Longitudinal changes in DNA methylation in IDH-mutant glioma fuel disease progression through altered cell state differentiation [Smart-seq2]

Here, we profiled a longitudinal cohort of 36 IDH-G samples from 19 patients by joint-capture multi-omic single-nucleus (sn) DNA methylation and snRNA-seq. We show that IDH-G progression is associated with increase in malignant stem-like states, decreased differentiation and with 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 based on high-resolution phylogenetic trees connects DNA methylation loss to alterations in glioma cell states encoding and heritability. Our study offers insights on how DNA methylation loss reshapes cellular transitions and how it may mark clinically more aggressive tumors across IDH-G subsets.