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Integrated array-CGH and expression microarray analyses on medulloblastomas in heterozygous Ptch1 mice, expression


ABSTRACT: 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.

ORGANISM(S): Mus musculus

SUBMITTER: Takashi Takabatake 

PROVIDER: E-GEOD-19360 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Genomic and gene expression signatures of radiation in medulloblastomas after low-dose irradiation in Ptch1 heterozygous mice.

Ishida Yuka Y   Takabatake Takashi T   Kakinuma Shizuko S   Doi Kazutaka K   Yamauchi Kazumi K   Kaminishi Mutsumi M   Kito Seiji S   Ohta Yuki Y   Amasaki Yoshiko Y   Moritake Hiroyuki H   Kokubo Toshiaki T   Nishimura Mayumi M   Nishikawa Tetsu T   Hino Okio O   Shimada Yoshiya Y  

Carcinogenesis 20100708 9


Accurate cancer risk assessment of low-dose radiation poses many challenges that are partly due to the inability to distinguish radiation-induced tumors from spontaneous ones. To elucidate characteristic features of radiation-induced tumors, we analyzed 163 medulloblastomas that developed either spontaneously or after X-ray irradiation at doses of 0.05-3 Gy in Ptch1 heterozygous mice. All spontaneous tumors showed loss of heterozygosity in broad regions on chromosome 13, with losses at all conse  ...[more]

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