The Thomsen-Friedenreich Antigen: A Highly Sensitive and Specific Predictor of Microsatellite Instability in Gastric Cancer

Abstract

Microsatellite instability (MSI) is a distinct molecular subtype of gastric cancer. In recent years, the clinical consequences of MSI and the therapeutic opportunities to target this peculiar cancer subtype became evident. However, despite the importance of MSI for the stratification of patients, the time and resources required for diagnosis still present an obstacle. In an attempt to identify a new marker for MSI in gastric cancer, we evaluated the expression of five cancer-associated glycan epitopes in a cohort of 13 MSI and 17 microsatellite stable (MSS) cases. Our analysis revealed a highly significant (p < 0.001) association between the expression of the Thomsen-Friedenreich (TF) antigen and MSI status. Hence, we present here the identification of the first single marker for MSI in gastric cancer, excelling with a specificity of 94% (16/17), sensitivity of 69.2% (9/13), negative predictive value of 80% (16/20), and positive predictive value of 90% (9/10). The TF antigen, detected by simple antibody-based assays, is highly specific for carcinoma being undetectable in gastric healthy and premalignant epithelia. This finding lays the basis for new studies and holds promise in improving the rapid identification of MSI in the clinical setting.

Keywords: O-glycan truncation; cancer biomarker; gastric cancer; glycosylation; microsatellite instability; mucin type glycans.

Figure 1

Thomsen-Friedenreich antigen (TF) expression in human gastric tissue samples. (a) Gastric mucosa is negative for TF, here represented by histologically normal mucosa adjacent to MSI positive and TF positive tumor. (b) Representative image of intestinal metaplasia showing that even goblet cells, which are commonly enriched in truncated O-glycan carriers, were negative for TF. (c) TF negative dysplasia next to TF positive carcinoma, showing the specificity of TF for malignant cells. (d–f) Well-differentiated gastric carcinomas show a typical membranous TF staining at the apical surface, including mucinous secretions. (g–i) Poorly differentiated gastric carcinomas were dominated by cytoplasmic staining. (i) TF positive carcinoma cells within an infiltrated vessel.