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 linked to chronic sun exposure. In psoralen and ultraviolet A-treated psoriatic patients, basal cell carcinomas may occur even more frequently; however, the exact etiology and mechanisms of tumorigenesis in psoriatic patients are unclear because psoralen and ultraviolet A is not only a carcinogen but also an immunosuppressor and because psoralen and ultraviolet A-treated psoriatic patients often have other (co)carcinogenic risk factors (e.g, therapeutic exposure to ultraviolet B, X-ray radiation, arsenic, tar, and/or chemotherapeutic agents such as methotrexate). In this study, we analyzed the DNA of 13 basal cell carcinomas from five psoralen and ultraviolet A-treated psoriatic patients for mutations of the p53 tumor suppressor gene. DNA sequencing revealed a total of 11 mis-sense, two non-sense, and four silent mutations 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 transitions and one CC-->TT transition). Three of the C-->T transitions occurred at dipyrimidine sites opposite a 5'-TpG sequence (a potential psoralen-binding site and target for psoralen and ultraviolet A mutagenesis). Thus, whether 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 psoralen binding and mutagenesis in cell and murine studies), and one (8%) involved a G-->T transversion. These results suggest that (i) the major initiator of p53 mutations in basal cell carcinoma in psoralen and ultraviolet A-treated psoriasis patients is environmental and/or therapeutic ultraviolet(B) exposure, and that (ii) psoralen and ultraviolet A itself causes only a smaller portion of p53 mutations in psoralen and ultraviolet A-associated basal cell carcinomas.
Seidl
H
H
Department of Dermatology and Institute of Pathology, Karl-Franzens University, Graz, Austria.
Kreimer-Erlacher
H
H
Bäck
B
B
Soyer
H P
HP
Höfler
G
G
Kerl
H
H
Wolf
P
P
D000328:Adult; D000368:Aged; D002280:Basal Cell Carcinoma / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005363:Ficusin / Q000009:adverse effects; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011701:PUVA Therapy / Q000009:adverse effects*; D017319:Photosensitizing Agents / Q000009:adverse effects; D017354:Point Mutation / Q000187:drug effects / Q000528:radiation effects; D018807:Polymorphism, Single-Stranded Conformational; D011565:Psoriasis / Q000150:complications / Q000188:drug therapy*; D012878:Skin Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014466:Ultraviolet Rays / Q000009:adverse effects*
D017319:Photosensitizing Agents; D016159:Tumor Suppressor Protein p53; D005363:Ficusin