Patients with xeroderma pigmentosum (XP) and ataxia-telangiectasia (A-T), diseases with ultraviolet (UV) and x-ray hypersensitivity, respectively, and with the dysplastic nevus syndrome of hereditary cutaneous melanoma (DNS) are being studied. Detailed examinations of the clinical features of affected individuals are being made. A prospective registry of XP patients is under way. Field studies in Israel detected a possible new form of XP with defective DNA repair without neoplasia. Patients with XP and a high frequency of skin cancer are being treated with 13 cis-retinoic acid in an attempt to prevent formation of new skin cancers. We demonstrated the suitability of SV40 virus-transformed XP cells as high efficiency recipients of transfected plasmids. XP cells stably integrated many copies of transfected genes and expressed linked genes with high frequency. We developed a host cell reactivation DNA repair assay that measures transient expression of chloramphenicol acetyl transferase (CAT) activity in XP and normal cells transfected with a UV-treated plasmid bearing the CAT gene. In the XP cells we showed that one pyrimidine dimer blocks expression of the transfected CAT gene. Studies in progress are measuring the sites and types mutations induced by ultraviolet radiation in shuttle vector plasmids replicated in XP and normal cells. Collaborative clinical studies of 14 NDS kindreds have demonstrated autosomal dominant inheritance of the melanoma trait, new melanomas only in family members with dysplastic nevi and greater than 100-fold increased melanoma risk in family members fith dysplastic nevi. Similar dysplastic nevi also occur in nonpfamilial settings. A new classification of DNS was proposed. Laboratory studies demonstrated UV-induced hypermutability in DNS lymphoblastoid cell lines and normal DNA repair. A-T is an autosomal recessive disorder with clinical and cellular x-ray hypersensitivity and a high incidence of neoplasms. Lymphoblastoid cell lines established from 10 kindreds with A-T are being tested for heterozygote detection.
