title: Analysis of dysplasia in patients with Barrett's esophagus based on expression pattern of 90 genes.
abstract: OBJECTIVE
  Diagnoses of dysplasia, based on histologic analyses, dictate management decisions for patients with Barrett's esophagus (BE). However, there is much intra- and inter-observer variation in identification of dysplasia-particularly low-grade dysplasia. We aimed to identify a biomarker that could be used to assign patients with low-grade dysplasia to a low- or high-risk group.
  
  
  METHODS
  We performed a stringent histologic assessment of 150 frozen esophageal tissues samples collected from 4 centers in the United Kingdom (from 2000 through 2006). The following samples with homogeneous diagnoses were selected for gene expression profiling: 28 from patients with nondysplastic BE, 10 with low-grade dysplasia, 13 with high-grade dysplasia (HGD), and 8 from patients with esophageal adenocarcinoma. A leave-one-out cross-validation analysis was used identify a gene expression signature associated with HGD vs nondysplastic BE. Functional pathways associated with gene signature sets were identified using the MetaCore analysis. Gene expression signature sets were validated using gene expression data on BE and esophageal adenocarcinoma accessed through National Center for Biotechnology Information Gene Expression Omnibus, as well as a separate set of samples (n = 169) collected from patients who underwent endoscopy in the United Kingdom or the Netherlands and analyzed histologically.
  
  
  RESULTS
  We identified an expression pattern of 90 genes that could separate nondysplastic BE tissues from those with HGD (P < .0001). Genes in a pathway regulated by retinoic acid-regulated nuclear protein made the largest contribution to this gene set (P < .0001); the transcription factor MYC regulated at least 30% of genes within the signature (P < .0001). In the National Center for Biotechnology Information Gene Expression Omnibus validation set, the signature separated nondysplastic BE samples from esophageal adenocarcinoma samples (P = .0012). In the UK and Netherlands validation cohort, the signature identified dysplastic tissues with an area under the curve value of 0.87 (95% confidence interval: 0.82-0.93). Of samples with low-grade dysplasia (LGD), 64% were considered high risk according to the 90-gene signature; these patients had a higher rate of disease progression than those with a signature categorized as low risk (P = .047).
  
  
  CONCLUSIONS
  We identified an expression pattern of 90 genes in esophageal tissues of patients with BE that was associated with low- or high-risk for disease progression. This pattern might be used in combination with histologic analysis of biopsy samples to stratify patients for treatment. It would be most beneficial for analysis of patients without definitive evidence of HGD but for whom early endoscopic intervention is warranted.
authors.affiliation: MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom.
authors.forename: Sibu
authors.initials: S
authors.lastname: Varghese
authors.affiliation: MRC Biostatistics Unit, Cambridge, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Newton
authors.affiliation: MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom.
authors.forename: Caryn S
authors.initials: CS
authors.lastname: Ross-Innes
authors.affiliation: MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lao-Sirieix
authors.affiliation: Amsterdam Medical Center, Amsterdam, Netherlands.
authors.forename: Kausilia K
authors.initials: KK
authors.lastname: Krishnadath
authors.affiliation: MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: O'Donovan
authors.affiliation: GI Services, University College Hospital, NHS Foundation Trust, London, United Kingdom.
authors.forename: Marco
authors.initials: M
authors.lastname: Novelli
authors.affiliation: MRC Biostatistics Unit, Cambridge, United Kingdom.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Wernisch
authors.affiliation: Amsterdam Medical Center, Amsterdam, Netherlands.
authors.forename: Jacques
authors.initials: J
authors.lastname: Bergman
authors.affiliation: MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom. Electronic address: rcf29@mrc-cu.cam.ac.uk.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fitzgerald
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D000368:Aged; D001471:Barrett Esophagus / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism*; D001706:Biopsy; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D004945:Esophagoscopy; D004947:Esophagus / Q000378:metabolism / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D006113:United Kingdom
chemical_list: D015415:Biomarkers
keywords: Biomarker; Detection; Diagnostic; Esophageal Cancer