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

## TL;DR

This study shows that DNA methylation changes in IDH-mutant brain tumors follow a shared pattern linked to TET enzyme activity, enabling a new way to predict tumor progression.

## Contribution

The study introduces a DNA methylation-based grading coefficient that improves upon WHO grading for IDH-mutant gliomas.

## Key findings

- IDH-mutant gliomas progress along a shared epigenetic axis marked by DNA methylation changes.
- Demethylation patterns correlate with TET enzyme sequence preferences.
- A continuous grading coefficient outperforms traditional WHO grading in predicting tumor aggressiveness.

## 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 (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.

•Oligodendrogliomas and astrocytomas progress along a shared epigenetic axis•A continuous grading coefficient is available as freely accessible computational model•Sequence context-specific demethylation correlates with TET enzyme sequence preference

Oligodendrogliomas and astrocytomas progress along a shared epigenetic axis

A continuous grading coefficient is available as freely accessible computational model

Sequence context-specific demethylation correlates with TET enzyme sequence preference

Hoogstrate et al. reveal that IDH-mutant oligodendrogliomas and astrocytomas undergo continuous DNA methylation changes over a shared epigenetic axis during progression. The extent of demethylation across sequence contexts reflects the preferences of TET enzymes demethylating DNA. The prognostic axis of DNA methylation changes is incorporated into a computer application.