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 and trichothiodystrophy (TTD) a genetic disease with similar cellular hypersensitivity but no increase in cancer risk. We identified several unusual XP patients. We found that mutations in the splice lariat branch point sequence of the XPC gene result in either severe or mild clinical symptoms depending on the amount of normal XPC mRNA produced. We found a common polymorphism in an intron in of the XPC gene in normal donors that is linked to a splice site polymorphism and is related to risk of squamous cell cancer and melanoma in the general population. We found that normal appearing parents of XPC patients have markedly reduced levels of XPC mRNA. We have begun a molecular epidemiology study to examine the cancer risk in carriers of mutations in XP DNA repair genes.UV exposure of the skin of pigmented mice produced more damage near melanin pigment-containing cells than UV exposure of albino mice with no pigment-containing cells. This describes a new mechanism of sun damage to skin.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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