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Significantly High Levels of Ultraviolet-specific Mutations in the Smoothened Gene in Basal Cell Carcinomas from DNA Repair-deficient Xeroderma Pigmentosum Patients¹

Laboratory of Genetic Instability and Cancer, UPR2169 CNRS, Institut André Lwoff, 94801 Villejuif, France [S. C-P., A. S., L. D-G.]; Institut Gustave Roussy, 94805 Villejuif, France [M. F. A.]; and Department of Dermato-Venerology, Centre Hospitalo-Universitaire de Bab El Oued, Algers, Algerie [B. B.]

The Sonic hedgehog (SHH) pathway is implicated in the etiology of the most common human cancer in Caucasians, the basal cell carcinoma (BCC). Mutations in the receptor of SHH, the patched gene, have been characterized in sporadic BCCs as well as those from patients with the rare genetic syndromes nevoid BCC and xeroderma pigmentosum (XP). To elucidate the role of UV in the deregulation of the SHH pathway, we analyzed for alterations of smoothened, a transmembrane signaling component regulated by patched, in BCCs and squamous cell carcinomas from UV hypersensitive XP patients. We find UV-specific smoothened mutations in 30% of XP BCCs, three times higher than those in sporadic Caucasian BCCs, confirming the high rate of UV-induced mutations in DNA repair-deficient XP patients. No alteration was found in XP squamous cell carcinomas, indicating the involvement of smoothened specifically in the development of BCC.

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