High Resolution Genomic Analysis of Amplicon Structure

描述（由申请人提供）：通过最近实施的基于微阵列的比较基因组杂交（阵列CGH）对乳腺肿瘤的分析表明，乳腺肿瘤显示出几种不同类型的基因组不稳定性，影响DNA拷贝数。肿瘤的一个亚群的特点是倾向于扩大局灶染色体区域，因此肿瘤显示“放大器”表型。该项目的长期目标是确定：(a)导致人类肿瘤中基因扩增倾向的基因，(b)影响扩增子范围及其幅度选择的基因组和选择中的基因的特征。由于扩增被认为需要在细胞周期中与未修复的双链断裂进行进展，本项目将研究特定细胞周期控制和DNA损伤修复途径的功能障碍与乳腺肿瘤“放大器”表型的关系，以及这些基因中一些突变对体外扩增选择的影响。这些研究的成功结论将定义乳腺肿瘤中放大器表型的特征，并将开始研究涉及该突变表型的遗传缺陷。此外，这些研究将有助于我们对人类肿瘤中扩增子组织的理解，从而有助于在扩增区域中识别目前未知的癌基因。由于遗传不稳定是肿瘤的持续状态，识别和理解相关机制对于设计针对功能失调基因的治疗方法非常重要，以稳定基因组并避免耐药性的发展，或者避免因功能失调基因而导致肿瘤耐药的治疗方法。

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.