Genetic Analysis of T Cell Lymphomas in Carbon Ion-Irradiated Mice Reveals Frequent Interstitial Chromosome Deletions: Implications for Second Cancer Induction in Normal Tissues during Carbon Ion Radiotherapy
Genetic Analysis of T Cell Lymphomas in Carbon Ion-Irradiated Mice Reveals Frequent Interstitial Chromosome Deletions: Implications for Second Cancer Induction in Normal Tissues during Carbon Ion Radiotherapy
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DOI：
10.1371/journal.pone.0130666
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发表时间：
2015-06-30
期刊：
影响因子：
3.7
通讯作者：
Shimada, Yoshiya
中科院分区：
文献类型：
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作者：
Blyth, Benjamin J.;Kakinuma, Shizuko;Shimada, Yoshiya
监测暴露于碳离子放射治疗的小鼠提供了一种间接方法来评估放射治疗目标体积之外的正常组织中诱发第二次癌症的可能性，因为根据历史患者数据尚无法进行这种估计。在这里，雄性和雌性 B6C3F1 小鼠在日本千叶的重离子医疗加速器中接受单能碳离子放射治疗束的单次或分次全身照射，与患者放射治疗方案期间在肿瘤体积之前传递到正常组织的辐射质量相匹配（平均线性能量转移 = 13 keV.mu m(-1)）。对小鼠的剩余寿命进行监测，并将这些小鼠中出现的大量 T 细胞淋巴瘤与等量 Cs-137 伽马射线照射后出现的 T 细胞淋巴瘤一起进行分析。使用全基因组 DNA 拷贝数分析来识别与辐射诱导的淋巴瘤发生有关的基因组位点，并随后对 Notch1、Ikzf1、Pten、Trp53 和 Bcl11b 基因进行详细分析，我们比较了碳离子和伽马射线诱导的肿瘤的遗传谱。在两个辐射组中均鉴定出先前与辐射诱导的 T 细胞淋巴瘤相关的一组典型基因。虽然各种途径的破坏模式在辐射类型之间有所不同，最显着的是 Pten 突变频率和 Bcl11b 侧翼杂合性丧失，但最引人注目的发现是在碳离子诱导的肿瘤中在基因组的各个位点观察到大的间质缺失，这种情况仅在分析的伽马射线诱导的肿瘤中很少见。如果这种大的间质染色体缺失是碳离子辐射的特征性病变，即使在放疗患者的正常组织中使用低线性能量转移辐射，了解这种DNA损伤的剂量反应和组织特异性可能是评估碳离子放疗患者的第二次癌症风险的关键。
Monitoring mice exposed to carbon ion radiotherapy provides an indirect method to evaluate the potential for second cancer induction in normal tissues outside the radiotherapy target volume, since such estimates are not yet possible from historical patient data. Here, male and female B6C3F1 mice were given single or fractionated whole-body exposure(s) to a monoenergetic carbon ion radiotherapy beam at the Heavy Ion Medical Accelerator in Chiba, Japan, matching the radiation quality delivered to the normal tissue ahead of the tumour volume (average linear energy transfer = 13 keV. mu m(-1)) during patient radiotherapy protocols. The mice were monitored for the remainder of their lifespan, and a large number of T cell lymphomas that arose in these mice were analysed alongside those arising following an equivalent dose of Cs-137 gamma ray-irradiation. Using genome-wide DNA copy number analysis to identify genomic loci involved in radiation-induced lymphomagenesis and subsequent detailed analysis of Notch1, Ikzf1, Pten, Trp53 and Bcl11b genes, we compared the genetic profile of the carbon ion-and gamma ray-induced tumours. The canonical set of genes previously associated with radiation-induced T cell lymphoma was identified in both radiation groups. While the pattern of disruption of the various pathways was somewhat different between the radiation types, most notably Pten mutation frequency and loss of heterozygosity flanking Bcl11b, the most striking finding was the observation of large interstitial deletions at various sites across the genome in carbon ion-induced tumours, which were only seen infrequently in the gamma ray-induced tumours analysed. If such large interstitial chromosomal deletions are a characteristic lesion of carbon ion irradiation, even when using the low linear energy transfer radiation to which normal tissues are exposed in radiotherapy patients, understanding the dose-response and tissue specificity of such DNA damage could prove key to assessing second cancer risk in carbon ion radiotherapy patients.