SMARCB1 loss creates patient-specificMYCtopologies that drive malignant rhabdoid tumor growth

Abstract

AbstractMalignant rhabdoid tumor (MRT) is a highly malignant and often lethal childhood cancer. MRTs are genetically defined by bi-allelic inactivating mutations inSMARCB1, a member of the BRG1/BRM-associated factors (BAF) chromatin remodeling complex. Mutations in BAF complex members are common in human cancer, yet their contribution to tumorigenesis remains in many cases poorly understood. Here, we studied derailed regulatory landscapes as a consequence ofSMARCB1loss in the context of MRT. Our multi-omics approach on patient-derived MRT organoids revealed a dramatic reshaping of the regulatory landscape uponSMARCB1reconstitution. Chromosome conformation capture experiments subsequently revealed patient-specific looping of distal enhancer regions with the promoter of theMYConcogene. This intertumoral heterogeneity inMYCenhancer utilization is also present in patient MRT tissues as shown by combined single-cell RNA-seq and ATAC-seq. We show that loss ofSMARCB1drives patient-specific epigenetic reprogramming underlying MRT tumorigenesis.