Microsatellite Instability in Cancer Genomics

Microsatellite instability (MSI) is a hallmark of defective DNA mismatch repair (MMR) and manifests as widespread length alterations in short tandem repeats throughout the genome. This hypermutability drives oncogenesis in a subset of colorectal, endometrial, gastric and other tumours, and serves both as a diagnostic marker and as a predictive biomarker for immune checkpoint blockade. Advances in next-generation sequencing (NGS) and computational analytics have transformed MSI detection from conventional PCR panels and immunohistochemistry (IHC) into high-throughput approaches capable of capturing tumour heterogeneity and non-coding alterations. MSI-High (MSI-H) status correlates with elevated tumour mutational burden, neoantigen load and favourable responses to anti-PD-1 therapies, while MSI-Low or microsatellite-stable (MSS) tumours follow alternative pathways of genomic instability. Understanding the molecular underpinnings of MSI across diverse cancer types has led to refined prognostic stratification, precision diagnostics and the emergence of pan-tumour therapeutic indications.

Research from Nature Portfolio

Large-scale genomic profiling has delineated the landscape of MSI across more than twenty cancer types by analysing thousands of exomes and whole genomes. This work revealed remarkable variability in MSI event frequency both between and within tumour categories, identified recurrently unstable loci in DNA repair and oncogenic pathways, and uncovered non-coding microsatellite hotspots. A predictive model built on exome-derived MSI signatures demonstrated high accuracy for MSI status, laying the groundwork for targeted panel designs and personalised immunotherapy selection. In parallel, comparative analyses of molecular and protein-based assays in colorectal and endometrial cohorts have shown that PCR-based panels, Idylla and NGS methods achieve near-perfect sensitivity and specificity in colorectal cancer when tumour cell content is adequate. However, lower sensitivity in endometrial cancers underscores the need to combine molecular MSI testing with IHC to ensure accurate detection of mismatch repair deficiency and optimise patient management.

Microsatellite Instability in Cancer Genomics publication trend

The graph below shows the total number of articles in microsatellite instability in cancer genomics across all publications each year (not limited to Nature Index journals).

Technical terms

Microsatellite instability (MSI): The phenomenon of length variations in short tandem repeats due to defective mismatch repair.

DNA mismatch repair (MMR): A cellular pathway that corrects replication errors; its deficiency leads to MSI.

MSI-High (MSI-H): A classification indicating extensive microsatellite length alterations across multiple loci.

Next-generation sequencing (NGS): High-throughput DNA sequencing technologies enabling comprehensive genomic profiling.

Immunohistochemistry (IHC): A protein-based assay that uses antibodies to detect the presence or loss of MMR proteins in tissue sections.

Tumour mutational burden (TMB): The total number of somatic mutations per coding area of a tumour genome, often correlated with neoantigen load.

References

1. MSIsensor-RNA: Microsatellite Instability Detection for Bulk and Single-cell Gene Expression Data. Genomics Proteomics & Bioinformatics (2024).
2. Comparison of standard mismatch repair deficiency and microsatellite instability tests in a large cancer series. Journal of Translational Medicine (2024).
3. A molecular portrait of microsatellite instability across multiple cancers. Nature Communications (2017).
4. Comparison of microsatellite instability detection by immunohistochemistry and molecular techniques in colorectal and endometrial cancer. Scientific Reports (2021).