Intestinal Stem Cell Marker, ASCL2 Is a Novel Prognostic Predictor in Esophageal Adenocarcinoma

Abstract Purpose: Stem cell markers play a significant role in esophageal adenocarcinoma carcinogenesis via Barrett’s esophagus; however, its utility as a prognostic biomarker has not been established. Methods: We analyzed the immunohistochemical expression of Ascl2 and Lgr5 utilizing whole slides (WS; 35 cases) and tissue microarray (TMA; 64 cases of esophageal adenocarcinoma with adjacent normal squamous epithelium, Barrett's esophagus, and dysplasia). Two pathologists semi-quantitatively scored stained slides independently/blindly, and the results were correlated with clinicopathologic factors and outcomes. Results: In WS, 51% and 57% expressed high Ascl2 and high Lgr5; in TMA, 69% and 88% expressed high Ascl2 and high Lgr5, respectively. In TMA, high Ascl2 and low Lgr5 expression significantly correlated to a higher number of involved lymph nodes (p=0.027 and p=0.0039), and Lgr5 expression significantly correlated to the pathological stage (p=0.0032). Kaplan-Meier analysis showed a negative impact of high Ascl2 expression on overall survival (OS; WS p=0.0168, TMA p=0.0276) as well as progression-free survival (PFS; WS p=0.000638, TMA p=0.0466), but not Lgr5. Multivariate Cox regression analysis revealed that Ascl2 expression is an independent prognostic factor for esophageal adenocarcinoma (OS; WS p=0.25, TMA p=0.011. PFS; WS p=0.012, TMA p=0.038). Analysis of the TCGA dataset showed that ASCL2 mRNA levels were correlated to nodal status but not overall survival.Conclusion: Intestinal stem cell marker, Ascl2 is an independent prognostic factor in esophageal adenocarcinoma. High Ascl2 levels were associated with nodal status in both immunohistochemical and mRNA expression. These findings may contribute to the development of prognosis-based subclassification of esophageal adenocarcinoma.