PMID- 18812553 OWN - NLM STAT- MEDLINE DCOM- 20081022 LR - 20211203 IS - 1460-2105 (Electronic) IS - 0027-8874 (Print) IS - 0027-8874 (Linking) VI - 100 IP - 19 DP - 2008 Oct 1 TI - Quantitation of Aurora kinase A gene copy number in urine sediments and bladder cancer detection. PG - 1401-11 LID - 10.1093/jnci/djn304 [doi] AB - BACKGROUND: Chromosome missegregation and the resulting aneuploidy is a common change in neoplasia. The Aurora kinase A (AURKA) gene, which encodes a key regulator of mitosis, is frequently amplified and/or overexpressed in cancer cells, and the level of AURKA amplification is associated with the level of aneuploidy. We examined whether AURKA gene amplification is a biomarker for the detection of bladder cancer. METHODS: The effect of ectopic expression of Aurora kinase A (AURKA) using an adenoviral vector in simian virus 40-immortalized urothelial cells (SV-HUC) on centrosome multiplication and chromosome copy number was measured in vitro by immunofluorescence and fluorescence in situ hybridization (FISH), respectively. The FISH test was also used to examine AURKA gene copy number in exfoliated cells in voided urine samples from 23 patients with bladder cancer and 7 healthy control subjects (training set), generating a model for bladder cancer detection that was subsequently validated in an independent set of voided urine samples from 100 bladder cancer patients and 148 control subjects (92 healthy individuals and 56 patients with benign urologic disorders). An AURKA gene score (the proportion of cells with three or more AURKA signals) was used to produce receiver operating characteristic (ROC) curves and to calculate the specificity and sensitivity of the AURKA FISH test. Differences between mean AURKA scores in different pathogenetic groups of bladder cancer stratified according to histological grade and stage were tested by unpaired Mann-Whitney t tests or one-way Wilcoxon tests. All statistical tests were two-sided. RESULTS: Forced overexpression of AURKA in urothelial cells induced amplification of centrosomes, chromosome missegregation, and aneuploidy, and natural overexpression was detectable in in situ lesions from patients with bladder cancer. The FISH test for the AURKA gene copy number performed on the validation set yielded a specificity of 96.6% (95% confidence interval [CI] = 92.3% to 98.5%) and sensitivity of 87% (95% CI = 79.0% to 92.2%) and an area under the ROC curve of 0.939 (95% CI = 0.906 to 0.971; P < .001). CONCLUSION: Overexpression of AURKA can cause aneuploidy in urothelial cells, and the AURKA gene copy number is a promising biomarker for detection of bladder cancer. FAU - Park, Hong-Seok AU - Park HS AD - Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. FAU - Park, Weon Seo AU - Park WS FAU - Bondaruk, Jolanta AU - Bondaruk J FAU - Tanaka, Noriyoshi AU - Tanaka N FAU - Katayama, Hiroshi AU - Katayama H FAU - Lee, Sangkyou AU - Lee S FAU - Spiess, Philippe E AU - Spiess PE FAU - Steinberg, Jordan R AU - Steinberg JR FAU - Wang, Zhi AU - Wang Z FAU - Katz, Ruth L AU - Katz RL FAU - Dinney, Colin AU - Dinney C FAU - Elias, Keren J AU - Elias KJ FAU - Lotan, Yair AU - Lotan Y FAU - Naeem, Rizwan C AU - Naeem RC FAU - Baggerly, Keith AU - Baggerly K FAU - Sen, Subrata AU - Sen S FAU - Grossman, H Barton AU - Grossman HB FAU - Czerniak, Bogdan AU - Czerniak B LA - eng GR - U01CA85078/CA/NCI NIH HHS/United States GR - R01 CA89716/CA/NCI NIH HHS/United States GR - R01CA066723/CA/NCI NIH HHS/United States GR - P50CA91846/CA/NCI NIH HHS/United States GR - R01 CA151489/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20080923 PL - United States TA - J Natl Cancer Inst JT - Journal of the National Cancer Institute JID - 7503089 RN - 0 (Biomarkers, Tumor) RN - 0 (DNA, Neoplasm) RN - 147336-22-9 (Green Fluorescent Proteins) RN - EC 2.7.11.1 (AURKA protein, human) RN - EC 2.7.11.1 (Aurora Kinase A) RN - EC 2.7.11.1 (Aurora Kinases) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) SB - IM EIN - J Natl Cancer Inst. 2008 Dec 3;100(23):1740 MH - *Aneuploidy MH - Aurora Kinase A MH - Aurora Kinases MH - Biomarkers, Tumor/*genetics/urine MH - Carcinoma in Situ/diagnosis/genetics MH - Carcinoma, Transitional Cell/*diagnosis/enzymology/*genetics/surgery/urine MH - Cell Line, Tumor MH - Cystectomy MH - DNA, Neoplasm/genetics/urine MH - Diagnosis, Differential MH - Gene Amplification MH - Gene Expression Regulation, Neoplastic MH - Green Fluorescent Proteins MH - Humans MH - Immunohistochemistry MH - In Situ Hybridization, Fluorescence MH - Protein Serine-Threonine Kinases/*genetics/urine MH - Reverse Transcriptase Polymerase Chain Reaction MH - Sensitivity and Specificity MH - Transfection MH - Up-Regulation MH - Urinary Bladder Neoplasms/*diagnosis/enzymology/*genetics/surgery/urine PMC - PMC2720731 EDAT- 2008/09/25 09:00 MHDA- 2008/10/23 09:00 PMCR- 2009/10/01 CRDT- 2008/09/25 09:00 PHST- 2008/09/25 09:00 [pubmed] PHST- 2008/10/23 09:00 [medline] PHST- 2008/09/25 09:00 [entrez] PHST- 2009/10/01 00:00 [pmc-release] AID - djn304 [pii] AID - 10.1093/jnci/djn304 [doi] PST - ppublish SO - J Natl Cancer Inst. 2008 Oct 1;100(19):1401-11. doi: 10.1093/jnci/djn304. Epub 2008 Sep 23.