ATRT-16. MAPPING THE DISORDERED METHYLOME IN ATRT

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Abstract BACKGROUND Atypical Teratoid Rhabdoid Tumor (ATRT) is an aggressive pediatric brain tumor driven by inactivation of the chromatin regulator SMARCB1, with remarkably few other mutations. SMARCB1 loss leads to epigenetic dysregulation which plays a pivotal role in ATRT development and progression, and DNA methylation profiling has distinguished molecular subgroups of this disease. However, studies that provide a static view of the epigenome may not capture epigenetic variability that drives cellular plasticity and heterogeneity. Mapping epigenetic variability is crucial to understanding the phenotypic plasticity of this tumor and its ability to evade therapeutic interventions in the clinic. METHODS We performed whole genome bisulfite sequencing (WGBS) on 22 ATRT samples, 4 normal fetal brain controls, and 1 hindbrain neural stem cell control, and applied a novel analytic pipeline (InformME) to generate DNA methylation potential energy landscapes encapsulating epigenetic stochasticity. This characterizes mean methylation as well as methylation entropy. We identified key genes and regulatory regions with the most stochastic methylation signatures. RESULTS We find that ATRT exhibits a globally destabilized epigenome, with markedly elevated methylation entropy (a measure of variability/disorder). Methylation discordance mapped to key regulatory regions including bivalent promoters, quiescent chromatin regions, and enhancers, and specific genes, with an enrichment for targets of the Polycomb repressive complex 2 and regulators of pluripotency and differentiation. CONCLUSIONS The disordered methylome of ATRT could play a critical role in the tumor’s ability to evade therapies. Mapping the targets of epigenetic instability can identify targets for intervention. Moreover, strategies to constrain epigenetic variability may have therapeutic benefit by limiting the number of epigenetic states available to cancer cells.