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Clinical Symptoms and DNA Repair Characteristics of Xeroderma Pigmentosum Patients from Germany¹

Institutes of Biochemistry [H. W. T., O. P.] and Epidemiology and Biometry [L. E.], German Cancer Research Center, D-6900 Heidelberg, and Department of Dermatology, Mannheim Medical School, University of Heidelberg, Theodor-Kutzer-Ufer, D-6800 Mannheim [E. G. J.], Federal Republic of Germany

Sixty-one xeroderma pigmentosum (XP) patients living in the Federal Republic of Germany were investigated. Clinical symptoms were correlated with DNA repair parameters measured in fibroblasts grown from skin biopsies. Classification according to the international complementation groups revealed that of the 61 patients 3 belonged to group A, 26 to group C, 16 to group D, 3 to group E, and 2 to group F; 11 were of the XP variant type. A striking clinical aspect was the frequency of histogenetically different skin tumors varying from one XP complementation group to the other: squamous and basal cell carcinomas predominated in XP group C; lentigo maligna melanomas were most frequent in group D; basal cell carcinomas occurred preferentially in group E and XP variants.

Three DNA repair parameters were determined for 46 fibroblast strains: colony-forming ability (D₀); DNA repair synthesis (G₀); and DNA-incising capacity (E₀). Dose-response experiments with up to 13 dose levels were performed throughout to achieve sufficient experimental accuracy. DNA-damaging treatments included UV light, the "UV-like" carcinogen N-acetoxy-2-acetylaminofluorene, and the alkylating carcinogens methyl methanesulfonate and N-methyl-N-nitrosourea.

Comparison of clinical signs and repair data was made on the basis of D₀, G₀, and E₀ values of both individual cell strains and weighted means of XP complementation groups. Despite considerable clinical and biochemical heterogeneity within complementation groups distinctive features emerged. In general, D₀, G₀, and E₀ values of all XP strains investigated, including XP variants, were found to be reduced upon treatment with UV light or N-acetoxy-2-acetylaminofluorene. After treatment with UV light or N-acetoxy-2-acetylaminofluorene, cell strains in which DNA-incising capacity was reduced also showed a similar reduction in both colony-forming ability and DNA repair synthesis. Consequently, the weighted mean D₀, G₀, and E₀ values of XP complementation groups and XP variants correlated with each other. Furthermore, the onset of both early dermatological symptoms of XP and tumor growth correlated with the extent of DNA repair defects.

Of 45 XP fibroblast strains checked for colony-forming ability after treatment with methyl methanesulfonate only 3 cell strains from group D were found to be more sensitive than normal controls, suggesting that overall repair in XP strains was equal to that in controls. Weighted means of DNA repair synthesis of XP complementation groups, however, showed reductions hinting at impaired excision of distinct alkylated bases. This held true for complementation groups D, A, E, and F.

Upon treatment with N-methyl-N-nitrosourea, the weighted mean G₀ values of the complementation groups did not differ significantly from that of controls, suggesting that excision repair of DNA bases methylated by this carcinogen was normal. However, the weighted mean D₀ value of complementation group D was significantly reduced, suggesting that DNA-restoring mechanisms other than excision repair and/or 6-methylguanine-DNA methyltransferase activity were impaired.

¹ This work was supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 136, and is dedicated to Professor Dr. E. Hecker on the occasion of his 65th birthday.

² To whom requests for reprints should be addressed.

Received 9/20/90. Accepted 4/22/91.

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