Gene Expression Patterns in Human Tumors Identified Using Transcript Sequencing

使用转录测序鉴定人类肿瘤中的基因表达模式

基本信息

批准号：
8925212
负责人：
David N Hayes
金额：
$ 50万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-29 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8925212
关键词：
Alternative Splicing Base Sequence Binding Sites Biological Assay Breast Cancer Etiology Characteristics Chromatin Clinical Code Coupled DNA DNA Methylation DNA Microarray Chip DNA Sequence DNA copy number Data Development Disease Distant Enhancers Epigenetic Process Event Formaldehyde Gene Expression Gene Expression Profile Gene Expression Profiling Gene Structure Genes Genome Genomic DNA Genomics Glioblastoma Head and neck structure Human Individual Infectious Agent Informatics Instruction Knowledge Lead Link Location Locus Control Region Malignant Neoplasms Malignant neoplasm of lung Mammalian Cell Maps Measurement Messenger RNA Methods MicroRNAs Molecular Profiling Mutate Mutation Nature Normal tissue morphology Nucleosomes Oligonucleotide Microarrays Outcome Output Paint Pathogen detection Patients Pattern Persons Phase Portraits Procedures Protein Isoforms Proteins RNA Splicing Regulation Regulatory Element Relative (related person)Research Infrastructure Role SNP genotyping Solid Technology Testing The Cancer Genome Atlas Time Tissues Transcript Tumor Biology Tumor Subtype Tumor Suppressor Genes Viral base cancer genome chromatin remodeling cost deep sequencing disorder subtype experience fusion gene gene function genome wide association study genome-wide histone modification improved infancy insight next generation next generation sequencing novel pathogen promoter research study tool transcription factor tumor

项目摘要

Gene expression provides a snapshot of the cellular changes that promote tumor malignancy. Quantitative gene expression analysis, especially as implemented by DNA microarrays, has proven to be an extremely valuable tool for cancer genome characterization, and has lead to the development of new genomic-based clinical tests. Our own experience with DNA microarrays to study gene expression patterns for breast, head & neck, and lung cancers has lead to the identification of novel subtypes of tumors with distinct patient outcomes and has identified new tumor suppressor genes. In the pilot phase of The Cancer Genome Atlas (TCGA) project, multiple platforms were used including tools to study gene expression (our role), tumor genomic DNA copy number alterations, SNP genotypes, DNA methylation and gene mutational analyses. Our collaborative efforts identified new tumor subtypes of glioblastoma and painted an integrated picture linking mutations to copy number changes to expression patterns, which identified biologically distinct subtypes of disease with differences in patient outcomes. For the second phase of TCGA project, we propose to continue to perform quantitative gene expression profiling of all protein-coding genes, non-protein coding mRNAs(ncRNAs) and microRNAs, on -2000 tumors per year. This approach has proven to be one of the most informative and comprehensive cancer genome characterization tools available. In addition, we propose to generate global chromatin organization profiles of cancer to identify regions of "open" chromatin domains (nucleosome-depleted regions). We will use FAIRE (Formaldehyde-Assisted isolation of Regulatory Elements), a simple, low-cost method amenable to use on small quantities of solid tissue, coupled to next-generation DNA sequencing. Since the function of most histone modifications and chromatin remodeling activities is to regulate nucleosome occupancy, FAIRE effectively summarizes the functional output of such epigenetic mechanisms in a single robust assay. Lastly, we propose to perform integrated analyses of transcript levels with chromatin stoicture to map important regulatory elements, which can be distant to the transcript(s) that they regulate. Our study of genome-wide transcript regulation with chromatin organization will provide a critical portrait of the cancer genome that can be integrated with (and indeed can sometimes generate) other important data, including mutations and copy number events.

基因表达提供了促进肿瘤恶性肿瘤的细胞变化的快照。定量基因表达分析，尤其是由DNA微阵列实施的，已被证明是极有价值的癌症基因组表征工具，并导致了新的发展基于基因组的临床测试。我们自己在DNA微阵列中研究基因表达模式的经验对于乳房，头颈和肺癌，可以鉴定出具有新型肿瘤亚型独特的患者结局，已经确定了新的肿瘤抑制基因。在癌症的试验阶段基因组地图集（TCGA）项目，使用了多个平台，包括研究基因表达的工具（我们角色），肿瘤基因组DNA拷贝数改变，SNP基因型，DNA甲基化和基因突变分析。我们的协作努力确定了胶质母细胞瘤的新肿瘤亚型，并绘制了整合的肿瘤亚型图片将突变连接到复制数字变化到表达模式，这些模式在生物学上差异很明显疾病的亚型，患者结局差异。对于TCGA项目的第二阶段，我们建议继续执行定量基因表达在-2000肿瘤上的所有蛋白质编码基因，非蛋白质编码mRNA（NCRNA）和microRNA的分析每年。这种方法已被证明是最有用，最全面的癌症基因组之一可用的表征工具。此外，我们建议生成全球染色质组织概况癌症以识别“开放”染色质结构域（核小体耗尽区域）的区域。我们将使用公平（甲醛辅助隔离调节元素），一种简单的低成本方法，可在少量的固体组织，耦合到下一代DNA测序。由于大多数功能组蛋白修饰和染色质重塑活性是调节核小体占用率有效地总结了单个强大测定中此类表观遗传机制的功能输出。最后，我们建议对具有染色质的转录水平进行转录水平的综合分析，以绘制重要调节元素，可能与它们调节的转录本相距甚远。我们对全基因组的研究染色质组织的成绩单调节将提供癌症基因组的批判肖像与（确实有时可以生成）其他重要数据集成，包括突变和复制数字事件。