Identification of Novel FGFR3 Gene Mutations in Actinic Cheilitis

Objective: Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are responsible for several autosomal dominant craniosynostosis and chondrodysplasia syndromes. Recently, activating FGFR3 mutations have been identified in several human cancers including bladder carcinoma, cervical carcinoma and multiple myeloma. Despite a reported high frequency in the benign skin disorders epidermal nevi and seborrheic keratosis, FGFR3 mutations have not been reported in cutaneous malignancy. Actinic cheilitis (AC) is a sun-induced epithelial premalignancy affecting the lower lip that frequently progresses to squamous cell carcinoma (SCC). The objective of this study was to genotype FGFR3 gene in AC and SCC of the lip.

Methods: DNA was extracted and purified from 20 micro-dissected formalin-fixed, paraffin embedded tissue sections of AC and SCC arising in AC. Exons 6, 13, and 15 were PCR amplified and direct sequenced in both the 3' and 5' directions.

Results: 4 novel mutations in the FGFR3 gene were identified: exon 6 mutation R248C (744C®T), exon 13 mutations D617G (1852A®G) and V630M (1890G®A), and exon 15 mutation E686K (2058G®A). Mutations located in the linker region between immunoglobulin-like domain II-III and tyrosine kinase domain II. Grade of dysplasia present in AC did not correlate with the presence of mutations.

Conclusions: We identified four novel mutations in the FGRF3 gene in AC and SCC. R248C mutation has been described in adenoid seborrheic keratosis, urothelial carcinoma, and epidermal nevi suggesting a functional role of the FGFR3 receptor in the development of epithelial disorders. Thus, the FGFR3 receptor may contribute to the pathogenesis of some AC and SCC.

Support: NIH grants: T32-DE017249 and RO1-CA095231.