TY - JOUR
T1 - Role of the transcription factor T (brachyury) in the pathogenesis of sporadic chordoma
T2 - A genetic and functional-based study
AU - Presneau, Nadège
AU - Shalaby, Asem
AU - Ye, Hongtao
AU - Pillay, Nischalan
AU - Halai, Dina
AU - Idowu, Bernadine
AU - Tirabosco, Roberto
AU - Whitwell, Duncan
AU - Jacques, Thomas S.
AU - Kindblom, Lars Gunnar
AU - Brüderlein, Silke
AU - Möller, Peter
AU - Leithner, Andreas
AU - Liegl, Bernadette
AU - Amary, Fernanda M.
AU - Athanasou, Nicholas N.
AU - Hogendoorn, Pancras Cw
AU - Mertens, Fredrik
AU - Szuhai, Karoly
AU - Flanagan, Adrienne M.
PY - 2011/2
Y1 - 2011/2
N2 - 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]γnull 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.
AB - 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]γnull 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.
KW - Amplification
KW - Chordoma
KW - Copy number gain
KW - Oncogene
KW - T
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U2 - 10.1002/path.2816
DO - 10.1002/path.2816
M3 - Article
C2 - 21171078
AN - SCOPUS:78650597625
SN - 0022-3417
VL - 223
SP - 327
EP - 335
JO - Journal of Pathology
JF - Journal of Pathology
IS - 3
ER -