Journal Article

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

Paola Monti, Alberto Inga, Anna Aprile, Paola Campomenosi, Paola Menichini, Laura Ottaggio, Silvia Viaggi, Giovanni Ghigliotti, Angelo Abbondandolo and Gilberto Fronza

in Mutagenesis

Published on behalf of United Kingdom Environmental Mutagen Society

Volume 15, issue 2, pages 127-132
Published in print March 2000 | ISSN: 0267-8357
Published online March 2000 | e-ISSN: 1464-3804 | DOI: http://dx.doi.org/10.1093/mutage/15.2.127
p53 mutations experimentally induced by 8-methoxypsoralen plus UVA (PUVA) differ from those found in human skin cancers in PUVA-treated patients

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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.

Journal Article.  5462 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics ; Genetics and Genomics

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