Application of genomic biomarkers to predict increased lung tumor incidence in 2-year rodent cancer bioassays
Application of genomic biomarkers to predict increased lung tumor incidence in 2-year rodent cancer bioassays
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DOI：
10.1093/toxsci/kfm023
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发表时间：
2007-05-01
影响因子：
3.8
通讯作者：
Halsey, Thomas A.
中科院分区：
文献类型：
--
作者：
Thomas, Russell S.;Pluta, Linda;Halsey, Thomas A.
啮齿动物癌症生物测定是安全测试遗产的一部分，在过去 30 年里没有发生重大变化。生物测定昂贵、耗时，并且需要使用数百只动物。与数千种尚未测试致癌活性的环境和工业化学品相比，在啮齿动物癌症生物测定中测试的化学品不到 1500 种。在这项研究中，我们使用国家毒理学计划 (NTP) 生成的现有数据来识别可以预测啮齿动物癌症生物测定结果的基因表达生物标志物。从 NTP 测试的化学物质中选出了一组 13 种不同的化学物质。七种化学物质对雌性 B6C3F1 小鼠肺部肿瘤发病率增加呈阳性，六种化学物质呈阴性。雌性小鼠亚慢性接触这 13 种化学物质，并对肺部进行微阵列分析。使用基因表达谱的统计分类分析确定了一组八个探针组，对应于六个基因，其表达正确预测了肺肿瘤发病率的增加，准确度为 93.9%。敏感性和特异性分别为 95.2% 和 91.8%。在预测特征的六个基因中，大多数是参与内源性和外源性代谢的酶，一个基因是参与肺发育的生长因子受体。结果表明，可以使用亚慢性暴露的基因生物标志物来预测雌性小鼠中化学诱导的肺肿瘤发病率的增加，并且可以为评估化学品致癌活性的更有效和更经济的方法奠定基础。
Rodent cancer bioassays are part of a legacy of safety testing that has not changed significantly over the past 30 years. The bioassays are expensive, time consuming, and use hundreds of animals. Fewer than 1500 chemicals have been tested in a rodent cancer bioassay compared to the thousands of environmental and industrial chemicals that remain untested for carcinogenic activity. In this study, we used existing data generated by the National Toxicology Program (NTP) to identify gene expression biomarkers that can predict results from a rodent cancer bioassay. A set of 13 diverse chemicals was selected from those tested by the NTP. Seven chemicals were positive for increased lung tumor incidence in female B6C3F1 mice and six were negative. Female mice were exposed subchronically to each of the 13 chemicals, and microarray analysis was performed on the lung. Statistical classification analysis using the gene expression profiles identified a set of eight probe sets corresponding to six genes whose expression correctly predicted the increase in lung tumor incidence with 93.9% accuracy. The sensitivity and specificity were 95.2 and 91.8%, respectively. Among the six genes in the predictive signature, most were enzymes involved in endogenous and xenobiotic metabolism, and one gene was a growth factor receptor involved in lung development. The results demonstrate that increases in chemically induced lung tumor incidence in female mice can be predicted using gene biomarkers from a subchronic exposure and may form the basis of a more efficient and economical approach for evaluating the carcinogenic activity of chemicals.