DEFINING THE REGULATORY, NON-CODING, MUTATIONAL LANDSCAPE OF BREAST CANCER

定义乳腺癌的监管、非编码突变景观

• 批准号: 8925830
• 负责人: Obi L. Griffith
• 金额: $ 17.17万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2017-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8925830
• 关键词: Address; Adopted; Adverse effects; Affect; Automobile Driving; Binding; Biological Markers; Biological Process; Breast Cancer Treatment; Code; Communities; Computer software; DNA Sequence Alteration; Data; Data Set; Databases; Development; Diagnostic; Disease; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genome; Goals; Health; High-Throughput Nucleotide Sequencing; Human; Knowledge; Location; Malignant Neoplasms; Methods; Molecular; Mutate; Mutation; Nucleic Acid Regulatory Sequences; Nucleotides; Oncogenes; Open Reading Frames; Pharmaceutical Preparations; Promoter Regions; Reagent; Recurrence; Regulator Genes; Regulatory Element; Research; Resources; Solid Neoplasm; Statistical Methods; Statistical Models; Therapeutic Intervention; Time; Untranslated RNA; Update; Validation; Variant; Viral; base; cancer therapy; design; exome; gene interaction; gene therapy; genome sequencing; improved; interest; knowledge base; malignant breast neoplasm; new technology; novel; prognostic; protein expression; research study; targeted sequencing; tool; transcription factor

DESCRIPTION (provided by applicant): Regulatory sequences determine the level, location and timing of gene expression. These sequences are important in nearly all biological processes and many disease conditions. In many cases, the onset of cancer is likely related to changes in these regulatory sequences. This might involve single nucleotide changes that destroy or create motifs for transcription factor binding. In other cases, structural variants migh translocate a gene from one location to another, placing it under the wrong regulatory control region entirely. In still other cases integration of viral regulatory sequences into the promoter region of genes might drive expression of oncogenes. The proposed project will develop new tools to identify genes that have undergone a change in their regulatory sequences leading to cancer. Specifically, we will develop new software for the identification and prioritization of non coding mutations from whole genome sequence data. We will also develop experimental reagents in the form of a hybridization-based targeted-capture reagent to allow sequencing of prioritized regulatory regions when whole genome sequencing is either too expensive or is lacking coverage of the regions of interest. Genes found to have recurrently mutated regulatory regions could make suitable targets for therapeutic intervention as well as having prognostic and diagnostic value. In the long term, a better understanding of regulatory elements and gene expression patterns could help in the development of gene- based therapies that reduce the undesired side effects of conventional cancer therapies.

描述（由申请人提供）：调控序列决定基因表达的水平、位置和时间。这些序列在几乎所有的生物过程和许多疾病状况中是重要的。在许多情况下，癌症的发生可能与这些调控序列的变化有关。这可能涉及破坏或创建转录因子结合基序的单核苷酸变化。在其他情况下，结构变异可能会将基因从一个位置转移到另一个位置，将其完全置于错误的调控区域。在其他情况下，病毒调节序列整合到基因的启动子区域中可能驱动癌基因的表达。拟议的项目将开发新的工具，以确定基因的调控序列发生了变化，导致癌症。具体来说，我们将开发新的软件，用于识别和优先考虑非 从全基因组序列数据编码突变。我们还将开发基于杂交的靶向捕获试剂形式的实验试剂，以便在全基因组测序过于昂贵或缺乏感兴趣区域的覆盖时对优先调控区域进行测序。发现具有反复突变的调控区的基因可以成为治疗干预的合适靶点，并具有预后和诊断价值。从长远来看，更好地了解调控元件和基因表达模式可以帮助开发基于基因的疗法，减少传统癌症疗法的不良副作用。