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Mutagenesis, Vol. 15, No. 2, 127-132, March 2000
© 2000 UK Environmental Mutagen Society/Oxford University Press

p53 mutations experimentally induced by 8-methoxypsoralen plus UVA (PUVA) differ from those found in human skin cancers in PUVA-treated patients

Paola Monti1, Alberto Inga1, Anna Aprile1, Paola Campomenosi1, Paola Menichini1, Laura Ottaggio1, Silvia Viaggi1,2, Giovanni Ghigliotti3, Angelo Abbondandolo1,2 and Gilberto Fronza1,4

1 Mutagenesis Laboratory, National Cancer Institute (IST), Largo Rosanna Benzi, 10, 16132-Genova, 2 Department of Oncology, Biology and Genetics, University of Genova, Genova, and 3 Dermatology Unit, National Cancer Institute (IST) Genova, Italy

8-Methoxypsoralen (8-MOP) plus UVA irradiation (PUVA therapy) has been used for the treatment of psoriasis. PUVA therapy has been associated with an increased risk of developing skin squamous cell carcinoma (SCC). In order to determine the PUVA-induced p53 mutation spectrum, a yeast expression vector harbouring a human wild-type p53 cDNA was incubated with 8-MOP, and UVA irradiated in vitro. PUVA-damaged and undamaged DNA was transfected into a yeast strain containing the ADE2 gene regulated by a p53-responsive promoter. An 8-MOP concentration-dependent decrease in survival and increase in mutant frequency were observed. At a fixed 8-MOP concentration, survival decreased and mutant frequency increased as UVA irradiation increased. Eleven mutant clones contained 11 mutations: 10 were single base pair substitutions, the remaining one being a complex mutation. All eight T:A-targeted mutations were at 5'-TpA sites, hallmark mutations of PUVA mutagenesis. Through a rigorous statistical test, the PUVA-induced p53 mutation spectrum appears to differ significantly (P < 0.0002) from that observed in SCC in PUVA-treated patients. The present work demonstrates that a specific PUVA-induced mutational fingerprint could be obtained and recognized on human p53 cDNA. This result may suggest that PUVA therapy can be a risk factor for the development of SCC in psoriasis patients through a mechanism not involving the induction of p53 mutations.

4 To whom correspondence should be addressed: Tel: +39 010 5600292; Fax: +39 010 5600992; Email: fronzagi{at}hp380.ist.unige.it


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 Toxicol PatholHome page
L. Lambertini, K. Surin, T.-V. T. Ton, N. Clayton, J. K. Dunnick, Y. Kim, H.-H. L. Hong, T. R. Devereux, and R. C. Sills
Analysis of p53 Tumor Suppressor Gene, H-ras Protooncogene and Proliferating Cell Nuclear Antigen (PCNA) in Squamous Cell Carcinomas of HRA/Skh Mice Following Exposure to 8-Methoxypsoralen (8-MOP) and UVA Radiation (PUVA Therapy)
Toxicol Pathol, February 1, 2005; 33(2): 292 - 299.
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