Varma Sudhir, Pommier Yves, Sunshine Margot, Weinstein John N, Reinhold William C
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America; HiThru Analytics LLC, Laurel, Maryland, United States of America.
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS One. 2014 Mar 26;9(3):e92047. doi: 10.1371/journal.pone.0092047. eCollection 2014.
Array-based comparative genomic hybridization (aCGH) is a powerful technique for detecting gene copy number variation. It is generally considered to be robust and convenient since it measures DNA rather than RNA. In the current study, we combine copy number estimates from four different platforms (Agilent 44 K, NimbleGen 385 K, Affymetrix 500 K and Illumina Human1Mv1_C) to compute a reliable, high-resolution, easy to understand output for the measure of copy number changes in the 60 cancer cells of the NCI-DTP (the NCI-60). We then relate the results to gene expression. We explain how to access that database using our CellMiner web-tool and provide an example of the ease of comparison with transcript expression, whole exome sequencing, microRNA expression and response to 20,000 drugs and other chemical compounds. We then demonstrate how the data can be analyzed integratively with transcript expression data for the whole genome (26,065 genes). Comparison of copy number and expression levels shows an overall medium high correlation (median r = 0.247), with significantly higher correlations (median r = 0.408) for the known tumor suppressor genes. That observation is consistent with the hypothesis that gene loss is an important mechanism for tumor suppressor inactivation. An integrated analysis of concurrent DNA copy number and gene expression change is presented. Limiting attention to focal DNA gains or losses, we identify and reveal novel candidate tumor suppressors with matching alterations in transcript level.
基于芯片的比较基因组杂交技术（aCGH）是一种检测基因拷贝数变异的强大技术。由于它测量的是DNA而非RNA，通常被认为是稳健且便捷的。在本研究中，我们整合了来自四个不同平台（安捷伦44K、NimbleGen 385K、Affymetrix 500K和Illumina Human1Mv1_C）的拷贝数估计值，以计算出一个可靠、高分辨率且易于理解的输出结果，用于衡量NCI-DTP（NCI-60）的60个癌细胞中的拷贝数变化。然后，我们将结果与基因表达相关联。我们解释了如何使用我们的CellMiner网络工具访问该数据库，并提供了一个与转录本表达、全外显子测序、微小RNA表达以及对20000种药物和其他化合物的反应进行比较的简便示例。接着，我们展示了如何将这些数据与全基因组（26065个基因）的转录本表达数据进行综合分析。拷贝数与表达水平的比较显示出总体中等偏高的相关性（中位数r = 0.247），对于已知的肿瘤抑制基因，相关性显著更高（中位数r = 0.408）。这一观察结果与基因缺失是肿瘤抑制基因失活的重要机制这一假设相一致。本文还对同时发生的DNA拷贝数和基因表达变化进行了综合分析。将注意力限制在局灶性DNA增加或减少上，我们识别并揭示了在转录水平上有匹配改变的新型候选肿瘤抑制基因。
