Journal Article

Genomic and gene expression signatures of radiation in medulloblastomas after low-dose irradiation in <i>Ptch1</i> heterozygous mice

Yuka Ishida, Takashi Takabatake, Shizuko Kakinuma, Kazutaka Doi, Kazumi Yamauchi, Mutsumi Kaminishi, Seiji Kito, Yuki Ohta, Yoshiko Amasaki, Hiroyuki Moritake, Toshiaki Kokubo, Mayumi Nishimura, Tetsu Nishikawa, Okio Hino and Yoshiya Shimada

in Carcinogenesis

Volume 31, issue 9, pages 1694-1701
Published in print September 2010 | ISSN: 0143-3334
Published online July 2010 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgq145
Genomic and gene expression signatures of radiation in medulloblastomas after low-dose irradiation in Ptch1 heterozygous mice

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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 consecutive markers distal to Ptch1 locus (S-type). In contrast, all tumors that developed after 3 Gy irradiation exhibited interstitial losses around Ptch1 with distal markers retained (R-type). There was a clear dose-dependent increase in the proportion of R-type tumors within the intermediate dose range, indicating that the R-type change is a reliable radiation signature. Importantly, the incidence of R-type tumors increased significantly (P = 0.007) at a dose as low as 50 mGy. Integrated array-comparative genomic hybridization and expression microarray analyses demonstrated that expression levels of many genes around the Ptch1 locus faithfully reflected the signature-associated reduction in genomic copy number. Furthermore, 573 genes on other chromosomes were also expressed differently between S-type and R-type tumors. They include genes whose expression changes during early cerebellar development such as Plagl1 and Tgfb2, suggesting a recapitulation of gene subsets functioning at distinct developmental stages. These findings provide, for the first time, solid experimental evidence for a significant increase in cancer risk by low-dose radiation at diagnostic levels and imply that radiation-induced carcinogenesis accompanies both genomic and gene expression signatures.

Journal Article.  6037 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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