The laboratory is studying molecular, cellular and clinical abnormalities in human cancer-prone genetic diseases. Current studies are focusing on xeroderma pigmentosum (XP) a cancer-prone genetic disease with cellular hypersensitivity to environmental agents. We developed new assays using plasmids to measure DNA repair and mutagenesis at the molecular level in human cells and to assign cells to XP complementation groups. A shuttle vector plasmid replicated in a mismatch repair defective human cell line showed sequence-dependent mutations. Studies of lymphoblastoid cells from normal donors showed increased plasmid UV mutability with increasing donor age indicating that aging is associated with decreasing ability to repair DNA damage. We identified several unusual XP patients. Cells from a patient with the rare xeroderma pigmentosum/ Cockayne syndrome complex with severe clinical symptoms of Cockayne syndrome had the cellular characteristics of the XP-G DNA repair defect. An unusual XP-C patient had neurological abnormalities and a metabolic defect (hypoglycinemia) associated with a splice mutation. Chemoprevention of skin cancer in XP with oral 13-cis retinoic acid was found to be effective in preventing skin cancers but very toxic. The lowest effective dose varied in different patients. - aging, DNA repair, melanoma, Plasmids, skin cancer, UV mutagenesis, xeroderma pigmentosum, Cancer genetics, Cancer Prevention, chemoprevention, Gene Mutation, Genetic polymorphism, - Human Subjects
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