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

Hoogstrate, Y.; Ghisai, S. A.; van Hijfte, L.; Head, R.; de Heer, I.; Padovan, M.; de Wit, M.; Vallentgoed, W. R.; Dipasquale, A.; Wijnenga, M. M. J.; Weenink, B.; Luning, R.; Maas, S. L. N.; Brzobohata, A.; Weller, M.; Weiss, T.; Mair, M. J.; Berghoff, A. S.; Woehrer, A.; Jeltsch, A.; Koekkoek, J. A. F.; Hazelbag, H. M.; Kouwehoven, M. C. M.; Kim, Y.; Westerman, B. A.; Ylstra, B.; Niers, J. M.; Johnson, K. C.; Verhaak, R. G. W.; Varn, F. S.; Khasraw, M.; van den Bent, M. J.; Wesseling, P.; French, P. J.

doi:10.1101/2025.10.09.681314

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bioRxiv · 10.1101/2025.10.09.681314

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

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Abstract

BackgroundTreatment decisions in IDH-mutant oligodendrogliomas are shaped by tumor aggressiveness, underscoring the need for objective grading of these malignant brain tumors. Material and MethodsWe collected 302 primary and recurrent resections from oligodendrogliomas and performed Ki-67 staining, proteomics and DNA methylation profiling. Results & conclusionDuring tumor progression, DNA methylation of oligodendrogliomas changed along a continuum. This continuum is linked to increased epigenetic aging, methylation of transcription factors and Ki-67+ cell density, and to large scale DNA demethylation. Demethylation was correlated with CpGs flanking sequences preferred by TET enzymes. We confirmed these findings in previously profiled astrocytomas, indicating IDH-mutant gliomas progress along a shared epigenetic axis. We developed an objective DNA methylation based prognostic continuous grading coefficient (CGC{psi}) that captured these changes and outperformed 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.

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Hoogstrate, Y., Ghisai, S. A., van Hijfte, L., Head, R., de Heer, I., Padovan, M., de Wit, M., Vallentgoed, W. R., Dipasquale, A., Wijnenga, M. M. J., Weenink, B., Luning, R., Maas, S. L. N., Brzobohata, A., Weller, M., Weiss, T., Mair, M. J., Berghoff, A. S., Woehrer, A., Jeltsch, A., Koekkoek, J. A. F., Hazelbag, H. M., Kouwehoven, M. C. M., Kim, Y., Westerman, B. A., Ylstra, B., Niers, J. M., Johnson, K. C., Verhaak, R. G. W., Varn, F. S., Khasraw, M., van den Bent, M. J., Wesseling, P., French, P. J.. 2025-10-10. TET CpG sequence context specific DNA demeth-ylation shapes progression of IDH-mutant gliomas. https://doi.org/10.1101/2025.10.09.681314

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