Microsatellite Instability (MSI) testing is a standard procedure in cancer diagnostics, particularly for solid tumors like colorectal, endometrial, and gastric cancers. This specialized genetic test examines the tumor’s stability at a molecular level, serving as an important biomarker. The results categorize the tumor based on the integrity of its genetic code, providing guidance on how the cancer is likely to behave and informing treatment decisions.
Understanding Microsatellite Instability
Microsatellites are short, repeating sequences of DNA nucleotides scattered throughout the genome. These sequences are prone to errors during cell division and DNA replication. Correcting these errors is the job of the Mismatch Repair (MMR) system, a complex of proteins that acts like the cell’s internal spell-check mechanism. When the genes responsible for the MMR system become defective, this function fails, leading to Mismatch Repair Deficiency (dMMR). Without the MMR proteins, replication errors accumulate rapidly within the microsatellite regions, resulting in changes in the length of the repeating sequences known as Microsatellite Instability (MSI). Tumors are categorized based on the extent of this instability.
Defining the Categories: MSI-H vs. MSS/MSI-L
A cancer diagnostic report indicating a “low probability of MSI-H” means the tumor lacks the widespread genetic instability characteristic of Microsatellite Instability-High (MSI-H) status. This result suggests the tumor is either Microsatellite Stable (MSS) or Microsatellite Instability-Low (MSI-L). MSI-H tumors have a completely non-functional MMR system, leading to instability in a large percentage of tested markers. Conversely, MSS tumors show no instability, signifying a functional MMR system. MSI-L tumors exhibit a small degree of instability, but are generally grouped with MSS tumors for clinical purposes because their clinical behavior and response to treatment are similar. In colorectal cancer, the MSS/MSI-L category represents the vast majority of cases, accounting for approximately 80 to 85% of all tumors.
Clinical Significance of MSI Status
Testing for MSI status is routinely performed on tumors such as colorectal, endometrial, and gastric cancers to determine the tumor’s biological profile. The MSI result provides important prognostic information about the likely course of the disease. Generally, early-stage MSI-H tumors often exhibit a better prognosis than MSS or MSI-L tumors. This improved outlook is related to the tumor’s high level of genetic errors, which makes them highly recognizable by the immune system. These numerous genetic mutations lead to the production of abnormal proteins, or neoantigens, that trigger a strong anti-tumor immune response. MSI-H tumors are frequently associated with a high infiltration of immune cells, suggesting the body is actively fighting the cancer.
Treatment Implications for MSS/MSI-L Tumors
The significance of an MSS or MSI-L result lies in its implications for treatment selection, especially regarding immune checkpoint inhibitors. MSI-H tumors are characterized by a high tumor mutation burden (TMB), making them vulnerable to immunotherapy drugs. In contrast, MSS/MSI-L tumors, which represent the “low probability of MSI-H” result, have a low TMB and a functional MMR system. These tumors are genetically stable, meaning they do not produce the massive amount of neoantigens that would make them visible to the immune system. Consequently, MSS/MSI-L tumors are described as “cold” tumors because they lack the strong immune cell infiltration seen in MSI-H cancers. Immunotherapy is typically ineffective for the majority of patients in this group when used as a single agent.
Patients with MSS or MSI-L tumors must therefore rely on conventional treatment approaches, such as traditional chemotherapy, targeted therapies, and surgery. Researchers are actively investigating combination strategies, such as adding targeted drugs to checkpoint inhibitors, to try and “heat up” these cold tumors and make them responsive to the immune system. Recent studies are beginning to show that specific combinations may offer an alternative to chemotherapy for a small subset of MSS patients.
Connection to Hereditary Cancer Syndromes
The MMR deficiency causing MSI-H status can arise sporadically (randomly in the tumor cell) or through inheritance. Lynch Syndrome is the most common hereditary condition associated with a deficient MMR system, significantly increasing a person’s lifetime risk for several cancers, including colorectal and endometrial cancers. When a tumor is identified as MSI-H, it raises the suspicion of Lynch Syndrome, which often triggers genetic testing for inherited mutations. A finding of MSS or MSI-L generally suggests the tumor is sporadic and not linked to an inherited syndrome. However, MSI testing is still recommended for all newly diagnosed colorectal and endometrial tumors as an initial screening step. Even when the tumor is MSS, a patient with a strong family history or young age at diagnosis may still be referred for genetic counseling.