Molecular analysis of p53 and patched (PTCH), two candidate tumor suppressor genes for non-melanocytic skin cancer, was performed in skin tumors from six patients aected by the cancer-prone disease xeroderma pigmentosum (XP). UV-speci®c 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 very high mutation frequency of this gene (90%) which exceeded that detected in the p53 gene in the same tumors (38%). PTCH mutations were predominantly UV-speci®c C4T transitions. This mutation pattern is dierent from that reported in BCC from normal donors where PTCH mutation frequency is 27% and mutations are frequently deletions and insertions. These ®ndings 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 PTCH mutations might signi®cantly contribute to the early and frequent appearance of BCC observed in these patients. Oncogene (2000) 19, 463 ± 467.Keywords: skin cancer; XP; p53; PATCHED; UV light Mutations in a number of genes have been associated with the genesis of human skin cancer. The inactivation and/or mutation of the p53 gene has been implicated as an important factor in the pathogenesis of UV lightinduced non-melanocytic skin cancers (NMSC), i.e. basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). All p53 mutations detected in these tumors are indeed consistent with the mutagenic action of UV light as inferred from in vitro studies (reviewed in Dogliotti et al., 1998). More recently, a set of members of the Sonic hedgehog (SHH) signaling pathway, which is required for correct embryonic patterning, have been shown to be directly and speci®cally involved in BCC development. In particular, inactivating mutations of patched (PTCH), a SHH receptor that acts negatively on this signaling pathway, have been found both in familial and sporadic BCC (reviewed in Gailani and Bale, 1997). Other alterations in the same signaling pathway have also been reported in sporadic BCC, namely the activation of the transcription factor Gli1 in basal cells (Dahmane et al., 1997) and activating mutations of shh (Oro et al., 1997) and smoothened (smo) . Interestingly, the analysis of PTCH mutations in BCC shows that, dierently from what was observed in the p53 gene, almost half of the mutations identi®ed are frameshift mutations or rearrangements which are not typical of UV mutagenesis (Hahn et al., 1996;Johnson et al., 1996;Gailani et al., 1996;Unden et al., 1996;Chidambaram et al., 1996;Wolter et al., 1997;Wicking et al., 1997;Aszterbaum et al., 1998). The role of UV radiation in the genesis of alterations of the PTCH gene is then questionable.In addition to p53 and PTCH, other genes which control the susceptibility to skin cancer are those defective in the cancer-prone hereditary disorder xeroderma pigmentosum (XP). The biochemical defect in most XP patients (seven comp...