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Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone

Nature Genetics volume 45, pages 1479–1482 (2013)Cite this article

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A Corrigendum to this article was published on 26 February 2014

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Abstract

It is recognized that some mutated cancer genes contribute to the development of many cancer types, whereas others are cancer type specific. For genes that are mutated in multiple cancer classes, mutations are usually similar in the different affected cancer types. Here, however, we report exquisite tumor type specificity for different histone H3.3 driver alterations. In 73 of 77 cases of chondroblastoma (95%), we found p.Lys36Met alterations predominantly encoded in H3F3B, which is one of two genes for histone H3.3. In contrast, in 92% (49/53) of giant cell tumors of bone, we found histone H3.3 alterations exclusively in H3F3A, leading to p.Gly34Trp or, in one case, p.Gly34Leu alterations. The mutations were restricted to the stromal cell population and were not detected in osteoclasts or their precursors. In the context of previously reported H3F3A mutations encoding p.Lys27Met and p.Gly34Arg or p.Gly34Val alterations in childhood brain tumors, a remarkable picture of tumor type specificity for histone H3.3 driver alterations emerges, indicating that histone H3.3 residues, mutations and genes have distinct functions.

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Figure 1: Prevalence and distribution of histone H3.3 somatic alterations in different tumor types.

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  • 06 February 2014

    In the version of this article initially published, the name of author Victoria Goody was misspelled, and the following statement was omitted from the Acknowledgments: "The EuroBoNeT consortium, a European Commission–granted Network of Excellence for studying the pathology and genetics of bone tumors, also contributed to the financial support for this study." These errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We are grateful to the patients for participating in the research and to the clinicians and support staff involved in their care. This work was supported by funding from the Wellcome Trust (grant 077012/Z/05/Z), the Skeletal Cancer Action Trust (SCAT), UK, and the Rosetrees Trust UK. The EuroBoNeT consortium, a European Commission–granted Network of Excellence for studying the pathology and genetics of bone tumors, also contributed to the financial support for this study. Material was obtained from the Royal National Orthopaedic Hospital Musculoskeletal Research Programme and Biobank, all of which was coordinated by D. Brooking and R. Grinnell, Biobank staff at the Royal National Orthopaedic Hospital. Support was provided to A.M.F. by the National Institute for Health Research, the University College London Hospitals Biomedical Research Centre and the Cancer Research UK University College London Experimental Cancer Centre. P.J.C. is personally funded through a Wellcome Trust Senior Clinical Research Fellowship (grant WT088340MA). O.M. is funded by the Norwegian Research Council (grant 218241/H10). P.V.L. is a postdoctoral researcher of the Research Foundation-Flanders (FWO). S.B. is funded through the Wellcome Trust PhD Programme for Clinicians.

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Author notes

  1. Sam Behjati and Patrick S Tarpey: These authors contributed equally to this work.

Authors and Affiliations

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

    Sam Behjati, Patrick S Tarpey, Peter Van Loo, David C Wedge, Susanna L Cooke, Gunes Gundem, Helen Davies, Serena Nik-Zainal, Sancha Martin, Stuart McLaren, Victoria Goody, Ben Robinson, Adam Butler, Jon W Teague, P Andrew Futreal, Michael R Stratton & Peter J Campbell

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

    Sam Behjati

  3. University College London Cancer Institute, London, UK

    Nadège Presneau, Susanne Scheipl, Nischalan Pillay, Rifat Hamoudi & Adrienne M Flanagan

  4. Sarah Cannon/University College London Advanced Diagnostics Molecular Profiling Research Laboratories, London, UK

    Nadège Presneau, Rifat Hamoudi & Adrienne M Flanagan

  5. Universitätsklinik für Orthopädie und Orthopädische Chirurgie, Medizinische Universität, Graz, Austria

    Susanne Scheipl

  6. Histopathology, Royal National Orthopaedic Hospital National Health Service (NHS) Trust, Stanmore, UK

    Nischalan Pillay, Dina Halai, Bhavisha Khatri, Roberto Tirabosco, M Fernanda Amary & Adrienne M Flanagan

  7. Department of Human Genetics, Human Genome Laboratory, VIB and KU Leuven, Leuven, Belgium

    Peter Van Loo

  8. Department of Tumour Biology, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway

    Ola Myklebost

  9. Bone Tumour Reference Centre, Institute of Pathology, University Hospital Basel, Basel, Switzerland

    Daniel Baumhoer & Gernot Jundt

  10. Department of Haematology, Addenbrooke's Hospital, Cambridge, UK

    Peter J Campbell

  11. Department of Haematology, University of Cambridge, Cambridge, UK

    Peter J Campbell

Authors
  1. Sam Behjati
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  2. Patrick S Tarpey
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Contributions

S.B. and P.S.T. performed analysis of the sequence data. N. Presneau and R.H. performed the extension screen. S.S. and A.M.F. performed in vitro studies. P.V.L. performed copy number analysis. D.C.W. performed statistical analyses. S.L.C. performed rearrangement analysis. N. Pillay, G.G., H.D. and S.N.-Z. contributed to data analysis. S. McLaren and S. Martin coordinated sample acquisition and processing. V.G. and B.R. performed technical investigations. A.B. and J.W.T. coordinated informatics analyses. D.H., D.B., G.J., B.K., O.M., M.F.A., R.T. and A.M.F. provided samples and clinical data. P.J.C., M.R.S., P.A.F. and A.M.F. directed the research. M.R.S., S.B. and P.S.T. wrote the manuscript, with contributions from P.J.C., A.M.F. and P.A.F.

Corresponding author

Correspondence to Adrienne M Flanagan.

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The authors declare no competing financial interests.

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Behjati, S., Tarpey, P., Presneau, N. et al. Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat Genet 45, 1479–1482 (2013). https://doi.org/10.1038/ng.2814

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