Nuclear Overexpression of Mitotic Regulatory Proteins in Biliary Tract Cancer: Correlation with Clinicopathologic Features and Patient Survival

  1. Ying-Chun Shen1,2,3,4,
  2. Fu-Chang Hu2,
  3. Yung-Ming Jeng5,
  4. Yu-Ting Chang6,
  5. Zhong-Zhe Lin3,
  6. Ming-Chu Chang6,
  7. Chiun Hsu2,3,6 and
  8. Ann-Lii Cheng1,3,6,7
  1. 1Institute of Toxicology, College of Medicine, National Taiwan University; 2National Center of Excellence for Clinical Trial and Research and Departments of 3Oncology, 4Medical Research, 5Pathology, and 6Internal Medicine, National Taiwan University Hospital; 7Division of Cancer Research, National Health Research Institutes, Taipei, Taiwan
  1. Requests for reprints:
    Chiun Hsu or Ann-Lii Cheng, Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan 100. Phone: 886-2-2312-3456, ext. 67011; Fax: 886-2-2371-1174. E-mail: hsuchiun{at}gmail.com or alcheng{at}ntu.edu.tw

Abstract

Mitosis dysregulation is common in cancers. This study explored the nuclear expression patterns and prognostic significance of mitotic regulatory proteins, including Aurora kinases, survivin, and p53, in biliary tract cancer (BTC). Archival tumor samples from 161 BTC patients who underwent surgery were tested for the expression of Aurora-A, Aurora-B, survivin, and p53 by immunohistochemistry. The potential endogeneity among the clinicopathologic variables and survival outcome was assessed by a generalized simultaneous equations model. Nuclear overexpression of Aurora-A, Aurora-B, survivin, and p53 was found in 79 (49.1%), 45 (28.0%), 55 (34.2%), and 55 (34.2%) patients, respectively. Intrahepatic cholangiocarcinoma, compared with the other two subtypes, had significantly higher proportions of nuclear overexpression of Aurora-B and survivin (37.8% and 47.3%, respectively). Simultaneous overexpression of Aurora-A and Aurora-B was correlated with that of p53. Overexpression of Aurora-B was also correlated with that of survivin and tumor grade. Our data indicate that simultaneous overexpression of Aurora-A and Aurora-B, suggesting dysregulated mitosis is associated with worse survival in patients with BTC. Independent prognostic factors for poor overall survival included simultaneous overexpression of Aurora-A and Aurora-B (hazard ratio, 1.997; 95% confidence interval, 1.239-3.219; P = 0.0045) and tumor grade (hazard ratio, 2.117; 95% confidence interval, 1.339-3.348; P = 0.0013) assessed by a multivariate analysis stratified by American Joint Committee on Cancer stage and p53 overexpression. Endogeneity testing suggested that nuclear overexpression of p53 and tumor type may influence patient survival through their interactions with Aurora-A/Aurora-B expression and tumor grade. (Cancer Epidemiol Biomarkers Prev 2009;18(2):417–23)

Footnotes

  • Grant support: Ministry of Education, Taiwan grant 95R0066-BM01-02, National Science Council, Taiwan grant 96-3112-B-002-036, and Liver Disease Prevention and Treatment Research Foundation, Taiwan and New Century Health Care Promotion Foundation, Taiwan research grants.

  • Note: Supplementary data for this article are available at Cancer Epidemiology, Biomarkers & Prevention Online (http://cebp.aacrjournals.org/).

    • Accepted November 10, 2008.
    • Received July 29, 2008.
    • Revision received October 25, 2008.
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  1. Published OnlineFirst February 3, 2009; doi: 10.1158/1055-9965.EPI-08-0691 Cancer Epidemiology, Biomarkers & Prevention February 1, 2009 18, 417
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