AURKA overexpression accompanies dysregulation of DNA-damage response genes in invasive urothelial cell carcinoma.
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.
Veerakumarasivam
Abhi
A
University of Cambridge, Department of Oncology, Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.
Goldstein
Leonard D
LD
Saeb-Parsy
Kasra
K
Scott
Helen E
HE
Warren
Anne
A
Thorne
Natalie P
NP
Mills
Ian G
IG
Venkitaraman
Ashok
A
Neal
David E
DE
Kelly
John D
JD
D064096:Aurora Kinase A; D064127:Aurora Kinases; D018797:Cell Cycle Proteins / Q000235:genetics; D002890:Chromosomes, Human, Pair 20; D015331:Cohort Studies; D004260:DNA Repair / Q000235:genetics*; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D009361:Neoplasm Invasiveness; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D014571:Urologic Neoplasms / Q000235:genetics* / Q000473:pathology*; D019459:Urothelium / Q000473:pathology
D018797:Cell Cycle Proteins; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases