The laboratory is studying molecular, cellular and clinical abnormalities in human cancer-prone genetic diseases. Current studies are focusing on two cancer-prone genetic diseases with cellular hypersensitivity to environmental agents: xeroderma pigmentosum (XP), and familial cutaneous melanoma (CM) with dysplastic nevi (DN). We developed new assays using plasmids to measure DNA repair and mutagenesis at the molecular level in human cells. We found that introduction of cloned DNA repair genes corrected the UV mutagenic defect in XP-D and XP-A cells. Using a novel system we found that plasmid DNA sequence was found to affect both nearby and distant UV mutagenic hotspots. In a large study of 6 families with CM we found that cells from all 13 patients with CM+DN had increased plasmid UV mutability - a possible cellular marker for this disorder. 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. 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. We found that the anatomic location of skin cancers in patients reported to the XP Registry indicates that although UV exposure causes both melanoma and non-melanoma cancer, the mechanism of skin cancer induction is different for each type of cancer.
Showing the most recent 10 out of 47 publications
