Genomic and gene expression signatures of radiation in medulloblastomas after low-dose irradiation in Ptch1 heterozygous mice (original) (raw)

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1 Department of Technical Support and Development, Fundamental Technology Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan

2 Department of Molecular Pathogenesis, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan

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These authors contributed equally to this work.

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3 Experimental Radiobiology for Children’s Health Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan

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These authors contributed equally to this work.

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3 Experimental Radiobiology for Children’s Health Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan

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4 Regulatory Sciences Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan

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3 Experimental Radiobiology for Children’s Health Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan

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3 Experimental Radiobiology for Children’s Health Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan

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5 Department of Advanced Technologies for Radiation Protection Research, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan

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5 Department of Advanced Technologies for Radiation Protection Research, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan

6 Science Service, Inc., 2-7, Nihombashi Ohdemma-cho, Chuo-ku, Tokyo 103-0011, Japan

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3 Experimental Radiobiology for Children’s Health Research Group, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan

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6 Science Service, Inc., 2-7, Nihombashi Ohdemma-cho, Chuo-ku, Tokyo 103-0011, Japan

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Revision received:

23 June 2010

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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, Yoshiya Shimada, Genomic and gene expression signatures of radiation in medulloblastomas after low-dose irradiation in Ptch1 heterozygous mice , Carcinogenesis, Volume 31, Issue 9, September 2010, Pages 1694–1701, https://doi.org/10.1093/carcin/bgq145
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Abstract

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.

© The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Topic:

• diagnostic radiologic examination
• roentgen rays
• gene expression
• chromosomes
• genes
• genome
• heterozygote
• loss of heterozygosity
• medulloblastoma
• cerebellum
• mice
• neoplasms
• carcinogenesis
• cancer risk
• ptch1 gene
• patched-1 receptor

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