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 (FRS2alpha), 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.