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

Journal of Pathology - Tập 223 Số 3 - Trang 327-335 - 2011
Nadège Presneau1,2, Asem Shalaby3,1,2, Hongtao Ye4, Nischalan Pillay4,2, Dina Halai4,2, Bernadine Idowu4,2, Roberto Tirabosco4,3, Duncan Whitwell5, Thomas S. Jacques6, Lars‐Gunnar Kindblom7, Silke Brüderlein8, Peter Möller8, Andreas Leithner9, Bernadette Liegl10, Fernanda Amary4, Nicholas N Athanasou5, Pancras C.W. Hogendoorn11, Fredrik Mertens12, Károly Szuhai13, Adrienne M. Flanagan4,3,2
1These authors contributed equally to this study
2UCL Cancer Institute, 72 Huntley Street, London WC1 6BT, UK
3Institute of Orthopaedics and Musculoskeletal Science, University College London, Stanmore, Middlesex HA7 4LP, UK
4Department of Histopathology, Royal National Orthopaedic Hospital, Stanmore, Middlesex HA7 4LP, UK
5Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK
6Neural Development Unit, UCL Institute of Child Health and Department of Histopathology, Great Ormond Street Hospital, London, UK
7Department of Pathology, Royal Orthopaedic Hospital, Birmingham B31 2AP, UK
8Institut of Pathology, University Hospitals of Ulm, Ulm, Germany
9Department of Orthopaedics and Orthopaedic Surgery, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria
10Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, 8036 Graz, Austria
11Department of Pathology, Leiden University Medical Centre, Leiden 2300 RC, The Netherlands
12Department of Clinical Genetics, Lund University Hospital, Lund, Sweden
13Department of Molecular Cell Biology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands

Tóm tắt

AbstractA 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]$\gamma^{\rm{null}}$ 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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Journal of Pathology

Tập 223 Số 3

327-335

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