DMG H3-K27M MAPK-altered methylation data
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER:
PROVIDER: E-MTAB-13471 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Mutations within FGFR1 and BRAF indicate superior outcome in diffuse midline gliomas, H3F3A K27M mutant
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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).
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Project description:Diffuse midline glioma (DMG) is a devastating disease that is defined by its localization, by the diffuse growth of astrocytic tumor cells, and by K27M mutations within Histone H3 proteins. In a large series of such tumor samples (n=83), we show here that 12 % of these cases (n=10) harbor concomitant hotspot mutations within FGFR1 or BRAF. Respective cases were all located in midline structures and matched with reference cases of DMG using global DNA methylation profiling. TP53 mutations were significantly more frequent in BRAF/FGFR1 wild type cases. Presence of hotspot mutations within FGFR1 or BRAF was associated with a significantly better overall survival, which was independent of the patients’ age and tumor localization. Thus, our results establish the relevance of FGFR1 or BRAF mutations in DMG as a prognostic marker and open new targeted therapy options in this subgroup of DMG.
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Project description:Pediatric high-grade gliomas, including diffuse midline gliomas (DMG), harbor mutually exclusive tumor location specific histone mutations. Using immunocompetent genetically engineered mouse models, we demonstrate the predominant non-neoplastic cell population are infiltrating myeloid cells, including peripheral monocytes and brain resident microglia. Single cell RNA sequencing, flow cytometry, and immunohistochemistry demonstrate the presence of unique myeloid cell populations distinctly shaped by the specific histone mutation. Disease associated myeloid cell phenotypes are identified, resembling those found in other neurodegenerative diseases, and demonstrate immune permissive characteristics. H3.3K27M DMGs, the most aggressive DMG subtype, demonstrate enrichment of disease associated myeloid cells as well as proliferating myeloid and tumor cells.
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Project description:The gene encoding fibroblast growth factor receptor 1 (FGFR1) amplification is associated with poor prognosis in estrogen receptor positive (ER+) breast cancer, and thus represents a potential therapeutic target. Fluorescent in situ hybridization (FISH) has been used as the gold standard methodology for detection of FGFR1 amplification, but it is a relatively long labor-intensive procedure and not efficient to process a large number of patient samples, especially formalin fixed paraffin embedded (FFPE) samples. This study sought to identify genes discriminative at the mRNA level for FGFR1 amplification and to construct a multi-gene test to facilitate efficient screening for FGFR1 amplified ER+ breast tumors.
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