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Cyclin-dependent kinase 4 overexpression is mostly independent of gene amplification and constitutes an independent prognosticator for nasopharyngeal carcinoma

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Tumor Biology

Abstract

Data mining in the public domain demonstrates that cyclin-dependent kinase 4 (CDK4) is highly expressed in nasopharyngeal carcinomas (NPC). Associated with cyclin-D, CDK4 phosphorylates and inactivates retinoblastoma (Rb) protein family members and mediates progression through the G1- to the S-phase of the cell cycle. Amplification and overexpression of CDK4 has been identified in various human malignancies. However, its expression and amplification has never been systemically evaluated in NPC. This study aimed to evaluate the amplification and expression status, correlation with clinicopathological features, and prognostic implications of CDK4 based on public domain dataset and in our well-defined cohort of NPC patients. The association between CDK4 transcript level and gene dosage was explored by analysis of an independent public domain dataset. We retrospectively assessed CDK4 immunoexpression in biopsies of 124 consecutive NPC patients devoid of initial distant metastasis and treated according to consistent guidelines. The results were correlated with clinicopathological features, local recurrence-free survival (LRFS), distant metastasis-free survival (DMeFS), and disease-specific survival (DSS). High levels of CDK4 protein were positively correlated with the T 3, 4 status (p = 0.024); N 2, 3 status (p < 0.001); and the American Joint Committee on Cancer stage 3, 4 (p < 0.001). Multivariate analysis suggested high CDK4 expression was an independent prognostic indicator of worse DMeFS (p = 0.001, hazard ratio (HR) = 3.226) and DSS (p = 0.037, HR = 1.838). Although CDK4 is frequently upregulated, its gene locus is very uncommonly amplified in NPC. CDK4 overexpression is mostly independent with gene amplification and represents a potential prognostic biomarker in NPC and may indicate tumor aggressiveness through cell cycle dysregulation.

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Abbreviations

NPC:

Nasopharyngeal carcinoma

EBV:

Epstein-Barr virus

WHO:

World Health Organization

CDK4:

Cyclin-dependent kinase 4

Rb:

Retinoblastoma

LRFS:

Local recurrence-free survival

DMeFS:

Distant metastasis-free survival

DSS:

Disease-specific survival

RT:

Radiotherapy

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Acknowledgements

This study is supported by Chi Mei Medical Center (CMFHR10303) and the Ministry of Health and Welfare (MOHW103-TD-B-111-05).

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Department of Pathology, Chi-Mei Foundation Medical Center, Tainan, Taiwan

    Tzu-Ju Chen & Chien-Feng Li

  2. Department of Radiation Oncology, Chi-Mei Medical Center, Liouying, Tainan, Taiwan

    Sung-Wei Lee

  3. Department of Radiation Oncology, Chi-Mei Medical Center, Tainan, Taiwan

    Li-Ching Lin

  4. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi-Mei Foundation Medical Center, Tainan, Taiwan

    Ching-Yih Lin

  5. Department of Leisure, Recreation, and Tourism Management, Southern Taiwan University of Science and Technology, Tainan, Taiwan

    Ching-Yih Lin

  6. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan

    Kwang-Yu Chang & Chien-Feng Li

  7. Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan

    Chien-Feng Li

  8. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Chien-Feng Li

Authors
  1. Tzu-Ju Chen
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  2. Sung-Wei Lee
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  3. Li-Ching Lin
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  4. Ching-Yih Lin
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Correspondence to Chien-Feng Li.

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Chen, TJ., Lee, SW., Lin, LC. et al. Cyclin-dependent kinase 4 overexpression is mostly independent of gene amplification and constitutes an independent prognosticator for nasopharyngeal carcinoma. Tumor Biol. 35, 7209–7216 (2014). https://doi.org/10.1007/s13277-014-1884-2

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  • DOI: https://doi.org/10.1007/s13277-014-1884-2

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