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Intratumoral heterogeneity in microsatellite instability status at single-cell resolution
Harrison Anthony1,2, Cathal Seoighe1,2
1School of Mathematical and Statistical Sciences, University of Galway, Galway, Ireland.
Iscience
|March 2, 2026
Summary
Microsatellite instability (MSI) may not be a simple binary biomarker. Many tumors show mixed high microsatellite instability (MSI-H) and microsatellite stable (MSS) subclones, challenging its use in cancer treatment.
Area of Science:
- Oncology
- Genomics
- Computational Biology
Background:
- Intratumoral heterogeneity complicates single-test biomarker interpretation.
- Microsatellite instability (MSI) is a biomarker guiding immune checkpoint inhibitor therapy, classified as MSI-High (MSI-H) or Microsatellite Stable (MSS).
Purpose of the Study:
- To investigate whether MSI is a heterogeneous phenomenon within tumors.
- To develop a computational method for quantifying intratumoral MSI heterogeneity.
Main Methods:
- Curated data from single-cell RNA sequencing studies with clinical MSI status.
- Developed a computational pipeline to quantify intratumoral heterogeneity in MSI.
Main Results:
- 15 out of 49 individuals exhibited divergent MSI status between cancer cell clusters.
- Most heterogeneous tumors contained distinct MSI-H and MSS subclones.
Conclusions:
- The binary classification of MSI as MSI-H or MSS may be insufficient due to intratumoral heterogeneity.
- Accounting for MSI heterogeneity could potentially enhance its predictive value for immune checkpoint inhibitor treatment.
- Further research is needed to determine the prevalence and clinical impact of MSI heterogeneity.
