title: Derivation of genetic biomarkers for cancer risk stratification in Barrett's oesophagus: a prospective cohort study.
abstract: The risk of developing adenocarcinoma in non-dysplastic Barrett's oesophagus is low and difficult to predict. Accurate tools for risk stratification are needed to increase the efficiency of surveillance. We aimed to develop a prediction model for progression using clinical variables and genetic markers.
  
  
  
  In a prospective cohort of patients with non-dysplastic Barrett's oesophagus, we evaluated six molecular markers: p16, p53, Her-2/neu, 20q, MYC and aneusomy by DNA fluorescence in situ hybridisation on brush cytology specimens. Primary study outcomes were the development of high-grade dysplasia or oesophageal adenocarcinoma. The most predictive clinical variables and markers were determined using Cox proportional-hazards models, receiver operating characteristic curves and a leave-one-out analysis.
  
  
  
  A total of 428 patients participated (345 men; median age 60 years) with a cumulative follow-up of 2019 patient-years (median 45 months per patient). Of these patients, 22 progressed; nine developed high-grade dysplasia and 13 oesophageal adenocarcinoma. The clinical variables, age and circumferential Barrett's length, and the markers, p16 loss, MYC gain and aneusomy, were significantly associated with progression on univariate analysis. We defined an 'Abnormal Marker Count' that counted abnormalities in p16, MYC and aneusomy, which significantly improved risk prediction beyond using just age and Barrett's length. In multivariate analysis, these three factors identified a high-risk group with an 8.7-fold (95% CI 2.6 to 29.8) increased HR when compared with the low-risk group, with an area under the curve of 0.76 (95% CI 0.66 to 0.86).
  
  
  
  A prediction model based on age, Barrett's length and the markers p16, MYC and aneusomy determines progression risk in non-dysplastic Barrett's oesophagus.
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Centre-University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Margriet R
authors.initials: MR
authors.lastname: Timmer
authors.affiliation: Evolution and Cancer Laboratory, Centre for Tumour Biology, Barts Cancer Institute, London, UK.
authors.forename: Pierre
authors.initials: P
authors.lastname: Martinez
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Centre-University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Chiu T
authors.initials: CT
authors.lastname: Lau
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Centre-University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Wytske M
authors.initials: WM
authors.lastname: Westra
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Centre-University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Silvia
authors.initials: S
authors.lastname: Calpe
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Centre-University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Agnieszka M
authors.initials: AM
authors.lastname: Rygiel
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Centre-University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Wilda D
authors.initials: WD
authors.lastname: Rosmolen
authors.affiliation: Department of Pathology, Academic Medical Centre-University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Sybren L
authors.initials: SL
authors.lastname: Meijer
authors.affiliation: Department of Pathology, Academic Medical Centre-University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Fiebo J W
authors.initials: FJ
authors.lastname: Ten Kate
authors.affiliation: Clinical Research Unit, Academic Medical Centre-University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Marcel G W
authors.initials: MG
authors.lastname: Dijkgraaf
authors.affiliation: Department of Gastroenterology, Flevoziekenhuis, Almere, The Netherlands.
authors.forename: Rosalie C
authors.initials: RC
authors.lastname: Mallant-Hent
authors.affiliation: Department of Gastroenterology, Tergooiziekenhuizen, Hilversum, The Netherlands.
authors.forename: Anton H J
authors.initials: AH
authors.lastname: Naber
authors.affiliation: Department of Gastroenterology, Medisch Centrum Alkmaar, Alkmaar, The Netherlands.
authors.forename: Arnoud H A M
authors.initials: AH
authors.lastname: van Oijen
authors.affiliation: Department of Gastroenterology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.
authors.forename: Lubbertus C
authors.initials: LC
authors.lastname: Baak
authors.affiliation: Department of Gastroenterology, Sint Lucas Andreas Ziekenhuis, Amsterdam, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Scholten
authors.affiliation: Department of Gastroenterology, Spaarne Ziekenhuis, Hoofddorp, The Netherlands.
authors.forename: Clarisse J M
authors.initials: CJ
authors.lastname: Böhmer
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Centre-University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: Fockens
authors.affiliation: Centre for Evolution and Cancer, University of California at San Francisco, San Francisco, California, USA.
authors.forename: Carlo C
authors.initials: CC
authors.lastname: Maley
authors.affiliation: Evolution and Cancer Laboratory, Centre for Tumour Biology, Barts Cancer Institute, London, UK.
authors.forename: Trevor A
authors.initials: TA
authors.lastname: Graham
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Centre-University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jacques J G H M
authors.initials: JJ
authors.lastname: Bergman
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Centre-University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Kausilia K
authors.initials: KK
authors.lastname: Krishnadath
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000209:etiology / Q000235:genetics / Q000473:pathology; D000367:Age Factors; D001471:Barrett Esophagus / Q000150:complications / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D043171:Chromosomal Instability; D015331:Cohort Studies; D018450:Disease Progression; D004724:Endoscopy / Q000379:methods; D004938:Esophageal Neoplasms / Q000175:diagnosis / Q000209:etiology / Q000235:genetics / Q000473:pathology; D004947:Esophagus / Q000473:pathology*; D005260:Female; D016259:Genes, myc; D019942:Genes, p16; D005819:Genetic Markers; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment / Q000379:methods*
chemical_list: D005819:Genetic Markers
keywords: BARRETT'S OESOPHAGUS; CANCER GENETICS; ENDOSCOPY; OESOPHAGEAL CANCER; SURVEILLANCE