An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis
An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis
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DOI：
10.1038/ng1490
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发表时间：
2005-01-01
期刊：
影响因子：
30.8
通讯作者：
Jacks, T
中科院分区：
文献类型：
--
作者：
Sweet-Cordero, A;Mukherjee, S;Jacks, T
使用先进的基因靶向方法，生成精确复制人类肿瘤中存在的遗传改变的癌症小鼠模型现在相对简单。目前的挑战是确定这些模型在多大程度上忠实地模拟了伴随肿瘤进展的潜在分子机制方面的人类疾病。在这里，我们描述了一种使用基因表达谱比较小鼠癌症模型与人类肿瘤的方法。我们将这种方法应用于Kras2介导的肺癌模型的分析，并发现与人肺腺癌的良好关系，从而验证了该模型。此外，我们发现，虽然KRAS 2激活的基因表达特征在单独分析具有已知KRAS 2突变状态的人类肿瘤时无法识别，但整合小鼠和人类数据发现了人类肺癌中KRAS 2突变的基因表达特征。我们通过短发夹RNA介导的致癌Kras2抑制的基因表达分析证实了这个特征的重要性。这些实验鉴定了指示KRAS 2突变的基因表达模式和人类癌症中致癌KRAS 2活性的潜在效应物。这种方法提供了一种使用动物模型的基因组分析来探测人类疾病的策略。
Using advanced gene targeting methods, generating mouse models of cancer that accurately reproduce the genetic alterations present in human tumors is now relatively straightforward. The challenge is to determine to what extent such models faithfully mimic human disease with respect to the underlying molecular mechanisms that accompany tumor progression. Here we describe a method for comparing mouse models of cancer with human tumors using gene-expression profiling. We applied this method to the analysis of a model of Kras2-mediated lung cancer and found a good relationship to human lung adenocarcinoma, thereby validating the model. Furthermore, we found that whereas a gene-expression signature of KRAS2 activation was not identifiable when analyzing human tumors with known KRAS2 mutation status alone, integrating mouse and human data uncovered a gene-expression signature of KRAS2 mutation in human lung cancer. We confirmed the importance of this signature by gene-expression analysis of short hairpin RNA-mediated inhibition of oncogenic Kras2. These experiments identified both a pattern of gene expression indicative of KRAS2 mutation and potential effectors of oncogenic KRAS2 activity in human cancer. This approach provides a strategy for using genomic analysis of animal models to probe human disease.