Epigenetic landscape reorganisation and reactivation of embryonic development genes are associated with malignancy in IDH-mutant astrocytoma.
Astrocytoma
DNA methylation
HOX
IDH
Molecular grading
RNA sequencing
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
09 Oct 2024
09 Oct 2024
Historique:
received:
06
06
2024
accepted:
30
09
2024
revised:
17
09
2024
medline:
9
10
2024
pubmed:
9
10
2024
entrez:
9
10
2024
Statut:
epublish
Résumé
Accurate grading of IDH-mutant gliomas defines patient prognosis and guides the treatment path. Histological grading is challenging, and aside from CDKN2A/B homozygous deletions in IDH-mutant astrocytomas, there are no other objective molecular markers used for grading. RNA-sequencing was conducted on primary IDH-mutant astrocytomas (n = 138) included in the prospective CATNON trial, which was performed to assess the prognostic effect of adjuvant and concurrent temozolomide. We integrated the RNA-sequencing data with matched DNA-methylation and NGS data. We also used multi-omics data from IDH-mutant astrocytomas included in the TCGA dataset and validated results on matched primary and recurrent samples from the GLASS-NL study. Since discrete classes do not adequately capture grading of these tumours, we utilised DNA-methylation profiles to generate a Continuous Grading Coefficient (CGC) based on classification scores from a CNS-tumour classifier. CGC was an independent predictor of survival outperforming current WHO-CNS5 and methylation-based classification. Our RNA-sequencing analysis revealed four distinct transcription clusters that were associated with (i) upregulation of cell cycling genes; (ii) downregulation of glial differentiation genes; (iii) upregulation of embryonic development genes (e.g. HOX, PAX, and TBX) and (iv) upregulation of extracellular matrix genes. The upregulation of embryonic development genes was associated with a specific increase of CpG island methylation near these genes. Higher grade IDH-mutant astrocytomas have DNA-methylation signatures that, on the RNA level, are associated with increased cell cycling, tumour cell de-differentiation and extracellular matrix remodelling. These combined molecular signatures can serve as an objective marker for grading of IDH-mutant astrocytomas.
Identifiants
pubmed: 39382765
doi: 10.1007/s00401-024-02811-0
pii: 10.1007/s00401-024-02811-0
doi:
Substances chimiques
Isocitrate Dehydrogenase
EC 1.1.1.41
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
50Subventions
Organisme : Brain Tumour Charity
ID : GN-000577
Organisme : KWF Kankerbestrijding
ID : 10685
Organisme : NRG Oncology
ID : U10CA180868
Organisme : NRG Oncology
ID : U10CA180822
Organisme : Cancer Research UK
ID : CRUK/07/028
Pays : United Kingdom
Organisme : Cancer Australia
ID : 1026842
Organisme : Cancer Australia
ID : 1078655
Informations de copyright
© 2024. The Author(s).
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