1. Epigenetic landscape reorganisation and reactivation of embryonic development genes are associated with malignancy in IDH-mutant astrocytoma.
- Author
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Ghisai, Santoesha A., van Hijfte, Levi, Vallentgoed, Wies R., Tesileanu, C. Mircea S., de Heer, Iris, Kros, Johan M., Sanson, Marc, Gorlia, Thierry, Wick, Wolfgang, Vogelbaum, Michael A., Brandes, Alba A., Franceschi, Enrico, Clement, Paul M., Nowak, Anna K., Golfinopoulos, Vassilis, van den Bent, Martin J., French, Pim J., and Hoogstrate, Youri
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RNA sequencing ,ASTROCYTOMAS ,EMBRYOLOGY ,GENETIC transcription ,DNA methylation - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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