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 showed that one pyrimidine dimer blocks expression of a transfected gene. Enzymatic removal of pyrimidine dimers by photolyase demonstrated that nondimer photoproducts also block expression in XP cells. In normal human cells, UV pretreatment of a shuttle vector plasmid, pZ189, resulted in appearance of transition and transversion mutations. Survival of UV-treated pZ189 was reduced in the XP cells. There was a restricted mutagenic spectrum found in pZ189 replicated in XP cells; 93% of the base substitution mutations were GC to AT transitions (p less than 0.002 vs normal). The major UV photoproduct, the thymine dimer, was only weakly mutagenic. We found that cultured lymphoblastoid cells from familial DNS patients were hypermutable to UV treatment. In a retrospective study of more than 800 XP patients, we have shown that they have a greater than 1000-fold increased risk of developing basal cell or squamous cell carcinoma or melanomas of the skin. The reported median age of first skin cancer was less than 10 years, a 50-year reduction in comparison to the United States general population. A prospective registry of xeroderma pigmentosum 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 possible chemopreventive agent.
