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Original article
Derivation of genetic biomarkers for cancer risk stratification in Barrett’s oesophagus: a prospective cohort study
  1. Margriet R Timmer1,
  2. Pierre Martinez2,
  3. Chiu T Lau1,
  4. Wytske M Westra1,
  5. Silvia Calpe1,
  6. Agnieszka M Rygiel1,
  7. Wilda D Rosmolen1,
  8. Sybren L Meijer3,
  9. Fiebo J W ten Kate3,
  10. Marcel G W Dijkgraaf4,
  11. Rosalie C Mallant-Hent5,
  12. Anton H J Naber6,
  13. Arnoud H A M van Oijen7,
  14. Lubbertus C Baak8,
  15. Pieter Scholten9,
  16. Clarisse J M Böhmer10,
  17. Paul Fockens1,
  18. Carlo C Maley11,
  19. Trevor A Graham2,
  20. Jacques J G H M Bergman1,
  21. Kausilia K Krishnadath1
  1. 1Department of Gastroenterology and Hepatology, Academic Medical Centre—University of Amsterdam, Amsterdam, The Netherlands
  2. 2Evolution and Cancer Laboratory, Centre for Tumour Biology, Barts Cancer Institute, London, UK
  3. 3Department of Pathology, Academic Medical Centre—University of Amsterdam, Amsterdam, The Netherlands
  4. 4Clinical Research Unit, Academic Medical Centre—University of Amsterdam, Amsterdam, The Netherlands
  5. 5Department of Gastroenterology, Flevoziekenhuis, Almere, The Netherlands
  6. 6Department of Gastroenterology, Tergooiziekenhuizen, Hilversum, The Netherlands
  7. 7Department of Gastroenterology, Medisch Centrum Alkmaar, Alkmaar, The Netherlands
  8. 8Department of Gastroenterology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
  9. 9Department of Gastroenterology, Sint Lucas Andreas Ziekenhuis, Amsterdam, The Netherlands
  10. 10Department of Gastroenterology, Spaarne Ziekenhuis, Hoofddorp, The Netherlands
  11. 11Centre for Evolution and Cancer, University of California at San Francisco, San Francisco, California, USA
  1. Correspondence to Dr Kausilia K Krishnadath, Department of Gastroenterology and Hepatology, Academic Medical Centre Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands; k.k.krishnadath{at}


Objective 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.

Methods 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.

Results 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).

Conclusions 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.


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