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

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Published on August 4, 2007

Author: ikovic

Source: slideshare.net

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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

Identification of Barrett’s esophagus patients at higher risk for adenocarcinoma development Ileana Lulic, Ivor Kovic

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

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%

Progression Squamous esophageal epithelium Intestinal metaplasia Dysplasia Esophageal adenocarcinoma

Progression Squamous esophageal epithelium GERD Intestinal metaplasia Dysplasia Esophageal adenocarcinoma

Progression Squamous esophageal epithelium Obesity Diet ? GERD Tobacco Alcohol Bacteria Intestinal metaplasia Dysplasia Esophageal adenocarcinoma

Progression Squamous esophageal epithelium Obesity Diet ? GERD Tobacco Alcohol Bacteria Intestinal metaplasia Dysplasia Low grade High grade Esophageal adenocarcinoma

Diagnosis Normal Metaplasia Adenocarcinoma Endoscopy Pathology

Diagnosis Normal Metaplasia Adenocarcinoma Endoscopy Pathology http://www.gastrointestinalatlas.com/

Diagnosis Normal Metaplasia Adenocarcinoma Endoscopy Pathology

Surveillance problems Endoscopy Pathology • • Intra-observer variability Difficulty of identifying early neoplastic lesions • Inter-observer variability • Sampling errors • Expensive and time consuming

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

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

Genetic markers p16/9p-loss p53/17p-loss Y chromosome loss Aneuploidy/tetraploidy Losses - 3p, 4p, 7q, 12q,17q Gains – 2p, 8q, 20q

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

Genetic markers p16/9p-loss p53/17p-loss Y chromosome loss Aneuploidy/tetraploidy Losses - 3p, 4p, 7q, 12q,17q Gains – 2p, 8q, 20q

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

Procedure Image cytometry Brush cytology Slides preparation FISH

FISH • Fluorescent probe • Fluorescent microscopy

FISH • Numerical chromosomal changes: aneuploidy • Locus specific losses: tumor suppressor genes • Amplifications: oncogenes and growth factor

Image cytometry • DNA ploidy analysis • Aneuploidy – from 2N to 4N, DNA index • Measurement of optical density

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

Image cytometry results

Image cytometry results

Results LGD HGD 6 5 4 3 2 1 0 Cep 1 gain p16 loss p53 loss

Results from 151 patients (n=114) (n=24) (n=13)

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

Agnieszka Rygiel Francesca Milano Sheila Krishnadath Wendy Bruins Willemijn van Dop

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