Epco-34. Integrative Dna Methylation Analysis of Pediatric Brain Tumors Reveals Tumor Type-Specific Developmental Trajectories and Epigenetic Signatures of Malignancy

Abstract

Understanding oncogenic epigenetic mechanisms in brain tumors is crucial for improved diagnosis and treatment. Recently DNA methylation has proven to be powerful for brain tumor characterization and diagnostic classification. To evaluate tumor type specific features, we compared atypical teratoid/rhabdoid tumors (AT/RTs), medulloblastomas (MBs), and choroid plexus tumors with each other by integrating DNA methylation (507 samples), gene expression (120 samples), and transcription factor (TF) -binding data. Different tumor entities were used to find unique changes affecting each of the entities and further to identify functions driven by these changes. Our results provide insight on how the aberrant DNA methylation induces oncogenesis of AT/RTs. These tumors are known for their aggressiveness and exceptionally low mutation rates. Our results suggest that in AT/RT, elevated DNA methylation masks the binding sites of TFs such as NEUROD1, ASCL1 and MYCN driving neural development. DNA methylation in AT/RTs is also associated with reduced gene expression for specific neural regulators such as NEUROG1 and NEUROD2. For MBs, DNA methylation patterns predict a more advanced differentiation state. In MB, we found masked TF binding sites for TFs such as REST and ZEB1 that normally inhibit neural differentiation. We then wanted to further characterize DNA methylation and compared these tumors to pluripotent stem cells (PSCs) and normal fetal brain samples. As a result, we were able to find two different regulatory programs in AT/RTs: One in which DNA methylation is similar to PSCs and which harbors mostly neural TF binding sites. Second program has AT/RT-specific DNA methylation, and these sites are uniquely associated with polycomb repressive complex 2 members. However, this second program also covers neural TF binding sites and is likely to have relevance in oncogenic regulation.