Molecular, cellular and clinical abnormalities are being studied in 2 genetic diseases with cellular hypersensitivity to environmental agents and increased cancer risk: xeroderma pigmentosum (XP) and dysplastic nevus syndrome (DNS) of familial melanoma. We developed new assays to measure DNA repair and mutagenesis at the molecular level in human cells using plasmid vectors. We found that introduction of cloned DNA repair genes substantially corrected the UV mutagenic defect in XP-D and XP-A cells. XP-D and XP-A fibroblasts containing transfected ERCC2 and XPAC genes, respectively, were found to have increased repair and decreased mutagenesis of UV-treated plasmids. The types of UV-induced mutations in the plasmids became more like those from normal cells. Studies of lymphoblastoid cells from normal donors showed increased plasmid UV mutability with increasing donor age. Lymphoblastoid cell lines from DNS patients with melanoma were found to have abnormally elevated mutability of UV-treated plasmids, a possible cellular marker for this genetic disorder. Chemoprevention of skin cancer in XP with oral 13-cis retinoic acid (RA) (Accutane) was studied. We found that a high dose (2 mg/kg/da) of 13-cis RA was effective in preventing skin cancers but very toxic, and that low dose (0.5 mg/kg/da) drug gave variable response in different patients ranging from almost complete tumor prevention to no beneficial effect. Despite extensive sun protection, XP patients had normal levels of serum vitamin D, indicating an adequate dietary intake of vitamin D. Therapeutic injection of intralesional interferon resulted in marked clearing of multiple melanoma in situ lesions in one XP patient. The anatomic location of skin cancers in XP patients 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.

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National Cancer Institute (NCI)
Intramural Research (Z01)
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National Cancer Institute Division of Basic Sciences
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Emmert, Steffen; Kraemer, Kenneth H (2013) Do not underestimate nucleotide excision repair: it predicts not only melanoma risk but also survival outcome. J Invest Dermatol 133:1713-7
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