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)项目的一部分的详细计划。这个CGCC将贡献两个平台，使用目前最有效和最有信息量的两种技术，每年准确分析1000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)技术对拷贝数变化进行全基因组分析。Illumina 550,000 SNP珠芯片将用于创建整个癌症基因组的高分辨率拷贝数图谱。我们对目前的300,000个SNP珠芯片和数字染色体核型进行了并列比较，结果表明，它以极低的成本提供了更高的分辨率。我们的数据表明，这项技术可以用来准确地检测缺失和扩增，这是感兴趣基因的强大指示器。特异性目标2将描述人类癌症中的CpG岛高甲基化组。癌症表观遗传学领域的主要专家已经证明了一种方法，可以定义由于高甲基化而导致表达沉默的一组可能的基因。这项分析将再次使用Illumina技术高通量和准确地分析整个基因组上功能选择的5‘CpG岛，以及位于第21和22号染色体上的所有CpG岛，以及位于这两条染色体上的随机选择的非CpG岛CpG位点。除了DNA突变和结构变化外，DNA甲基化是导致异常基因沉默的重要原因，与癌症的发展有关。在具体目标3中提出的信息学和数据核查方面，我们制定了一种综合办法，利用符合CABIG标准的数据馈送，有组织地将原始数据和核实后的数据传输到国家信息和通信委员会数据协调中心。我们还将提供作为该项目的一部分开发的数据分析工具。这些方法包括整合来自正常基因组和癌症基因组的各种基因组数据、用户友好的可视化工具、数据共享的门户网站，以及使用机器学习在可用的TCGA数据中导出系统生物学关联，所有这些都是为CaBIG Silver或更好的合规性而设计的。在成功完成这些目标后，我们将拥有一种快速有效的手段来分析数以万计的癌症基因组，并迅速产生关于拷贝数变化和超甲基化的具有生物学意义的数据。该项目与公共卫生有直接关系。对引起改变的主要癌症的类型和频率的准确了解将使我们能够为新的治疗开发选择最佳的分子靶点。

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.