ACTIVATING SMOOTHENED MUTATIONS IN SPORADIC BASAL-CELL CARCINOMA

Basal-cell carcinomas (BCCs) are the commonest human cancer(1). Insigh t into their genesis came from identification of mutations in the PATC HED gene (PTCH) in patients with the basal-cell nevus syndrome, a here ditary disease characterized by multiple BCCs and by developmental abn ormalities(2-7). The binding of Sonic hedgehog (SHH) to its receptor, PTCH, is thought to prevent normal inhibition by PTCH of Smoothened (S MO), a seven-span transmembrane protein(8,9). According to this model, the inhibition of SMO signalling is relieved following mutational ina ctivation of PTCH in basal-cell nevus syndrome, We report here the ide ntification of activating somatic missense mutations in the SMO gene i tself in sporadic BCCs from three patients. Mutant SMO, unlike wild ty pe, can cooperate with adenovirus E1A to transform rat embryonic fibro blast cells in culture, Furthermore, skin abnormalities similar to BCC s developed in transgenic murine skin overexpressing mutant SMO. These findings support the role of SMO as a signalling component of the SHH -receptor complex and provide direct evidence that mutated SMO can fun ction as an oncogene in BCCs.