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dc.contributor.authorCastel, Den_US
dc.contributor.authorPhilippe, Cen_US
dc.contributor.authorKergrohen, Ten_US
dc.contributor.authorSill, Men_US
dc.contributor.authorMerlevede, Jen_US
dc.contributor.authorBarret, Een_US
dc.contributor.authorPuget, Sen_US
dc.contributor.authorSainte-Rose, Cen_US
dc.contributor.authorKramm, CMen_US
dc.contributor.authorJones, Cen_US
dc.contributor.authorVarlet, Pen_US
dc.contributor.authorPfister, SMen_US
dc.contributor.authorGrill, Jen_US
dc.contributor.authorJones, DTWen_US
dc.contributor.authorDebily, M-Aen_US
dc.identifier.citationActa Neuropathol Commun, 2018, 6 (1), pp. 117 - ?en_US
dc.description.abstractDiffuse midline glioma (DMG), H3 K27M-mutant, is a new entity in the updated WHO classification grouping together diffuse intrinsic pontine gliomas and infiltrating glial neoplasms of the midline harboring the same canonical mutation at the Lysine 27 of the histones H3 tail.Two hundred and fifteen patients younger than 18 years old with centrally-reviewed pediatric high-grade gliomas (pHGG) were included in this study. Comprehensive transcriptomic (n = 140) and methylation (n = 80) profiling was performed depending on the material available, in order to assess the biological uniqueness of this new entity compared to other midline and hemispheric pHGG.Tumor classification based on gene expression (GE) data highlighted the similarity of K27M DMG independently of their location along the midline. T-distributed Stochastic Neighbor Embedding (tSNE) analysis of methylation profiling confirms the discrimination of DMG from other well defined supratentorial tumor subgroups. Patients with diffuse intrinsic pontine gliomas (DIPG) and thalamic DMG exhibited a similarly poor prognosis (11.1 and 10.8 months median overall survival, respectively). Interestingly, H3.1-K27M and H3.3-K27M primary tumor samples could be distinguished based both on their GE and DNA methylation profiles, suggesting that they might arise from a different precursor or from a different epigenetic reorganization.These differences in DNA methylation profiles were conserved in glioma stem-like cell culture models of DIPG which mimicked their corresponding primary tumor. ChIP-seq profiling of H3K27me3 in these models indicate that H3.3-K27M mutated DIPG stem cells exhibit higher levels of H3K27 trimethylation which are correlated with fewer genes expressed by RNAseq. When considering the global distribution of the H3K27me3 mark, we observed that intergenic regions were more trimethylated in the H3.3-K27M mutated cells compared to the H3.1-K27M mutated ones.H3 K27M-mutant DMG represent a homogenous group of neoplasms compared to other pediatric gliomas that could be further separated based on the type of histone H3 variant mutated and their respective epigenetic landscapes. As these characteristics drive different phenotypes, these findings may have important implication for the design of future trials in these specific types of neoplasms.en_US
dc.format.extent117 - ?en_US
dc.subjectDNA methylation profilingen_US
dc.subjectDiffuse intrinsic pontine gliomaen_US
dc.subjectDiffuse midline gliomaen_US
dc.subjectGene expression profilingen_US
dc.subjectGlioma stem cellen_US
dc.subjectH3 K27M-mutanten_US
dc.subjectH3K27me3 landscapeen_US
dc.subjectPediatric high-grade gliomaen_US
dc.titleTranscriptomic and epigenetic profiling of 'diffuse midline gliomas, H3 K27M-mutant' discriminate two subgroups based on the type of histone H3 mutated and not supratentorial or infratentorial location.en_US
dc.typeJournal Article
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfActa Neuropathol Communen_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Glioma Team
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team
pubs.publication-statusPublished onlineen_US
pubs.embargo.termsNot knownen_US
icr.researchteamGlioma Teamen_US
dc.contributor.icrauthorJones, Chrisen_US

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