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dc.contributor.authorCastel, D
dc.contributor.authorPhilippe, C
dc.contributor.authorKergrohen, T
dc.contributor.authorSill, M
dc.contributor.authorMerlevede, J
dc.contributor.authorBarret, E
dc.contributor.authorPuget, S
dc.contributor.authorSainte-Rose, C
dc.contributor.authorKramm, CM
dc.contributor.authorJones, C
dc.contributor.authorVarlet, P
dc.contributor.authorPfister, SM
dc.contributor.authorGrill, J
dc.contributor.authorJones, DTW
dc.contributor.authorDebily, M-A
dc.date.accessioned2019-02-20T07:47:58Z
dc.date.issued2018-11-05
dc.identifier.citationActa neuropathologica communications, 2018, 6 (1), pp. 117 - ?
dc.identifier.issn2051-5960
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3061
dc.identifier.eissn2051-5960
dc.identifier.doi10.1186/s40478-018-0614-1
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.
dc.formatElectronic
dc.format.extent117 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectBrain
dc.subjectTumor Cells, Cultured
dc.subjectHumans
dc.subjectGlioma
dc.subjectBrain Neoplasms
dc.subjectLysine
dc.subjectMethionine
dc.subjectHistones
dc.subjectGene Expression Profiling
dc.subjectDNA Methylation
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectMutation
dc.subjectPrincipal Component Analysis
dc.subjectAdolescent
dc.subjectChild
dc.subjectChild, Preschool
dc.subjectFemale
dc.subjectMale
dc.subjectEpigenomics
dc.subjectTranscriptome
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.
dc.typeJournal Article
dcterms.dateAccepted2018-10-10
rioxxterms.versionofrecord10.1186/s40478-018-0614-1
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-11-05
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfActa neuropathologica communications
pubs.issue1
pubs.notesNot known
pubs.organisational-group/ICR
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.organisational-group/ICR
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
pubs.volume6
pubs.embargo.termsNot known
icr.researchteamGlioma Teamen_US
dc.contributor.icrauthorJones, Chrisen


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