Ultraviolet exposure as the main initiator of p53 mutations in basal cell carcinomas from psoralen and ultraviolet A-treated patients with psoriasis

Basal cell carcinoma, the most frequent skin cancer in humans, is often lin ked to chronic sun exposure. In psoralen and ultraviolet A-treated psoriati c patients, basal cell carcinomas may occur even more frequently; however, the exact etiology and mechanisms of tumorigenesis in psoriatic patients ar e unclear because psoralen and ultraviolet A is not only a carcinogen but a lso an immunosuppressor and because psoralen and ultraviolet A-treated psor iatic patients often have other (co) carcinogenic risk factors (e.g, therap eutic exposure to ultraviolet B, X-ray radiation, arsenic, tar, and/or chem otherapeutic agents such as methotrexate). In this study, we analyzed the D NA of 13 basal cell carcinomas from five psoralen and ultraviolet A-treated psoriatic patients for mutations of the p53 tumor suppressor gene. DNA seq uencing revealed a total of 11 mis-sense, two non-sense, and four silent mu tations in seven of the 13 basal cell carcinomas (54%). Of the 13 total mis -sense or non-sense mutations, 12 (92%) occurred at dipyrimidine sites and nine (69%) were of the ultraviolet fingerprint type (eight C -->T transitio ns and one CC --> TT transition). Three of the C -->T transitions occurred at dipyrimidine sites opposite a 5'-TpG sequence (a potential psoralen-bind ing site and target for psoralen and ultraviolet A mutagenesis). Thus, whet her these mutations were induced by ultraviolet or psoralen and ultraviolet A was not clear. In addition, two other mutations (15%) occurred at 5'-TpG sites, one (8%) occurred at a 5'-TpA site (the most frequent site of psora len binding and mutagenesis in cell and murine studies), and one (8%) invol ved a G -->T transversion. These results suggest that (i) the major initiat or of p53 mutations in basal cell carcinoma in psoralen and ultraviolet A-t reated psoriasis patients is environmental and/or therapeutic ultraviolet(B ) exposure, and that (ii) psoralen and ultraviolet A itself causes only a s maller portion of p53 mutations in psoralen and ultraviolet A-associated ba sal cell carcinomas.