Loss-of-function fibroblast growth factor receptor-2 mutations in melanoma

Michael G. Gartside, Huaibin Chen, Omar A. Ibrahimi, Sara A. Byron, Amy V. Curtis, Candice L. Wellens, Ana Bengston, Laura M. Yudt, Anna V. Eliseenkova, Jinghong Ma, John A. Curtin, Pilar Hyder, Ursula L. Harper, Erica Riedesel, Graham J. Mann, Jeffrey M. Trent, Boris C. Bastian, Paul S. Meltzer, Moosa Mohammadi, Pamela M. Pollock

Research output: Contribution to journalArticlepeer-review

Abstract

We report that 10% of melanoma tumors and cell lines harbor mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. These novel mutations include three truncating mutations and 20 missense mutations occurring at evolutionary conserved residues in FGFR2 as well as among all four FGFRs. The mutation spectrum is characteristic of those induced by UV radiation. Mapping of these mutations onto the known crystal structures of FGFR2 followed by in vitro and in vivo studies show that these mutations result in receptor loss of function through several distinct mechanisms, including loss of ligand binding affinity, impaired receptor dimerization, destabilization of the extracellular domains, and reduced kinase activity. To our knowledge, this is the first demonstration of loss-of-function mutations in a class IV receptor tyrosine kinase in cancer. Taken into account with our recent discovery of activating FGFR2 mutations in endometrial cancer, we suggest that FGFR2 may join the list of genes that play context-dependent opposing roles in cancer. (Mol Cancer Res 2009;7(1):41-54)

Original languageEnglish (US)
Pages (from-to)41-54
Number of pages14
JournalMolecular Cancer Research
Volume7
Issue number1
DOIs
StatePublished - Jan 1 2009
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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