Youri Hoogstrate, Santoesha A. Ghisai, Levi van Hijfte, Rania Head, Iris de Heer, Marta Padovan, Maurice de Wit, Wies 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 Marten Hazelbag, Mathilde C.M. Kouwenhoven, Yongsoo Kim, Bart A. Westerman, Bauke Ylstra, Anneke Niers, Kevin C. Johnson, Frederick S. Varn, Roel G.W. Verhaak, Mustafa Khasraw, Martin J. van den Bent, Pieter Wesseling, Pim J. French
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.