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Overexpression of CDT1 Is a Predictor of Poor Survival in Patients with Hepatocellular Carcinoma

  • Original Article
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Journal of Gastrointestinal Surgery Aims and scope

Abstract

Background

Genomic instability is a common feature in hepatocellular carcinoma. Deregulation of replication licensing factors has been shown to trigger DNA damage response contributing to genomic instability. Overexpression of DNA replication licensing factors chromatin licensing and DNA replication factor 1 (CDT1) and minichromosome maintenance complex component 7 (MCM7) has been previously reported in several human cancers. The aim of the present study was to evaluate the expression and prognostic significance of CDT1 and MCM7 in association with DNA damage response markers and p53 in patients with hepatocellular carcinoma.

Methods

Expression of CDT1, MCM7, p-H2A histone family member X (H2AX), phospho-ataxia telangiectasia-mutated (ATM)/ataxia telangiectasia rad3-related (ATR) substrate, and p53 was evaluated by immunohistochemistry on formalin-fixed paraffin-embedded surgical specimens from 111 patients who underwent hepatectomy for hepatocellular carcinoma. Statistical analysis was performed to evaluate associations between the studied proteins, clinicopathological parameters, and patient survival.

Results

CDT1 expression correlated with p-H2AX (p = 0.038), while MCM7 correlated with p-H2AX and phospho-ATM/ATR substrate (p < 0.001). Increased CDT1 expression was associated with higher tumor grade (p = 0.006) and tumor-node-metastasis (TNM) stage (p = 0.033). High CDT1 expression correlated significantly with reduced overall survival (60.8 and 26.5 % vs 82.8 and 53.0 %, for low CDT1 expression, at 2 and 5 years, respectively, p = 0.012) and was identified by multivariate analysis as an independent predictor of poor overall survival (p = 0.049).

Conclusions

Overexpression of CDT1 and MCM7 in hepatocellular carcinoma correlates with DNA damage response, and CDT1 overexpression is a significant prognostic biomarker in hepatocellular carcinoma.

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Abbreviations

HCC:

Hepatocellular carcinoma

RLF:

Replication licensing factors

DDR:

DNA damage response

CDT1:

Chromatin licensing and DNA replication factor 1

MCM7:

Minichromosome maintenance complex component 7

H2AX:

H2A histone family member X

ATM:

Ataxia telangiectasia-mutated

ATR:

Ataxia telangiectasia rad3-related

TNM:

Tumor-node-metastasis

DSB:

Double-strand breaks

ORC:

Origin recognition complex

HBV:

Hepatitis B virus

HCV:

Hepatitis C virus

H-score:

Histoscore

ROC:

Receiver operating characteristics

AUC:

Area under ROC curve

IQR:

Interquartile range

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Acknowledgments

The authors would like to thank Nancy Mead, MSc, PhD for editing the manuscript and Georgios Lampropoulos, MD, PhD for his guidance and input during the statistical analysis.

Conflict of Interest

The authors do not have any disclosures to report.

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Authors and Affiliations

  1. Department of Surgery, University Hospital of Patras, Rio, 26500, Greece

    Dimitrios Karavias, Ioannis Maroulis & Dionissios Karavias

  2. Department of Anatomy, Histology and Embryology, School of Medicine, University of Patras, Rio, Greece

    Helen Papadaki & Vasiliki Bravou

  3. Department of Internal Medicine, University Hospital of Patras, Rio, Greece

    Charalambos Gogos

  4. Department of Vascular Surgery, University Hospital of Patras, Rio, Greece

    Stavros Kakkos

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  1. Dimitrios Karavias
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  2. Ioannis Maroulis
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Correspondence to Dimitrios Karavias.

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Karavias, D., Maroulis, I., Papadaki, H. et al. Overexpression of CDT1 Is a Predictor of Poor Survival in Patients with Hepatocellular Carcinoma. J Gastrointest Surg 20, 568–579 (2016). https://doi.org/10.1007/s11605-015-2960-7

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  • DOI: https://doi.org/10.1007/s11605-015-2960-7

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