切尔诺贝利核事故后甲状腺癌中辐射剂量与基因突变和融合的关系研究。
Investigation of the Relationship Between Radiation Dose and Gene Mutations and Fusions in Post-Chernobyl Thyroid Cancer.
机构信息
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.
出版信息
J Natl Cancer Inst. 2018 Apr 1;110(4):371-378. doi: 10.1093/jnci/djx209.
BACKGROUND
Exposure to ionizing radiation during childhood is a well-established risk factor for thyroid cancer. However, the genetic mechanisms of radiation-associated carcinogenesis remain not fully understood.
METHODS
In this study, we used targeted next-generation sequencing and RNA-Seq to study 65 papillary thyroid cancers (PTCs) from patients in the Ukrainian-American cohort with measurement-based iodine-131 (I-131) thyroid doses received as a result of the Chernobyl accident. We fitted linear regression models to evaluate differences in distribution of risk factors for PTC according to type of genetic alteration and logistic regression models to evaluate the I-131 dose response. All statistical tests were two-sided.
RESULTS
Driver mutations were identified in 96.9% of these thyroid cancers, including point mutations in 26.2% and gene fusions in 70.8% of cases. Novel driver fusions such as POR-BRAF, as well as STRN-ALK fusions that have not been implicated in radiation-associated cancer before, were found. The mean I-131 dose in cases with point mutations was 0.2 Gy (range = 0.013-1.05 Gy), statistically significantly lower than 1.4 Gy (range = 0.009-6.15 Gy) for cases with fusions (P < .001). No driver point mutations were found in tumors from individuals who received more than 1.1 Gy of radiation. Relative to tumors with point mutations, the proportion of tumors with gene fusions increased with radiation dose, reaching 87.8% among individuals exposed to 0.3 Gy or higher. With a limited study sample size, the estimated odds ratio at 1 Gy was 20.01 (95% confidence interval = 2.57 to 653.02, P < .001). In addition, after controlling for I-131 dose, we found higher odds ratios for gene fusion-positive PTCs associated with several specific demographic and geographic features.
CONCLUSIONS
Our data provide support for a link between I-131 thyroid dose and generation of carcinogenic gene fusions, the predominant mechanism of thyroid cancer associated with radiation exposure from the Chernobyl accident.
背景
儿童时期接触电离辐射是甲状腺癌的一个明确的风险因素。然而，辐射相关致癌的遗传机制仍不完全清楚。
方法
在这项研究中，我们使用靶向下一代测序和 RNA-Seq 来研究 65 例来自乌克兰裔美国人队列的甲状腺乳头状癌（PTC）患者，这些患者的碘-131（I-131）甲状腺剂量是由于切尔诺贝利事故而接受的测量。我们拟合线性回归模型来评估根据遗传改变类型 PTC 风险因素的分布差异，并用逻辑回归模型来评估 I-131 剂量反应。所有统计检验均为双侧检验。
结果
这些甲状腺癌中 96.9%存在驱动基因突变，包括 26.2%的点突变和 70.8%的基因融合。发现了新的驱动融合，如 POR-BRAF，以及之前与辐射相关癌症无关的 STRN-ALK 融合。点突变病例的平均 I-131 剂量为 0.2Gy（范围为 0.013-1.05Gy），显著低于融合病例的 1.4Gy（范围为 0.009-6.15Gy）（P<.001）。在接受 1.1Gy 以上辐射的个体的肿瘤中未发现驱动点突变。与点突变肿瘤相比，具有基因融合的肿瘤比例随着辐射剂量的增加而增加，在暴露于 0.3Gy 或更高剂量的个体中达到 87.8%。由于研究样本量有限，在 1Gy 时的估计比值比为 20.01（95%置信区间为 2.57 至 653.02，P<.001）。此外，在控制 I-131 剂量后，我们发现与切尔诺贝利事故辐射暴露相关的基因融合阳性 PTC 与一些特定的人口统计学和地理特征相关的比值比更高。
结论
我们的数据为 I-131 甲状腺剂量与致癌基因融合的产生之间存在联系提供了支持，这是与切尔诺贝利事故辐射暴露相关的甲状腺癌的主要机制。
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