Role of the Transcription Factor T (Brachyury) in the Pathogenesis of Sporadic Chordoma: A Genetic and Functional-Based Study

J Pathol. 2011 Feb;223(3):327-35. doi: 10.1002/path.2816. Epub 2010 Nov 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Chordoma / genetics*
  • Chordoma / metabolism
  • Chordoma / pathology
  • Chromosome Aberrations
  • DNA Copy Number Variations
  • DNA, Neoplasm / genetics
  • Fetal Proteins / genetics*
  • Fetal Proteins / metabolism
  • Gene Knockdown Techniques
  • Genetic Predisposition to Disease
  • Humans
  • In Situ Hybridization, Fluorescence
  • Mice
  • Mice, SCID
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neoplasm Transplantation
  • Polymerase Chain Reaction / methods
  • T-Box Domain Proteins / genetics*
  • T-Box Domain Proteins / metabolism
  • Transplantation, Heterologous
  • Tumor Cells, Cultured

Substances

  • DNA, Neoplasm
  • Fetal Proteins
  • Neoplasm Proteins
  • T-Box Domain Proteins
  • Brachyury protein