High Resolution Genomic Analysis of Amplicon Structure

描述(申请人提供)：通过最近实施的基于微阵列的比较基因组杂交形式(ARRAY CGH)对乳腺肿瘤的分析显示，乳腺肿瘤表现出几种不同类型的基因组不稳定，这些类型影响DNA拷贝数。肿瘤的一个子集的特征是有放大局部染色体区域的倾向，因此肿瘤表现为“放大”表型。该项目的长期目标是确定：(A)有助于人类肿瘤基因放大倾向的基因，以及(B)基因组和被选择的基因(S)的特征，这些特征影响扩增片段的范围和幅度的选择。由于扩增被认为需要在未修复的双链断裂的细胞周期中进行，本项目将研究功能障碍，特别是细胞周期控制和DNA损伤修复途径与乳腺肿瘤中“放大”表型的关系，以及其中一些基因的突变对体外扩增选择的影响。这些研究的成功结论将确定乳腺肿瘤中扩增表型的特征，并将开始研究与该突变表型有关的遗传缺陷。此外，这些研究将有助于我们了解人类肿瘤中扩增子的组织结构，从而有助于在扩增区域识别目前尚未发现的癌基因。由于遗传不稳定性是肿瘤的一种持续状态，识别和了解相关机制对于设计针对功能障碍基因的治疗方案、稳定基因组和避免产生耐药性或避免肿瘤因功能障碍基因而产生耐药性的治疗具有重要意义。

DESCRIPTION (provided by applicant): Analysis of breast tumors by the recently implemented microarray-based form of comparative genomic hybridization (array CGH) has revealed that breast tumors display several distinct types of genomic instability that affect DNA copy number. One subset of tumors is characterized by the propensity to amplify focal chromosomal regions, and therefore the tumors display the "amplifier" phenotype. The long term goals of this project are to identify: (a) genes that contribute to the propensity for gene amplification in human tumors and (b) features of the genome and the gene(s) under selection that affect the selection of the extent of an amplicon and its amplitude. Since amplification is thought to require progression through the cell cycle with un-repaired double strand breaks, this project will investigate the association of dysfunction in particular cell cycle control and DNA damage repair pathways with the "amplifier" phenotype in breast tumors and the effects of mutations in some of these genes on selection for amplifications in vitro. The successful conclusion of these studies will define the features of the amplifier phenotype in breast tumors and will begin the investigation of the genetic defects involved in this mutator phenotype. In addition, these studies will contribute to our understanding of amplicon organization in human tumors, which can facilitate identification of oncogenes in regions of amplification with no currently known oncogene. Since genetic instability is a continuing state of tumors, identifying and understanding the involved mechanisms will be important for the design of therapies that target the dysfunctional genes in order to stabilize the genome and avoid development of drug resistance, or to avoid therapies to which the tumor is resistant due to the dysfunctional genes.