TY - JOUR
T1 - TET CpG sequence-context-specific DNA demethylation shapes progression of IDH-mutant gliomas
AU - Hoogstrate, Youri
AU - Ghisai, Santoesha A.
AU - van Hijfte, Levi
AU - Head, Rania
AU - de Heer, Iris
AU - Padovan, Marta
AU - de Wit, Maurice
AU - Vallentgoed, Wies R.
AU - Dipasquale, Angelo
AU - Wijnenga, Maarten M.J.
AU - Weenink, Bas
AU - Luning, Rosa
AU - Maas, Sybren L.N.
AU - Brzobohata, Adela
AU - Weller, Michael
AU - Weiss, Tobias
AU - Mair, Maximilian J.
AU - Berghoff, Anna S.
AU - Wöhrer, Adelheid
AU - Jeltsch, Albert
AU - Koekkoek, Johan A.F.
AU - Hazelbag, Hans M.
AU - Kouwenhoven, Mathilde C.M.
AU - Kim, Yongsoo
AU - Westerman, Bart A.
AU - Ylstra, Bauke
AU - Niers, Anneke M.
AU - Johnson, Kevin C.
AU - Varn, Frederick S.
AU - Verhaak, Roel G.W.
AU - Khasraw, Mustafa
AU - van den Bent, Martin J.
AU - Wesseling, Pieter
AU - French, Pim J.
N1 - Publisher Copyright:
© 2026 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license. http://creativecommons.org/licenses/by/4.0/
PY - 2026/3/17
Y1 - 2026/3/17
N2 - 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 (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.
AB - 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 (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.
UR - https://www.scopus.com/pages/publications/105033694630
U2 - 10.1016/j.xcrm.2026.102682
DO - 10.1016/j.xcrm.2026.102682
M3 - Article
C2 - 41850239
AN - SCOPUS:105033694630
SN - 2666-3791
VL - 7
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 3
M1 - 102682
ER -