UV mutation signature in tumor suppressor genes involved in skin carcinogenesis in xeroderma pigmentosum patients

Molecular analysis of p53 and patched (PTCH), two candidate tumor suppresso r genes for non-melanocytic skin cancer, was performed in skin tumors from six patients affected by the cancer-prone disease xeroderma pigmentosum (XP ), UV-specific p53 mutations were detected at a frequency of 38-50% in all the tumor types analysed, including melanomas, Additional analysis of PTCH mutations in the subset of eight basal call carcinomas (BCC) revealed a ver y high mutation frequency of this gene (90%) which exceeded that detected i n the p53 gene in the same tumors (38%), PTCH mutations were predominantly UV-specific C > T transitions, This mutation pattern is different from that reported in BCC from normal donors where PTCH mutation frequency is 27% an d mutations are frequently deletions and insertions. These findings suggest that PTCH mutations represent an earlier event in BCC development than p53 alterations and that the inability of XP patients to repair UV-induced PTC H mutations might significantly contribute to the early and frequent appear ance of BCC observed in these patients.