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

Gartside, Michael, Chen, Huaibin, Ibrahimi, Omar, Byron, Sara, Curtis, Amy, Wellens, Candice, Bengston, Ana, Yudt, Laura, Eliseenkova, Anna, Ma, Jinghong, & Pollock, Pamela (2009) Loss-of-function fibroblast growth factor receptor-2 mutations in melanoma. Molecular Cancer Research, 7(1), pp. 41-54.

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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.

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70 citations in Scopus
66 citations in Web of Science®
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ID Code: 45013
Item Type: Journal Article
Refereed: Yes
Keywords: Melanoma, mutation, FGFR2, mislocalization, loss of function
DOI: 10.1158/1541-7786.MCR-08-0021
ISSN: 1541-7786
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200)
Divisions: Past > QUT Faculties & Divisions > Faculty of Science and Technology
Copyright Owner: Copyright 2009 American Association for Cancer Research
Deposited On: 24 Aug 2011 22:16
Last Modified: 23 Jul 2012 22:52

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