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

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.

FGFR3 mutations in prostate cancer: association with low-grade tumors

“…As FGFR3 is a gene involved in bladder carcinogenesis and the presence of FGFR3 mutations is also a common event in benign skin tumors, [30][31][32]35,37,41 this association between bladder, skin, and prostate cancer could suggest a common role for FGFR3 in their pathogenesis. However, the mutational analysis of the corresponding bladder tumors and normal prostate samples in some of the patients from our study revealed the wild-type status of the gene.…”

“…Mutations in this gene have been reported in bladder and cervix carcinoma, multiple myeloma, colon cancer and, more recently, in benign skin tumors. [25][26][27][28][29][30][31][32][33] The relatively high prevalence of FGFR3 mutations in benign skin tumors and in noninvasive bladder tumors suggests an association of FGFR3 mutation with low risk cancers. 35,41 Although it seems that anomalous FGF signaling is involved in prostate carcinogenesis, the functional role of FGFR3 and its alterations in prostate cancer are unknown.…”

“…[22][23][24] FGFR3 mutations identical to those found in these disorders have been reported in multiple myelomas, cervix and bladder cancer, colon cancer, and benign skin tumors. [25][26][27][28][29][30][31][32][33] This gene constitutes a promising marker in the clinical management of patients with low-grade, non-muscle-invasive bladder tumors. 29 However, very few authors have analyzed the mutational status of the FGFR3 gene in prostate tumors.…”

FGFR3 mutations in seborrheic keratoses are already present in flat lesions and associated with age and localization

“…FGFR3 mutations have been identified in 39-85% of human seborrheic keratoses. 5,6 In patients with FGFR3 mutant seborrheic keratoses, normal skin showed a wild-type FGFR3 sequence confirming the somatic nature of these mutations. Albeit an important role of FGFR3 mutations in the pathogenesis of seborrheic keratoses is suggested by previous studies, details of the mechanisms causing these mutations in human epidermis and of the signaling pathways mediating the growth of acanthotic tumors in FGFR3 mutant skin are unknown.…”

“…Recently, activating FGFR3 mutations in the epidermis were shown to be involved in the development of seborrheic keratoses. 5 Transgenic mice expressing the S249C FGFR3 mutation in the basal layer of the epidermis under the control of the keratin 5 promoter developed thickening of the skin and verrucous skin tumors with histological features similar to human seborrheic keratoses. FGFR3 mutations have been identified in 39-85% of human seborrheic keratoses.…”