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

Abstract

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, carcinogenesissusceptible (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-Sderived 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.

Hair Cycle–Dependent Basal Cell Carcinoma Tumorigenesis in Ptc1neo67/+ Mice Exposed to Radiation

“…Analogously to human BCCs, LOH at the Ptc1 locus is implicated in BCC tumorigenesis in Ptc1 neo67/+ mice and has been reported in previous experiments with UV (9) or ionizing radiation (10,39). To determine whether the different histologic features of BCC subtypes were associated with altered allelic patterns at the Ptc1 locus, we examined Ptc1 allelic imbalance in DNAs from both BCC variants.…”

MK-4101, a Potent Inhibitor of the Hedgehog Pathway, Is Highly Active against Medulloblastoma and Basal Cell Carcinoma

“…This tumor is locally aggressive and can present multiple recurrences. The skin of irradiated Ptch1 þ/À mice develops large infiltrative BCC-like tumors that faithfully recapitulate the etiology and histopathology of human BCC and closely resemble the genetics of the human counterpart in the complete loss of Ptch1 (22,29). We evaluated the ability of MK-4101 to act as therapeutic agent against BCC in this model.…”

“…Large infiltrative BCCs in irradiated Ptch1 þ/À mice develop through microscopically detectable preneoplastic stages, providing an ideal in vivo model to test chemotherapy or chemoprevention in BCC (22,29). To test the effects of MK-4101 on early BCC stages, we established a group (n ¼ 23) of Ptch1 Fig.…”

Cell Population Analyses During Skin Carcinogenesis

“…In mice, wild-type mice do not develop BCCs, even under heavy doses of carcinogens, UV or ionizing radiation. In contrast, Ptch1 +/-mice are susceptible to BCC development 17,18 . The penetrance of BCC development in Ptch1 +/-mice is over 50% 18,19 although Ptch1+/-mice rarely develop full-grown BCCs if kept under normal conditions.…”