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

Hoogstrate Y, Ghisai SA, van Hijfte L, Head R, de Heer I, Padovan M, de Wit M, Vallentgoed WR, Dipasquale A, Wijnenga MM, Weenink B, Luning R, Maas SL, Brzobohata A, Weller M, Weiss T, Mair MJ, Berghoff AS, Wöhrer A, Jeltsch A, Koekkoek JA, Hazelbag HM, Kouwenhoven MC, Kim Y, Westerman BA, Ylstra B, Niers AM, Johnson KC, Varn FS, Verhaak RG, Khasraw M, van den Bent MJ, Wesseling P, French PJ (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Cell Reports Medicine Elsevier

Book Volume: 7

Article Number: 102682

Journal Issue: 3

DOI: 10.1016/j.xcrm.2026.102682

Abstract

SummaryTreatment 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 (CGCψ) 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.

Authors with CRIS profile

Levi van Hijfte Department of Neurosurgery

Involved external institutions

Erasmus University Medical Center (MC) NL Netherlands (NL) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra NL Netherlands (NL) Yale University US United States (USA) (US) Jackson Laboratory US United States (USA) (US) Duke University US United States (USA) (US) Istituto Oncologico Veneto (IOV), IRCCS IT Italy (IT) Humanitas Research Hospital / IRCCS Istituto Clinico Humanitas IT Italy (IT) Universitätsspital Zürich (USZ) CH Switzerland (CH) Medizinische Universität Wien AT Austria (AT) Medizinische Universität Innsbruck AT Austria (AT) Universität Stuttgart DE Germany (DE) Leiden University Medical Center NL Netherlands (NL) Haaglanden Medical Center (HMC) NL Netherlands (NL)

How to cite

APA:

Hoogstrate, Y., Ghisai, S.A., van Hijfte, L., Head, R., de Heer, I., Padovan, M.,... French, P.J. (2026). TET CpG sequence-context-specific DNA demethylation shapes progression of IDH-mutant gliomas. Cell Reports Medicine, 7(3). https://doi.org/10.1016/j.xcrm.2026.102682

MLA:

Hoogstrate, Youri, et al. "TET CpG sequence-context-specific DNA demethylation shapes progression of IDH-mutant gliomas." Cell Reports Medicine 7.3 (2026).

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