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

Ning Qing Liu, Irene Paassen, Lars Custers, Peter Zeller, Hans Teunissen, Dilara Ayyildiz, Jiayou He, Juliane Laura Buhl, Eelco Wieger Hoving, Alexander Oudenaarden, Elzo Wit () and Jarno Drost ()
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Ning Qing Liu: Netherlands Cancer Institute
Irene Paassen: Princess Máxima Center for Pediatric Oncology
Lars Custers: Princess Máxima Center for Pediatric Oncology
Peter Zeller: Oncode Institute
Hans Teunissen: Netherlands Cancer Institute
Dilara Ayyildiz: Princess Máxima Center for Pediatric Oncology
Jiayou He: Princess Máxima Center for Pediatric Oncology
Juliane Laura Buhl: Princess Máxima Center for Pediatric Oncology
Eelco Wieger Hoving: Princess Máxima Center for Pediatric Oncology
Alexander Oudenaarden: Oncode Institute
Elzo Wit: Netherlands Cancer Institute
Jarno Drost: Princess Máxima Center for Pediatric Oncology

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract 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 study derailed regulatory landscapes as a consequence of SMARCB1 loss in the context of MRT. Our multi-omics approach on patient-derived MRT organoids reveals a dramatic reshaping of the regulatory landscape upon SMARCB1 reconstitution. Chromosome conformation capture experiments subsequently reveal 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 activates patient-specific epigenetic reprogramming underlying MRT tumorigenesis.

Date: 2023
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DOI: 10.1038/s41467-023-43498-3

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