title: Overexpression of CDT1 Is a Predictor of Poor Survival in Patients with Hepatocellular Carcinoma.
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.
authors.affiliation: Department of Surgery, University Hospital of Patras, Rio, 26500, Greece. dimitriskaravias@gmail.com.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Karavias
authors.affiliation: Department of Surgery, University Hospital of Patras, Rio, 26500, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Maroulis
authors.affiliation: Department of Anatomy, Histology and Embryology, School of Medicine, University of Patras, Rio, Greece.
authors.forename: Helen
authors.initials: H
authors.lastname: Papadaki
authors.affiliation: Department of Internal Medicine, University Hospital of Patras, Rio, Greece.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Gogos
authors.affiliation: Department of Vascular Surgery, University Hospital of Patras, Rio, Greece.
authors.forename: Stavros
authors.initials: S
authors.lastname: Kakkos
authors.affiliation: Department of Surgery, University Hospital of Patras, Rio, 26500, Greece.
authors.forename: Dionissios
authors.initials: D
authors.lastname: Karavias
authors.affiliation: Department of Anatomy, Histology and Embryology, School of Medicine, University of Patras, Rio, Greece.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Bravou
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000401:mortality* / Q000601:surgery; D018797:Cell Cycle Proteins / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000382:microbiology* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D064168:Minichromosome Maintenance Complex Component 7 / Q000378:metabolism*; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; D064168:Minichromosome Maintenance Complex Component 7
keywords: CDT1; Hepatocellular carcinoma; MCM7