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. We found that the XPC protein leads to selective repair of UV-induced cyclobutane pyrimidine dimers in DNA. 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 XP-G DNA repair defect leading to loss of the XPG gene. A patient with mild XP symptoms had a partially functional mutation in the XPG gene. An unusual XP-C patient had neurological abnormalities and a metabolic defect (hypoglycinemia) associated with a splice mutation. We found a common polymorphism in an intron in of the XPC gene in normal donors. 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.
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