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Modulation of Patched-Associated Susceptibility to Radiation Induced Tumorigenesis by Genetic Background

¹ Biotechnology Unit, ENEA-Ente per le Nuove tecnologie, l’Energia e l’Ambiente, Centro Ricerche Casaccia, Casaccia, Rome, Italy; ² Institute of Pathology, GSF-National Research Center of Environment and Health, Munich, Germany; ³ Radiation Protection Unit, ENEA-Ente per le Nuove tecnologie, l’Energia e l’Ameiente, Centro Richerche Casaccia, Rome, Italy; and ⁴ Institute of Human Genetics, University of Goettingen, Goettingen, Germany

We described previously a basal cell carcinoma (BCC) and medulloblastoma (MB) phenotype for CD1Ptch1^neo67/+ mice exposed to ionizing radiation. Ptch1 heterozygous mice mimic the predisposition to BCC and MB development of patients affected by nevoid BCC syndrome that inherit a mutant Patched (Ptch1) allele. To examine the impact of genetic background on development of BCCs and other tumors we used two outbred mouse lines characterized by extremely high, carcinogenesis-susceptible (Car-S), and low, carcinogenesis-resistant (Car-R), susceptibility to skin carcinogenesis. Crosses between Ptch1^neo67/+ mice and Car-S (F1S) or Car-R mice (F1R) were exposed to ionizing radiation. F1SPtch1^neo67/+ mice were highly susceptible to radiation-induced BCCs, whereas F1RPtch1^neo67/+ mice were completely resistant, indicating that tumor penetrance can be modulated by genetic background. Development of microscopic and macroscopic BCC lesions was influenced by Car-S and Car-R genotypes, suggesting a genetic-background effect on both initiation and progression of BCC. Susceptibility was additionally increased in N2 backcross mice (Car-S x F1SPtch1^neo67/+), showing a contribution from recessive-acting Car-S modifiers. The modifying effects of Car-S-derived susceptibility alleles were tissue specific. In fact, despite higher susceptibility to BCC induction, Car-S-derived lines had lower MB incidence compared with CD1Ptch1^neo67/+ mice. BCC-associated somatic events were not influenced by genetic background, as shown by similar rate of wild-type Ptch1 loss in BCCs from F1SPtch1^neo67/+ (93%) and CD1Ptch1^neo67/+ mice (100%). Finally, microsatellite analysis of BCCs showed Ptch1 loss through interstitial deletion. These results are relevant to humans, in which BCC is the commonest malignancy, because this model system may be used to study genes modifying BCC development.

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				M. Mancuso, S. Leonardi, M. Tanori, E. Pasquali, M. Pierdomenico, S. Rebessi, V. Di Majo, V. Covelli, S. Pazzaglia, and A. Saran Hair Cycle-Dependent Basal Cell Carcinoma Tumorigenesis in Ptc1neo67/+ Mice Exposed to Radiation. Cancer Res., July 1, 2006; 66(13): 6606 - 6614. [Abstract] [Full Text] [PDF]