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. 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. We found a common polymorphism in an intron in of the XPC gene in normal donors that is linked toa splice site polymorphism and is related to risk of squamous cell cancer in the general population. We have begun a molecular epidemiology study to examine the cancer risk in carriers of mutations in XP DNA repair genes. 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.