Microsatellite instability: A 2024 update

Abstract

Deficient mismatch repair (dMMR) results in microsatellite instability (MSI), a pronounced mutator phenotype. High-frequency MSI (MSI-H)/dMMR is gaining increasing interest as a biomarker for advanced cancer patients to determine their eligibility for immune checkpoint inhibitors (ICIs). Various methods based on next-generation sequencing (NGS) have been developed to assess the MSI status. Comprehensive genomic profiling (CGP) testing can precisely ascertain the MSI status as well as genomic alterations in a single NGS test. The MSI status can be also ascertained through the liquid biopsy-based CGP assays. MSI-H has thus been identified in various classes of tumors, resulting in a greater adoption of immunotherapy, which is hypothesized to be effective against malignancies that possess a substantial number of mutations and/or neoantigens. NGS-based studies have also characterized MSI-driven carcinogenesis, including significant rates of fusion kinases in colorectal cancers (CRCs) with MSI-H that are targets for therapeutic kinase inhibitors, particularly in MLH1-methylated CRCs with wild-type KRAS/BRAF. NTRK fusion is linked to the colorectal serrated neoplasia pathway. Recent advances in investigations of MSI-H malignancies have resulted in the development of novel diagnostic or therapeutic techniques, such as a synthetic lethal therapy that targets the Werner gene. DNA sensing in cancer cells is required for antitumor immunity induced by dMMR, opening up novel avenues and biomarkers for immunotherapy. Therefore, clinical relevance exists for analyses of MSI and MSI-H-associated genomic alterations in malignancy. In this article, we provide an update on MSI-driven carcinogenesis, with an emphasis on unique landscapes of diagnostic and immunotherapeutic strategies.

Keywords: DNA mismatch repair; fusion kinases; immunotherapy; microsatellite instability; next‐generation sequencing.

FIGURE 1

DNA mismatch repair (MMR) model, DNA methylation and demethylation model, and pathogenesis of high‐frequency microsatellite instability (MSI‐H) colorectal cancers (CRCs). Upper left: DNA MMR model based on DNA mismatch. Lower left: DNA methylation and demethylation model. 5caC, 5‐carboxylcytosine; 5fC, 5‐formylcytosine; 5hmC, 5‐hydroxy methylcytosine; 5mC, 5‐methylcytosine; BER, base excision repair; DNMT, DNA methyltransferase; TDG, thymine DNA glycosylase; TET, Tet methylcytosine dioxygenase. Right: a model of pathogenesis of MSI‐H CRCs based on hereditary and sporadic cases. CMMRD, constitutional mismatch repair deficiency; MAFG, MAF BZIP transcription factor G.

FIGURE 2

High‐frequency microsatellite instability (MSI‐H) and TMB and evaluation of the MSI status. Upper left: an association of MSI‐H with TMB. HM‐SNV, hypermutated‐single nucleotide variant. Upper right: evaluation of TMB. GM, germline mutations; NCC‐OP, National Cancer Center‐OncoPanel; NSM, nonsynonymous mutations; SM, synonymous mutations. Lower: the MSI status is evaluated by immunohistochemistry, PCR‐based assays, next‐generation sequencing (NGS)‐based techniques, and ctDNA‐based techniques.

FIGURE 3

Immune microenvironment and immunotherapy in cancer. Upper left: classification of gastric cancer (GC) based on immunogram. ACRG, Asian Cancer Research Group; EMT, epithelial to mesenchymal transition; GS, genomically stable. Lower left: classification of colorectal cancer (CRC) based on CMS. Right: The immune response against high‐microsatellite instability (MSI‐H) cancers can be interfered with immune evasion mechanisms, such as inactivation of HLA and B2M. APOBEC3 alterations, APOBEC3 overexpression, and kataegis play roles in the overexpression of PD‐L1/2. cGAS, cyclic GMP‐AMP synthase; CTL/ICK, tumor‐infiltrating T cell/immune checkpoint; DC, dendritic cell; TBK1, TANK binding kinase 1; TIL, tumor‐infiltrating lymphocyte.

FIGURE 4

Carcinogenesis of sporadic high‐microsatellite instability (MSI‐H) colorectal cancers (CRCs). A model for MSI‐H CRC progression is presented based on genetic, epigenetic, and miRNA alterations with target therapies. Mutations that promote cancer cell growth are considered to be the driving force of MSI‐H carcinogenesis and are referred to as driver mutations or Real Common Target genes. SSL, sessile serrated lesions; SSLD, serrated lesions with dysplasia.

FIGURE 5

Representative genes altered in high‐microsatellite instability (MSI‐H) cancers. Coding microsatellites in cancer‐associated genes are potential targets of frameshift mutations in MSI‐H cancers. A number of cancer‐associated genes mutated in MSI‐H cancers have been reported. The relevance of each mutation has not necessarily been proven. Because MSI‐H cancers accumulate many mutations, disruption of cell growth and/or survival regulation can be accomplished in different cancers by mutations in different genes of the same signaling pathways.

FIGURE 6

Overview of current and future pathobiology of high‐microsatellite instability (MSI‐H) and precision medicine. MSI‐H‐driven tumorigenesis, focusing on a novel landscape for diagnostic and therapeutic approach, is shown. Abbreviations in this figure are summarized with brief explanations in Table 1.