Integration of a radiation biomarker into modeling of thyroid carcinogenesis and post-Chernobyl risk assessment
Integration of a radiation biomarker into modeling of thyroid carcinogenesis and post-Chernobyl risk assessment
复制标题
DOI：
10.1093/carcin/bgw102
复制
发表时间：
2016-12-01
期刊：
影响因子：
4.7
通讯作者：
Jacob, Peter
中科院分区：
文献类型：
--
作者：
Kaiser, Jan Christian;Meckbach, Reinhard;Jacob, Peter
切尔诺贝利事故后进行的流行病学研究为甲状腺癌提供了强有力的证据，证明辐射照射与疾病之间存在统计学关联。然而，用流行病学方法来探讨健康风险，特别是在低剂量辐射下的健康风险，其局限性是显而易见的。由于小病例数造成的统计波动主宰了风险估计的不确定性。分子辐射标志物已被广泛研究，以区分辐射诱发的癌症病例和零星病例。CLIP2基因的过表达是这些标记中最有希望的。在包括切尔诺贝利组织库在内的年轻患者的大多数乳头状甲状腺癌（ptc）中发现了它。受CLIP2研究结果的启发，我们提出了一个机制模型，该模型将PTC的发展描述为CLIP2相关和多阶段癌变两种不同途径中的一系列限速事件。该研究将141名患者的二分类CLIP2标记的分子测量结果整合到乌克兰裔美国人队列中约13000名受试者的流行病学风险分析中，这些受试者年龄在19岁以下，自1998年以来一直处于加强的医疗监测之下。这是第一次，仅通过标记测量来估计辐射风险。与流行病学估计和模型验证的交叉检验表明，CLIP2是一个高精度的标记。CLIP2在流行病学发病率数据中留下印记，这是驱动基因的典型特征。利用机理模型，探讨了辐射对PTC分子景观的影响。该模型构成了分子生物学和辐射流行病学之间的独特接口。
Strong evidence for the statistical association between radiation exposure and disease has been produced for thyroid cancer by epidemiological studies after the Chernobyl accident. However, limitations of the epidemiological approach in order to explore health risks especially at low doses of radiation appear obvious. Statistical fluctuations due to small case numbers dominate the uncertainty of risk estimates. Molecular radiation markers have been searched extensively to separate radiation-induced cancer cases from sporadic cases. The overexpression of the CLIP2 gene is the most promising of these markers. It was found in the majority of papillary thyroid cancers (PTCs) from young patients included in the Chernobyl tissue bank. Motivated by the CLIP2 findings we propose a mechanistic model which describes PTC development as a sequence of rate-limiting events in two distinct paths of CLIP2-associated and multistage carcinogenesis. It integrates molecular measurements of the dichotomous CLIP2 marker from 141 patients into the epidemiological risk analysis for about 13 000 subjects from the Ukrainian-American cohort which were exposed below age 19 years and were put under enhanced medical surveillance since 1998. For the first time, a radiation risk has been estimated solely from marker measurements. Cross checking with epidemiological estimates and model validation suggests that CLIP2 is a marker of high precision. CLIP2 leaves an imprint in the epidemiological incidence data which is typical for a driver gene. With the mechanistic model, we explore the impact of radiation on the molecular landscape of PTC. The model constitutes a unique interface between molecular biology and radiation epidemiology.