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

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

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

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

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