MSI positive (Microsatellite Instability positive) means that a tumor's DNA shows a high degree of instability in specific DNA sequences called microsatellites, when compared to normal tissue. This instability, also known as MSI-High (MSI-H), suggests a defect in the mismatch repair (MMR) system, which normally corrects errors during DNA replication.
Understanding Microsatellite Instability (MSI)
Microsatellites are short, repetitive DNA sequences found throughout the genome. Because of their repetitive nature, they are prone to errors during DNA replication. The mismatch repair (MMR) system acts as a "spell checker" to correct these errors. When the MMR system is not functioning correctly, these errors accumulate, leading to changes in the length of microsatellites.
Implications of MSI-High
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Defective Mismatch Repair (MMR): MSI-H strongly indicates that the tumor has a deficient MMR system. This deficiency can be caused by:
- Inherited mutations: In genes such as MLH1, MSH2, MSH6, and PMS2.
- Epigenetic silencing: Such as methylation of the MLH1 gene promoter.
- Somatic mutations: Mutations acquired during the lifetime of the individual.
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Cancer Types: MSI-H is observed in several cancer types, most notably:
- Colorectal cancer (CRC), occurring in approximately 15% of cases.
- Endometrial cancer
- Gastric cancer
- Other cancers less frequently
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Prognosis and Treatment: MSI-H status has important implications for cancer prognosis and treatment:
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Better Prognosis (in some cancers): In colorectal cancer, MSI-H tumors are generally associated with a better prognosis compared to microsatellite stable (MSS) tumors, especially in early stages.
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Predictive of Immunotherapy Response: MSI-H tumors are highly responsive to immune checkpoint inhibitors (a type of immunotherapy) because they have a high mutation burden, leading to the production of neoantigens that the immune system can recognize and attack.
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Potential Resistance to Certain Chemotherapies: Some studies suggest that MSI-H colorectal cancers may not benefit from certain chemotherapy regimens, like fluorouracil (5-FU) alone.
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Testing for MSI
MSI testing is typically performed on tumor tissue samples and compared to normal tissue from the same patient. There are two main methods:
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PCR-based MSI testing: This method amplifies specific microsatellite markers by PCR and compares the fragment sizes in the tumor and normal tissue. Changes in fragment size in the tumor indicate MSI.
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Immunohistochemistry (IHC): IHC stains for the MMR proteins (MLH1, MSH2, MSH6, PMS2). If one or more of these proteins are absent in the tumor cells, it suggests a deficiency in the MMR system and is suggestive of MSI.
| Test | Description | Result Interpretation |
|---|---|---|
| PCR-based MSI testing | Amplifies microsatellite markers and compares fragment sizes between tumor and normal tissue | Changes in fragment size in tumor tissue indicate MSI-High (MSI-H). No changes indicate Microsatellite Stable (MSS). |
| Immunohistochemistry (IHC) | Stains for MMR proteins (MLH1, MSH2, MSH6, PMS2) | Absence of one or more MMR proteins suggests MMR deficiency and potential MSI-H. |
In Summary
Being MSI positive indicates a high degree of microsatellite instability in the tumor, reflecting a malfunctioning DNA mismatch repair system. This status carries significant implications for predicting response to immunotherapy, prognosis in some cancers, and potentially guiding treatment decisions.
