title: Aneuploidy and overexpression of Ki67 and p53 as markers for neoplastic progression in Barrett's esophagus: a case-control study.
abstract: OBJECTIVE
  Surveillance of patients with Barrett's esophagus (BE) aims at early detection and treatment of neoplastic changes, particularly esophageal adenocarcinoma (EAC). The histological evaluation of biopsy samples has its limitations, and biomarkers may improve early identification of BE patients at risk for progression to EAC. The aim of this study was to determine the predictive value of p53, Ki67, and aneuploidy as markers of neoplastic progression in BE.
  
  
  METHODS
  A total of 27 BE patients with histologically proven progression to high-grade dysplasia (HGD) or EAC (cases) and 27 BE patients without progression (controls) were selected and matched for age, gender, and duration of follow-up. Dysplasia grade was determined in 212 biopsy samples obtained during surveillance endoscopies from cases and in 231 biopsy samples collected from controls. DNA ploidy status was determined by flow cytometry, whereas Ki67 and p53 expression was determined by immunohistochemistry. Hazard ratios (HRs) were calculated by Cox regression adjusted for potentially confounding variables.
  
  
  RESULTS
  A univariate analysis showed that low-grade dysplasia (LGD) increased the risk of developing HGD/EAC compared with no dysplasia (HR 3.6; 95% confidence interval (CI): 1.6 - 8.1). Aneuploidy (HR 3.5; 95% CI: 1.3-9.4), strong Ki67 overexpression (HR 5.2; 95% CI: 1.5-17.6), and moderate p53 overexpression (HR 6.5; 95% CI: 2.5-17.1) were also associated with an increased risk of developing HGD/EAC, independent of the histological result. A multivariable analysis showed that in the presence of LGD, p53 overexpression, and to a lesser extent, Ki67 overexpression remained important risk factors for neoplastic progression, whereas aneuploidy was no longer predictive.
  
  
  CONCLUSIONS
  p53 overexpression and, to a lesser extent, Ki67 overexpression could predict neoplastic progression in BE irrespective of the histological result. These markers may be useful for identifying patients at an increased risk of developing EAC, either alone or used as a panel.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands. m.sikkema@erasmusmc.nl
authors.forename: Marjolein
authors.initials: M
authors.lastname: Sikkema
authors.forename: Marjon
authors.initials: M
authors.lastname: Kerkhof
authors.forename: Ewout W
authors.initials: EW
authors.lastname: Steyerberg
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Kusters
authors.forename: Paulina M H
authors.initials: PM
authors.lastname: van Strien
authors.forename: Caspar W N
authors.initials: CW
authors.lastname: Looman
authors.forename: Herman
authors.initials: H
authors.lastname: van Dekken
authors.forename: Peter D
authors.initials: PD
authors.lastname: Siersema
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Kuipers
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000782:Aneuploidy; D001471:Barrett Esophagus / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000032:analysis; D001707:Biopsy, Needle; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004945:Esophagoscopy / Q000379:methods; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011230:Precancerous Conditions / Q000473:pathology*; D011336:Probability; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D016159:Tumor Suppressor Protein p53