Molecular, cellular and clinical abnormalities in patients with xeroderma pigmentosum (XP) and with the dysplastic nevus syndrome (DNS) of hereditary cutaneous melanoma are being studied. We have developed new assays utilizing plasmids as tools to measure DNA repair and mutagenesis at the molecular level. In DNA repair-deficient XP cells, we demonstrated that both dimer and non-dimer photoproducts block expression of a transfected gene to a greater extent than with normal cells, while apurinic sites yield normal expression. We established the first permanent simian virus 40 (SV40) transformed cell line from XP complementation group D. We used the shuttle vector plasmid pZ189 to determine that there is a restricted spectrum of mutations induced in UV-treated DNA replicating in XP cells of complementation groups A and D. There are fewer plasmids found with multiple mutations and with transversion-type base substitution mutations than with normal cells. The major UV- photoproduct, the T-T cyclobutane dimer, was found to be only weakly mutagenic with XP and normal lines. Cytosine containing photoproducts produced 90-95% of the mutations and both cyclobutane dimer and non-dimer photoproducts were mutagenic. We determined that photoproduct frequency was not the major determinant of UV mutation frequency in DNA replicated in human cells. We found evidence for activity of an error-prone polymerase in human cells that may be relevant to generation of immunoglobulin diversity. We compiled the largest retrospective study of XP patients to date (830 patients) and found the median age of onset of skin cancer to be 8 years, a 50-year reduction in comparison to the US general population. There was a greater than 1000-fold increase in basal cell or squamous cell carcinomas or melanomas of the skin and in tumors of the anterior (sun exposed) portion of the eye and tongue. A prospective Registry of XP patients has been established. A clinical trial of skin cancer prevention in XP patients is in progress studying oral 13-cis retinoic acid as a chemopreventive agent. We formulated the most widely used classification for DNS and estimated that there is a sevenfold increased melanoma risk for people with dysplastic nevi without a personal or family history of melanoma.
