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Human Molecular Genetics Advance Access published online on March 16, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi127
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Published by Oxford University Press 2005
Received December 31, 2004
Revised March 3, 2005
Accepted March 9, 2005

Article

Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans

Armelle Logié 1, Claire Dunois-Lardé 1, Christophe Rosty 2, Olivier Levrel 1, Martine Blanche 1, Agnès Ribeiro 1, Jean-Marie Gasc 3, Jose Jorcano 4, Sabine Werner 5, Xavier Sastre-Garau 6, Jean Paul Thiery 7, and François Radvanyi 1*

1 UMR 144, Centre National de la Recherche Scientifique, Institut Curie, Section de Recherche, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
2 UMR 144, Centre National de la Recherche Scientifique, Institut Curie, Section de Recherche, 26 rue d'Ulm, 75248 Paris Cedex 05, France.; Département de Pathologie, Institut Curie, Section Médicale, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
3 Collège de France and INSERM U36, 11 Place Marcelin Berthelot, 75231 Paris Cedex 05, France.
4 Project on Cell and Molecular Biology and Gene Therapy, CIEMAT, Ave. Complutense 22, E-28040 Madrid, Spain.
5 Institute of Cell Biology, Department of Biology, ETH Zürich, Hönggerberg, CH-8093 Zürich, Switzerland.
6 Département de Pathologie, Institut Curie, Section Médicale, 26 rue d'Ulm, 75248 Paris Cedex 05, France.; Département de Biologie des Tumeurs, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
7 UMR 144, Centre National de la Recherche Scientifique, Institut Curie, Section de Recherche, 26 rue d'Ulm, 75248 Paris Cedex 05, France.; Département de Transfert, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.

* To whom correspondence should be addressed.
François Radvanyi, E-mail: francois.radvanyi{at}curie.fr


  Abstract

Specific germline activating point mutations in the gene encoding the tyrosine kinase receptor FGFR3 (fibroblast growth factor receptor 3) result in autosomal dominant human skeletal dysplasias. The identification in multiple myeloma and in two epithelial cancers - bladder and cervical carcinomas - of somatic FGFR3 mutations identical to the germinal activating mutations found in skeletal dysplasias, together with functional studies, have suggested an oncogenic role for this receptor. Although acanthosis nigricans, a benign skin tumor, has been found in some syndromes associated with germinal activating mutations of FGFR3, the role of activated FGFR3 in the epidermis has never been investigated. Here, we targeted an activated receptor mutant (S249C FGFR3) to the basal cells of the epidermis of transgenic mice. Mice expressing the transgene developed benign epidermal tumors with no sign of malignancy. These skin lesions had features in common with acanthosis nigricans and other benign human skin tumors, including seborrheic keratosis, one of the most common benign epidermal tumors in humans. We therefore screened a series of 62 cases of seborrheic keratosis for FGFR3 mutations. A large proportion of these tumors (39%) harbored somatic activating FGFR3 mutations, identical to those associated with skeletal dysplasia syndromes and bladder and cervical neoplasms. Our findings directly implicate FGFR3 activation as a major cause of benign epidermal tumors in humans.


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