# Low microsatellite instability revisited: a review

## TL;DR

This paper reviews low-level microsatellite instability (MSI-L), its diagnostic challenges, and potential clinical significance in cancers like colorectal and gastric cancer.

## Contribution

The paper provides a comprehensive review of MSI-L, focusing on its diagnostic variability, clinical associations, and potential therapeutic implications.

## Key findings

- MSI-L is associated with distinct clinical features like poorer prognosis and increased tumor mutational burden.
- MSI-L may correlate with better response to certain chemotherapies like platinum/5-fluorouracil-based regimens.
- Instability at dinucleotide markers suggests a specific subset of MSI-L with potential therapeutic vulnerability.

## Abstract

Microsatellite instability (MSI), caused by impaired mismatch repair (MMR), has gained prominence as a biomarker predicting response to immune checkpoint inhibitors in various cancers. MSI-high (MSI-H) tumours exhibit widespread instability across multiple microsatellite loci and are well-characterized. In contrast, low-level microsatellite instability (MSI-L)—marked by instability at a low number of loci—is poorly understood and its biological relevance remains controversial. MSI-L has often been grouped together with microsatellite stable (MSS) tumours, given the lack of consistent molecular distinctions. However, some studies, particularly in colorectal and gastric cancers, have reported that MSI-L correlates with distinct clinical and molecular features, including poorer prognosis, increased tumour mutational burden (TMB) following chemotherapy, and better response to platinum/5-fluorouracil-based neoadjuvant chemotherapy. Notably, these associations frequently involve instability at dinucleotide repeat markers, hinting at a specific subset of MSI-L. Moreover, recent data provide initial evidence that MSI-L may be associated with subtle alterations of genes involved in DNA damage tolerance pathways. This review aims to clarify the current understanding of MSI-L by (a) comparing diagnostic methods and their influence on MSI-L classification, (b) summarizing clinical and molecular associations of MSI-L specifically in gastric and colorectal cancer, (c) highlighting new aspects regarding potential mechanisms underlying MSI-L, focusing on the particular unstable marker and a possible role of the DNA damage tolerance pathways, and (d) discussing whether MSI-L, particularly defined by dinucleotide repeat instability, may serve as a marker for therapeutic vulnerability.