SMARCB1 loss activates patient-specific distal oncogenic enhancers in malignant rhabdoid tumors

Malignant rhabdoid tumor (MRT) is a highly malignant and often lethal childhood cancer. MRTs are genetically defined by bi-allelic inactivating mutations in SMARCB1, 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 of SMARCB1 loss in the context of MRT. Our multi-omics approach on patient-derived MRT organoids revealed a dramatic reshaping of the regulatory landscape upon SMARCB1 reconstitution. Chromosome conformation capture experiments subsequently revealed patient-specific looping of distal enhancer regions with the promoter of the MYC oncogene. This intertumoral heterogeneity in MYC enhancer utilization is also present in patient MRT tissues as shown by combined single-cell RNA-seq and ATAC-seq. We show that loss of SMARCB1 drives patient-specific epigenetic reprogramming underlying MRT tumorigenesis.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

3 Datasets 1 Publication

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Dataset ID	Description	Technology	Samples
EGAD00001011819	Study describing the dynamics of chromatin organization within malignant rhabdoid tumors. This study describes how this chromatin organization changes upon SMARCB1 rescue within patient-derived organoid models from malignant rhabdoid tumors. Identification of a novel super-enhancer of MYC and identification of patient-specific enhancer utilization to activate MYC expression in these tumors.	NextSeq 550	8
EGAD00001011820	Study describing the dynamics of chromatin organization within malignant rhabdoid tumors. This study describes how this chromatin organization changes upon SMARCB1 rescue within patient-derived organoid models from malignant rhabdoid tumors. Identification of a novel super-enhancer of MYC and identification of patient-specific enhancer utilization to activate MYC expression in these tumors.	Illumina HiSeq 2500 Illumina NovaSeq 6000 NextSeq 550	8
EGAD00001011821	Study describing the dynamics of chromatin organization within malignant rhabdoid tumors. This study describes how this chromatin organization changes upon SMARCB1 rescue within patient-derived organoid models from malignant rhabdoid tumors. Identification of a novel super-enhancer of MYC and identification of patient-specific enhancer utilization to activate MYC expression in these tumors.	Illumina HiSeq 2500 Illumina NovaSeq 6000 NextSeq 2000	5

Publications	Citations
SMARCB1 loss activates patient-specific distal oncogenic enhancers in malignant rhabdoid tumors. Liu NQ, Paassen I, Custers L, Zeller P, Teunissen H, Ayyildiz D, He J, Buhl JL, Hoving EW, van Oudenaarden A, de Wit E, Drost J. Nat Commun 14: 2023 7762	5