Microsatellite Instability (MSI) testing is a diagnostic tool in oncology that provides insight into a tumor’s biology. The test analyzes specific components of a cell’s DNA structure, serving as a predictive and prognostic biomarker. While a positive result often points toward hereditary cancer and specific treatment options, a negative result, which is far more common, dictates a different clinical pathway. This information helps oncologists select effective, personalized therapeutic strategies.
What is Microsatellite Instability Testing?
Microsatellite instability testing assesses the cell’s DNA repair machinery. Microsatellites are short, repetitive DNA sequences scattered throughout the human genome, typically one to six base pairs long. Due to their repetitive nature, these sequences are vulnerable to errors, such as insertions or deletions, during cell division.
Cells rely on the Mismatch Repair (MMR) system to correct these errors. MMR proteins, such as MLH1, MSH2, MSH6, and PMS2, identify and excise mistakes, ensuring DNA sequence stability. When the MMR system functions correctly, the lengths of the microsatellites remain consistent between normal and tumor cells.
A breakdown in the MMR system, often due to genetic mutations, prevents these errors from being fixed. This failure leads to a high accumulation of changes in the length of the microsatellites within the tumor DNA, known as microsatellite instability (MSI). Testing for MSI status is standard practice for several cancer types, including colorectal, endometrial, and gastric cancers, as it informs treatment response.
Interpreting an MSI-Negative Result
An MSI-Negative result is synonymous with Microsatellite Stable (MSS). This outcome indicates that the tumor’s Mismatch Repair (MMR) system is functioning normally, or “proficient” (pMMR). The MMR system successfully maintains the integrity of the microsatellite sequences, meaning the lengths of the microsatellites in the tumor tissue are stable. For example, approximately 80% to 85% of colorectal cancer cases are classified as MSS, making it the most frequent finding.
An MSS classification suggests the tumor lacks the high mutational burden characteristic of MSI-High tumors. MSS tumors are less likely to be associated with hereditary conditions like Lynch syndrome, though a negative result does not rule out all hereditary risk. For early-stage colorectal cancer, MSS status is often associated with a less favorable outcome compared to MSI-High tumors, though prognosis depends on the cancer type and stage.
The MSS result is distinct from MSI-Low (MSI-L), which indicates a small degree of instability but is generally grouped with MSS for clinical management. MSS tumors are sometimes referred to as “cold” tumors because they typically do not provoke a strong immune response. This lack of immune response directly impacts treatment selection.
Treatment Pathways for MSI-Negative Cancers
The clinical significance of an MSI-Negative (MSS) diagnosis is predicting the tumor’s lack of sensitivity to immune checkpoint inhibitors. These immunotherapies, such as PD-1 and PD-L1 blockers, are effective against MSI-High tumors because their high mutation count makes them recognizable by immune cells. MSS tumors, having a low mutational burden, do not elicit this strong immune reaction, making checkpoint inhibitors generally ineffective as a standalone treatment.
For patients with an MSS tumor, treatment planning relies on established, conventional approaches, including surgery, standard chemotherapy, and targeted therapy. In colorectal cancer, fluorouracil-based chemotherapy regimens remain a mainstay of treatment, and MSS patients benefit from these agents. The focus shifts to identifying other specific genetic alterations within the tumor that can be targeted with specialized drugs.
Oncologists frequently order additional molecular testing to look for actionable mutations, especially in metastatic disease. The presence of these biomarkers can guide the use of targeted agents, such as anti-EGFR therapies or BRAF inhibitors, often administered with chemotherapy. Examples of such mutations include KRAS, NRAS, BRAF, or HER2 amplification. Research continues into novel combination therapies that can make the “cold” MSS tumor more visible to the immune system.