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Invasive 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.

Original publication

DOI

10.4161/cc.7.22.7042

Type

Journal article

Journal

Cell Cycle

Publication Date

15/11/2008

Volume

7

Pages

3525 - 3533

Keywords

Aurora Kinase A, Aurora Kinases, Cell Cycle Proteins, Chromosomes, Human, Pair 20, Cohort Studies, DNA Repair, Gene Dosage, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genomics, Humans, Neoplasm Invasiveness, Phenotype, Protein-Serine-Threonine Kinases, Urologic Neoplasms, Urothelium