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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE81319 | GEO | 2017/04/26

SECONDARY ACCESSION(S): PRJNA321291

REPOSITORIES: GEO

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Project description:Genomic radiation signature illuminates low-dose effects with sharply reflected transcriptome in Ptch1-deficient medulloblastomas. Cancer risks of low-dose radiation are of great concern especially in relation to rapidly increasing medical exposures; however, their accurate assessments cope with many challenges and difficulties, partly due to the inability to distinguish radiation-induced tumors from spontaneous ones. Here, we analyzed the dose-dependent effect of radiation on medulloblastoma development in Ptch1 heterozygous mice on C3B6F1 background. The incidence and latency of medulloblastoma increased and shortened with increasing radiation dose, respectively. Amazingly, radiation contributed to tumorigenesis even at 50 mGy and 100% of mice got medulloblastoma with 1.5 Gy. Loss of heterozygosity (LOH) analysis on a total of 164 tumors indicated that spontaneous tumors showed LOH in broad regions on chromosome 13, including Ptch1 and distally-extending telomeric portion (S-type). In contrast, tumors developed after 3 Gy irradiation exhibited interstitial losses around Ptch1 (R-type). A clear dose-dependent increase in the proportion of R-type tumor at intermediate doses suggested R-type to be a reliable radiation signature. Array-CGH analysis indicated the R-type-specific copy-number reduction around Ptch1 and LOH-type-independent frequent gains of whole chromosome 6. Integrated expression microarray analysis indicated that expression levels of many genes within the altered genomic regions faithfully reflected the genomic copy-number changes. Furthermore, it was also suggested that these expression changes in turn influenced on many other genes, such as Tgfb2 and Tgfb3, on widespread genomic regions. This is the first demonstration that radiation-induced tumors developed after low-dose irradiation can be characterized quite precisely by interstitial deletion of Ptch1 and by associated gene expression profile. Gene expression in 3 normal cerebellum tissues and 12 medulloblastomas was measured.

Project description:Genomic radiation signature illuminates low-dose effects with sharply reflected transcriptome in Ptch1-deficient medulloblastomas. Cancer risks of low-dose radiation are of great concern especially in relation to rapidly increasing medical exposures; however, their accurate assessments cope with many challenges and difficulties, partly due to the inability to distinguish radiation-induced tumors from spontaneous ones. Here, we analyzed the dose-dependent effect of radiation on medulloblastoma development in Ptch1 heterozygous mice on C3B6F1 background. The incidence and latency of medulloblastoma increased and shortened with increasing radiation dose, respectively. Amazingly, radiation contributed to tumorigenesis even at 50 mGy and 100% of mice got medulloblastoma with 1.5 Gy. Loss of heterozygosity (LOH) analysis on a total of 164 tumors indicated that spontaneous tumors showed LOH in broad regions on chromosome 13, including Ptch1 and distally-extending telomeric portion (S-type). In contrast, tumors developed after 3 Gy irradiation exhibited interstitial losses around Ptch1 (R-type). A clear dose-dependent increase in the proportion of R-type tumor at intermediate doses suggested R-type to be a reliable radiation signature. Array-CGH analysis indicated the R-type-specific copy-number reduction around Ptch1 and LOH-type-independent frequent gains of whole chromosome 6. Integrated expression microarray analysis indicated that expression levels of many genes within the altered genomic regions faithfully reflected the genomic copy-number changes. Furthermore, it was also suggested that these expression changes in turn influenced on many other genes, such as Tgfb2 and Tgfb3, on widespread genomic regions. This is the first demonstration that radiation-induced tumors developed after low-dose irradiation can be characterized quite precisely by interstitial deletion of Ptch1 and by associated gene expression profile. Three medulloblastomas were analyzed by array-CGH method.

Project description:Genomic radiation signature illuminates low-dose effects with sharply reflected transcriptome in Ptch1-deficient medulloblastomas. Cancer risks of low-dose radiation are of great concern especially in relation to rapidly increasing medical exposures; however, their accurate assessments cope with many challenges and difficulties, partly due to the inability to distinguish radiation-induced tumors from spontaneous ones. Here, we analyzed the dose-dependent effect of radiation on medulloblastoma development in Ptch1 heterozygous mice on C3B6F1 background. The incidence and latency of medulloblastoma increased and shortened with increasing radiation dose, respectively. Amazingly, radiation contributed to tumorigenesis even at 50 mGy and 100% of mice got medulloblastoma with 1.5 Gy. Loss of heterozygosity (LOH) analysis on a total of 164 tumors indicated that spontaneous tumors showed LOH in broad regions on chromosome 13, including Ptch1 and distally-extending telomeric portion (S-type). In contrast, tumors developed after 3 Gy irradiation exhibited interstitial losses around Ptch1 (R-type). A clear dose-dependent increase in the proportion of R-type tumor at intermediate doses suggested R-type to be a reliable radiation signature. Array-CGH analysis indicated the R-type-specific copy-number reduction around Ptch1 and LOH-type-independent frequent gains of whole chromosome 6. Integrated expression microarray analysis indicated that expression levels of many genes within the altered genomic regions faithfully reflected the genomic copy-number changes. Furthermore, it was also suggested that these expression changes in turn influenced on many other genes, such as Tgfb2 and Tgfb3, on widespread genomic regions. This is the first demonstration that radiation-induced tumors developed after low-dose irradiation can be characterized quite precisely by interstitial deletion of Ptch1 and by associated gene expression profile. Twelve medulloblastomas were analyzed by array-CGH method.

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

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