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 sporadic 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 BCCs from patients with the hyperphotosensitive genodermatosis xeroderma pigmentosum (XP). Patients with XP are deficient in the repair of UV-induced DNA lesions and are characterized by their predisposition to cancers in sun-exposed skin. Analysis using PCR-single-strand conformation polymorphism of the hptc gene identified 19 alterations in 16 of 22 (73%) of the BCCs examined. Only two (11%) deletions of the hptc gene were found in XP BCCs compared with >30% rearrangement observed in non-XP sporadic BCCs, and 17 of 19 (89%) were base substitutions. Among the 17 base substitutions, 11 (65%) were CC --> TT tandem mutations, and 4 (23%) were C --> T substitutions, all targeted at bipyrimidine sites. Hence, a significantly higher number (15 of 19; 79%) of UV-specific alterations are seen in XP tumors, in contrast to non-XP sporadic BCCs. Interestingly, we have found that in 7 of 14 (50%) XP BCCs 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 development of BCCs, they also have substantiated the link between unrepaired UV-induced DNA lesions and skin carcinogenesis, as exemplified by the UV-specific alterations of different genes in the same tumors.
Bodak
N
N
Laboratory of Molecular Genetics, Institut de Recherches Scientifiques sur le Cancer, Boîte Postale 8, 94801 Villejuif, France.
Queille
S
S
Avril
M F
MF
Bouadjar
B
B
Drougard
C
C
Sarasin
A
A
Daya-Grosjean
L
L
D000818:Animals; D002280:Basal Cell Carcinoma / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair; D004330:Drosophila; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D012878:Skin Neoplasms / Q000235:genetics*; D014983:Xeroderma Pigmentosum / Q000235:genetics*
D008565:Membrane Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface