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lüll AURKA overexpression accompanies dysregulation of DNA-damage response genes in invasive urothelial cell carcinoma Veerakumarasivam A; Goldstein LD; Saeb-Parsy K; Scott HE; Warren A; Thorne NP; Mills IG; Venkitaraman A; Neal DE; Kelly JDCell Cycle 2008[Nov]; 7 (22): 3525-33Invasive urothelial cell carcinoma (UCC) is characterized by increased chromosomal instability and follows an aggressive clinical course in contrast to non-invasive disease. To identify molecular processes that confer and maintain an aggressive malignant phenotype, we used a high-throughput genome-wide approach to interrogate a cohort of high and low clinical risk UCC tumors. Differential expression analyses highlighted cohesive dysregulation of critical genes involved in the G(2)/M checkpoint in aggressive UCC. Hierarchical clustering based on DNA Damage Response (DDR) genes separated tumors according to a pre-defined clinical risk phenotype. Using array-comparative genomic hybridization, we confirmed that the DDR was disrupted in tumors displaying high genomic instability. We identified DNA copy number gains at 20q13.2-q13.3 (AURKA locus) and determined that overexpression of AURKA accompanied dysregulation of DDR genes in high risk tumors. We postulated that DDR-deficient UCC tumors are advantaged by a selective pressure for AURKA associated override of M phase barriers and confirmed this in an independent tissue microarray series. This mechanism that enables cancer cells to maintain an aggressive phenotype forms a rationale for targeting AURKA as a therapeutic strategy in advanced stage UCC.|*Gene Expression Regulation, Neoplastic[MESH]|Aurora Kinase A[MESH]|Aurora Kinases[MESH]|Cell Cycle Proteins/genetics[MESH]|Chromosomes, Human, Pair 20[MESH]|Cohort Studies[MESH]|DNA Repair/*genetics[MESH]|Gene Dosage[MESH]|Gene Expression Profiling[MESH]|Genomics[MESH]|Humans[MESH]|Neoplasm Invasiveness[MESH]|Phenotype[MESH]|Protein Serine-Threonine Kinases/*genetics[MESH]|Urologic Neoplasms/*genetics/*pathology[MESH]|Urothelium/pathology[MESH] |