Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders

Abstract

Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are responsible for several autosomal dominant craniosynostosis syndromes and chondrodysplasias i.e. hypochondroplasia, achondroplasia, SADDAN and thanatophoric dysplasia -a neonatal lethal dwarfism syndrome. Recently, activating FGFR3 mutations have also been found to be present in cancer, i.e. at high frequency in carcinoma of the bladder and rarely in multiple myeloma and carcinoma of the cervix. Almost all reported mutations in carcinomas corresponded to the mutations identified in thanatophoric dysplasia. We here screened a series of 297 bladder tumours and found three FGFR3 somatic mutations (G380/ 382R; K650/652M and K650/652T) that were not previously identified in carcinomas or thanatophoric dysplasia. Another novel finding was the occurrence of two simultaneous FGFR3 mutations in four tumours. Two of the three new mutations in bladder cancer, the G380/382R and the K650/652M mutations, were previously reported in achondroplasia and SADDAN, respectively. These syndromes entail a longer life span than thanatophoric dysplasia. The K650/652T mutation has not previously been detected in patients with skeletal disorders, but affects a codon that has been shown to be affected in some cases of thanatophoric dysplasia, SADDAN and hypochondroplasia. From a clinical perspective, the patients with FGFR3-related, non-lethal skeletal disorders might be at a higher risk for development of bladder tumours than the general population.

The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3

“…Nonetheless, our results confirm that the K/E-FR3 protein has the potential to be oncogenic. Therefore, FR3 overexpression with or without activating mutations found in a variety of cancers (Ueki et al, 1995;Hallek et al, 1998;Chesi et al, 2002;Van Rhijn et al, 2002) may imply its involvement in tumor initiation and/or progression.…”

“…For instance, activating point mutations of FGFR2 and FGFR3 were identified in gastric and colorectal cancers, respectively (Jang et al, 2001). In addition, activating mutations of FGFR3 were found in bladder and cervical carcinomas as well as in multiple myeloma (MM) (Hallek et al, 1998;Chesi et al, 2002;Van Rhijn et al, 2002). Interestingly, the most frequent finding in MM is the deregulated expression of functional FGFR3 due to translocation to the immunoglobulin heavy chain switch region (the t(4:14)(p16:q32) translocation), a hot spot of chromosomal abnormality in lymphoid cells (Chesi et al, 1997;Richelda et al, 1997).…”

“…It was shown to be a critical mediator of FGFR signals in development (Saxton et al, 1997(Saxton et al, , 2000. SHP2 possesses two tandemly arranged SH2 domains in its N-terminal region and a phosphatase domain in its C-terminal domain (Feng et al, 1993Hallek et al, 1998;Chesi et al, 2002;Van Rhijn et al, 2002). It also possesses a stretch of proline-rich sequences and tyrosine phosphorylation sites in its extreme C-terminal region.…”

Receptor tyrosine kinase transmembrane domains

“…Often these mutations substitute aliphatic amino acids that participate in the dimer interface with Glu or Asp, which have hydrogen bonding capabilities. One example is the Ala391Glu mutation in FGFR3, which has been identified as a somatic mutation in bladder cancer 36 and as a germ-line mutation in Crouzon syndrome with acanthosis nigricans, 37 an autosomal dominant disorder characterized by the following three phenotypic features: (1) mild disturbances of the growth plate of the long bones, (2) premature ossification of the skull (craniosynostosis) and (3) skin hyperpigmentation and hyperkeratosis. A second example is the Val664Glu mutation in rat Neu which has been shown to be oncogenic.…”

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

“…Mutations in FGFR3 are found in approximately 50% of cases of bladder cancers, and the most common are extracellular domain mutations that lead to constitutive receptor activation ( 27 ). Actions intended to target FGFR3 reduced cell proliferation and tumor growth in both bladder cancer cells and mouse models ( 43 ).…”