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

被引:150
作者
Presneau, Nadege [1 ]
Shalaby, Asem [1 ,2 ]
Ye, Hongtao [3 ]
Pillay, Nischalan [1 ,3 ]
Halai, Dina [1 ,3 ]
Idowu, Bernadine [1 ,3 ]
Tirabosco, Roberto [2 ,3 ]
Whitwell, Duncan [4 ]
Jacques, Thomas S. [5 ,6 ]
Kindblom, Lars-Gunnar [7 ]
Bruederlein, Silke [8 ]
Moeller, Peter [8 ]
Leithner, Andreas [9 ]
Liegl, Bernadette [10 ]
Amary, Fernanda M. [3 ]
Athanasou, Nicholas N. [4 ]
Hogendoorn, Pancras C. W. [11 ]
Mertens, Fredrik [12 ]
Szuhai, Karoly [13 ]
Flanagan, Adrienne M. [1 ,2 ,3 ]
机构
[1] UCL Canc Inst, London WC1 6BT, England
[2] Univ Coll London, Inst Orthopaed & Musculoskeletal Sci, Stanmore HA7 4LP, Middx, England
[3] Royal Natl Orthopaed Hosp, Dept Histopathol, Stanmore HA7 4LP, Middx, England
[4] Univ Oxford, Botnar Res Ctr, Nuffiel Dept Orthopaed Rheumatol & Musculoskeleta, Oxford OX3 7LD, England
[5] Great Ormond St Hosp Sick Children, Dept Histopathol, London, England
[6] UCL Inst Child Hlth, Neural Dev Unit, London, England
[7] Royal Orthopaed Hosp, Dept Pathol, Birmingham B31 2AP, W Midlands, England
[8] Univ Hosp Ulm, Inst Pathol, Ulm, Germany
[9] Med Univ Graz, Dept Orthopaed & Orthopaed Surg, A-8036 Graz, Austria
[10] Med Univ Graz, Inst Pathol, A-8036 Graz, Austria
[11] Leiden Univ, Med Ctr, Dept Pathol, NL-2300 RC Leiden, Netherlands
[12] Univ Lund Hosp, Dept Clin Genet, S-22185 Lund, Sweden
[13] Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands
关键词
chordoma; T; amplification; copy number gain; oncogene; COMPARATIVE GENOMIC HYBRIDIZATION; CELL LUNG-CANCER; FAMILIAL CHORDOMA; MESODERM INDUCTION; REQUIRES FGF; TUMOR; EXPRESSION; SENESCENCE; BIOMARKER; PATHWAY;
D O I
10.1002/path.2816
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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]gamma(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 (C) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
引用
收藏
页码:327 / 335
页数:9
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