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Tumor Biology

, Volume 35, Issue 7, pp 7209–7216 | Cite as

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

  • Tzu-Ju Chen
  • Sung-Wei Lee
  • Li-Ching Lin
  • Ching-Yih Lin
  • Kwang-Yu Chang
  • Chien-Feng Li
Research Article

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.

Keywords

Nasopharyngeal carcinoma Transcriptome CDK4 Prognosis 

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

Notes

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

Supplementary material

13277_2014_1884_MOESM1_ESM.doc (51 kb)
Supplementary Table 1 (DOC 51 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Tzu-Ju Chen
    • 1
  • Sung-Wei Lee
    • 2
  • Li-Ching Lin
    • 3
  • Ching-Yih Lin
    • 4
    • 5
  • Kwang-Yu Chang
    • 6
  • Chien-Feng Li
    • 1
    • 6
    • 7
    • 8
  1. 1.Department of PathologyChi-Mei Foundation Medical CenterTainanTaiwan
  2. 2.Department of Radiation OncologyChi-Mei Medical Center, LiouyingTainanTaiwan
  3. 3.Department of Radiation OncologyChi-Mei Medical CenterTainanTaiwan
  4. 4.Division of Gastroenterology and Hepatology, Department of Internal MedicineChi-Mei Foundation Medical CenterTainanTaiwan
  5. 5.Department of Leisure, Recreation, and Tourism ManagementSouthern Taiwan University of Science and TechnologyTainanTaiwan
  6. 6.National Institute of Cancer ResearchNational Health Research InstitutesTainanTaiwan
  7. 7.Department of BiotechnologySouthern Taiwan University of Science and TechnologyTainanTaiwan
  8. 8.Graduate Institute of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan

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