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The Day-To-Day Practice of MMR and MSI Assessment in Colorectal Adenocarcinoma: What We Know and What We Still Need
Paola Parente1, Federica Grillo2,3, Alessandro Vanoli4
1Unit of Pathology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
Background:
The DNA mismatch repair (MMR) system is a highly preserved protein complex recognizing short insertions, short deletions, and single base mismatches during DNA replication and recombination. MMR protein status is identified using immunohistochemistry. Deficit in one or more MMR proteins, configuring deficient MMR status (dMMR), leads to frameshift mutations particularly clustered in microsatellite repeats. Thus, microsatellite instability (MSI) is the epiphenomenon of dMMR. In colorectal cancer (CRC), MMR/MSI status is a biomarker with prognostic and predictive value of resistance to 5-fluorouracil and response to immune checkpoint inhibitor therapy.
Summary:
In this Review, we describe the challenges the practicing pathologist may face in relation to the assessment of MMR/MSI status and any open issues which still need to be addressed, focusing on pre-analytic issues, pitfalls in the interpretation, and technical aspects of the different assays.
Key Messages:
The current methods of detecting dMMR/MSI status have been optimized for CRCs, and whether these techniques can be applied to all tumor and specimen types is still not fully understood. Following the Food and Drug Administration (FDA), tissue/site agnostic drug approval of pembrolizumab for advanced/metastatic MSI tumors, MMR/MSI status in gastrointestinal tract is a common request from the oncologist. In this setting, several issues still need to be addressed, including criteria for sample adequacy.
Insights
DNA mismatch repair (MMR) protein status, indicating microsatellite instability (MSI), is crucial for colorectal cancer prognosis and treatment. This review addresses challenges in MMR/MSI assessment for pathologists.
Area of Science:
- Molecular biology
- Oncology
- Pathology
Background:
- The DNA mismatch repair (MMR) system corrects replication errors, and its deficiency (dMMR) causes microsatellite instability (MSI).
- MMR/MSI status is a key biomarker in colorectal cancer (CRC), predicting treatment response and prognosis.
- Immunohistochemistry is used to determine MMR protein status.
Purpose of the Study:
- To review challenges and open issues in assessing MMR/MSI status for practicing pathologists.
- To discuss pre-analytic factors, interpretive pitfalls, and technical assay aspects.
- To address the application of current MMR/MSI detection methods across diverse tumor types and specimens.
Main Methods:
- Review of current literature and clinical practices regarding MMR/MSI assessment.
- Analysis of pre-analytic, analytic, and interpretive challenges.
- Discussion of assay methodologies and their limitations.
Main Results:
- Pathologists face challenges in MMR/MSI assessment, including pre-analytic issues and interpretation pitfalls.
- Current MMR/MSI detection methods are optimized for CRC, with limitations in other tumor types.
- Sample adequacy criteria require further definition, especially for gastrointestinal tract tumors.
Conclusions:
- Accurate MMR/MSI assessment is critical for personalized cancer therapy.
- Standardization and validation of assays across different tumor types are needed.
- Addressing current challenges will improve the clinical utility of MMR/MSI testing.
