Genetics and Genomics of Malignant Rhabdoid Tumours


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.

Keywords: malignant rhabdoid tumour; SWI/SNF complex; SNF5; INI1; chromatin remodeling; epigenetics

Figure 1.

Histopathology of MRT. Hematoxylin and eosin staining of a brain malignant rhabdoid tumour (AT/RT) from a young paediatric patient. The black arrow denotes a rhabdoid cell with significant accumulation of intermediate filaments within the cytoplasm. The white arrows demonstrate the prominent single nucleolus often observed in MRTs. Photograph courtesy of Dr. Dmitri Trembath, University of North Carolina, Chapel Hill, NC.

Figure 2.

SNF5 comprises all SWI/SNF complexes. Each SWI/SNF complex identified by previous studies varies in their subunit composition. However, all SWI/SNF complexes contain the SNF5 protein suggesting that its loss would affect all SWI/SNF complex activities.



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Further Reading

Gadd S, Sredni ST, Huang CC and Perlman EJ (2010) Rhabdoid tumor: gene expression clues to pathogenesis and potential therapeutic targets. Laboratory Investigation (Research Support, N.I.H., Extramural) 90(5): 724–738.

Hasselblatt M, Isken S, Linge A et al. (2013) High‐resolution genomic analysis suggests the absence of recurrent genomic alterations other than SMARCB1 aberrations in atypical teratoid/rhabdoid tumors. Genes, Chromosomes and Cancer 52(2): 185–190.

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Lee RS and Roberts CW (2013) Rhabdoid tumors: an initial clue to the role of chromatin remodeling in cancer. Brain Pathology 23(2): 200–205.

Venneti S, Le P, Martinez D et al. (2011) p16INK4A and p14ARF tumor suppressor pathways are deregulated in malignant rhabdoid tumors. Journal of Neuropathology and Experimental Neurology 70(7): 596–609.

Venneti S, Le P, Martinez D et al. (2011) Malignant rhabdoid tumors express stem cell factors, which relate to the expression of EZH2 and Id proteins. American Journal of Surgical Pathology 35(10): 1463–1472.

Weissman B and Knudsen KE (2009) Hijacking the chromatin remodeling machinery: impact of SWI/SNF perturbations in cancer. Cancer Research 69(21): 8223–8230.

Wilson BG and Roberts CW (2011) SWI/SNF nucleosome remodellers and cancer. Nature Reviews Cancer (Review) 11(7): 481–492.

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Wei, Darmood, and Weissman, Bernard E(Mar 2014) Genetics and Genomics of Malignant Rhabdoid Tumours. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025012]