Genetics and Genomics of Malignant Rhabdoid Tumours

Abstract

Abstract Malignant rhabdoid tumours (MRTs) represent an aggressive paediatric cancer with limited treatment options. Although MRTs mainly arise in the kidney and brain of patients under the age of 8 years, they may appear in other major organs as well as in soft tissues. Remarkably, these tumours possess few mutations other than the ones that inactivate the SNF5/INI1 gene, the smallest member of the SWI/SNF chromatin‐remodelling complex. In addition, these cancers lack other hallmarks of adult malignancies including genomic instability, aberrant karyotypes and abnormal regulation of cellular stress‐response pathways. Their major defect appears to arise from epigenetic instability, presumably through changes in nucleosome positioning due to defective chromatin‐remodelling activity. Recent reports have shown that SNF5 loss affects key signalling pathways such as cell cycle regulation, deoxyribonucleic acid (DNA) damage repair and gene transcription. Thus, MRTs offer a unique model for studying the role of epigenetics in driving tumourigenesis and for the development of novel treatment approaches. Key Concepts: Malignant rhabdoid tumours are rare and aggressive paediatric cancers. MRT was the first tumour in which mutations in the SWI/SNF chromatin‐remodelling complex were identified. Inactivation of the SNF5/INI1 tumour suppressor gene drives MRT development. MRTs often show no changes in copy number or karyotype. The key mechanisms by which SNF5/INI1 loss induces MRT development remain unclear. MRTs offer a unique model for epigenetic‐driven tumourigenesis.