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Deficient Mismatch Repair and Microsatellite Instability in Solid Tumors
Joy A Awosika1, James L Gulley2, Danielle M Pastor2
1Gastrointestinal Malignancies Section, Thoracic & GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
International Journal of Molecular Sciences
|May 14, 2025
Summary
Deficient mismatch repair (dMMR) leads to microsatellite instability-high (MSI-H) tumors. These tumors, with high mutation rates and unique immune profiles, respond well to immune checkpoint inhibitors (ICIs).
Area of Science:
- Genomics
- Cancer Biology
- Immunology
Background:
- Genomic integrity is crucial, maintained by mismatch repair (MMR) proteins.
- Defective MMR causes genome instability and mutations, leading to deficient MMR (dMMR) or microsatellite instability-high (MSI-H) tumors.
- dMMR/MSI-H tumors differ significantly from microsatellite stable (MSS) tumors in clinical, pathological, and molecular aspects.
Purpose of the Study:
- To highlight the distinct molecular and immunological characteristics of dMMR/MSI-H tumors.
- To explain why these tumors are particularly responsive to immune checkpoint inhibitors (ICIs).
- To discuss the ongoing refinement of treatment strategies for dMMR/MSI-H patients.
Main Methods:
- Comparative analysis of dMMR/MSI-H and MSS tumors.
- Review of molecular and immunological profiles.
- Evaluation of treatment responses to ICIs.
Main Results:
- dMMR/MSI-H tumors exhibit high mutational burden and genetic instability.
- These tumors possess a distinct immune profile.
- dMMR/MSI-H tumors show increased susceptibility to immune checkpoint inhibitors.
Conclusions:
- The unique genetic and immune characteristics of dMMR/MSI-H tumors make them highly responsive to ICIs.
- Biomarker-driven therapies and novel combinations are refining treatment for this population.
- Understanding dMMR/MSI-H tumor response may inform immunotherapy strategies for proficient MMR (pMMR)/MSS tumors.
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