. A small, highly conserved peptide sequence located in the C-terminal region of CXorf67 mimics the H3K27M peptide and binds to the SET domain of EZH2. This interaction blocks EZH2 methyltransferase activity and causes H3K27 hypomethylation, an oncogenic mechanism that may be exploited for targeted therapy in PFA ependymoma. Based on its function, we have renamed CXorf67 into EZH2 Inhibitory Protein (EZHIP).

2019-07-08 | PXD012318 | Pride

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