Abstract
Malignant rhabdoid tumours (MRTs) are extremely aggressive cancers of early childhood. They can occur in various locations, mainly the kidney, brain and soft tissues1,2. Cytogenetic and molecular analyses have shown that the deletion of region 11.2 of the long arm of chromosome 22 (22q11.2) is a recurrent genetic characteristic of MRTs, indicating that this locus may encode a tumour suppressor gene3,4,5,6,7,8. Here we map the most frequently deleted part of chromosome 22q11.2 from a panel of 13 MRT cell lines. We observed six homozygous deletions that delineate the smallest region of overlap between the cell lines. This region is found in the hSNF5/INI1 gene, which encodes a member of the chromatin-remodelling SWI/SNF multiprotein complexes9,10,11,12. We analysed the sequence of hSNF5/INI1 and found frameshift or nonsense mutations of this gene in six other cell lines. These truncating mutations of one allele were associated with the loss of the other allele. Identical alterations were observed in corresponding primary tumour DNAs but not in matched constitutional DNAs, indicating that they had been acquired somatically. The observation of bi-allelic alterations of hSNF5/INI1 in MRTs suggests that loss-of-function mutations of hSNF5/INI1 contribute to oncogenesis.
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Acknowledgements
We thank M. Yaniv and C. Muchardt for discussions; T. Melot, A. Laugé, S. Pagès, M.Peter, I. Legrand, C. Rosty, J. Couturier and D. Stoppa-Lyonnet for their help; and the following clinicians for providing samples used in this study: F. Doz, J. Michon, H. Pacquement, E. Quintana, P.Ruck and J.-M. Zucker. I.V. and N.S. are recipients of fellowships from the European Union and the Ministère de l'Education Nationale, de la Recherche et de la Technologie, respectively. This work was supported by grants from the Association pour la Recherche contre le Cancer, the Ligue Nationale Contre le Cancer, the Institut Curie and the Programme Hospitalier de Recherche Clinique.
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Versteege, I., Sévenet, N., Lange, J. et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206 (1998). https://doi.org/10.1038/28212
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DOI: https://doi.org/10.1038/28212