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Identification of Barrett’s esophagus patients at higher risk for adenocarcinoma development

Final presentation given by Ileana Lulic and Ivor Kovic at the end of Scientific research in gastro-intestinal & liver diseases
Sunday, July 8 - Friday, August 3, 2007
Amsterdam, Academisch Medisch Centrum

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Identification of Barrett’s esophagus patients at higher risk for adenocarcinoma development

  1. 1. Identification of Barrett’s esophagus patients at higher risk for adenocarcinoma development Ileana Lulic, Ivor Kovic
  2. 2. Definition “... a change in the esophageal epithelium of any length that can be recognized at endoscopy and is confirmed to have intestinal metaplasia by biopsy ...” American College of Gastroenterology
  3. 3. Characteristics • Caucasian males – middle age • Rapidly rising incidence in Western countries • Around 150x higher risk of esophageal adenocarcinoma compared to general population • 0.5% of BE patients will develop EAC • Overall survival rate of EAC = 20-25%
  4. 4. Progression Squamous esophageal epithelium Intestinal metaplasia Dysplasia Esophageal adenocarcinoma
  5. 5. Progression Squamous esophageal epithelium GERD Intestinal metaplasia Dysplasia Esophageal adenocarcinoma
  6. 6. Progression Squamous esophageal epithelium Obesity Diet ? GERD Tobacco Alcohol Bacteria Intestinal metaplasia Dysplasia Esophageal adenocarcinoma
  7. 7. Progression Squamous esophageal epithelium Obesity Diet ? GERD Tobacco Alcohol Bacteria Intestinal metaplasia Dysplasia Low grade High grade Esophageal adenocarcinoma
  8. 8. Diagnosis Normal Metaplasia Adenocarcinoma Endoscopy Pathology
  9. 9. Diagnosis Normal Metaplasia Adenocarcinoma Endoscopy Pathology http://www.gastrointestinalatlas.com/
  10. 10. Diagnosis Normal Metaplasia Adenocarcinoma Endoscopy Pathology
  11. 11. Surveillance problems Endoscopy Pathology • • Intra-observer variability Difficulty of identifying early neoplastic lesions • Inter-observer variability • Sampling errors • Expensive and time consuming
  12. 12. Surveillance problems Endoscopy Pathology • • Intra-observer variability Difficulty of identifying early neoplastic lesions • Inter-observer variability • Sampling errors • Expensive and time consuming Questionable cost-effectiveness
  13. 13. Potential of genetic markers • Prediction of risk for disease progression in endoscopic surveillance program • Early detection of high grade dysplasia and invasive adenocarcinoma • Staging and prognosis • Prediction of chemosensitivity • Novel targets for anticancer therapies
  14. 14. Genetic markers p16/9p-loss p53/17p-loss Y chromosome loss Aneuploidy/tetraploidy Losses - 3p, 4p, 7q, 12q,17q Gains – 2p, 8q, 20q
  15. 15. Genetic markers p16/9p-loss No dysplasia p53/17p-loss Low grade dysplasia Y chromosome loss Aneuploidy/tetraploidy High grade dysplasia Losses - 3p, 4p, 7q, 12q,17q Esophageal adenocarcinoma Gains – 2p, 8q, 20q
  16. 16. Genetic markers p16/9p-loss p53/17p-loss Y chromosome loss Aneuploidy/tetraploidy Losses - 3p, 4p, 7q, 12q,17q Gains – 2p, 8q, 20q
  17. 17. Genetic markers p16/9p-loss Fluorescent in situ hybridization p53/17p-loss Y chromosome loss Image cytometry Aneuploidy/tetraploidy Losses - 3p, 4p, 7q, 12q,17q Gains – 2p, 8q, 20q
  18. 18. Procedure Image cytometry Brush cytology Slides preparation FISH
  19. 19. FISH • Fluorescent probe • Fluorescent microscopy
  20. 20. FISH • Numerical chromosomal changes: aneuploidy • Locus specific losses: tumor suppressor genes • Amplifications: oncogenes and growth factor
  21. 21. Image cytometry • DNA ploidy analysis • Aneuploidy – from 2N to 4N, DNA index • Measurement of optical density
  22. 22. FISH results Cep1 p16 p53 Patient Hystology loss gain loss gain loss gain + + 1 LGD + 2 LGD + + + 3 HGD + + 4 HGD + + + 5 HGD + + 6 HGD Total 2 3 5 0 3 0
  23. 23. Image cytometry results
  24. 24. Image cytometry results
  25. 25. Results LGD HGD 6 5 4 3 2 1 0 Cep 1 gain p16 loss p53 loss
  26. 26. Results from 151 patients (n=114) (n=24) (n=13)
  27. 27. Conclusion • p53 loss and aneuploidy are promising markers for dysplasia development in BE • Ongoing follow up study to demonstrate the true predictive value of these markers
  28. 28. Agnieszka Rygiel Francesca Milano Sheila Krishnadath Wendy Bruins Willemijn van Dop

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