5702

Loss-of-function mutations in Patched (Ptch1) are implicated in constitutive activation of the Sonic hedgehog pathway in human basal cell carcinomas, and inherited Ptch1 mutations underlie basal cell nevus syndrome (BCNS), in which a typical feature is multiple basal cell carcinoma (BCC) occurring with greater incidence in portals of radiotherapy. Mice in which one copy of Ptch1 is inactivated show increased susceptibility to spontaneous tumor development, and hypersensitivity to radiation-induced tumorigenesis, providing an ideal in vivo model to study the typical pathologies associated with BCNS. We examined BCC development in control and irradiated Ptch1neo67/+ mice. Ptch1neo67/+ mice and wild type littermates of both sexes were whole-body irradiated with 3 Gy of X rays as newborns (4 days) or adults (90 days). In addition, two months old mice were subjected to local irradiation of the dorsal skin with a single dose of 4 Gy of X rays. We show that unirradiated mice develop putative BCC precursor lesions, i.e., basaloid hyperproliferation areas arising from both follicular and interfollicular epithelium, and that these lesions progress to nodular and infiltrative BCCs only in irradiated mice. Data of BCC incidence, multiplicity, and latency support the notion of epidermal hyperproliferations, nodular and infiltrative BCC-like tumors representing different stages of tumor development. This is further supported by the pattern of p53 protein expression observed in BCC subtypes, and by the finding of retention of the normal remaining Ptch1 allele in all nodular, circumscribed BCCs analysed compared to its constant loss in infiltrative BCCs. Our data suggest chronological tumor progression from basaloid hyperproliferations to nodular and then infiltrative BCC occurring in a step-wise fashion through the accumulation of sequential genetic alterations. (Partially supported by the Radiation Protection Action of the EC, contract FI6R-CT-2003-508842)

[Proc Amer Assoc Cancer Res, Volume 46, 2005]