Integrative DNA methylation analysis of pediatric brain tumors reveals tumor type-specific developmental trajectories and epigenetic signatures of malignancy

Understanding oncogenic epigenetic mechanisms in brain tumors is crucial for improved diagnosis and treatment. To evaluate tumor type-specific features, we compared atypical teratoid/rhabdoid tumors (AT/RTs), medulloblastomas, and choroid plexus tumors with each other by integrating DNA methylation (507 samples), gene expression (120 samples), and transcription factor (TF) -binding data. Our results suggest that aberrant DNA methylation plays a vital role in the oncogenesis of AT/RTs, which are known for their aggressiveness and exceptionally low mutation rates. In AT/RT, elevated DNA methylation masks the binding sites of TFs driving neural development and is associated with reduced gene expression for specific neural regulators, whereas DNA methylation patterns predict a more advanced differentiation state for MB. By analyzing the data together with pluripotent stem cells, we found two regulatory programs in AT/RT: pluripotent stem cell -like DNA methylation patterns and AT/RT-specific DNA methylation uniquely associated with polycomb repressive complex 2 (PRC2) members. Both methylation patterns cover neural TF binding sites in a TF-specific manner, suggesting their relevance for oncogenic regulation. ### Competing Interest Statement The authors have declared no competing interest.