Psoriasis, PUVA, and Skin Cancer – Molecular Epidemiology: The Curious Question of T → A Transversions

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      Inspector Gregory – “Is there any other point to which you wish to draw my attention, Mr Holmes?”
      Sherlock Holmes – “To the curious incident of the dog in the night time.”
      Inspector Gregory – “But the dog did nothing in the night time!”
      Sherlock Holmes – “That was the curious incident!”
      from Silver Blaze by Sir Arthur Conan Doyle
      Photochemotherapy with 8-methoxypsoralen and long wavelength ultraviolet radiation (PUVA) is commonly used to treat psoriasis and vitiligo. These vastly different diseases respond to the therapy by different mechanisms even though the immediate effects of the therapy – photoadduct formation – is the same for both. Because psoriasis is not cured by PUVA, patients receive many treatments over their lifetime and develop a significant risk for the development of skin cancers (primarily squamous cell carcinomas). In this review the basic aspects of psoralen photobiology are reviewed briefly. In addition the impact of the analysis of mutations in the tumor suppressor gene, p53, are summarized. An unexpected mutation spectrum (very few T→A trans-versions and frequent UVB signature C→T transitions) suggest that effects other than direct DNA photoadduct formation may be at play. The roles of reactive oxygen species-induced base changes as well as other clastogenic factors are discussed. This analysis suggests that it may be possible to improve the therapeutic efficacy of PUVA by a careful evaluation of the mode of delivery.