Genome-Wide DNA Methylation Profiling as Frontline Diagnostics for Central Nervous System Embryonal Tumors in Hong Kong

SIMPLE SUMMARY: Genome-wide DNA methylation profiling has emerged as an important diagnostic tool that complements histopathology for characterizing central nervous system (CNS) tumors. The literature describing its application in Asian countries is limited. We report the feasibility and utility of adopting such profiling for children with diagnosed CNS tumors in Hong Kong. The study included samples of 97 patients with CNS embryonal or high-grade neuroepithelial tumors (HGNETs). In our DNA methylation-profiled cohort, 67% of results correlated with the diagnosis and assigned molecular subgroup and 12% of results led to revision/reassignment of diagnosis. Patient outcomes correlated significantly with methylation-based subgroups. In addition, novel clinical–histologic–molecular associations were described. Taken together, epigenomic profiling enabled clinically relevant refinement of disease classification of pediatric CNS tumors. The availability of such methodology in Asia sets the stage for international collaborations in molecularly driven trials. ABSTRACT: This paper examines the link between CNS tumor biology and heterogeneity and the use of genome-wide DNA methylation profiling as a clinical diagnostic platform. CNS tumors are the most common solid tumors in children, and their prognosis remains poor. This study retrospectively analyzed pediatric patients with CNS embryonal tumors in Hong Kong between 1999 and 2017, using data from the territory-wide registry and available formalin-fixed paraffin-embedded tumor tissue. After processing archival tumor tissue via DNA extraction, quantification, and methylation profiling, the data were analyzed by using the web-based DKFZ classifier (Molecular Neuropathology (MNP) 2.0 v11b4) and t-SNE analysis. Methylation profiles were deemed informative in 85 samples. Epigenetic data allowed molecular subgrouping and confirmed diagnosis in 65 samples, verified histologic diagnosis in 8, and suggested an alternative diagnosis in 12. This study demonstrates the potential of DNA methylation profiling in characterizing pediatric CNS embryonal tumors in a large cohort from Hong Kong, which should enable regional and international collaboration in future pediatric neuro-oncology research.