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Induction of Nevi and Skin Tumors in Ink4a/Arf Xpa Knockout Mice by Neonatal, Intermittent, or Chronic UVB Exposures

¹ Dermatology Department, University Medical Centre Utrecht, Utrecht, the Netherlands; Departments of ² Dermatology and ³ Toxicogenetics, Leiden University Medical Centre, Leiden, the Netherlands; ⁴ Laboratory of Vaccine-Preventable Diseases; and ⁵ Toxicology, Pathology, and Genetics Department, National Institute of Public Health and the Environment, Bilthoven, the Netherlands

Requests for reprints: Frank de Gruijl, Dermatology Department, Leiden University Medical Centre, PO Box 9600, 2300RC Leiden, the Netherlands. Phone: 31-71-5262497; E-mail: f.r.de_gruijl{at}lumc.nl.

Nevi and melanomas correlate to childhood and intermittent solar UV exposure, xeroderma pigmentosum patients run increased risk, and p16^Ink4a expression is often lost in malignant progression. To ascertain the effect of these risk factors, pigmented hairless Ink4a/Arf–, Xpa– knockout mice were subjected to various combinations of neonatal [7,12-dimethylbenz(a)anthracene (DMBA) or UVB exposure] and adult treatments (12-O-tetradecanoylphorbol-13-acetate or subacute daily UVB exposure or intermittent overexposure). Nevi occurred earliest, grew largest, and were most numerous in mice exposed to DMBA followed by intermittent UVB overexposure [effect of six minimal edemal doses (MED), 1x/2 weeks > 4 MED 1x/wk]. Neonatal UV exposure enhanced nevus induction but lost its effect after 200 days. The Xpa^–/– mice proved exquisitely sensitive to UV-driven nevus induction, indicating the involvement of pyrimidine dimer DNA lesions, but Xpa^+/+ mice developed many more nevi (>40 per mouse) at high UV dosages not tolerated by Xpa^–/– mice. Ink4a/Arf^–/– mice developed most skin tumors faster, but surprisingly developed nevi slower than their heterozygous counterparts especially after neonatal UV exposure. Despite raising >1,600 nevi, only six melanomas arose in our experiments with Ink4a/Arf knockout mice (five of which in Xpa^+/+ mice at high UV dosages). In contrast to human nevi, these nevi lacked hotspot mutations in Braf or Ras genes, possibly explaining the lack of malignant progression in the Ink4a/Arf^–/– mice. Hence, although our experiments did not effectively emulate human melanoma, they provided clear evidence that intermittent UV overexposure strongly stimulates and the Ink4a/Arf^–/– genotype may actually impair nevus development. (Cancer Res 2006; 66(5): 2608-15)

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