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.

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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
Wang, Yun; Digiovanna, John J; Stern, Jere B et al. (2009) Evidence of ultraviolet type mutations in xeroderma pigmentosum melanomas. Proc Natl Acad Sci U S A 106:6279-84
Oh, Kyu-Seon; Imoto, Kyoko; Boyle, Jennifer et al. (2007) Influence of XPB helicase on recruitment and redistribution of nucleotide excision repair proteins at sites of UV-induced DNA damage. DNA Repair (Amst) 6:1359-70
Kraemer, Kenneth H; Sander, Miriam; Bohr, Vilhelm A (2007) New areas of focus at workshop on human diseases involving DNA repair deficiency and premature aging. Mech Ageing Dev 128:229-35
Kraemer, K H; Patronas, N J; Schiffmann, R et al. (2007) Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship. Neuroscience 145:1388-96
Schlucker, S; Liang, C; Strehle, K R et al. (2006) Conformational differences in protein disulfide linkages between normal hair and hair from subjects with trichothiodystrophy: a quantitative analysis by Raman microspectroscopy. Biopolymers 82:615-22
Oh, Kyu-Seon; Khan, Sikandar G; Jaspers, N G J et al. (2006) Phenotypic heterogeneity in the XPB DNA helicase gene (ERCC3): xeroderma pigmentosum without and with Cockayne syndrome. Hum Mutat 27:1092-103
Emmert, Steffen; Wetzig, Tino; Imoto, Kyoko et al. (2006) A novel complex insertion/deletion mutation in the XPC DNA repair gene leads to skin cancer in an Iraqi family. J Invest Dermatol 126:2542-4
Khan, Sikandar G; Oh, Kyu-Seon; Shahlavi, Tala et al. (2006) Reduced XPC DNA repair gene mRNA levels in clinically normal parents of xeroderma pigmentosum patients. Carcinogenesis 27:84-94
Hirai, Yuko; Kodama, Yoshiaki; Moriwaki, Shin-Ichi et al. (2006) Heterozygous individuals bearing a founder mutation in the XPA DNA repair gene comprise nearly 1% of the Japanese population. Mutat Res 601:171-8

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