Cancer Genome Characterization Center at Johns Hopkins

描述（由申请人提供）：本提案描述了癌症基因组表征中心（CGCC）作为癌症基因组图谱（TCGA）项目一部分的详细计划。CGCC将提供两个平台，使用目前最有效和信息量最大的两种技术，每年准确分析1,000多个癌症基因组。在具体目标1中，我们提出了第一个平台，使用Illumina BeadArray（TM）技术进行拷贝数变化的全基因组分析。Illumina 550，000 SNP BeadChip将用于创建整个癌症基因组的高分辨率拷贝数图谱。我们对当前30万SNP BeadChip与数字核型分析的并排比较表明，它以显著降低的成本提供了更高的分辨率。我们的数据表明，该技术可用于准确检测缺失和扩增，这是感兴趣基因的有力指标。具体目标2将表征人类癌症中的CpG岛超甲基化。癌症表观遗传学领域的领先专家有一种经过验证的方法来定义一组可能的基因，这些基因由于超甲基化而具有表达沉默。该测定将再次使用Illumina技术来高通量和准确测定基因组中功能性选择的5' CpG岛，以及位于染色体21和22上的所有CpG岛，以及随机选择位于这两条染色体上的非CpG岛CpG位点。除了DNA突变和结构变化之外，DNA甲基化是与癌症发展相关的异常基因沉默的重要原因。在具体目标3中提出的信息学和数据验证中，我们开发了一种综合方法，使用符合CaBIG的数据馈送将原始和验证数据有组织地传输到NCICB数据协调中心。我们还将提供作为该项目一部分开发的数据分析工具。这些包括整合来自正常和癌症基因组的不同基因组数据的手段、用户友好的可视化工具、用于数据共享的门户网站，以及使用机器学习来导出可用TCGA数据之间的系统生物学相关性，所有这些都是为CaBIG银或更好的合规性而设计的。在成功完成这些目标后，我们将有一种快速有效的方法来分析成千上万的癌症基因组，并快速产生关于拷贝数变化和超甲基化的有生物学意义的数据。该项目与公共卫生直接相关。准确了解主要癌症导致改变的类型和频率将允许选择最佳分子靶点用于新疗法开发。

DESCRIPTION (provided by applicant): This proposal describes a detailed plan for a Cancer Genome Characterization Center (CGCC) to act as part of The Cancer Genome Atlas (TCGA) project. This CGCC will contribute two platforms to accurately analyze over 1,000 cancer genomes per year using two of the most efficient and informative technologies currently available. In Specific Aim 1 we propose the first platform, a whole genome analysis of copy number changes using Illumina BeadArray(tm) technology. The Illumina 550,000 SNP BeadChip will be used to create high- resolution copy number maps of whole cancer genomes. Our side-by- side comparison of the current 300,000 SNP BeadChip to Digital Karyotyping shows that it provides higher resolution at a dramatically lower cost. Our data show that this technology can be used to accurately detect deletions and amplifications, powerful indicators of genes of interest. Specific Aim 2 will characterize the CpG island hypermethylome in human cancer. Leading experts in the field of cancer epigenetics have a proven approach to define the set of possible genes that have expression silencing as a result of hypermethylation. This assay will again use the Illumina technology for high-throughput and accurate assay of functionally selected 5' CpG islands across the genome, as well as all CpG islands located on chromosomes 21 and 22, and a random selection of non- CpG island CpG sites located on these two chromosomes. In addition to DNA mutations and structural changes, DNA methylation is a significant cause of abnormal gene silencing linked to the development of cancer. In the informatics and data verification proposed in Specific Aim 3 we have developed an integrated approach to organized transmission of raw and verified data to the NCICB Data Coordinating Center using CaBIG-compliant data feeds. We will also make available data analysis tools developed as part of this project. These include means to integrate diverse genomic data from normal and cancer genomes, user- friendly visualization tools, web portals for data sharing, and use machine learning to derive systems biology correlates among available TCGA data, all designed for CaBIG silver or better compliance. Upon successful completion of these aims, we will have a rapid and efficient means to assay tens of thousands of cancer genomes, and rapidly produce biologically meaningful data on copy number changes and hypermethylation. This project has direct relevance to public health. Precise knowledge of the type and frequency of the major cancer causing alterations will allow the best molecular targets to be selected for new therapy development.