Abstract
With Ptch1+/- mouse, which develop medulloblastoma, the most common childhood brain tumor, we analyzed dose-dependent and age-dependent effects of radiation during fetal and postnatal stages. We found here that the incidence of medulloblastoma increased and the latency shortened, with increasing dose, after whole-body exposure to seven different doses (0.05-3Gy) at postnatal day 1. Importantly, the significant increase in incidence and decrease of latency was evident for low-dose irradiations of 0.05Gy and 0.1Gy. In order to explore the molecular mechanisms for radiation-induced medulloblastomas, we analyzed loss of heterozygosity (LOH) status at 6 SSLP markers on chromosome 13, where Ptch1 locus is located. It was revealed that all 17 spontaneously developed tumors in non-irradiated mice showed LOH in broad regions including Ptch1 locus and distally-extending telomeric portion (designated as S-type), while all 19 tumors induced after 3Gy irradiation exhibited losses only at interstitial markers around Ptch1 locus (designated as R-type), indicating that the inactivation mechanism of a wild-type Ptch1 allele in radiation-induced tumors was different from that in spontaneous ones. This was consistent with a previous report in a different strain by Pazzaglia et al. (2006). Interestingly, both S- and R-types were observed in the irradiated-groups with lower doses, and that there was a clear dose-dependent increase in the ratio of R-type to S-type. Data on the age-dependent change in radiosensitivity to medulloblastoma in Ptch1 heterozygous mice will be also presented.
