Histone H3-wild type diffuse midline gliomas with H3K27me3 loss are a distinct entity with exclusive EGFR or ACVR1 mutation and differential methylation of homeobox genes

Ajuyah, P; Mayoh, C; Lau, LMS; Barahona, P; Wong, M; Chambers, H; Valdes-Mora, F; Senapati, A; Gifford, AJ; D&#39;Arcy, C; Hansford, JR; Manoharan, N; Nicholls, W; Williams, MM; Wood, PJ; Cowley, MJ; Tyrrell, V; Haber, M; Ekert, PG; Ziegler, DS; Khuong-Quang, DA

Author(s): Ajuyah, P; Mayoh, C; Lau, LMS; Barahona, P; Wong, M; Chambers, H; Valdes-Mora, F; Senapati, A; Gifford, AJ; D'Arcy, C; Hansford, JR; Manoharan, N; Nicholls, W; Williams, MM; Wood, PJ; Cowley, MJ; Tyrrell, V; Haber, M; Ekert, PG; Ziegler, DS; Khuong-Quang, DA;
Details: Publication Year 2023-03-07,Volume 13,Issue #1,Page 3775
Journal Title: Scientific Reports
Publication Type: Research article
Abstract: Diffuse midline gliomas (DMG) harbouring H3K27M mutation are paediatric tumours with a dismal outcome. 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). 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. 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. 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. 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. 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 study has been retrospectively registered on clinicaltrial.gov on 8 November 2017 under the registration number NCT03336931 ( https://clinicaltrials.gov/ct2/show/NCT03336931 ).
Publisher: Springer Nature
Keywords: Child; Humans; *Genes, Homeobox; Histones/genetics; Methylation; *Glioma/genetics; Mutation; ErbB Receptors/genetics; Activin Receptors, Type I
Department(s): Laboratory Research
PubMed ID: 36882456
Publisher's Version: https://doi.org/10.1038/s41598-023-30395-4
Open Access at Publisher's Site: https://doi.org/10.1038/s41598-023-30395-4
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-06-22 07:56:45

Last Modified: 2023-06-22 07:57:28