High Resolution Genomic Analysis of Amplicon Structure

用最近实施的基于微阵列的比较基因组形式分析乳腺肿瘤 杂交(阵列CGH)揭示了乳腺肿瘤表现出几种不同类型的基因组 影响DNA拷贝数的不稳定性。肿瘤的一个子集的特征是有放大的倾向 集中在染色体区域，因此肿瘤表现为“放大”表型。长期目标 该项目的目的是确定：(A)有助于人类基因扩增倾向的基因 肿瘤和(B)基因组的特征和所选择的基因(S)影响选择的程度 放大子和它的幅度。因为扩增被认为需要在细胞周期中进行 对于未修复的双链断裂，这个项目将特别调查功能障碍的关联 乳腺肿瘤中具有“放大”表型的细胞周期控制和DNA损伤修复途径 其中一些基因的突变对体外扩增选择的影响。成功者 这些研究的结论将确定乳腺肿瘤的扩增表型的特征，并将开始 对突变体表型所涉及的遗传缺陷的调查。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，从而有助于鉴定 目前尚无已知癌基因的扩增区域的癌基因。因为遗传不稳定是一种 肿瘤的持续状态，识别和了解其所涉及的机制将对 设计针对功能失调基因的治疗方法，以稳定基因组并避免 产生抗药性，或避免肿瘤因功能障碍而产生抗药性的治疗 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.