Integrative Cancer Epigenomic Data Analysis Center (ICE-DAC)

综合癌症表观基因组数据分析中心（ICE-DAC）

• 批准号: 10005291
• 负责人: PETER W LAIRD
• 金额: $ 50.45万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005291
• 关键词: Attention; Base Sequence; Binding Sites; Biological; Cancer Biology; Cancer Model; Cells; Cellularity; Clinical; Clinical Data; Clinical Trials; Cluster Analysis; Code; Computers; Custom; Cytosine; DNA Integration; DNA Methylation; DNA Modification Process; DNA Sequence Alteration; Data; Data Analyses; Data Set; Defect; Development; Enhancers; Epigenetic Process; Event; Formalin; Frequencies; Genes; Genetic Fingerprintings; Genome; Genome Data Analysis Network; Genomics; Growth; Human; MLH1 gene; Malignant Neoplasms; Methods; Methylation; Microsatellite Instability; Mismatch Repair; Molecular; Mutation; Non-Malignant; Outcome; Paraffin Embedding; Pathway Analysis; Play; Principal Investigator; Production; Proteins; Proteomics; Publishing; Quality Control; Reader; Role; Scientist; Somatic Mutation; Specimen; Structure; Techniques; The Cancer Genome Atlas; Time; Tumor Suppressor Genes; Tumor-Derived; Untranslated RNA; Variant; Visualization; analysis pipeline; base; bioinformatics tool; bisulfite; bisulfite sequencing; cancer genome; cancer subtypes; clinical trial analysis; clinically relevant; computerized data processing; epigenomics; experience; flexibility; gene repair; genome analysis; genome annotation; improved; innovation; insight; mouse model; novel; sample fixation; skills; subclonal heterogeneity; tool; tool development; transcription factor; transcriptome sequencing; transcriptomics; tumor; tumor heterogeneity; tumorigenesis

PROJECT SUMMARY / ABSTRACT The past three decades have witnessed an accumulating body of evidence that epigenetic mechanisms play an instrumental role in human cancer. Epigenetic alterations can serve as driver events in cancer by inactivating tumor-suppressor genes. The finding that these silencing events are mutually exclusive with structural or mutational inactivation of the same gene reinforces the functional significance of epigenetic silencing. The majority of cases of microsatellite instability in sporadic human tumors can be attributed to epigenetic silencing of the MLH1 mismatch repair gene. One of the most striking discoveries to emerge from cancer genome projects has been the previously unappreciated preponderance of somatic mutations in epigenetic regulators in most types of human cancer. Clearly, epigenetic mechanisms play a key role in human cancer, and a comprehensive molecular characterization of cancer should include epigenomic profiling. We propose to create an Integrative Cancer Epigenomic Data Analysis Center (ICE-DAC) to provide specialized analysis pipelines and expertise as part of the Genome Data Analysis Network (GDAN). We anticipate that epigenomic data will be provided as bisulfite-based sequence data or as DNA methylation BeadArray data, and we provide an analysis workflow that can accommodate either. We propose to apply specialized epigenetic analyses we have developed for both data types in our extensive experience in cancer genome consortia. In Specific Aim 1, we will develop, improve and implement analytic bioinformatic tools for epigenomic data analysis, including improvements to analysis tools for processing bisulfite sequence data. We will continue the development of analysis tools that use DNA methylation data to analyze tumor heterogeneity and subclonal structure, including the deconstruction of non-malignant cellular composition of the tumor. In Specific Aim 2, we will provide advanced specialized analysis of cancer epigenomic data generated by the Genome Characterization Center and/or provided through the Data Processing GDAC. Our automated workflow will provide timely primary data analysis for AWGs, and can accommodate both sequence-based or array-based DNA methylation data. This workflow will call differentially methylated regions (DMRs), identify cancer subtypes through stratified cluster analysis, analyze CpH methylation, and analyze tumor purity and subclonal heterogeneity. Performing variant analysis from bisulfite sequence data allows us to determine the impact of non-coding mutations on epigenetic state. In Specific Aim 3, we will integrate epigenomic data with other genomic, transcriptomic, proteomic, and clinical data to derive biologically and clinically relevant novel insights. Integration of DNA methylation and RNA-Seq data will be used for epigenetic silencing calls and for our custom enhancer identification ELMER pipeline, both of which will feed into pathway and network analyses.

项目概要/摘要 过去三十年见证了越来越多的证据表明表观遗传机制 在人类癌症中发挥重要作用。表观遗传改变可以通过以下方式作为癌症的驱动事件 使肿瘤抑制基因失活。研究发现这些沉默事件与 同一基因的结构或突变失活增强了表观遗传的功能意义 沉默。散发性人类肿瘤中微卫星不稳定性的大多数病例可归因于 MLH1 错配修复基因的表观遗传沉默。最引人注目的发现之一 癌症基因组计划之前一直没有意识到体细胞突变的优势 大多数类型的人类癌症中的表观遗传调节因子。显然，表观遗传机制在人类中起着关键作用。 癌症的全面分子特征应包括表观基因组分析。我们 提议建立一个综合癌症表观基因组数据分析中心（ICE-DAC），以提供专门的 作为基因组数据分析网络 (GDAN) 一部分的分析管道和专业知识。我们预计 表观基因组数据将作为基于亚硫酸氢盐的序列数据或 DNA 甲基化 BeadArray 数据提供， 我们提供了一个可以适应这两种情况的分析工作流程。我们建议申请专业 我们凭借在癌症基因组方面的丰富经验，为这两种数据类型开发了表观遗传分析 财团。在具体目标 1 中，我们将开发、改进和实施生物信息分析工具 表观基因组数据分析，包括改进用于处理亚硫酸氢盐序列数据的分析工具。我们 将继续开发利用DNA甲基化数据分析肿瘤异质性的分析工具 和亚克隆结构，包括肿瘤非恶性细胞成分的解构。在 具体目标 2，我们将为癌症表观基因组数据提供先进的专业分析 基因组表征中心和/或通过数据处理 GDAC 提供。我们的自动化 工作流程将为 AWG 提供及时的主要数据分析，并且可以适应基于序列或 基于阵列的 DNA 甲基化数据。此工作流程将调用差异甲基化区域 (DMR)，识别 通过分层聚类分析癌症亚型，分析CpH甲基化，分析肿瘤纯度和 亚克隆异质性。从亚硫酸氢盐序列数据中进行变异分析使我们能够确定 非编码突变对表观遗传状态的影响。在具体目标 3 中，我们将整合表观基因组数据 其他基因组、转录组、蛋白质组和临床数据，以获得生物学和临床相关的新颖数据 见解。 DNA 甲基化和 RNA-Seq 数据的整合将用于表观遗传沉默调用和 我们的定制增强子识别 ELMER 管道，两者都将输入路径和网络分析。