High Resolution Genomic Analysis of Amplicon Structure

利用最近实施的基于微阵列的比较基因组学方法分析乳腺肿瘤 杂交（阵列CGH）显示乳腺肿瘤显示几种不同类型的基因组 影响DNA拷贝数不稳定性。肿瘤的一个子集的特征是倾向于扩增 因此，肿瘤显示“放大器”表型。长期目标 该项目的主要目的是确定：（a）有助于人类基因扩增倾向的基因 肿瘤和（B）基因组和选择中的基因的影响程度选择的特征 一个扩增子和它的振幅。由于扩增被认为需要通过细胞周期的进展 对于未修复的双链断裂，本项目将特别研究功能障碍的相关性。 乳腺肿瘤中具有“放大器”表型的细胞周期控制和DNA损伤修复途径， 这些基因中的一些突变对体外扩增选择的影响。成功 这些研究的结论将定义乳腺肿瘤中放大器表型的特征，并将开始 对这种增变基因表型所涉及的遗传缺陷的研究。此外，这些研究将 有助于我们理解人类肿瘤中的扩增子组织，这有助于识别 在扩增区域的癌基因，目前还没有已知的癌基因。由于遗传不稳定性是一个 肿瘤的持续状态，识别和理解相关机制将是重要的， 设计针对功能失调基因的治疗方法，以稳定基因组， 耐药性的发展，或避免由于功能障碍而导致肿瘤耐药的治疗。 基因.

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.