Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/ brachyury signalling pathway in chordomas

Asem Ae Shalaby, Nadege Presneau, Bernadine D. Idowu, Lisa Thompson, Timothy Rw Briggs, Roberto Tirabosco, Timothy C. Diss, Adrienne M. Flanagan

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Chordomas are rare primary malignant bone tumours that derive from notochord precursor cells and express brachyury, a molecule involved in notochord development. Little is known about the genetic events responsible for driving the growth of this tumour, but it is well established that brachyury is regulated through fibroblastic growth factor receptors (FGFRs) through RAS/RAF/MEK/ERK and ETS2 in ascidian, Xenopus and zebrafish, although little is known about its regulation in mammals. The aim of this study was to attempt to identify the molecular genetic events that are responsible for the pathogenesis of chordomas with particular focus on the FGFR signalling pathway on the basis of the evidence in the ascidian and Xenopus models that the expression of brachyury requires the activation of this pathway. Immunohistochemistry showed that 47 of 50 chordomas (94%) expressed at least one of the FGFRs, and western blotting showed phosphorylation of fibroblast growth factor receptor substrate 2 alpha (FRS2α), an adaptor signalling protein, that links FGFR to the RAS/RAF/MEK/ERK pathway. Screening for mutations in brachyury (all coding exons and promoter), FGFRs 1-4 (previously reported mutations), KRAS (codons 12, 13, 51, 61) and BRAF (exons 11 and 15) failed to show any genetic alterations in 23 chordomas. Fluorescent in situ hybridisation analysis on FGFR4, ETS2 and brachyury failed to show either amplification of these genes, although there was minor allelic gain in brachyury in three tumours, or translocation for ERG and ETS2 loci. The key genetic events responsible for the initiation and progression of chordomas remain to be discovered.

Original languageEnglish
Pages (from-to)996-1005
Number of pages10
JournalModern Pathology
Volume22
Issue number8
DOIs
Publication statusPublished - Aug 2009

Fingerprint

Chordoma
Growth Factor Receptors
Mitogen-Activated Protein Kinase Kinases
Notochord
Urochordata
Xenopus
Exons
Receptor, Fibroblast Growth Factor, Type 2
Neoplasms
Mutation
MAP Kinase Signaling System
Gene Amplification
Zebrafish
Fluorescence In Situ Hybridization
Codon
Brachyury protein
Molecular Biology
Mammals
Western Blotting
Immunohistochemistry

Keywords

  • Amplification
  • Brachyury
  • Chordoma
  • ETS2
  • FGFR
  • Genetics

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/ brachyury signalling pathway in chordomas. / Shalaby, Asem Ae; Presneau, Nadege; Idowu, Bernadine D.; Thompson, Lisa; Briggs, Timothy Rw; Tirabosco, Roberto; Diss, Timothy C.; Flanagan, Adrienne M.

In: Modern Pathology, Vol. 22, No. 8, 08.2009, p. 996-1005.

Research output: Contribution to journalArticle

Shalaby, AA, Presneau, N, Idowu, BD, Thompson, L, Briggs, TR, Tirabosco, R, Diss, TC & Flanagan, AM 2009, 'Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/ brachyury signalling pathway in chordomas', Modern Pathology, vol. 22, no. 8, pp. 996-1005. https://doi.org/10.1038/modpathol.2009.63
Shalaby, Asem Ae ; Presneau, Nadege ; Idowu, Bernadine D. ; Thompson, Lisa ; Briggs, Timothy Rw ; Tirabosco, Roberto ; Diss, Timothy C. ; Flanagan, Adrienne M. / Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/ brachyury signalling pathway in chordomas. In: Modern Pathology. 2009 ; Vol. 22, No. 8. pp. 996-1005.
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