Mutations truncating the EP300 acetylase in human cancers (original) (raw)

Nature Genetics volume 24, pages 300–303 (2000)Cite this article

Abstract

The EP300 protein is a histone acetyltransferase1,2 that regulates transcription via chromatin remodelling3 and is important in the processes of cell proliferation4 and differentiation5. EP300 acetylation of TP53 in response to DNA damage regulates its DNA-binding and transcription functions6,7,8,9. A role for EP300 in cancer has been implied by the fact that it is targeted by viral oncoproteins, it is fused to MLL in leukaemia and two missense sequence alterations in EP300 were identified in epithelial malignancies10,11,12,13. Nevertheless, direct demonstration of the role of EP300 in tumorigenesis by inactivating mutations in human cancers has been lacking. Here we describe EP300 mutations, which predict a truncated protein, in 6 (3%) of 193 epithelial cancers analysed. Of these six mutations, two were in primary tumours (a colorectal cancer and a breast cancer) and four were in cancer cell lines (colorectal, breast and pancreatic). In addition, we identified a somatic in-frame insertion in a primary breast cancer and missense alterations in a primary colorectal cancer and two cell lines (breast and pancreatic). Inactivation of the second allele was demonstrated in five of six cases with truncating mutations and in two other cases. Our data show that EP300 is mutated in epithelial cancers and provide the first evidence that it behaves as a classical tumour-suppressor gene.

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Acknowledgements

We thank I. Scott, R. Sud, I. Talbot and V. Basham for help with collecting tumour material and technical assistance, and the three anonymous reviewers for their thoughtful criticism of the manuscript. This research was supported by The Cancer Research Campaign (CRC).

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Authors and Affiliations

  1. Departments of Oncology, University of Cambridge, Cambridge, UK
    Simon A. Gayther, Sarah J. Batley, Lori Linger, Karen Thorpe, Suet-Feung Chin, Yataro Daigo, Paul Russell, Bruce A.J. Ponder & Carlos Caldas
  2. Department of Pathology, University of Cambridge, Cambridge, UK
    Andy Bannister & Tony Kouzarides
  3. Department of Strangeways Research Laboratories, University of Cambridge, Cambridge, UK
    Simon A. Gayther, Lori Linger, Karen Thorpe, Paul Russell & Bruce A.J. Ponder
  4. Department of Cambridge Institute for Medical Research/The Wellcome Trust Centre for the Study of Molecular Mechanisms in Disease, University of Cambridge, Cambridge, UK
    Sarah J. Batley, Suet-Feung Chin, Yataro Daigo, Bruce A.J. Ponder & Carlos Caldas
  5. Wellcome/CRC Institute, University of Cambridge, Cambridge, UK
    Andy Bannister & Tony Kouzarides
  6. Oncology Research Laboratory, Derby City General Hospital , Derby, UK
    Annie Wilson
  7. Cambridge University Department of Obstetrics and Gynaecology, The Rosie Hospital, Cambridge, UK
    Heidi M. Sowter
  8. Department of Obstetrics and Gynaecology, University College, London Medical School, London, UK
    Joy D.A. Delhanty

Authors

  1. Simon A. Gayther
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  2. Sarah J. Batley
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  3. Lori Linger
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  4. Andy Bannister
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  5. Karen Thorpe
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  6. Suet-Feung Chin
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  7. Yataro Daigo
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  8. Paul Russell
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  9. Annie Wilson
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  10. Heidi M. Sowter
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  11. Joy D.A. Delhanty
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  12. Bruce A.J. Ponder
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  13. Tony Kouzarides
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  14. Carlos Caldas
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Corresponding author

Correspondence toCarlos Caldas.

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Gayther, S., Batley, S., Linger, L. et al. Mutations truncating the EP300 acetylase in human cancers.Nat Genet 24, 300–303 (2000). https://doi.org/10.1038/73536

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