Elevated microsatellite instability at selected tetranucleotide (EMAST) repeats in gastric cancer: a distinct microsatellite instability type with potential clinical impact?

Abstract

We investigated the clinical impact of elevated microsatellite instability at selected tetranucleotide (EMAST) repeats in the context of neoadjuvant chemotherapy (CTx) in gastric/gastro-oesophageal adenocarcinomas. We analysed 583 resected tumours (272 without and 311 after CTx) and 142 tumour biopsies before CTx. If at least two or three of the five tetranucleotide repeat markers tested showed instability, the tumours were defined as EMAST (2+) or EMAST (3+), respectively. Expression of mismatch repair proteins including MSH3 was analysed using immunohistochemistry. Microsatellite instability (MSI) and Epstein-Barr virus (EBV) positivity were determined using standard assays. EMAST (2+) and (3+) were detected in 17.8 and 11.5% of the tumours, respectively. The frequency of EMAST (2+) or (3+) in MSI-high (MSI-H) tumours was 96.2 or 92.5%, respectively, demonstrating a high overlap with this molecular subtype, and the association of EMAST and MSI status was significant (each overall p < 0.001). EMAST (2+ or 3+) alone in MSI-H and EBV-negative tumours demonstrated only a statistically significant association of EMAST (2+) positivity and negative lymph node status (42.3% in EMAST (2+) and 28.8% in EMAST negative, p = 0.045). EMAST alone by neither definition was significantly associated with overall survival (OS) of the patients. The median OS for EMAST (2+) patients was 40.0 months (95% confidence interval [CI] 16.4-63.6) compared with 38.7 months (95% CI 26.3-51.1) for the EMASTnegative group (p = 0.880). The median OS for EMAST (3+) patients was 46.7 months (95% CI 18.2-75.2) and 38.7 months (95% CI 26.2-51.2) for the negative group (p = 0.879). No statistically significant association with response to neoadjuvant CTx was observed (p = 0.992 and p = 0.433 for EMAST (2+) and (3+), respectively). In conclusion, our results demonstrate a nearly complete intersection between MSI-H and EMAST and they indicate that EMAST alone is not a distinct instability type associated with noticeable clinico-pathological characteristics of gastric carcinoma patients.

Low microsatellite instability: A distinct instability type in gastric cancer?

“…The MSI-L phenotype has been associated with the expression of MSH3 in colorectal cancer (Plaschke et al 2012 ). However, in a previous study, we did not find any association between the expression of MSH3 or the other classical MMR proteins and our MSI-L tumors (Herz et al 2022 ).…”

EMAST Type of Microsatellite Instability—A Distinct Entity or Blurred Overlap between Stable and MSI Tumors

“…Studies in other types of cancer aiming to resolve the role of MSI and EMAST in tumorigenesis are scarce. In the study aiming to clarify whether EMAST is a distinct type of microsatellite instability with potential clinical impact in gastric cancer, Herz et al, in addition to using the standard Bethesda panel for initial MSI screening, also used another panel with three additional mononucleotides [77]. The purpose of this second panel was to distinguish between MSI-H and MSI-L in samples in which, by using the Bethesda panel, only dinucleotides were affected.…”