Abstract
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.
Highlights
Esophageal cancer is the sixth most common cause of cancer related mortality in men, with3-fold higher rates in men than women [1, 2]
Patients diagnosed with high grade dysplasia (BE-HGD) are treated with endoscopic mucosal resection, radiofrequency ablation or surgery, in an attempt to halt further disease progression (1012)
As the first step to developing blood-based esophageal adenocarcinoma (EAC) diagnostic test, we focused on differential glycosylation of serum glycoproteins during EAC pathogenesis
Summary
Esophageal cancer is the sixth most common cause of cancer related mortality in men, with. The significant cost of endoscopy plus the low annual progression rate to HGD or EAC means that the cost-effectiveness of endoscopic surveillance is questioned at the population level [13,14,15,16]. We established a new glycoprotein biomarker pipeline which couples lectin-based glycoprotein isolation with state-ofthe-art discovery and targeted proteomics [20,21,22,23]. We applied it to identify and verify changes in lectin binding profile of serum glycoproteins between healthy, BE and EAC patients [22]. We report results from validation in independent cohorts, and evaluation of biomarker panels for surveillance of BE patients
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