The role of DNA methylation in directing treatment in medulloblastoma

Medulloblastoma is the most common malignant childhood brain tumor. The disease exhibits significant clinical and molecular heterogeneity which leads to significant differences in outcome. Although survival rates have improved in recent years, outcome for patients with high-risk disease remains poor and survival is associated with significant treatment associated morbidity. Traditional risk stratification was established largely on the basis of clinical and histological factors, but these are not sufficient to capture the full biologic complexity of the disease. Recent advances have underscored the role of DNA methylation as a powerful epigenetic biomarker for precise subgroup stratification and prognostic classification of medulloblastoma into four primary molecular subtypes: WNT, SHH, Group 3, and Group 4. This review summarizes mechanisms of DNA methylation in cancer biology, methylation profiling analytical approaches, and their application in delineating medulloblastoma subtypes. Specific attention is placed on the clinical utility of methylation-based classifiers for guiding therapeutic decisions and clinical trial design.