AN UNEXPECTED SPECTRUM OF P53 MUTATIONS FROM SQUAMOUS-CELL CARCINOMASIN PSORIASIS PATIENTS TREATED WITH PUVA

Photochemotherapy employing 8-methoxypsoralen and long-wavelength ultr aviolet radiation (UVA, 320-400 nmr is widely used in the treatment of psoriasis. The photoactivation of psoralens in skin cells leads to fo rmation of DNA photoadducts which may be responsible, at least in part , for the efficacy of these photochemotherapies. However, mutations ar ising from these adducts may also lead to the well-characterized incre ased incidence of squamous cell carcinoma, Mutations in the p53 tumor suppressor gene have been detected in many human cancers, To determine whether p53 mutations occur in squamous cell carcinomas in PUVA patie nts, PCR was used to amplify the exons (5-9) in which other studies ha ve found a high frequency of point mutations, Gel electrophoresis was used to detect single-strand conformational polymorphisms, Aberrantly migrating bands were excised, reamplified and sequenced, Thirty-four s pecimens from 10 patients were examined, Specimens from one patient wh o had received no phototherapy as well as from normal controls were al so analyzed, Five of the 10 patients showed at least one p53 mutation, In contrast to previously reported. psoralen-induced p53 mutations in mice, the expected psoralen type mutations at alternating AT sites we re not detected, All but two of the altered sequences occurred at dipy rimidine sites which is typical of solar type mutations, Two C-->T mut ations and two dipyrimidine mutations (CC-->TT) were found, Other muta tions included: C-->G, G-->T, C-->A acid an 18 bp deletion, A review o f therapeutic history of these patients showed that some had also rece ived UVB phototherapy. Furthermore, because sunlight is thought to be beneficial far psoriasis, nontherapeutic, casual UVB exposure cannot b e excluded, Our observations suggest that the SCC may have arisen from the solar mutations and that PUVA may enhance tumor progression or im mune suppression.