Abstract 2120: Interrogation of regulatory and expression changes in Malignant Rhabdoid Tumours to identify new therapeutic approaches

Malignant Rhabdoid Tumors (MRTs) are a textbook model of epigenetic dysregulation within cancer. The biallelic inactivation of a single gene SMARCB1 in >95% of MRTs is sufficient to provoke a lethal pediatric cancer. SMARCB1 encodes a core subunit of the SWI/SNF complex and inactivation results in genome-wide deregulation of gene expression/pathways. SMARCB1 loss was previously shown to impair SWI/SNF enhancer targeting at TSS-distal enhancers and a model proposed whereby mutant residual SWI/SNF complexes preferentially binds to super-enhancers over typical-enhancers; thereby inappropriately maintaining progenitor lineage processes and blocking differentiation. This model deemphasizes the action of mutant SWI/SNF complexes upon cell cycle/oncogenic processes. We performed a consensus analysis on a cohort of novel and published ChIP-seq profiles (n=6 +/- SMARCB1 models) to define consensus SMARCB1-dependent epigenetic changes. We further used parallel RNA-seq, methylation and whole-genome CRISPR screen data to emphasize the significance of specific regulatory processes from the perspective of likely biological effects and functional essentiality. We bioinformatically identified consensus super and typical-enhancers from H3K27ac peaks, multiple datasets enabled high confidence regions to be called. SMARCB1 loss did not significantly impact SWI/SNF occupancy of super-enhancers, permutation test revealed significant (p