DNA Methylation Profiling Reveals a Novel Subtype Harboring IDH Mutation in H3-altered Gliomas - PubMed
6 hours ago
- #IDH mutation
- #H3-altered gliomas
- #DNA methylation
- H3-altered gliomas are classified as WHO grade 4 neoplasms with histone H3 mutations (H3K27M and H3G34R/V), showing molecular heterogeneity and poor survival.
- DNA methylation profiling identified four subtypes: DMG_K27M, GBM_RTK, DHG_G34, and a novel IDH/H3_comut subtype with co-occurring IDH and H3 mutations.
- The IDH/H3_comut subtype exhibits global DNA hypermethylation, neurodevelopmental gene enrichment, and improved survival compared to other subtypes.
- GBM_RTK tumors show hypomethylation of cell-cycle enhancers and aggressive phenotypes, while DHG_G34 and DMG_K27M display distinct epigenetic features.
- Single-cell transcriptomics revealed distinct lineage compositions and microenvironments, with IDH/H3_comut tumors enriched in NPC-like cells.
- Clonal and spatial analyses suggest cooperative evolution between IDH- and H3-mutant cells rather than exclusive evolution.
- The study identifies subtype-specific therapeutic vulnerabilities, including potential responsiveness to hypomethylating agents or CDK4/6 inhibitors.