Molecular, cellular and clinical abnormalities in patients with xeroderma pigmentosum (XP), with dysplastic nevus syndrome (DNS) of familial cutaneous melanoma, with Cockayne syndrome (CS) and with Bloom's syndrome (BS) are being studied. We developed new assays using plasmids as tools to measure DNA repair, end joining, and mutagenesis at the molecular level in cultured human cells. Utilizing a shuttle vector plasmid, pZI89, we found that DNS cells induced more mutations into the UV treated plasmid than normal cells but these included fewer tandem mutations. Both lymphoblastoid cells and fibroblasts from the same XP patient in complementation group A induced more mutations into the UV treated plasmid than normal controls and the types of mutations were similar. However, there was an additional mutagenic hotspot with the lymphoblasts not seen with the fibroblasts. This demonstrates variability of mutagenic hotspots with different cell types. CS cells had reduced repair of photoproducts in the UV treated plasmid. Utilizing a linearized replicating plasmid, we demonstrated reduced ability of BS cells to ligate plasmids in vivo and that this ligation process was error-prone. A registry of XP patients has been established. A long-term clinical study of chemoprevention of skin cancer in XP with 13-cis retinoic acid (Accutane) is continuing. We found high dose (2 mg/kg/da) oral 13-cis retinoic acid to be effective in preventing skin cancers but very toxic. A variable response to low dose (0.5 mg/kg/da) oral 13-cis retinoic acid was found in different patients ranging from almost complete tumor prevention to no beneficial effect. Immune abnormalities were studied in XP patients.
