Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans.
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.
Logié
Armelle
A
UMR 144, Centre National de la Recherche Scientifique, Section de Recherche, Institut Curie, Paris, France.
Dunois-Lardé
Claire
C
Rosty
Christophe
C
Levrel
Olivier
O
Blanche
Martine
M
Ribeiro
Agnès
A
Gasc
Jean-Marie
JM
Jorcano
Jose
J
Werner
Sabine
S
Sastre-Garau
Xavier
X
Thiery
Jean Paul
JP
Radvanyi
François
F
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D004252:DNA Mutational Analysis; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D017492:Keratosis, Seborrheic / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D019076:Transgenes
D017468:Receptors, Fibroblast Growth Factor; C496365:FGFR3 protein, human; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D001973:Bromodeoxyuridine