Microsatellite Instability-High (MSI-H) is a genetic change found in the DNA of certain tumors. This marker identifies a tumor with a high degree of genetic instability, which occurs when the cell’s natural error-correction machinery fails. Detecting this status is now a routine part of cancer diagnosis because it offers crucial information about how a tumor is likely to behave and, most importantly, how it should be treated. MSI-H status has changed the therapeutic landscape for several cancer types, moving treatment toward highly effective targeted immunotherapies.
The Biology of MSI-H: DNA Mismatch Repair Failure
The basis of Microsatellite Instability-High lies in a breakdown of the cell’s maintenance system. Every human cell contains short, repetitive DNA sequences known as microsatellites. When a cell divides, DNA replication copies the entire genetic code, but errors frequently occur during this copying process, especially within the repetitive microsatellite regions.
To correct these mistakes, the cell relies on a quality control mechanism called the Mismatch Repair (MMR) system. The MMR system acts like a cellular proofreader, recognizing and excising incorrectly paired bases or small insertions and deletions that arise during replication. In a healthy cell, the MMR system ensures that the length of the microsatellite sequence remains stable.
MSI-H occurs when the genes responsible for the MMR system become non-functional, a state known as deficient Mismatch Repair (dMMR). Without a working MMR system, errors in the microsatellites go uncorrected, leading to a high accumulation of mutations. This genetic instability causes the microsatellites in the tumor cells to become drastically different in length compared to the patient’s normal cells, which defines an MSI-H tumor.
Determining MSI Status: Testing Methods and Categories
Determining a tumor’s MSI status is performed through specialized laboratory tests on a tissue sample, typically from a biopsy or surgical resection. This testing is routinely recommended for all colorectal, endometrial, and many gastric cancers due to the high prevalence of MSI-H in these tumor types. The results guide treatment decisions and can indicate a potential hereditary risk, such as Lynch syndrome.
One primary method is Immunohistochemistry (IHC), which checks for the presence or absence of the Mismatch Repair (MMR) proteins in the tumor cells. The loss of one or more of these proteins indicates a deficient MMR system, which is functionally equivalent to an MSI-H status. Another common approach is Polymerase Chain Reaction (PCR)-based testing, which directly compares the length of microsatellite markers between the tumor and normal tissue.
Based on the degree of instability detected, tumors are categorized into three main groups:
- MSI-High (MSI-H): A high percentage of tested markers show length variations, indicating the MMR system is non-functional.
- Microsatellite Stable (MSS): No instability is detected, and the MMR system is proficient.
- MSI-Low (MSI-L): Only a single marker shows instability.
For clinical purposes, MSI-H is the most important category, as MSI-L tumors are typically treated the same as MSS tumors.
MSI-H as a Guide for Cancer Treatment
MSI-H status strongly predicts a tumor’s response to specific therapies. This genetic feature is linked to a high number of genetic errors, resulting in a high Tumor Mutational Burden (TMB). These uncorrected mutations cause cancer cells to produce many abnormal proteins, called neoantigens, on their surface.
These neoantigens make the cancer cell appear “foreign” to the body’s immune system, which is constantly scanning for abnormal proteins. This visibility causes the immune system to recognize and attack the tumor, leading to MSI-H tumors often being heavily infiltrated with immune cells, making them “hot” tumors. However, the tumor attempts to evade this attack by activating immune checkpoints, which act as a brake on the immune response.
This mechanism explains why checkpoint inhibitor immunotherapy, such as PD-1 inhibitors, is exceptionally effective. These drugs work by releasing the immune system’s brakes, allowing activated immune cells to recognize and destroy the highly mutated cancer cells. Clinical trials have shown that patients with MSI-H tumors across various cancer types experience significantly higher response rates and longer progression-free survival with immunotherapy compared to traditional chemotherapy.
The strong correlation between MSI-H status and immunotherapy response led to the U.S. Food and Drug Administration (FDA) granting accelerated approval for a checkpoint inhibitor to treat any unresectable or metastatic solid tumor that is MSI-H, regardless of its original location. This “tumor-agnostic” approval established MSI-H as a universal predictive biomarker, showing that the tumor’s genetic characteristic is more important than its anatomical site for treatment selection. Furthermore, MSI-H tumors often respond poorly to certain conventional chemotherapies, such as 5-fluorouracil (5-FU), making the identification of this status important for appropriate treatment.