Oncogenic pathway signatures in human cancers as a guide to targeted therapies
Oncogenic pathway signatures in human cancers as a guide to targeted therapies
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DOI：
10.1038/nature04296
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发表时间：
2006-01-19
期刊：
影响因子：
64.8
通讯作者：
Nevins, JR
中科院分区：
文献类型：
--
作者：
Bild, AH;Yao, G;Nevins, JR
致癌状态的发展是一个复杂的过程，涉及多个独立突变的积累，导致细胞信号传导途径的失调，而细胞信号传导途径对控制细胞生长和细胞命运至关重要（1-3）。使用基于DNA微阵列的基因表达特征来定义癌症亚型、疾病复发和对特定疗法的反应的能力已在多项研究中得到证实（4）。各种研究也证明了使用基因表达谱分析致癌途径的潜力（5-11）。在这里，我们表明，基因表达的签名可以确定，反映了几个致癌途径的激活状态。当在几个大型人类癌症集合中进行评估时，这些基因表达特征识别了肿瘤中通路失调的模式以及与疾病结局的临床相关性。结合几种途径的基于特征的预测，确定了区分特定癌症和肿瘤亚型的途径失调的协调模式。基于通路特征的肿瘤聚类进一步定义了相应患者亚组的预后，表明致癌通路失调的模式是致癌表型发展的基础，并反映了特定癌症的生物学和结果。预测癌细胞系中的通路失调也显示出预测对靶向通路组分的治疗剂的敏感性。将通路失调与对靶向通路组分的治疗剂的敏感性联系起来，提供了利用这些致癌通路特征来指导靶向治疗剂的使用的机会。
The development of an oncogenic state is a complex process involving the accumulation of multiple independent mutations that lead to deregulation of cell signalling pathways central to the control of cell growth and cell fate(1-3). The ability to define cancer subtypes, recurrence of disease and response to specific therapies using DNA microarray-based gene expression signatures has been demonstrated in multiple studies(4). Various studies have also demonstrated the potential for using gene expression profiles for the analysis of oncogenic pathways(5-11). Here we show that gene expression signatures can be identified that reflect the activation status of several oncogenic pathways. When evaluated in several large collections of human cancers, these gene expression signatures identify patterns of pathway deregulation in tumours and clinically relevant associations with disease outcomes. Combining signature-based predictions across several pathways identifies coordinated patterns of pathway deregulation that distinguish between specific cancers and tumour subtypes. Clustering tumours based on pathway signatures further defines prognosis in respective patient subsets, demonstrating that patterns of oncogenic pathway deregulation underlie the development of the oncogenic phenotype and reflect the biology and outcome of specific cancers. Predictions of pathway deregulation in cancer cell lines are also shown to predict the sensitivity to therapeutic agents that target components of the pathway. Linking pathway deregulation with sensitivity to therapeutics that target components of the pathway provides an opportunity to make use of these oncogenic pathway signatures to guide the use of targeted therapeutics.