Malignant rhabdoid tumor (MRT) is one of the most aggressive and lethal malignancies in pediatric oncology. It is a rare childhood tumor that commonly starts in the kidneys but also can occur in other soft tissues or in the brain. There is no exact cause, but researchers have discovered that a gene called SMARCB1 mutates in nearly all rhabdoid tumors, including MRT. Now, researchers from the Wellcome Sanger Institute, the Princess Máxima Center for Pediatric Oncology in the Netherlands, and their collaborators report finding the origins of this rare disease.

Their study, “Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumors,” published in Nature Communications, found that MRT arises from developmental cells in the neural crest whose maturation is blocked by a genetic defect. The team also identified two drugs that could be used to overcome this block and resume normal development, bringing hope of new treatments for the disease.

“MRT is an often lethal childhood cancer that, like many pediatric tumors, is thought to arise from aberrant fetal development,” the researchers wrote. “The embryonic root and differentiation pathways underpinning MRT are not firmly established. Here, we study the origin of MRT by combining phylogenetic analyses and single-cell mRNA studies in patient-derived organoids.”

With only 20–25 cases in the United States and 4–5 cases per year in the U.K., combined with its aggressiveness, clinical trials have been extremely difficult to conduct. Two cases of MRT were sequenced at the Wellcome Sanger Institute, alongside corresponding normal tissues. Phylogenetic analyses of the somatic mutations in the diseased and healthy tissue were conducted in order to mimic the timeline of normal and abnormal development.

The analyses confirmed that MRT develops from progenitor cells on their way to becoming Schwann cells, a cell type found in the neural crest, due to a mutation in the SMARCB1 gene. The researchers then inserted the SMARCB1 gene into patient-derived MRT organoids to overcome the maturation block that had prevented normal development and led to cancer.

The SMARCB1 gene provides instructions for making a protein that forms one piece of several different protein groupings called SWI/SNF protein complexes. SWI/SNF complexes regulate gene activity (expression) by a process known as chromatin remodeling. However, the role of the SMARCB1 protein within the SWI/SNF complex is not fully understood.

“To be able to identify where MRT comes from for the first time is an important step in being able to treat this disease, but to confirm that it is possible to overcome the genetic flaw that can cause these tumors is incredibly exciting,” explained Jarno Drost, PhD, co-lead author of the study from the Princess Máxima Center for Pediatric Oncology. “The fact that two drugs already exist that we think can be used to treat the disease gives us hope that we can improve outcomes for children diagnosed with MRT.”

“Our study defines the developmental block of MRT and reveals potential differentiation therapies,” concluded the researchers. Further evaluation and studies are needed for clinical trials to evaluate potential treatment that would not adversely affect postnatal development. However, this study paves a way for discovering the origin of other childhood cancers and may provide insights into diseases that are related to the mutation in the SMARCB1 gene.