High Resolution Genomic Analysis of Amplicon Structure

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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.