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Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas

Nature Genetics volume 23, pages 18–20 (1999)Cite this article

Fibroblast growth factor receptor 3 (FGFR3) belongs to a family of structurally related tyrosine kinase receptors encoded by four different genes. These receptors are glycoproteins composed of two to three extracellular immunoglobulin (Ig)-like domains, a transmembrane domain and a split tyrosine-kinase domain. Specific point mutations in different domains of FGFR3 are associated with autosomal dominant human skeletal disorders such as hypochondroplasia, achondroplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and thanatophoric dysplasia1,2. Several reports have demonstrated that these mutations lead to constitutive activation of the receptor1,2,3. Introduction of activating mutations into the mouse gene Fgfr3 using 'knock-in' approaches4,5 and the targeting of activated Fgfr3 to growth plate cartilage in mice6 result in dwarfism. Conversely, the targeted disruption of Fgfr3 in mice results in the overgrowth of long bones and vertebrae7,8. These observations suggest that Fgfr3 is a negative regulator of bone growth. In contrast with this inhibitory role, an oncogenic role has been proposed for FGFR3 in multiple myeloma (MM). In this lymphoid neoplasm, a t(4;14)(p16.3;q32.3) chromosomal translocation with breakpoints on 4p16 located 50–100 kb centromeric to FGFR3 is present in 20–25% of tumours, and associated with overexpression of FGFR3 (refs 9,10). In rare cases (2/12 MM cell lines and 1/85 primary MM tumours), activating mutations of FGFR3 previously identified in human skeletal disorders have been found, always accompanied by the t(4;14)(p16.3;q32.3) translocation9,10,11. The real contribution of FGFR3 in MM oncogenesis is not clearly established, as it has recently been shown that the 4p16 breakpoints in MM occur in a novel gene (MMEST/WHSC1), creating fusion transcripts between the new gene and the immunoglobulin heavy chain (IgH) locus at 14q32.3, disrupted in a switch region by the translocation12,13. Nothing is known about the role of FGFR3 in epithelial cancers (carcinomas), which account for 90% of malignant neoplasms. Having detected FGFR3 expression in normal bladder and cervix epithelia (data not shown), we examined the expression and mutational status of FGFR3 in a series of bladder and cervix carcinomas to determine whether FGFR3 is involved in epithelial tumorigenesis.

The expression of a constitutively activated FGFR3 in a large proportion of two common epithelial cancers is the first evidence of an oncogenic role for FGFR3 in carcinomas. FGFR3 currently appears to be the most frequently mutated oncogene in bladder cancer: it is mutated in more than 30% of cases. FGFR3 seems to mediate opposite signals, acting as a negative regulator of growth in bone and as an oncogene in several tumour types. Complete elucidation of the role of FGFR3 in normal and malignant tissues requires further investigation, but we have shown that FGFR3 is an important target in bladder and cervix carcinogenesis.

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Figure 1: FGFR3 mutations in human carcinomas.

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Acknowledgements

We thank O. Delattre, T. Melot and N. Sevenet for help and J. Jouanneau and J. Bonaventure for comments. This study was funded by the CNRS, the Institut Curie and by grants from the Ligue contre le Cancer, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer, the association Claude Bernard, the Université Paris XII and the Assistance Publique Hôpitaux de Paris (PHRC number AOA 94105).

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  1. Laboratoire de Morphogenèse Cellulaire et Progression Tumorale, UMR 144, Centre National de la Recherche Scientifique, Institut Curie, Section de Recherche, 26 rue d'Ulm, 75248 Cedex 05, Paris, France

    David Cappellen, Catherine De Oliveira, David Ricol, Sixtina de Medina, Jérôme Bourdin, Jean Paul Thiery & François Radvanyi

  2. Département de Pathologie, Institut Curie, Section Médicale, 26 rue d'Ulm, 75248 Cedex 05, Paris, France

    Jérôme Bourdin & Xavier Sastre-Garau

  3. Centre de Recherches Chirurgicales et Service d'Urologie, Centre Hospitalier Universitaire Henri Mondor, 94010 Cedex, Créteil, France

    Sixtina de Medina & Dominique Chopin

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  1. David Cappellen
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Correspondence to François Radvanyi.

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Cappellen, D., De Oliveira, C., Ricol, D. et al. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas . Nat Genet 23, 18–20 (1999). https://doi.org/10.1038/12615

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