title: The Discovery and Validation of Biomarkers for the Diagnosis of Esophageal Squamous Dysplasia and Squamous Cell Carcinoma.
abstract: The 5-year survival rate of esophageal cancer is less than 10% in developing countries, where more than 90% of these cancers are esophageal squamous cell carcinomas (ESCC). Endoscopic screening is undertaken in high incidence areas. Biomarker analysis could reduce the subjectivity associated with histologic assessment of dysplasia and thus improve diagnostic accuracy. The aims of this study were therefore to identify biomarkers for esophageal squamous dysplasia and carcinoma. A publicly available dataset was used to identify genes with differential expression in ESCC compared with normal esophagus. Each gene was ranked by a support vector machine separation score. Expression profiles were examined, before validation by qPCR and IHC. We found that 800 genes were overexpressed in ESCC compared with normal esophagus (P < 10(-5)). Of the top 50 genes, 33 were expressed in ESCC epithelium and not in normal esophagus epithelium or stroma using the Protein Atlas website. These were taken to qPCR validation, and 20 genes were significantly overexpressed in ESCC compared with normal esophagus (P < 0.05). TNFAIP3 and CHN1 showed differential expression with IHC. TNFAIP3 expression increased gradually through normal esophagus, mild, moderate and severe dysplasia, and SCC (P < 0.0001). CHN1 staining was rarely present in the top third of normal esophagus epithelium and extended progressively towards the surface in mild, moderate, and severe dysplasia, and SCC (P < 0.0001). Two novel promising biomarkers for ESCC were identified, TNFAIP3 and CHN1. CHN1 and TNFAIP3 may improve diagnostic accuracy of screening methods for ESCC. Cancer Prev Res; 9(7); 558-66. ©2016 AACR.
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Couch
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom.
authors.forename: James E
authors.initials: JE
authors.lastname: Redman
authors.affiliation: MRC Biostatistics Unit, Robinson Way, Cambridge, United Kingdom.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Wernisch
authors.affiliation: MRC Biostatistics Unit, Robinson Way, Cambridge, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Newton
authors.affiliation: Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
authors.forename: Shalini
authors.initials: S
authors.lastname: Malhotra
authors.affiliation: Division of Cancer Epidemiology & Genetics, NCI, Bethesda, Maryland.
authors.forename: Sanford M
authors.initials: SM
authors.lastname: Dawsey
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lao-Sirieix
authors.affiliation: MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom. RCF29@MRC-CU.cam.ac.uk.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fitzgerald
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis*; D020848:Chimerin 1 / Q000096:biosynthesis*; D004938:Esophageal Neoplasms / Q000175:diagnosis*; D000077277:Esophageal Squamous Cell Carcinoma; D020869:Gene Expression Profiling; D006801:Humans; D011230:Precancerous Conditions / Q000175:diagnosis*; D059467:Transcriptome; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000096:biosynthesis*
chemical_list: D014408:Biomarkers, Tumor; D020848:Chimerin 1; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3