DNA methylation profiling in central nervous system tumors: Where do we draw the line of clinical utility?

DNA methylation profiling has emerged as a transformative tool in the epigenetic classification and diagnosis of central nervous system (CNS) tumors, offering unprecedented resolution in distinguishing morphologically overlapping entities. The advent of methylation-based classifiers has refined the diagnostic landscape, enabling improved tumor stratification, prognostication, and even therapeutic decision-making. In CNS malignancies, DNA methylation profiling offers tumor-specific epigenetic "fingerprints" that improve diagnostic accuracy and repeatability. It improves the classification of glioneuronal tumors, ependymomas, and juvenile gliomas, eliminates 9%-25% of histopathological discrepancies, improves grading in up to 18% of instances, and achieves > 70% concordance with integrated histo-molecular diagnosis. However, its application in routine neuropathology practice raises critical questions regarding necessity, accessibility, and cost-effectiveness. While methylation signatures have proven indispensable in diagnostically ambiguous or rare cases, their universal application to all CNS tumors remains debatable, especially in settings where robust histopathology, immunohistochemistry, and targeted molecular assays already provide reliable diagnostic accuracy. This editorial explores the strengths and limitations of DNA methylation profiling, examining its role as a complementary vs mandatory tool in routine practice. We argue for a balanced approach, where methylation is deployed selectively, prioritized for diagnostically challenging, morphologically ambiguous tumors or in the context of clinical trials rather than applied indiscriminately. Such an evidence-driven framework may optimize resource utilization while ensuring diagnostic precision in CNS tumor pathology.