TET CpG sequence-context-specific DNA demethylation shapes progression of IDH-mutant gliomas.

Authors

• Youri Hoogstrate
• Santoesha A Ghisai
• Levi van Hijfte
• Rania Head
• Iris de Heer
• Marta Padovan
• Maurice de Wit
• Wies R Vallentgoed
• Angelo Dipasquale
• Maarten M J Wijnenga
• Bas Weenink
• Rosa Luning
• Sybren L N Maas
• Adela Brzobohata
• Michael Weller
• Tobias Weiss
• Maximilian J Mair
• Anna S Berghoff
• Adelheid Wöhrer
• Albert Jeltsch
• Johan A F Koekkoek
• Hans M Hazelbag
• Mathilde C M Kouwenhoven
• Yongsoo Kim
• Bart A Westerman
• Bauke Ylstra
• Anneke M Niers
• Kevin C Johnson
• Frederick S Varn, The Jackson LaboratoryFollow
• Roel G W Verhaak
• Mustafa Khasraw
• Martin J van den Bent
• Pieter Wesseling
• Pim J French

Document Type

Article

Publication Date

3-17-2026

Original Citation

Hoogstrate Y, Ghisai S, van Hijfte L, Head R, de Heer I, Padovan M, de Wit M, Vallentgoed W, Dipasquale A, Wijnenga M, Weenink B, Luning R, Maas S, Brzobohata A, Weller M, Weiss T, Mair M, Berghoff A, Wöhrer A, Jeltsch A, Koekkoek J, Hazelbag H, Kouwenhoven M, Kim Y, Westerman B, Ylstra B, Niers A, Johnson K, Varn F, Verhaak R, Khasraw M, van den Bent M, Wesseling P, French P. TET CpG sequence-context-specific DNA demethylation shapes progression of IDH-mutant gliomas. Cell Rep Med. 2026;7(3):102682.

Keywords

JGM, Humans, Isocitrate Dehydrogenase, CpG Islands, Mutation, Glioma, Brain Neoplasms, Disease Progression, DNA Methylation, Female, DNA Demethylation, Oligodendroglioma, Male, Middle Aged, Epigenesis, Genetic, Adult, Neoplasm Grading, Proto-Oncogene Proteins, Prognosis

JAX Source

Cell Rep Med. 2026;7(3):102682.

ISSN

2666-3791

PMID

41850239

DOI

https://doi.org/10.1016/j.xcrm.2026.102682

Abstract

Treatment decisions in IDH-mutant oligodendrogliomas are shaped by tumor aggressiveness, underscoring the need for objective grading of these malignant brain tumors. We collect 302 primary and recurrent resections from oligodendrogliomas and perform Ki-67 staining, proteomics, and DNA methylation profiling. During tumor progression, DNA methylation of oligodendrogliomas changes along a continuum. This continuum is linked to increased epigenetic aging, methylation of transcription factors and Ki-67+ cell density, and large-scale DNA demethylation. Demethylation correlates with CpG flanking sequences preferred by TET enzymes. We confirm these findings in previously profiled astrocytomas, indicating IDH-mutant gliomas progress along a shared epigenetic axis. We develop an objective DNA methylation-based prognostic continuous grading coefficient (CGC^ψ) that captures these changes and outperforms the World Health Organization (WHO) grading for oligodendrogliomas. Our findings underscore the potential of DNA methylation-based grading to more accurately reflect tumor biology and inform clinical decision-making in IDH-mutant gliomas.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.