Longitudinal changes in DNA methylation in IDH-mutant glioma fuel disease progression through altered cell state...

The progression of isocitrate dehydrogenase-mutant glioma (IDH-G) from slow-growing tumor to fatal disease is associated with transcriptional and DNA methylation changes that remain poorly understood. Here, we profiled a longitudinal cohort of 36 IDH-G samples from 19 patients by joint-capture multi-omic single-nucleus DNA methylation, single-nucleus RNA sequencing and bulk exome sequencing. We show that IDH-G progression is associated with an increase in malignant stem-like states, decreased differentiation and methylation loss, which marks tumors with worse clinical outcome. Methylation loss was uniformly observed across malignant cells within individual tumors, suggesting that it may underlie rather than result from the increase in stem-like states. Analysis of cell-state heritability and plasticity using high-resolution phylogenetic trees links DNA methylation loss to alterations in glioma cell-state encoding and heritability. Our study offers insights into how DNA methylation loss reshapes cellular transitions and how it may mark clinically more aggressive tumors across IDH-G subsets.