DNA Methylation Profiling in IDH-Mutant Gliomas: Biological Evolution, Molecular Grading and Clinical Implementation

Mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) define a major subgroup of adult-type diffuse gliomas and induce accumulation of D-2-hydroxyglutarate, resulting in extensive DNA and histone methylation changes. This epigenetic reprogramming underlies the glioma CpG island methylator phenotype (G-CIMP) and contributes to tumour lineage, differentiation state and clinical behaviour. DNA methylation profiling has consequently evolved from a research tool into an important ancillary method for CNS tumour classification, molecular subclassification and copy-number analysis. This narrative review examines the biological basis, analytical platforms and clinical applications of DNA methylation profiling in IDH-mutant gliomas. Particular attention is given to the distinction between research-defined G-CIMP-high and G-CIMP-low states and classifier-defined lower-grade and high-grade methylation subclasses. High-grade signatures, including A_IDH_HG and G-CIMP-low, are associated with adverse genomic features and outcome but should not be considered interchangeable or used in isolation to assign CNS WHO grade. Their interpretation requires integration with histology and established molecular criteria, including homozygous CDKN2A/B deletion. The review also discusses array-based profiling, emerging Nanopore and long-read approaches, computational quality control, and the integration of methylation data with genomic and transcriptomic alterations. Longitudinal studies indicate that a subset of IDH-mutant astrocytomas undergoes methylation loss, copy-number accumulation and altered cell-state differentiation during progression, although these changes are not universal. The clinical relevance of MGMT promoter methylation is more context-dependent than in IDH-wildtype glioblastoma. Moreover, the INDIGO trial established the clinical activity of mutant IDH inhibition in selected Grade 2 gliomas but did not validate methylation class as a predictive biomarker or demonstrate complete epigenetic reversal. Emerging applications, including single-cell and spatial epigenomics, tumour microenvironment deconvolution and CSF methylation profiling, remain investigational. Overall, DNA methylation profiling is most valuable when used as integrated diagnostic and risk-stratification evidence within the complete histological, genomic and clinical context.