AURKA overexpression accompanies dysregulation of DNA-damage response genes in invasive urothelial cell carcinoma

Abhi Veerakumarasivam, Leonard D Goldstein, Kasra Saeb-Parsy, Helen E Scott, Anne Warren, Natalie P Thorne, Ian G Mills, Ashok Venkitaraman, David E Neal, John D Kelly

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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 languageEnglish
Pages (from-to)3525-33
Number of pages9
JournalCell Cycle
Volume7
Issue number22
Publication statusPublished - 15 Nov 2008

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

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    Veerakumarasivam, A., Goldstein, L. D., Saeb-Parsy, K., Scott, H. E., Warren, A., Thorne, N. P., Mills, I. G., Venkitaraman, A., Neal, D. E., & Kelly, J. D. (2008). AURKA overexpression accompanies dysregulation of DNA-damage response genes in invasive urothelial cell carcinoma. Cell Cycle , 7(22), 3525-33.