Lgr5 and stem/progenitor gene expression in gastric/gastroesophageal junction carcinoma - Significance of potentially retained stemness

Abstract

Background: Gastric/gastroesophageal junction (GEJ) adenocarcinomas are heterogeneous, comprising four molecularly distinct subtypes, namely EBV-positive, microsatellite instability (MSI), chromosomal instability (CIN) and genomically stable (GS) subtypes, and a part of this heterogeneity may hypothesized to be different cells-of-origin. Stem/progenitor cell hierarchy in the stomach is complex, which include the Lgr5(+) gastric stem cells (GSCs). Methods: While previous studies have focused on non-nuclear Lgr5 expression, nuclear Lgr5 expression has been reported in a subset of stem cells, and we examined nuclear Lgr5 expression in a local cohort of 95 cases of gastric/GEJ adenocarcinoma. mRNA levels for LGR5 and other stem cell marker genes were examined in the TCGA cohort. Results: We observed nuclear Lgr5 expression in a 18/95 cases. Near mutual exclusivity was seen between nuclear Lgr5 and strong non-nuclear Lgr5. Both strong non-nuclear and nuclear Lgr5 expression tended to be seen more frequently with the intestinal histotype and approximated CIN molecular subtype. With respect to overall survival (OS), nuclear Lgr5 expression appears to be protective, with the worst survival being seen in the cases lacking nuclear Lgr5 and with low non-nuclear Lgr5 expression. When compared to other stem/progenitor cell markers, LGR5 mRNA expression clusters with other GSC marker genes, including VIL1. Higher expression of these GSC marker genes was associated with better OS. Conclusions: Our results show that Lgr5 expression is dynamic in gastric/GEJ adenocarcinoma and heterogeneous across the several disease attributes. We postulate that this may reflect "retained stemness"in the form of Lgr5High-GSC signature that appears to be associated with better survival.