Tsuruoka Chizuru, Blyth Benjamin J, Morioka Takamitsu, Kaminishi Mutsumi, Shinagawa Mayumi, Shimada Yoshiya, Kakinuma Shizuko
Department of Radiation Effects Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
Radiat Res. 2016 Oct;186(4):407-414. doi: 10.1667/RR14499.1. Epub 2016 Sep 30.
Recently reported studies have led to a heightened awareness of the risks of cancer induced by diagnostic radiological imaging, and in particular, the risk of brain cancer after childhood CT scans. One feature of Ptch1 mice is their sensitivity to radiation-induced medulloblastomas (an embryonic cerebellar tumor) during a narrow window of time centered on the days around birth. Little is known about the dynamics of how dose protraction interacts with such narrow windows of sensitivity in individual tissues. Using medulloblastomas from irradiated Ptch1 mice with a hybrid C3H × C57BL/6 F1 genetic background, we previously showed that the alleles retained on chromosome 13 (which harbors the Ptch1 gene) reveal two major mechanisms of loss of the wild-type allele. The loss of parental alleles from the telomere extending up to or past the Ptch1 locus by recombination (spontaneous type) accounts for almost all medulloblastomas in nonirradiated mice, while tumors in irradiated mice often exhibited interstitial deletions, which start downstream of the wild-type Ptch1 and extend up varying lengths towards the centromere (radiation type). In this study, Ptch1 mice were exposed to an acute dose of either 100 or 500 mGy gamma rays in utero or postnatally, or the same radiation doses protracted over a four-day period, and were monitored for medulloblastoma development. The results showed dose- and age-dependent radiation-induced type tumors. Furthermore, the size of the radiation-induced deletion differed with the dose rate. The results of this work suggest that tumor latency may be related to the size of the deletion. In this study, 500 mGy exposure produced radiation-induced type tumors at all ages and dose rates, while 100 mGy exposure did not significantly produce radiation-induced type tumors. The radiation signature allows for unique mechanistic insight into the action of radiation to induce DNA lesions with known causal relationship to a specific tumor type, particularly for doses and dose rates that are relevant to both diagnostic and accidental radiological exposures.
最近报道的研究使人们更加意识到诊断性放射成像诱发癌症的风险，尤其是儿童期CT扫描后患脑癌的风险。Ptch1小鼠的一个特点是，在以出生前后几天为中心的狭窄时间段内，它们对辐射诱发的髓母细胞瘤（一种胚胎性小脑肿瘤）敏感。关于剂量延长如何与各个组织中如此狭窄的敏感窗口相互作用的动态过程，人们了解甚少。利用具有C3H×C57BL/6 F1杂交遗传背景的受辐照Ptch1小鼠的髓母细胞瘤，我们之前表明保留在13号染色体（该染色体含有Ptch1基因）上的等位基因揭示了野生型等位基因丢失的两种主要机制。通过重组（自发类型）从端粒延伸至Ptch1基因座或超过该基因座导致的亲本等位基因丢失，几乎占未受辐照小鼠中所有髓母细胞瘤的原因，而受辐照小鼠中的肿瘤通常表现为间质缺失，这种缺失从野生型Ptch1下游开始，并向着丝粒延伸不同长度（辐射类型）。在本研究中，对Ptch1小鼠在子宫内或出生后给予100或500 mGy的急性γ射线剂量，或在四天内给予相同的延长辐射剂量，并监测髓母细胞瘤的发生情况。结果显示了剂量和年龄依赖性的辐射诱发型肿瘤。此外，辐射诱发的缺失大小因剂量率而异。这项工作的结果表明肿瘤潜伏期可能与缺失大小有关。在本研究中，500 mGy的照射在所有年龄和剂量率下均产生了辐射诱发型肿瘤，而100 mGy照射未显著产生辐射诱发型肿瘤。这种辐射特征有助于对辐射诱导DNA损伤的作用进行独特的机制性洞察，而这种损伤与特定肿瘤类型存在已知的因果关系，尤其适用于与诊断性和意外放射性暴露相关的剂量和剂量率。
