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
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,...
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-03-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-30395-4 |
| _version_ | 1797864703588827136 |
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| author | Pamela Ajuyah Chelsea Mayoh Loretta M. S. Lau Paulette Barahona Marie Wong Hazel Chambers Fatima Valdes-Mora Akanksha Senapati Andrew J. Gifford Colleen D’Arcy Jordan R. Hansford Neevika Manoharan Wayne Nicholls Molly M. Williams Paul J. Wood Mark J. Cowley Vanessa Tyrrell Michelle Haber Paul G. Ekert David S. Ziegler Dong-Anh Khuong-Quang |
| author_facet | Pamela Ajuyah Chelsea Mayoh Loretta M. S. Lau Paulette Barahona Marie Wong Hazel Chambers Fatima Valdes-Mora Akanksha Senapati Andrew J. Gifford Colleen D’Arcy Jordan R. Hansford Neevika Manoharan Wayne Nicholls Molly M. Williams Paul J. Wood Mark J. Cowley Vanessa Tyrrell Michelle Haber Paul G. Ekert David S. Ziegler Dong-Anh Khuong-Quang |
| author_sort | Pamela Ajuyah |
| collection | DOAJ |
| description | 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 ). |
| first_indexed | 2024-04-09T22:57:26Z |
| format | Article |
| id | doaj.art-8e8fabf3268f4381b287194aa795890c |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-09T22:57:26Z |
| publishDate | 2023-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-8e8fabf3268f4381b287194aa795890c2023-03-22T11:13:25ZengNature PortfolioScientific Reports2045-23222023-03-0113111310.1038/s41598-023-30395-4Histone H3-wild type diffuse midline gliomas with H3K27me3 loss are a distinct entity with exclusive EGFR or ACVR1 mutation and differential methylation of homeobox genesPamela Ajuyah0Chelsea Mayoh1Loretta M. S. Lau2Paulette Barahona3Marie Wong4Hazel Chambers5Fatima Valdes-Mora6Akanksha Senapati7Andrew J. Gifford8Colleen D’Arcy9Jordan R. Hansford10Neevika Manoharan11Wayne Nicholls12Molly M. Williams13Paul J. Wood14Mark J. Cowley15Vanessa Tyrrell16Michelle Haber17Paul G. Ekert18David S. Ziegler19Dong-Anh Khuong-Quang20Lowy Cancer Research Centre, Children’s Cancer Institute, UNSW SydneyLowy Cancer Research Centre, Children’s Cancer Institute, UNSW SydneyLowy Cancer Research Centre, Children’s Cancer Institute, UNSW SydneyLowy Cancer Research Centre, Children’s Cancer Institute, UNSW SydneyLowy Cancer Research Centre, Children’s Cancer Institute, UNSW SydneyDepartment of Anatomical Pathology, Royal Children’s Hospital, University of MelbourneLowy Cancer Research Centre, Children’s Cancer Institute, UNSW SydneyKids Cancer Centre, Sydney Children’s HospitalLowy Cancer Research Centre, Children’s Cancer Institute, UNSW SydneyDepartment of Anatomical Pathology, Royal Children’s Hospital, University of MelbourneChildren’s Cancer Centre, Royal Children’s HospitalSchool of Clinical Medicine, UNSW Medicine & Health, UNSW SydneyOncology Service, Children’s Health Queensland Hospital & Health ServiceChildren’s Cancer Centre, Royal Children’s HospitalDepartment of Paediatrics, School of Clinical Sciences at Monash Health, Monash UniversityLowy Cancer Research Centre, Children’s Cancer Institute, UNSW SydneyLowy Cancer Research Centre, Children’s Cancer Institute, UNSW SydneyLowy Cancer Research Centre, Children’s Cancer Institute, UNSW SydneyLowy Cancer Research Centre, Children’s Cancer Institute, UNSW SydneyLowy Cancer Research Centre, Children’s Cancer Institute, UNSW SydneyChildren’s Cancer Centre, Royal Children’s HospitalAbstract 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 ).https://doi.org/10.1038/s41598-023-30395-4 |
| spellingShingle | Pamela Ajuyah Chelsea Mayoh Loretta M. S. Lau Paulette Barahona Marie Wong Hazel Chambers Fatima Valdes-Mora Akanksha Senapati Andrew J. Gifford Colleen D’Arcy Jordan R. Hansford Neevika Manoharan Wayne Nicholls Molly M. Williams Paul J. Wood Mark J. Cowley Vanessa Tyrrell Michelle Haber Paul G. Ekert David S. Ziegler Dong-Anh Khuong-Quang 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 Scientific Reports |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | https://doi.org/10.1038/s41598-023-30395-4 |
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