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Human Molecular Genetics Advance Access originally published online on March 16, 2005
Human Molecular Genetics 2005 14(9):1153-1160; doi:10.1093/hmg/ddi127
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Published by Oxford University Press 2005.

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

Armelle Logié1,{dagger}, Claire Dunois-Lardé1,{dagger}, Christophe Rosty1,2,{dagger}, Olivier Levrel1, Martine Blanche1, Agnès Ribeiro1, Jean-Marie Gasc5, Jose Jorcano6, Sabine Werner7, Xavier Sastre-Garau2,3, Jean Paul Thiery1,4 and François Radvanyi1,*

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

* To whom correspondence should be addressed. Tel: +33 142346339; Fax: +33 142346349; Email: francois.radvanyi{at}curie.fr

Received December 31, 2004; Accepted March 9, 2005

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.

{dagger} The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.


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