Agrin loss in Barrett's esophagus-related neoplasia and its utility as a diagnostic and predictive biomarker.

PURPOSE There is an unmet need for identifying novel biomarkers in Barrett's esophagus (BE) that could stratify patients with regards to neoplastic progression. We investigate the expression patterns of extracellular matrix (ECM) molecules in BE and BE-related neoplasia, and assess their value as biomarkers for the diagnosis of BE-related neoplasia and to predict neoplastic progression. EXPERIMENTAL DESIGN Gene expression analyses of ECM matrisome gene sets were performed using publicly available data on human BE, BE-related dysplasia, esophageal ADCA and normal esophagus. Immunohistochemical expression of basement membrane (BM) marker agrin (AGRN) and p53 was analyzed in biopsies of BE-related neoplasia from 321 patients in three independent cohorts. RESULTS Differential gene expression analysis revealed significant enrichment of ECM matrisome gene sets in dysplastic BE and ADCA compared with controls. Loss of BM AGRN expression was observed in both BE-related dysplasia and ADCA. The mean AGRN loss in BE glands was significantly higher in BErelated dysplasia and ADCA compared to non-dysplastic BE (NDBE; p<0.001; specificity=82.2% and sensitivity=96.4%). Loss of AGRN was significantly higher in NDBE samples from progressors compared to non-progressors (p<0.001) and identified patients who progressed to advanced neoplasia with a specificity of 80.2% and sensitivity of 54.8%. Moreover, the combination of AGRN loss and abnormal p53 staining identified progression to BE-related advanced neoplasia with a specificity and sensitivity of 86.5% and 58.7%. CONCLUSIONS We highlight ECM changes during BE progression to neoplasia. BM AGRN loss is a novel diagnostic biomarker that can identify NDBE patients at increased risk of developing advanced neoplasia.