Microsatellite Instability-High (MSI-H) is a specific characteristic found in the genetic makeup of some cancers. It serves as a powerful biomarker, providing important information about a tumor’s behavior and its likely response to certain treatments. This instability occurs when a cell loses its ability to correct errors that happen during DNA replication. Identifying a tumor as MSI-High is a crucial step in modern cancer diagnostics, guiding doctors toward personalized and effective therapeutic strategies.
Understanding the Genetics Behind MSI-High
The mechanism behind MSI-High involves tiny, repetitive stretches of DNA called microsatellites, which are short sequences of one to six base pairs repeated multiple times throughout the genome. During cell division, the entire DNA sequence, including these microsatellites, must be copied. The cell relies on a system of proteins, collectively known as the Mismatch Repair (MMR) system, to act as a kind of genetic spell-checker.
The MMR system is responsible for scanning the newly copied DNA strand and correcting any mistakes, such as single base pair errors or small insertions and deletions that occur during replication. When the genes that produce these MMR proteins are themselves mutated, the entire system becomes deficient, or dMMR. This deficiency means the cell can no longer effectively fix the errors accumulating in the highly repetitive microsatellites.
As these copying errors build up, the length of the microsatellites becomes highly variable, a condition known as Microsatellite Instability. A cancer is designated as MSI-High when a large number of these microsatellites—typically 30% or more of the tested sequences—show instability. The resulting MSI-High tumor is a hypermutated cell mass, carrying a vastly increased number of genetic alterations compared to a stable tumor.
The Testing Process for MSI Status
Determining a tumor’s MSI status is a standard part of the diagnostic process for many cancers and is achieved through two primary methods. The first method is Immunohistochemistry (IHC), which directly examines the tumor tissue for the presence of the MMR proteins. If one or more of the MMR proteins are absent, the test indicates a deficient Mismatch Repair (dMMR) system.
The second method is a molecular test, typically using Polymerase Chain Reaction (PCR) or Next-Generation Sequencing (NGS), which assesses length changes in the microsatellite sequences. This test compares the length of specific microsatellites in the tumor DNA to those in the patient’s normal DNA. In clinical practice, a tumor identified as dMMR by IHC is considered MSI-High, as the two terms describe the same underlying genetic defect.
Clinical Significance and Disease Prognosis
The MSI-High biomarker holds value for predicting the natural course of a patient’s disease. Tumors with this genetic profile often exhibit specific biological characteristics, such as a high number of immune cells infiltrating the tissue. This immune presence suggests that the body is attempting to recognize and fight the cancer.
In early-stage cancers, such as colorectal cancer, the MSI-High status is associated with a more favorable prognosis compared to Microsatellite Stable (MSS) tumors. Patients with early-stage MSI-High tumors often have a lower risk of recurrence after surgery. The presence of MSI-High also influences the effectiveness of traditional chemotherapy. Studies show that certain agents, like fluorouracil, may provide limited benefit in this tumor subset.
MSI-High and Immunotherapy
The primary importance of the MSI-High status lies in its predictive power for response to modern immunotherapy. The deficient Mismatch Repair system causes cancer cells to accumulate thousands of mutations, resulting in the production of abnormal proteins. This high number of mutations is known as a high Tumor Mutational Burden (TMB).
These abnormal proteins make the cancer cell look “foreign” to the immune system. Immunotherapy drugs, specifically checkpoint inhibitors (like PD-1 blockers), work by taking the brakes off the immune system’s T-cells. For MSI-High tumors, this release allows the T-cells to recognize and launch an effective attack against the mutated cancer cells.
Response rates to checkpoint inhibitors in patients with MSI-High tumors are high, often exceeding 50%, which is better than for tumors without this marker. The strength of this relationship led the United States Food and Drug Administration (FDA) to approve a checkpoint inhibitor to treat any unresectable or metastatic solid tumor that is MSI-High, regardless of where the cancer originated. This “tissue-agnostic” approval confirmed MSI-High as a powerful and clinically actionable biomarker in cancer care.