Original Paper

Role of the transcription factor T (brachyury) in the pathogenesis of sporadic chordoma: a genetic and functional-based study†

  1. Nadège Presneau1,‡,
  2. Asem Shalaby1,2,‡,
  3. Hongtao Ye3,
  4. Nischalan Pillay1,3,
  5. Dina Halai1,3,
  6. Bernadine Idowu1,3,
  7. Roberto Tirabosco2,3,
  8. Duncan Whitwell4,
  9. Thomas S Jacques5,
  10. Lars-Gunnar Kindblom6,
  11. Silke Brüderlein7,
  12. Peter Möller7,
  13. Andreas Leithner8,
  14. Bernadette Liegl9,
  15. Fernanda M Amary3,
  16. Nicholas N Athanasou4,
  17. Pancras CW Hogendoorn10,
  18. Fredrik Mertens11,
  19. Karoly Szuhai12,
  20. Adrienne M Flanagan1,2,3,*

Article first published online: 24 NOV 2010

DOI: 10.1002/path.2816

Issue

The Journal of Pathology

The Journal of Pathology

Volume 223, Issue 3, pages 327–335, February 2011

Additional Information

How to Cite

Presneau, N., Shalaby, A., Ye, H., Pillay, N., Halai, D., Idowu, B., Tirabosco, R., Whitwell, D., Jacques, T. S., Kindblom, L.-G., Brüderlein, S., Möller, P., Leithner, A., Liegl, B., Amary, F. M., Athanasou, N. N., Hogendoorn, P. C., Mertens, F., Szuhai, K. and Flanagan, A. M. (2011), Role of the transcription factor T (brachyury) in the pathogenesis of sporadic chordoma: a genetic and functional-based study. J. Pathol., 223: 327–335. doi: 10.1002/path.2816

Author Information

  1. 1

    UCL Cancer Institute, 72 Huntley Street, London WC1 6BT, UK

  2. 2

    Institute of Orthopaedics and Musculoskeletal Science, University College London, Stanmore, Middlesex HA7 4LP, UK

  3. 3

    Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, UK

  4. 4

    Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK

  5. 5

    Neural Development Unit, UCL Institute of Child Health and Department of Histopathology, Great Ormond Street Hospital, London, UK

  6. 6

    Department of Pathology, Royal Orthopaedic Hospital, Birmingham B31 2AP, UK

  7. 7

    Institut of Pathology, University Hospitals of Ulm, Ulm, Germany

  8. 8

    Department of Orthopaedics and Orthopaedic Surgery, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria

  9. 9

    Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria

  10. 10

    Department of Pathology, Leiden University Medical Centre, Leiden 2300 RC, The Netherlands

  11. 11

    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden

  12. 12

    Department of Molecular Cell Biology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands

  1. ‡

    These authors contributed equally to this study.

*UCL, Institute of Orthopaedics and Musculoskeletal Science, Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, UK

  1. †

    No conflicts of interest were declared.

  2. ‡

    These authors contributed equally to this study.

Publication History

  1. Issue published online: 20 DEC 2010
  2. Article first published online: 24 NOV 2010
  3. Accepted manuscript online: 20 OCT 2010 07:51AM EST
  4. Manuscript Accepted: 15 OCT 2010
  5. Manuscript Revised: 5 OCT 2010
  6. Manuscript Received: 9 SEP 2010

Funded by

  • Skeletal Cancer Action Trust (SCAT), UK
  • Rosetrees Trust, UK
  • Chordoma Foundation

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Keywords:

  • chordoma;
  • T;
  • amplification;
  • copy number gain;
  • oncogene

Abstract

A variety of analyses, including fluorescence in situ hybridization (FISH), quantitative PCR (qPCR) and array CGH (aCGH), have been performed on a series of chordomas from 181 patients. Twelve of 181 (7%) tumours displayed amplification of the T locus and an additional two cases showed focal amplification; 70/181 (39%) tumours were polysomic for chromosome 6, and 8/181 (4.5%) primary tumours showed a minor allelic gain of T as assessed by FISH. No germline alteration of the T locus was identified in non-neoplastic tissue from 40 patients. Copy number gain of T was seen in a similar percentage of sacrococcygeal, mobile spine and base of skull tumours. Knockdown of T in the cell line, U-CH1, which showed polysomy of chromosome 6 involving 6q27, resulted in a marked decrease in cell proliferation and morphological features consistent with a senescence-like phenotype. The U-CH1 cell line was validated as representing chordoma by the generation of xenografts, which showed typical chordoma morphology and immunohistochemistry in the NOD/SCID/interleukin 2 receptor [IL2r]equation image mouse model. In conclusion, chromosomal aberrations resulting in gain of the T locus are common in sporadic chordomas and expression of this gene is critical for proliferation of chordoma cells in vitro. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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