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Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer

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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Figure 1: The commonly deleted region in MRTs contains markers A006E25, SGC32593, MMP11 and GCT10.
Figure 2: Homozygous deletion of exons 4 and 5 of hSNF5/INI1 in the KD cell line.
Figure 3: Genomic organization of the hSNF5/INI1 gene and position of the stop codons generated by mutations of the coding sequence.

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References

  1. Parham, D. M., Weeks, D. A. & Beckwith, J. B. The clinicopathologic spectrum of putative extrarenal rhabdoid tumours. An analysis of 42 cases studied with immunohistochemistry or electron microscopy. Am. J. Surg. Pathol. 18, 1010–1029 (1994).

    Article  CAS  Google Scholar 

  2. Wick, M. R., Ritter, J. H. & Dehner, L. P. Malignant rhabdoid tumours: a clinicopathologic review and conceptual discussion. Semin. Diagn. Pathol. 12, 233–248 (1995).

    PubMed  CAS  Google Scholar 

  3. Douglass, E. C. et al. Malignant rhabdoid tumour: a highly malignant childhood tumour with minimal karyotypic changes. Gene Chromosom. Cancer 2, 210–216 (1990).

    Article  CAS  Google Scholar 

  4. Shashi, V., Lovell, M. A., von Kap-herr, C., Waldron, P. & Golden, W. L. Malignant rhabdoid tumour of the kidney: involvement of chromosome 22. Gene Chromosom. Cancer 10, 49–54 (1994).

    Article  CAS  Google Scholar 

  5. Fort, D. W., Tonk, V. S., Tomlinson, G. E., Timmons, C. F. & Schneider, N. R. Rhabdoid tumour of the kidney with primitive neuroectodermal tumour of the central nervous system: associated tumours with different histologic, cytogenetic, and molecular findings. Gene Chromosom. Cancer 11, 146–152 (1994).

    Article  CAS  Google Scholar 

  6. Schofield, D. E., Beckwith, J. B. & Sklar, J. Loss of heterozygosity at chromosome regions 22q11-12 and 11p15.5 in renal rhabdoid tumours. Gene Chromosom. Cancer 15, 10–17 (1996).

    Article  CAS  Google Scholar 

  7. Biegel, J. A. et al. Narrowing the critical region for a rhabdoid tumour locus in 22q11. Gene Chromosom. Cancer 16, 94–105 (1996).

    Article  CAS  Google Scholar 

  8. Rosty, C. et al. Cytogenetic and molecular analysis of a t(1;22)(p36;q11.2) in a rhabdoid tumour with a putative homozygous deletion of chromosome 22. Gene Chromosom. Cancer 21, 82–89 (1998).

    Article  CAS  Google Scholar 

  9. Muchardt, C., Sardet, C., Bourachot, B., Onufryk, C. & Yaniv, M. Ahuman protein with homology to Saccharomyces cerevisiae SNF5 interacts with the potential helicase hbrm. Nucleic Acid. Res. 23, 1127–1132 (1995).

    Article  CAS  Google Scholar 

  10. Kalpana, G. V., Marmon, S., Wang, W., Crabtree, G. R. & Goff, S. P. Binding and stimulation of HIV-1 integrase by a human homolog of yeast transcription factor SNF5. Science 266, 2002–2006 (1994).

    Article  ADS  CAS  Google Scholar 

  11. Peterson, C. L. Multiple SWItches to turn on chromatin? Curr. Opin. Genet. Dev. 6, 171–175 (1996).

    Article  CAS  Google Scholar 

  12. Wang, W. et al. Diversity and specialisation of mammalian SWI/SNF complexes. Genes Dev. 10, 2117–2130 (1996).

    Article  CAS  Google Scholar 

  13. Kwon, H., Imbalzano, A. N., Khavari, P. A., Kingston, R. E. & Green, M. R. Nucleosome disruption and enhancement of activator binding by a human SW1/SNF complex. Nature 370, 477–485 (1994).

    Article  ADS  CAS  Google Scholar 

  14. Owen-Hughes, T., Utley, R. T., Côté, J., Peterson, C. L. & Workman, J. L. Persistent site-specific remodeling of a nucleosome array by transient action of the SWI/SNF complex. Science 273, 513–516 (1996).

    Article  ADS  CAS  Google Scholar 

  15. Côté, J., Quinn, J., Workman, J. L. & Peterson, C. L. Stimulation of GAL4 derivative binding to nucleosomal DNA by the yeast SWI/SNF complex. Science 265, 53–60 (1994).

    Article  ADS  Google Scholar 

  16. Lynch, H. T. et al. Paravertebral malignant rhabdoid tumour in infancy. In vitro studies of a familial tumour. Cancer 52, 290–296 (1983).

    Article  CAS  Google Scholar 

  17. Morozov, A., Yung, E. & Kalpana, G. V. Structure-function analysis of integrase interactor 1/hSNF5L1 reveals differential properties of two repeat motifs present in the highly conserved region. Proc. Natl Acad. Sci. USA 95, 1120–1125 (1998).

    Article  ADS  CAS  Google Scholar 

  18. Sobulo, O. M. et al. MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3). Proc. Natl Acad. Sci. USA 94, 8732–8737 (1997).

    Article  ADS  CAS  Google Scholar 

  19. Magnaghi-Jaulin, L. et al. Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature 391, 601–604 (1998).

    Article  ADS  CAS  Google Scholar 

  20. Brehm, A. et al. Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 391, 597–601 (1998).

    Article  ADS  CAS  Google Scholar 

  21. Lin, R. J. et al. Role of histone deacetylase complex in acute promyelocytic leukaemia. Nature 391, 811–814 (1998).

    Article  ADS  CAS  Google Scholar 

  22. Grignani, F. Fusion proteins of the retinoic acid receptor-α recruit histone deacetylase in promyelocytic leukaemia. Nature 391, 815–818 (1998).

    Article  ADS  CAS  Google Scholar 

  23. Dunaief, J. L. et al. The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest. Cell 79, 119–130 (1994).

    Article  CAS  Google Scholar 

  24. Trouche, D., Le Chalony, C., Muchardt, C., Yaniv, M. & Kouzarides, T. RB and hbrm cooperate to repress the activation functions of E2F1. Proc. Natl Acad. Sci. USA 94, 11268–11273 (1997).

    Article  ADS  CAS  Google Scholar 

  25. Muchardt, C., Bourachot, B., Reyes, J-C. & Yaniv, M. ras transformation is associated with decreased expression of the brm/SNF2α ATPase from the mammalian SWI-SNF complex. EMBO J. 16, 101–109 (1998).

    Google Scholar 

  26. Soulié, J., Rousseau-Merck, M.-F., Mouly, H. & Nezelof, C. Cytogenetic study of cell lines from an infantile hypercalcemic renal tumour. Cancer Genet. Cytogenet. 21, 117–122 (1985).

    Article  Google Scholar 

  27. Handgretinger, R. et al. Establishment and characterisation of a cell line (Wa-2) derived from an extrarenal rhabdoid tumour. Cancer Res. 50, 2177–2182 (1990).

    PubMed  CAS  Google Scholar 

  28. Iaonnou, P. et al. Anew bacteriophage P1-derived vector for the propagation of large human DNA fragments. Nature Genet. 6, 84–89 (1994).

    Article  Google Scholar 

  29. Dib, C. et al. Acomprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152–154 (1996).

    Article  ADS  CAS  Google Scholar 

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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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Correspondence to Olivier Delattre.

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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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