RHABDOMYOSARCOMAS AND RADIATION HYPERSENSITIVITY IN A MOUSE MODEL OF GORLIN SYNDROME

Gorlin (or nevoid basal cell carcinoma) syndrome is characterized by a variety of clinical problems including generalized overgrowth of the body, cysts, developmental abnormalities of the skeleton and a predisp osition to benign and malignant tumors(1,2). The syndrome results from germline mutations of the human homolog of the drosophila segment pol arity gene patched (ptc)(3,4). Here we report that mice heterozygous f or ptc develop many of the features characteristic of Gorlin syndrome and that they exhibit a high incidence of rhabdomyosarcomas (RMS), the most common soft-tissue sarcoma in children(5). The downstream signal ling partner of ptc, gli1, was overexpressed in all RMSs analyzed, ind icating that abnormal signalling of the ptc-gli1 pathway may be common for the various tumors(6,7) associated with the syndrome. igf2, impli cated in the formation of RMSs(8), was also overexpressed, suggesting cross-talk between the ptc and igf2 pathways in tumorigenesis. Develop emental defects in Gorlin syndrome resemble those induced by ionizing radiation(9). We show that ptc heterozygous mice exhibit increased inc idence of radiation-induced teratogenesis. This suggests a role for pt c in the response to ionizing radiation and provides a model for both the systemic (developmental) and stochastic (cancer) abnormalities obs erved in Gorlin syndrome.