title: Role of the transcription factor T (brachyury) in the pathogenesis of sporadic chordoma: a genetic and functional-based study.
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]gammanull 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.
authors.affiliation: UCL Cancer Institute, 72 Huntley Street, London WC1 6BT, UK.
authors.forename: Nadège
authors.initials: N
authors.lastname: Presneau
authors.forename: Asem
authors.initials: A
authors.lastname: Shalaby
authors.forename: Hongtao
authors.initials: H
authors.lastname: Ye
authors.forename: Nischalan
authors.initials: N
authors.lastname: Pillay
authors.forename: Dina
authors.initials: D
authors.lastname: Halai
authors.forename: Bernadine
authors.initials: B
authors.lastname: Idowu
authors.forename: Roberto
authors.initials: R
authors.lastname: Tirabosco
authors.forename: Duncan
authors.initials: D
authors.lastname: Whitwell
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Jacques
authors.forename: Lars-Gunnar
authors.initials: LG
authors.lastname: Kindblom
authors.forename: Silke
authors.initials: S
authors.lastname: Brüderlein
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.forename: Andreas
authors.initials: A
authors.lastname: Leithner
authors.forename: Bernadette
authors.initials: B
authors.lastname: Liegl
authors.forename: Fernanda M
authors.initials: FM
authors.lastname: Amary
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Athanasou
authors.forename: Pancras Cw
authors.initials: PC
authors.lastname: Hogendoorn
authors.forename: Fredrik
authors.initials: F
authors.lastname: Mertens
authors.forename: Karoly
authors.initials: K
authors.lastname: Szuhai
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Flanagan
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002817:Chordoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002869:Chromosome Aberrations; D056915:DNA Copy Number Variations; D004273:DNA, Neoplasm / Q000235:genetics; D005326:Fetal Proteins / Q000235:genetics* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D016133:Polymerase Chain Reaction / Q000379:methods; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D000098908:Brachyury Protein
chemical_list: D004273:DNA, Neoplasm; D005326:Fetal Proteins; D009363:Neoplasm Proteins; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein