Cross-Platform DNA Methylation Classifier for the Eight Molecular Subtypes of Group 3 & 4 Medulloblastoma

Abstract

Medulloblastoma is a malignant pediatric brain cancer, and the discovery of molecular subgroups is enabling personalized treatment strategies. In 2019, a consensus identified eight novel subtypes within Groups 3 and 4, each displaying heterogeneous characteristics. Classifiers are essential for translating these findings into clinical practice by supporting clinical trials, personalized therapy development and application, and patient monitoring. This study presents a DNA methylation-based, cross-platform machine learning classifier capable of distinguishing these subtypes on both HM450 and EPIC methylation array samples. Across two independent test sets, the model achieved weighted F1 = 0.95 and balanced accuracy = 0.957, consistent across platforms. As the first cross-platform solution, it provides backward compatibility while extending applicability to a newer platform, also enhancing accessibility. It also has the potential to become the first publicly available classifier for these subtypes once deployed through a web application, as planned in the future. This work overall takes steps in the direction of advancing precision medicine and improving clinical outcomes for patients within the majority prevalence medulloblastoma subgroups, groups 3 and 4.