Sensitive detection of radiation-induced medulloblastomas after acute or protracted gamma ray exposures in Ptch1 heterozygous mice using a radiation-specific molecular signature

Recent studies have further heightened awareness of the risk of radiation-induced cancer after diagnostic radiology imaging, in particular, brain cancer following childhood CT scans. One feature of Ptch1+/- mice is that they are sensitive to radiation-induced medulloblastomas (an embryonic cerebellar tumor) during a narrow time window centered on the days around birth. The dynamics of how dose-protraction interacts with such narrow windows of sensitivity in individual tissues is still unknown. Using medulloblastomas from irradiated Ptch1+/- mice on a hybrid C3H × C57BL/6 F1 background, we have previously shown that the alleles retained on chromosome 13 (which harbors the Ptch1 gene) reveal two major mechanisms of loss of the wildtype allele. The loss of parental alleles from the telomere extending up to or past the Ptch1 locus by recombination (spontaneous-type) accounts for almost all medulloblastomas in unirradiated mice, while tumors in irradiated mice often exhibited interstitial deletions which start downstream of the wildtype Ptch1 and extend up varying lengths towards the centromere (radiation-type). Here, Ptch1+/- mice were exposed to an acute dose of 0.1 or 0.5 Gy gamma rays in utero or postnatally, or the same radiation doses protracted over a 4-day period, and were monitored for medulloblastoma development. The results show dose-dependent and age-dependent induction of radiation-type tumors; that the size of the radiation-induced deletion differs with the dose-rate; and, that tumor latency may be related to the size of the deletion. The radiation signature allows for unique mechanistic insight into the action of radiation to induce DNA lesions with known causal relationship to a specific tumor type, particularly for doses and dose-rates more relevant to diagnostic radiology imaging and accidental exposure of populations to radiation. 29 medulloblastomas arising in Ptch1 heterozygous mice were analysed for DNA copy number changes by array CGH, using each mouse's ear DNA as a reference. The medulloblastomas are from three groups, an acute exposure of 500 mGy on PN1, a protracted exposure of 500 mGy from PN1 to PN4, and from an unirradiated mouse.