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

Authors

  • Nadège Presneau,

    1. UCL Cancer Institute, 72 Huntley Street, London WC1 6BT, UK
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    • These authors contributed equally to this study.

  • Asem Shalaby,

    1. UCL Cancer Institute, 72 Huntley Street, London WC1 6BT, UK
    2. Institute of Orthopaedics and Musculoskeletal Science, University College London, Stanmore, Middlesex HA7 4LP, UK
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    • These authors contributed equally to this study.

  • Hongtao Ye,

    1. Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, UK
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  • Nischalan Pillay,

    1. UCL Cancer Institute, 72 Huntley Street, London WC1 6BT, UK
    2. Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, UK
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  • Dina Halai,

    1. UCL Cancer Institute, 72 Huntley Street, London WC1 6BT, UK
    2. Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, UK
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  • Bernadine Idowu,

    1. UCL Cancer Institute, 72 Huntley Street, London WC1 6BT, UK
    2. Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, UK
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  • Roberto Tirabosco,

    1. Institute of Orthopaedics and Musculoskeletal Science, University College London, Stanmore, Middlesex HA7 4LP, UK
    2. Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, UK
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  • Duncan Whitwell,

    1. Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK
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  • Thomas S Jacques,

    1. Neural Development Unit, UCL Institute of Child Health and Department of Histopathology, Great Ormond Street Hospital, London, UK
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  • Lars-Gunnar Kindblom,

    1. Department of Pathology, Royal Orthopaedic Hospital, Birmingham B31 2AP, UK
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  • Silke Brüderlein,

    1. Institut of Pathology, University Hospitals of Ulm, Ulm, Germany
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  • Peter Möller,

    1. Institut of Pathology, University Hospitals of Ulm, Ulm, Germany
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  • Andreas Leithner,

    1. Department of Orthopaedics and Orthopaedic Surgery, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria
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  • Bernadette Liegl,

    1. Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria
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  • Fernanda M Amary,

    1. Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, UK
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  • Nicholas N Athanasou,

    1. Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK
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  • Pancras CW Hogendoorn,

    1. Department of Pathology, Leiden University Medical Centre, Leiden 2300 RC, The Netherlands
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  • Fredrik Mertens,

    1. Department of Clinical Genetics, Lund University Hospital, Lund, Sweden
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  • Karoly Szuhai,

    1. Department of Molecular Cell Biology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands
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  • Adrienne M Flanagan

    Corresponding author
    1. UCL Cancer Institute, 72 Huntley Street, London WC1 6BT, UK
    2. Institute of Orthopaedics and Musculoskeletal Science, University College London, Stanmore, Middlesex HA7 4LP, UK
    3. Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, UK
    • UCL, Institute of Orthopaedics and Musculoskeletal Science, Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, UK
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  • No conflicts of interest were declared.

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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