Evaluation of Serum Glycoprotein Biomarker Candidates for Detection of Esophageal Adenocarcinoma and Surveillance of Barrett's Esophagus

• Published in: Molecular & cellular proteomics Vol. 17; no. 12; pp. 2324 - 2334
• Main Authors: Shah, Alok K., Hartel, Gunter, Brown, Ian, Winterford, Clay, Na, Renhua, Cao, Kim-Anh Lê, Spicer, Bradley A., Dunstone, Michelle A., Phillips, Wayne A., Lord, Reginald V., Barbour, Andrew P., Watson, David I., Joshi, Virendra, Whiteman, David C., Hill, Michelle M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2018; The American Society for Biochemistry and Molecular Biology
• Subjects: Adenocarcinoma - blood; Adenocarcinoma - diagnosis; Adenocarcinoma - etiology; Adenocarcinoma - pathology; Aged; Area Under Curve; Aryldialkylphosphatase - blood; Australia; Barrett Esophagus - blood; Barrett Esophagus - complications; Barrett Esophagus - diagnosis; Barrett Esophagus - pathology; Barrett's esophagus; Biomarker: Diagnostic; Biomarkers - blood; Biopsy; Cancer biomarker(s); Cohort Studies; Complement C9 - analysis; Complement pathway; Diagnosis, Differential; Esophageal adenocarcinoma; Esophageal Neoplasms - blood; Esophageal Neoplasms - diagnosis; Esophageal Neoplasms - etiology; Esophageal Neoplasms - pathology; Female; Gastrointestinal disease; Gelsolin - blood; Glycoproteins; Humans; Male; Mass Spectrometry - methods; Middle Aged; Multiple reaction monitoring; Multivariate Analysis; Public Health Surveillance; Serum/Plasma; Targeted mass spectrometry; United States; Australia; United States; Targeted mass spectrometry; Multiple reaction monitoring; Barrett's esophagus; Glycoproteins; Cancer biomarker(s); Complement pathway; Biomarker: Diagnostic; Esophageal adenocarcinoma; Gastrointestinal disease; Serum/Plasma
• ISSN: 1535-9476; 1535-9484; 1535-9484
• DOI: 10.1074/mcp.RA118.000734

This paper reports independent cohort validation of previously discovered esophageal adenocarcinoma (EAC) serum diagnostic glycoprotein biomarker candidates. To demonstrate their potential clinical application in evaluating patients during endoscopy-biopsy surveillance, we developed a panel of 10 biomarker candidates (AUC 0.93) to discriminate Barrett's esophagus (BE) patients not requiring intervention [BE+/− low-grade dysplasia] from those requiring intervention [BE with high-grade dysplasia or EAC]. Complement pathway proteins appear to be dysregulated during EAC, with C9 detected in BE and EAC tissue. [Display omitted] Highlights •C9, GSN, PON1, and PON3 validated as serum biomarker candidates of EAC.•Multimarker panel with AUROC of 0.93 to aid current endoscopy surveillance of BE.•Induction of tissue C9 in BE, dysplastic BE and EAC.•Alteration of complement pathway glycoproteins during BE-EAC pathogenesis. Esophageal adenocarcinoma (EAC) is thought to develop from asymptomatic Barrett's esophagus (BE) with a low annual rate of conversion. Current endoscopy surveillance of BE patients is probably not cost-effective. Previously, we discovered serum glycoprotein biomarker candidates which could discriminate BE patients from EAC. Here, we aimed to validate candidate serum glycoprotein biomarkers in independent cohorts, and to develop a biomarker candidate panel for BE surveillance. Serum glycoprotein biomarker candidates were measured in 301 serum samples collected from Australia (4 states) and the United States (1 clinic) using previously established lectin magnetic bead array (LeMBA) coupled multiple reaction monitoring mass spectrometry (MRM-MS) tier 3 assay. The area under receiver operating characteristic curve (AUROC) was calculated as a measure of discrimination, and multivariate recursive partitioning was used to formulate a multi-marker panel for BE surveillance. Complement C9 (C9), gelsolin (GSN), serum paraoxonase/arylesterase 1 (PON1) and serum paraoxonase/lactonase 3 (PON3) were validated as diagnostic glycoprotein biomarkers in lectin pull-down samples for EAC across both cohorts. A panel of 10 serum glycoprotein biomarker candidates discriminated BE patients not requiring intervention (BE± low grade dysplasia) from those requiring intervention (BE with high grade dysplasia (BE-HGD) or EAC) with an AUROC value of 0.93. Tissue expression of C9 was found to be induced in BE, dysplastic BE and EAC. In longitudinal samples from subjects that have progressed toward EAC, levels of serum C9 were significantly (p < 0.05) increased with disease progression in EPHA (erythroagglutinin from Phaseolus vulgaris) and NPL (Narcissus pseudonarcissus lectin) pull-down samples. The results confirm alteration of complement pathway glycoproteins during BE-EAC pathogenesis. Further prospective clinical validation of the confirmed biomarker candidates in a large cohort is warranted, prior to development of a first-line BE surveillance blood test.