High levels of patched gene mutations in basal-cell carcinomas from patients with xeroderma pigmentosum

Recently, hptc, a human gene homologous to the Drosophila segment polarity gene patched (ptc), has been implicated in the nevoid basal-cell carcinoma (BCC) syndrome, and somatic mutations of hptc also have been found in spora dic BCCs, the most frequent cancers found in the white population. We have analyzed the hptc gene, postulated to be a tumor suppressor gene, in 22 BCC s from patients with the hyperphotosensitive genodermatosis xeroderma pigme ntosum (XP), Patients with XP are deficient in the repair of UV-induced DNA lesions and are characterized by their predisposition to cancers in sun ex posed skin. Analysis using PCR-single-strand conformation polymorphism of t he hptc gene identified 19 alterations in 16 of 22 (73%) of the BCCs examin ed. Only two (11%) deletions of the hptc gene were found in XP BCCs compare d with >30% rearrangement observed in non-XP sporadic BCCs, and 17 of 19 (8 9%) were base substitutions. Among the 17 base substitutions, 11 (65%) were CC --> TT tandem mutations, and 4 (23%) were C --> T substitutions, all ta rgeted at bipyrimidine sites. Hence, a significantly higher number (15 of 1 9; 79%) of UV-specific alterations are seen in XP tumors, in contrast to no n-XP sporadic BCCs, Interestingly, we have found that in 7 of 14 (50%) XP B CCs analyzed, both hptc and the tumor suppressor gene p53 are mutated. Not only have our data indicated the key; role played by hptc in the developmen t of BCCs, they also have substantiated the link between unrepaired UV-indu ced DNA lesions and skin carcinogenesis, as exemplified by the UV-specific alterations of: different genes in the same tumors.