Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Implication of Nos2 inactivation on genomic changes in Ptch1+/- medulloblastomas (array-CGH)

ABSTRACT: The Ptch1+/- strain constitues an established mouse model for the Shh-driven type of medulloblastoma. Combined Ptch1+/- Nos2-/- mice show a two-fold increased incidence for this tumor. Here, the impact of Nos2 inactivation on copy number alterations during medulloblastoma development was investigated by array-based comparative genomic hybridization (arrayCGH) of tumor samples from both genotypes. Medulloblastoma samples from five Ptch1+/- and seven compound Ptch1+/- Nos2-/- mice were analyzed. Cy5-labeled tumor DNA was combined with corresponding Cy3-labeled reference healthy wildtype genomic DNA to receive either sex-matched sample pairs or pairs of different gender for internal negative or positive control.

ORGANISM(S): Mus musculus

SUBMITTER: Daniel Haag

PROVIDER: E-GEOD-29199 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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. 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.

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.

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Implication of Nos2 inactivation on genomic changes in Ptch1+/- medulloblastomas (array-CGH)

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