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

Journal article

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: Presneau, N; Shalaby, A; Ye, H; Pillay, N; Halai, D

• Publication status: Published
• Journal: Journal of pathology
• Volume: 223
• Issue: 3
• Pages: 327-335
• Publication date: 2011-02-01
• DOI: 10.1002/path.2816
• EISSN: 1096-9896
• ISSN: 0022-3417
• Language: English
• Keywords: Humans; Neoplasm Transplantation; Polymerase Chain Reaction; Genetic Predisposition to Disease; Chordoma; Fetal Proteins; DNA Copy Number Variations; T-Box Domain Proteins; Mice, SCID; In Situ Hybridization, Fluorescence; Mice; Gene Knockdown Techniques; Cell Proliferation; Chromosome Aberrations; Tumor Cells, Cultured; Neoplasm Proteins; Transplantation, Heterologous; Animals; DNA, Neoplasm