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Relative Susceptibilities of XPA Knockout Mice and Their Heterozygous and Wild-Type Littermates to UVB-induced Skin Cancer¹

Department of Dermatology, University Hospital Utrecht, P. O. Box 85500, 3508 GA Utrecht [R. J. W. B., F. R. d. G.], and Department of Carcinogenesis, Mutagenesis, and Genetics, National Institute of Public Health and Environmental Protection, P. O. Box I, 3720 BA Bilthoven [A. d. V., H. v. S.], the Netherlands

Although xeroderma pigmentosum (XP) patients are rare, carriers of XP genes (heterozygotes) are much more common. Whether such carriers have an increased skin cancer risk is unknown. Recently developed mouse models for XP have opened up the possibility of determining the skin cancer risk of heterozygotes relative to wild types. Therefore, the XPA knockout trait has been crossed into hairless mice, and squamous cell carcinomas of the skin have been induced by low daily UVB exposures for 500 days in all three genotypes (-/-, +/-, and +/+). The carcinogenic response of the heterozygotes did not significantly differ from that of their wild-type littermates. Tumors in the XPA -/- animals appeared with a latency time that was decreased by a factor of 4.2. From this, we estimate that a functional XPA gene provides a "protection factor" of 60 (95% confidence interval, 15–250) against UV carcinogenesis, which is greater protection than that against acute UV effects, such as erythema and edema (protection factor between 7 and 16). Deficient nucleotide excision repair appears to have a more dramatic impact on skin cancer susceptibility than on sensitivity to acute UV effects.

¹ Financed by Grants EV5V-CT91-0030 and ENV4-CT96-0172 from the Environment Program of the European Community.

² To whom requests for reprints should be addressed.

Received 12/ 3/96. Accepted 1/ 2/97.

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