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Kenneth H. Kraemer, M.D.
DNA Repair in Human Cancer-Prone Genetic Diseases
Human cancer-prone genetic diseases are being studied to identify groups of people with an increased susceptibility to environmental agents. Present emphasis is on the skin cancer-prone disease, xeroderma pigmentosum (XP). We are attempting to: (1) understand the molecular basis of the cellular hypersensitivity of these diseases; (2) correlate cellular hypersensitivity with clinical abnormalities; (3) determine the degree of genetic heterogeneity within such groups, and (4) explore methods of cancer prevention. We developed plasmid assays to measure DNA repair and mutagenesis at the molecular level in human cells and to assign cells to complementation groups. These studies provide strong evidence that DNA repair genes play a major part in UV induction of skin cancer in XP. 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. We also found an age-dependent increase in plasmid UV mutability in cultured blood cells from normal donors. This finding suggests that the ability to process UV-damaged DNA decreases with increasing donor age in the normal population. This may play a role in the greatly increased frequency of UV-induced skin cancer with age. Oral retinoids are effective in prevention of skin cancers in patients with XP although there are substantial side effects.
Collaborators on our research include Margaret Tucker, GEB, DCEG, NCI, Q. Wei, M.D. Anderson Hospital, Houston, Texas, and H. Slor, Tel Aviv University, Tel Aviv, Israel
This page was last updated on 2/20/2013.