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Purpose: Ptch1 germ-line mutations in mice predispose to radiation-induced basal cell carcinoma of the skin, with tumor incidence modulated by the genetic background. Here, we examined the possible mechanisms underlying skin response to radiation in F1 progeny of Ptch1 neo67/+ mice crossed with either skin tumor-susceptible (Car-S) or -resistant (Car-R) mice and X-irradiated (3 Gy) at 2 days of age or left untreated. Methods and Materials: We conducted a gene expression profile analysis in mRNA samples extracted from the skin of irradiated or control mice, using Affymetrix whole mouse genome expression array. Confirmation of the results was done using real-time reverse-transcriptase polymerase chain reaction. Results: Analysis of the gene expression profile of normal skin of F1 mice at 4 weeks of age revealed a similar basal profile in the nonirradiated mice, but alterations in levels of 71 transcripts in irradiated Ptch1 neo67/+ mice of the Car-R cross and modulation of only eight genes in irradiated Ptch1 neo67/+ mice of the Car-S cross. Conclusions: These results indicate that neonatal irradiation causes a persistent change in the gene expression profile of the skin. The tendency of mice genetically resistant to skin tumorigenesis to show a more complex pattern of transcriptional response to radiation than do genetically susceptible mice suggests a role for this response in genetic resistance to basal cell tumorigenesis. [Copyright &y& Elsevier]

Purpose: To address the tumorigenic potential of exposure to low/intermediate doses of ionizing radiation and to identify biological factors influencing tumor response in a mouse model highly susceptible to radiogenic cancer. Methods and Materials: Newborn Ptc1 heterozygous mice were exposed to X-ray doses of 100, 250, and 500 mGy, and tumor development was monitored for their lifetime. Additional groups were irradiated with the same doses and sacrificed at fixed times for determination of short-term endpoints, such as apoptosis and early preneoplastic lesions in cerebellum. Finally, groups of Ptc1 heterozygous mice were bred on the C57BL/6 background to study the influence of common variant genes on radiation response. Results: We have identified a significant effect of low-intermediate doses of radiation (250 and 500 mGy) in shortening mean survival and inducing early and more progressed stages of tumor development in the cerebellum of Ptc1+/– mice. In addition, we show that age at exposure and heritable factors are potent modifiers of radiation-related cancer risk. Conclusions: The Ptc1 knockout mouse model offers a highly sensitive system that may potentially help to improve understanding and quantification of risk at low doses, such as doses experienced in occupational and medical exposures, and clarify the complex interactions between genetic and environmental factors underlying cancer susceptibility. [Copyright &y& Elsevier]