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首页> 外文期刊>Nature >Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins
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Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins

机译：使用肿瘤病毒蛋白的系统宿主网络扰动来解释癌症基因组

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摘要

Genotypic differences greatly influence susceptibility and resistance to disease. Understanding genotype-phenotype relationships requires that phenotypes be viewed as manifestations of network properties, rather than simply as the result of individual genomic variations~1. Genome sequencing efforts have identified numerous germline mutations, and large numbers of somatic genomic alterations, associated with a predisposition to cancer~2. However, it remains difficult to distinguish background, or 'passenger', cancer mutations from causal, or 'driver', mutations in these data sets. Human viruses intrinsically depend on their host cell during the course of infection and can elicit pathological phenotypes similar to those arising from mutations~3. Here we test the hypothesis that genomic variations and tumour viruses may cause cancer through related mechanisms, by systematically examining host interactome and transcriptome network perturbations caused by DNA tumour virus proteins. The resulting integrated viral perturbation data reflects rewiring of the host cell networks, and highlights pathways, such as Notch signalling and apoptosis, that go awry in cancer. We show that systematic analyses of host targets of viral proteins can identify cancer genes with a success rate on a par with their identification through functional genomics and large-scale cataloguing of tumour mutations. Together, these complementary approaches increase the specificity of cancer gene identification. Combining systems-level studies of pathogen-encoded gene products with genomic approaches will facilitate the prioritization of cancer-causing driver genes to advance the understanding of the genetic basis of human cancer.
机译：基因型差异极大地影响了疾病的易感性和抵抗力。了解基因型与表型的关系要求将表型视为网络特性的体现，而不是简单地将其视为个体基因组变异的结果〜1。基因组测序工作已经确定了许多种系突变，以及大量的体细胞基因组改变，与癌症的易感性相关[2]。然而，仍然难以区分这些数据集中的背景或“客运”癌症突变与因果或“驾驶员”突变。人类病毒在感染过程中本质上依赖于其宿主细胞，并且可以引发类似于由突变〜3引起的病理表型。在这里，我们通过系统地检查由DNA肿瘤病毒蛋白引起的宿主相互作用组和转录组网络扰动，来检验基因组变异和肿瘤病毒可能通过相关机制导致癌症的假说。所得的综合病毒扰动数据反映了宿主细胞网络的重新布线，并突出了癌症中难以理解的诸如Notch信号传导和凋亡的途径。我们表明，病毒蛋白宿主靶标的系统分析可以通过功能基因组学和肿瘤突变的大规模分类，将癌症基因的成功率与癌症基因的鉴定相提并论。这些互补的方法共同提高了癌症基因鉴定的特异性。将病原体编码基因产物的系统级研究与基因组学方法相结合，将有助于确定致癌驱动基因的优先级，以加深对人类癌症遗传基础的理解。

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  • 来源
    《Nature》 |2012年第7408期|p.491-495|共5页
  • 作者

    Orit Rozenblatt-Rosen; Rahul C. Deo; Megha Padi; Guillaume Adelmant; Michael A. Calderwood; et al;

  • 作者单位

    Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science, Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA,Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston,Massachusetts 02115, USA;

    Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science, Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA,Cardiovascular Research Institute,Department of Medicine and Institute for Human Genetics, University of California, San Francisco, California 94143, USA;

    Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science, Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA,Center for Cancer Computational Biology (CCCB), Department of Biostatistics and Computational Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA,Department of Biostatistics, Harvard School of Public Health, Boston,Massachusetts 02115, USA;

    Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science, Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA,Blais Proteomics Center and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;

    Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science, Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA,Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA,Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA,Infectious Diseases Division, The Channing Laboratory, Brigham and Women's Hospital and Departments of Medicine and of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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