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

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中都很重要。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。这可能涉及单核苷酸改变，破坏或创建转录因子结合的基序。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，将病毒调控序列整合到基因的启动子区域可能会驱动癌基因的表达。拟议中的项目将开发新的工具来识别导致癌症的调控序列发生变化的基因。具体地说，我们将开发新的软件来识别和确定非 从全基因组序列数据中编码突变。我们还将开发以杂交为基础的靶向捕获试剂的形式的实验试剂，以便在全基因组测序过于昂贵或缺乏对感兴趣区域的覆盖时，能够对优先考虑的调控区域进行测序。被发现具有反复突变的调节区的基因可能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能有助于开发基于基因的疗法，减少传统癌症疗法的不良副作用。

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.