FGFR3 encodes a member of the fibroblast growth factor receptor (FGFR) family with tyrosine kinase activity; binding of ligand (fibroblast growth factor –FGF-) induces receptor dimerization, autophosphorylation and signal transduction.
FGFR family members differ from one another in their ligand affinities and tissue distribution. This particular family member binds acidic and basic FGF and plays a role in bone development and maintenance. Mutations in this gene lead to craniosynostosis and multiple types of skeletal dysplasia. Three alternatively spliced transcript variants that encode different protein isoforms have been described.
Somatic mutations in the FGFR3 gene are mainly associated with bladder cancer. These mutations overactivate the FGFR3 protein, which likely directs bladder cells to grow and divide abnormally. In addition to bladder cancer, somatic FGFR3 mutations have been associated with multiple myeloma (MM) and cervical cancer. In MM, a t(4;14)(p16.3;q32.3) translocation leading to a FGFR3-IgH fusion gene has been observed. Mutations that have been associated with cervical cancer are point mutations, mainly substitutions, in FGFR3.
FGFR3 mutations that lead to multiple myeloma and cervical cancer are thought to overactivate the FGFR3 protein.
The same FGFR3 mutations known from bladder carcinoma have been shown to cause benign human skin tumors such as seborrheic keratoses and epidermal nevi.
Somatic mutation hot spots: substitutions at codons 249 (S249C), 373 (Y373C), 248 (R248C)
References (open access):
Incidence of fibroblast growth factor receptor 3 gene (FGFR3) A248C, S249C, G372C, and T375C mutations in bladder cancer. Dodurga Y, Tataroglu C, Kesen Z, Satiroglu-Tufan NL. Genet Mol Res. 2011 Jan 18;10(1):86-95.
Detection of somatic mutations by high-resolution DNA melting (HRM) analysis in multiple cancers. Detection of somatic mutations by high-resolution DNA melting (HRM) analysis in multiple cancers. PLoS One. 2011 Jan 17;6(1):e14522.
Multiple oncogenic mutations and clonal relationship in spatially distinct benign human epidermal tumors. Hafner C, Toll A, Fernández-Casado A, Earl J, Marqués M, Acquadro F, Méndez-Pertuz M, Urioste M, Malats N, Burns JE, Knowles MA, Cigudosa JC, Hartmann A, Vogt T, Landthaler M, Pujol RM, Real FX. Proc Natl Acad Sci U S A. 2010 Nov 30;107(48):20780-5.
Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. Qing J, Du X, Chen Y, Chan P, Li H, Wu P, Marsters S, Stawicki S, Tien J, Totpal K, Ross S, Stinson S, Dornan D, French D, Wang QR, Stephan JP, Wu Y, Wiesmann C, Ashkenazi A. J Clin Invest. 2009 May;119(5):1216-29.