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

• 批准号: 9193153
• 负责人: David N Hayes
• 金额: $ 15.13万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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/9193153
• 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 Chips; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Structure; Genes; Genome; Genomic DNA; Genomics; Glioblastoma; Head and neck structure; Human; Individual; Infectious Agent; 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; Output; Paint; Pathogen detection; Patient-Focused Outcomes; Pattern; Persons; Phase; Portraits; Procedures; Protein Isoforms; Proteins; RNA Splicing; Regulation; Regulatory Element; 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; genome-wide analysis; histone modification; improved; infancy; informatics infrastructure; insight; next generation; next generation sequencing; novel; pathogen; promoter; research study; tool; transcription factor; tumor; tumor DNA

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，尤其是通过 DNA 微阵列实现的分析，已被证明是一种 癌症基因组表征的极其有价值的工具，并导致了新的开发 基于基因组的临床测试。我们利用 DNA 微阵列研究基因表达模式的经验 乳腺癌、头颈癌和肺癌的研究已导致新的肿瘤亚型的鉴定 不同的患者结果，并确定了新的肿瘤抑制基因。在癌症试验阶段 基因组图谱（TCGA）项目，使用了多个平台，包括研究基因表达的工具（我们的 作用）、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。我们的合作确定了胶质母细胞瘤的新肿瘤亚型，并绘制了一个综合的 将突变与拷贝数变化与表达模式联系起来的图片，确定了生物学上的不同 疾病亚型的患者结果存在差异。 对于TCGA项目的第二阶段，我们建议继续进行定量基因表达 对 -2000 个肿瘤的所有蛋白质编码基因、非蛋白质编码 mRNA (ncRNA) 和 microRNA 进行分析 每年。这种方法已被证明是信息最丰富、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 癌症识别“开放”染色质结构域的区域（核小体耗尽区域）。我们将使用 FAIRE （甲醛辅助的调节元件分离），一种简单、低成本的方法，适合用于 少量实体组织，结合下一代 DNA 测序。由于大多数的功能 组蛋白修饰和染色质重塑活动是为了调节核小体占据，FAIRE 在一次稳健的测定中有效总结了此类表观遗传机制的功能输出。最后， 我们建议对转录水平与染色质结构进行综合分析，以绘制重要的图谱 调控元件，可能远离它们所调控的转录本。我们的全基因组研究 染色质组织的转录调控将提供癌症基因组的重要肖像， 与其他重要数据集成（有时确实可以生成），包括突变和复制 数字事件。

项目成果

Genetic Landscape of Human Papillomavirus-Associated Head and Neck Cancer and Comparison to Tobacco-Related Tumors.

人乳头瘤病毒相关头颈癌的遗传景观以及与烟草相关肿瘤的比较。

• DOI: 10.1200/jco.2015.62.1086
• 发表时间: 2015-09-08
• 期刊: Journal of clinical oncology : official journal of the American Society of Clinical Oncology
• 作者: D. Hayes;C. Van Waes;T. Seiwert
• 通讯作者: T. Seiwert

Gene expression profiling of gliomas: merging genomic and histopathological classification for personalised therapy.

神经胶质瘤的基因表达谱：合并基因组和组织病理学分类以进行个性化治疗。

• 发表时间: 2011-02-15
• 影响因子: 8.8
• 作者: Vitucci, M;Hayes, D N;Miller, C R
• 通讯作者: Miller, C R