Genomic and gene expression signatures of radiation in medulloblastomas after low-dose irradiation in Ptch1 heterozygous mice.
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.
Ishida
Yuka
Y
Department of Technical Support and Development, Fundamental Technology Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
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
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D055028:Comparative Genomic Hybridization; D004273:DNA, Neoplasm / Q000235:genetics; D004307:Dose-Response Relationship, Radiation; D020869:Gene Expression Profiling; D023281:Genomics; D006579:Heterozygote; D019656:Loss of Heterozygosity; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology* / Q000532:radiotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000473:pathology* / Q000532:radiotherapy; D020411:Oligonucleotide Array Sequence Analysis; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D011956:Receptors, Cell Surface / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014965:X-Rays
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011956:Receptors, Cell Surface