Microsatellite Instability in Colorectal Cancer

Microsatellite instability (MSI) arises when the DNA mismatch repair (MMR) system fails to correct errors in short repetitive sequences, or microsatellites, during replication. In colorectal cancer (CRC), MSI characterises approximately 15 % of tumours and defines a distinct molecular subtype with unique clinical and biological features. These include a high mutational burden, frequent frameshift mutations in coding regions, a pronounced lymphocytic infiltrate and generally improved prognosis compared with microsatellite-stable disease. MSI may result from germline mutations in MMR genes, as seen in Lynch syndrome, or from somatic hypermethylation of the MLH1 promoter in sporadic cases. The resulting cascade of insertion–deletion events generates novel peptide sequences, or neoantigens, which render MSI-positive tumours particularly sensitive to immune checkpoint blockade. Detection of MSI by polymerase chain reaction or immunohistochemistry has become integral to CRC diagnosis, prognostication and therapeutic stratification. Recent advances have refined our understanding of intratumour heterogeneity, revealed the impact of non-canonical peptide repertoires on antitumour immunity and prompted development of non-invasive imaging and machine-learning approaches to predict MMR status. Collectively, these insights underscore the global significance of MSI as both a biomarker and a potential Achilles’ heel of colorectal malignancies.

Research from Nature Portfolio

Recent studies have shown that in mismatch repair-deficient colorectal cancers, stochastic frameshift toggling within mononucleotide homopolymers of key MMR genes can dynamically modulate subclonal mutation rates. Patient-derived organoids revealed that spontaneous mutation and reversion in homopolymer tracts of MSH6 and MSH3 alter both neoantigen diversity and immune visibility, suggesting that intratumour heterogeneity is fuelled by adaptive mutability under immune selection. Experimental models and simulations indicate that incremental impairment of the MMR machinery confers a selective advantage by balancing elevated mutagenesis against immune elimination.

Microsatellite Instability in Colorectal Cancer publication trend

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

Technical terms

Microsatellite instability (MSI): A condition of genetic hypermutability resulting from defective DNA mismatch repair that leads to insertion and deletion errors in repetitive sequences.

Mismatch repair (MMR): A DNA repair pathway that recognises and corrects base–base mismatches and insertion–deletion loops arising during replication.

Homopolymer: A sequence of consecutive identical nucleotides (e.g. AAAAA) prone to frameshift errors when MMR is deficient.

Neoantigen: A novel peptide derived from tumour-specific mutations, presented by MHC molecules and recognised by T cells.

EMAST: Elevated microsatellite alterations at selected tetranucleotide repeats, a form of MSI associated with MSH3 dysfunction.

Organoid: A three-dimensional cell culture model derived from patient tumours that recapitulates key aspects of tumour biology in vitro.

References

1. Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer. Nature Genetics (2024).
2. Non-canonical antigens are the largest fraction of peptides presented by MHC class I in mismatch repair deficient murine colorectal cancer. Genome Medicine (2024).
3. Compound heterozygous MSH3 germline variants and associated tumor somatic DNA mismatch repair dysfunction. npj Precision Oncology (2024).
4. CT-based deep learning model for the prediction of DNA mismatch repair deficient colorectal cancer: a diagnostic study. Journal of Translational Medicine (2023).
5. Microsatellite Instability as a Biomarker for PD-1 Blockade. Clinical Cancer Research (2016).