Quantitation of Aurora kinase A gene copy number in urine sediments and bladder cancer detection

Hong Seok Park, Weon Seo Park, Jolanta Bondaruk, Noriyoshi Tanaka, Hiroshi Katayama, Sangkyou Lee, Philippe E. Spiess, Jordan R. Steinberg, Zhi Wang, Ruth L. Katz, Colin Dinney, Keren J. Elias, Yair Lotan, Rizwan C. Naeem, Keith Baggerly, Subrata Sen, H. Barton Grossman, Bogdan Czerniak

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1401-1411
Number of pages11
JournalJournal of the National Cancer Institute
Volume100
Issue number19
DOIs
StatePublished - Oct 2008

Fingerprint

Aurora Kinase A
Gene Dosage
Urinary Bladder Neoplasms
Urine
Aneuploidy
Fluorescence In Situ Hybridization
Centrosome
Chromosomes
Confidence Intervals
ROC Curve
Healthy Volunteers
Biomarkers
Simian virus 40
Gene Amplification

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Park, H. S., Park, W. S., Bondaruk, J., Tanaka, N., Katayama, H., Lee, S., ... Czerniak, B. (2008). Quantitation of Aurora kinase A gene copy number in urine sediments and bladder cancer detection. Journal of the National Cancer Institute, 100(19), 1401-1411. https://doi.org/10.1093/jnci/djn304

Quantitation of Aurora kinase A gene copy number in urine sediments and bladder cancer detection. / Park, Hong Seok; Park, Weon Seo; Bondaruk, Jolanta; Tanaka, Noriyoshi; Katayama, Hiroshi; Lee, Sangkyou; Spiess, Philippe E.; Steinberg, Jordan R.; Wang, Zhi; Katz, Ruth L.; Dinney, Colin; Elias, Keren J.; Lotan, Yair; Naeem, Rizwan C.; Baggerly, Keith; Sen, Subrata; Grossman, H. Barton; Czerniak, Bogdan.

In: Journal of the National Cancer Institute, Vol. 100, No. 19, 10.2008, p. 1401-1411.

Research output: Contribution to journalArticle

Park, HS, Park, WS, Bondaruk, J, Tanaka, N, Katayama, H, Lee, S, Spiess, PE, Steinberg, JR, Wang, Z, Katz, RL, Dinney, C, Elias, KJ, Lotan, Y, Naeem, RC, Baggerly, K, Sen, S, Grossman, HB & Czerniak, B 2008, 'Quantitation of Aurora kinase A gene copy number in urine sediments and bladder cancer detection', Journal of the National Cancer Institute, vol. 100, no. 19, pp. 1401-1411. https://doi.org/10.1093/jnci/djn304
Park, Hong Seok ; Park, Weon Seo ; Bondaruk, Jolanta ; Tanaka, Noriyoshi ; Katayama, Hiroshi ; Lee, Sangkyou ; Spiess, Philippe E. ; Steinberg, Jordan R. ; Wang, Zhi ; Katz, Ruth L. ; Dinney, Colin ; Elias, Keren J. ; Lotan, Yair ; Naeem, Rizwan C. ; Baggerly, Keith ; Sen, Subrata ; Grossman, H. Barton ; Czerniak, Bogdan. / Quantitation of Aurora kinase A gene copy number in urine sediments and bladder cancer detection. In: Journal of the National Cancer Institute. 2008 ; Vol. 100, No. 19. pp. 1401-1411.
@article{5ed7122a7aa1496ca7513d22289e7204,
title = "Quantitation of Aurora kinase A gene copy number in urine sediments and bladder cancer detection",
abstract = "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.",
author = "Park, {Hong Seok} and Park, {Weon Seo} and Jolanta Bondaruk and Noriyoshi Tanaka and Hiroshi Katayama and Sangkyou Lee and Spiess, {Philippe E.} and Steinberg, {Jordan R.} and Zhi Wang and Katz, {Ruth L.} and Colin Dinney and Elias, {Keren J.} and Yair Lotan and Naeem, {Rizwan C.} and Keith Baggerly and Subrata Sen and Grossman, {H. Barton} and Bogdan Czerniak",
year = "2008",
month = "10",
doi = "10.1093/jnci/djn304",
language = "English (US)",
volume = "100",
pages = "1401--1411",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
publisher = "Oxford University Press",
number = "19",

}

TY - JOUR

T1 - Quantitation of Aurora kinase A gene copy number in urine sediments and bladder cancer detection

AU - Park, Hong Seok

AU - Park, Weon Seo

AU - Bondaruk, Jolanta

AU - Tanaka, Noriyoshi

AU - Katayama, Hiroshi

AU - Lee, Sangkyou

AU - Spiess, Philippe E.

AU - Steinberg, Jordan R.

AU - Wang, Zhi

AU - Katz, Ruth L.

AU - Dinney, Colin

AU - Elias, Keren J.

AU - Lotan, Yair

AU - Naeem, Rizwan C.

AU - Baggerly, Keith

AU - Sen, Subrata

AU - Grossman, H. Barton

AU - Czerniak, Bogdan

PY - 2008/10

Y1 - 2008/10

N2 - 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.

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.

UR - http://www.scopus.com/inward/record.url?scp=53249129076&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=53249129076&partnerID=8YFLogxK

U2 - 10.1093/jnci/djn304

DO - 10.1093/jnci/djn304

M3 - Article

VL - 100

SP - 1401

EP - 1411

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 19

ER -