DNA methylation in glioma: clinical biomarkers and emerging biosensor-based diagnostics

Gliomas are the most common malignant primary tumors of the central nervous system (CNS) and are characterized by marked molecular heterogeneity, aggressive clinical behavior, and poor patient outcomes. Among the epigenetic alterations implicated in glioma pathogenesis, DNA methylation has emerged as a key regulatory mechanism with important diagnostic, prognostic, and predictive value. Clinically established biomarkers, including O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and the glioma CpG island methylator phenotype (G-CIMP), have transformed patient stratification and therapeutic decision-making, while additional methylation signatures continue to expand the molecular classification of glioma. Conventional methylation detection methods, although highly accurate, remain limited by their cost, complexity, and dependence on specialized laboratory infrastructure. This review summarizes current knowledge of DNA methylation biology in glioma, discusses established and emerging methylation biomarkers, and critically examines recent advances in biosensor-based detection technologies, including electrochemical, optical, microfluidic, and nanopore-based platforms, together with enzyme-assisted and immunoaffinity-based molecular recognition strategies that can be combined with these transducers. These technologies, particularly when combined with nanomaterials, signal amplification strategies, and liquid biopsy approaches, offer highly sensitive, rapid, and minimally invasive detection of methylated circulating tumor DNA, supporting the development of point-of-care diagnostics. Despite encouraging progress, challenges related to analytical standardization, tumor heterogeneity, cross-reactivity, large-scale clinical validation, and regulatory translation remain significant barriers to routine implementation. By integrating recent advances in glioma epigenetics with emerging biosensing technologies, this review provides a comprehensive overview of the current landscape and highlights future opportunities for translating DNA methylation biomarkers into clinically accessible precision diagnostic platforms.