![]() ![]() Thus, they were defined as a new entity, called diffuse midline glioma, H3K27M-mutant (H3K27M DMG) in the 2016 WHO Classification of Tumours of the Central Nervous System (CNS) 4. About half of these tumours occur in midline locations 3, and unique recurrent K27M missense mutations in genes encoding the histone H3 characterise approximately 84% of diffuse intrinsic pontine gliomas and 60% of other midline tumours 2. The advent of next generation sequencing has defined distinct genomic profiles that cluster with age at presentation and anatomical location 1, 2. High grade gliomas (HGG) remain a leading cause of death in childhood, with a five-year overall survival of less than 20% despite aggressive therapeutic approaches. This study has been retrospectively registered on on 8 November 2017 under the registration number NCT03336931 ( ). ![]() ![]() It also gives new insights into the possible mechanism and pathway regulation in these tumours, potentially opening new therapeutic avenues for these tumours which have no known effective treatment. This in-depth exploration of H3-WT tumours further characterises this novel DMG, H3K27-altered sub-group, characterised by a specific immunohistochemistry profile with H3K27me3 loss, wild-type H3K27M and positive EZHIP. Affected patients share a similar poor prognosis as patients with H3K27M DMG. Global molecular analysis of H3-WT and H3K27M DMG reveal distinct transcriptome and methylome profiles including differential methylation of homeobox genes involved in development and cellular differentiation. Patients have distinct clinical features, with a trend demonstrating ACVR1 mutations occurring in H3-WT tumours at an older age. We show that these tumours have recurrent and mutually exclusive mutations in either ACVR1 or EGFR and are characterised by high expression of EZHIP associated to its promoter hypomethylation. Here, we report a cohort of five H3-WT tumours profiled by whole-genome sequencing, RNA sequencing and DNA methylation profiling and combine their analysis with previously published cases. Recently, a new subtype of midline gliomas has been described with similar features to DMG, including loss of H3K27 trimethylation, but lacking the canonical H3K27M mutation (H3-WT). Diffuse midline gliomas (DMG) harbouring H3K27M mutation are paediatric tumours with a dismal outcome. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |