Activating Smoothened mutations in sporadic basal-cell carcinoma

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Abstract

Basal-cell carcinomas (BCCs) are the commonest human cancer1. Insight into their genesis came from identification of mutations in the PATCHED gene (PTCH) in patients with the basal-cell nevus syndrome, a hereditary disease characterized by multiple BCCs and by developmental abnormalities2,3,4,5,6,7. The binding of Sonic hedgehog (SHH) to its receptor, PTCH, is thought to prevent normal inhibition by PTCH of Smoothened (SMO), a seven-span transmembrane protein8,9. According to this model, the inhibition of SMO signalling is relieved following mutational inactivation of PTCH in basal-cell nevus syndrome. We report here the identification of activating somatic missense mutations in the SMO gene itself in sporadic BCCs from three patients. Mutant SMO, unlike wild type, can cooperate with adenovirus E1A to transform rat embryonic fibroblast cells in culture. Furthermore, skin abnormalities similar to BCCs 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 function as an oncogene in BCCs.

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Figure 1: Human SMO genomic structure and localization.
Figure 2: SMO mutations in sporadic BCC tumours.
Figure 3: Predicted structure of the human SMO protein8.
Figure 4: Skin of SMO-M2 transgenic mice display the features of basal-cell carcinoma.

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Acknowledgements

We thank D. Sherman and V. Bhagwandin for technical help, J. Ramirez for histology, K. Hagler for immunohistochemistry, E. Nelson for help with the animals, the Genentech DNA synthesis group, C. Hoffman and W. Anstine for preparing the figures, E. Fuchs for the K5 promoter, J.Gitscher for facilitating our collaboration and F. McCormick and M. Scott for advice and discussions. J.X. was the recipient of a Neutrogena fellowship of the Dermatology Foundation. Research in San Francisco was supported by the National Institute of Arthritis, Musculoskeletal and Skin Diseases.

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Correspondence to Ervin H. Epstein Jr or Frederic J. de Sauvage.

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