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Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer

Nature Genetics volume 41, pages 521–523 (2009)Cite this article

Abstract

Somatically acquired epigenetic changes are present in many cancers. Epigenetic regulation is maintained via post-translational modifications of core histones. Here, we describe inactivating somatic mutations in the histone lysine demethylase gene UTX, pointing to histone H3 lysine methylation deregulation in multiple tumor types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes. These data identify UTX as a new human cancer gene.

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Figure 1: Protein expression and functional studies.

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Acknowledgements

Funding was provided by the Wellcome Trust. G.v.H. is supported by an EMBO fellowship and P.J.C. by a Kay Kendall Leukaemia Fund fellowship. R.A.D. is supported by the Robert A. and Renee E. Belfer Foundation for Innovative Cancer Science. G.T. is supported by a fellowship from the Leukemia and Lymphoma Society. GlaxoSmithKline provided support for the SNP 6.0 microarray analyses. UTX antibodies were a kind gift from E. Canaani (Weizmann Institute of Science).

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Author notes

  1. Gijs van Haaften & Giovanni Tonon

    Present address: Present addresses: The Netherlands Cancer Institute, Amsterdam, The Netherlands (G.v.H.) and Multiple Myeloma Unit, Division of Molecular Oncology, San Raffaele del Monte Tabor Scientific Foundation, Milan, Italy (G.Tonon).,

  2. Gijs van Haaften, Gillian L Dalgliesh and Helen Davies: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK

    Gijs van Haaften, Gillian L Dalgliesh, Helen Davies, Lina Chen, Graham Bignell, Chris Greenman, Sarah Edkins, Claire Hardy, Sarah O'Meara, Jon Teague, Adam Butler, Jonathan Hinton, Calli Latimer, Jenny Andrews, Syd Barthorpe, Dave Beare, Gemma Buck, Peter J Campbell, Jennifer Cole, Simon Forbes, Mingming Jia, David Jones, Chai Yin Kok, Catherine Leroy, Meng-Lay Lin, David J McBride, Mark Maddison, Simon Maquire, Kirsten McLay, Andrew Menzies, Tatiana Mironenko, Lee Mulderrig, Laura Mudie, Erin Pleasance, Rebecca Shepherd, Raffaella Smith, Lucy Stebbings, Philip Stephens, Gurpreet Tang, Patrick S Tarpey, Rachel Turner, Kelly Turrell, Jennifer Varian, Sofie West, Sara Widaa, Paul Wray, Michael R Stratton & P Andrew Futreal

  2. Department of Pathology, University of Cambridge, Cambridge, UK

    V Peter Collins & Koichi Ichimura

  3. Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong

    Simon Law & John Wong

  4. Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Hong Kong

    Siu Tsan Yuen & Suet Yi Leung

  5. Departments of Medical Oncology and Medicine and Genetics, Center for Applied Cancer Science of the Belfer Institute for Innovative Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Giovanni Tonon & Ronald A DePinho

  6. Lebow Insitute for Myeloma Therapeutics and Lipper Myeloma Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Yu-Tzu Tai & Kenneth C Anderson

  7. Department of Urology, Spectrum Health Hospital, Grand Rapids, Michigan, USA

    Richard J Kahnoski & Aaron Massie

  8. Laboratory of Cancer Genetics, Van Andel Institute, Grand Rapids, Michigan, USA

    Sok Kean Khoo & Bin Tean Teh

  9. Institute of Cancer Research, Sutton, Surrey, UK

    Michael R Stratton

Authors
  1. Gijs van Haaften
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  2. Gillian L Dalgliesh
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  3. Helen Davies
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  4. Lina Chen
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Contributions

G.v.H., G.L.D. and H.D. performed the functional work and directed the analytical aspects of the study. L.C. performed the expression analyses. C.G. contributed statistical analyses. G.B., S.E., C.H., S.O., J.T., A.B., J.H., C. Latimer, J.A., S.B., D.B., G.B., P.J.C., J.C., S.F., M.J., D.J., C.Y.K., C. Leroy, M.-L.L., D.J.M., S.M., K.M., A. Menzies, T.M., L. Mulderrig, L. Mudie, E.P., R. Shepherd, R. Smith, L.S., P.S., G. Tang, P.S.T., R.T., K.T., J.V., S. West, S. Widaa, P.W., and M.M. performed the sequencing, copy number and data analyses. V.P.C., K.I., S.L., J.W., S.T.Y., S.Y.L., G. Tonon, R.A.D., Y.-T.T., K.C.A., R.J.K., A. Massie, S.K.K. and B.T.T. contributed samples, data and comments on the manuscript. M.R.S. and P.A.F. conceived and directed the study and wrote the manuscript.

Corresponding authors

Correspondence to Michael R Stratton or P Andrew Futreal.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

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Supplementary Methods, Supplementary Figure 1 and Supplementary Tables 1–5 (PDF 1533 kb)

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van Haaften, G., Dalgliesh, G., Davies, H. et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet 41, 521–523 (2009). https://doi.org/10.1038/ng.349

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