title: The Presence of Genetic Mutations at Key Loci Predicts Progression to Esophageal Adenocarcinoma in Barrett's Esophagus.
abstract: OBJECTIVE
  Risk stratification in Barrett's esophagus (BE) is challenging. We evaluated the ability of a panel of genetic markers to predict progression to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC).
  
  
  METHODS
  In this case-control study, we assessed a measure of genetic instability, the mutational load (ML), in predicting progression to HGD or EAC. Cases had nondysplastic BE or low-grade dysplasia (LGD) at baseline and developed HGD/EAC ≥1 year later. Controls were matched 2:1, had nondysplastic BE or LGD, and no progression at follow-up. Formalin-fixed, paraffin-embedded tissue was microdissected for the epithelium. Loss of heterozygosity (LOH) and microsatellite instability (MSI) were assessed. ML was calculated from derangements in 10 genomic loci. High-clonality LOH mutations were assigned a value of 1, low-clonality mutations were assigned a value of 0.5, and MSI 0.75 at the first loci, and 0.5 for additional loci. These values were summed to the ML. Receiver operator characteristic (ROC) curves were created.
  
  
  RESULTS
  There were 69 patients (46 controls and 23 cases). Groups were similar in age, follow-up time, baseline histology, and the number of microdissected targets. Mean ML in pre-progression biopsies was higher in cases (2.21) than in controls (0.42; P<0.0001). Sensitivity was 100% at ML ≥0.5 and specificity was 96% at ML ≥1.5. Accuracy was highest at 89.9% for ML ≥1. ROC curves for ML ≥1 demonstrated an area under the curve (AUC) of 0.95.
  
  
  CONCLUSIONS
  ML in pre-progression BE tissue predicts progression to HGD or EAC. Although further validation is necessary, ML may have utility as a biomarker in endoscopic surveillance of BE.
authors.affiliation: Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Swathi
authors.initials: S
authors.lastname: Eluri
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Brugge
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Ebubekir S
authors.initials: ES
authors.lastname: Daglilar
authors.affiliation: Interpace Diagnostics Corporation, Pittsburgh, Pennsylvania, USA.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Jackson
authors.affiliation: Interpace Diagnostics Corporation, Pittsburgh, Pennsylvania, USA.
authors.forename: Mindi A
authors.initials: MA
authors.lastname: Styn
authors.affiliation: Interpace Diagnostics Corporation, Pittsburgh, Pennsylvania, USA.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Callenberg
authors.affiliation: Pathgroup, Brentwood, Tennessee, USA.
authors.forename: Derek C
authors.initials: DC
authors.lastname: Welch
authors.affiliation: Department of Pathology and Laboratory Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Barr
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Lucas C
authors.initials: LC
authors.lastname: Duits
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Jacques J
authors.initials: JJ
authors.lastname: Bergman
authors.affiliation: Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Shaheen
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D001471:Barrett Esophagus / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics*; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D012372:ROC Curve