Microsatellite Instability-High (MSI-High) refers to a distinct genetic characteristic found within the DNA of certain cancer cells. This biomarker signals a high number of errors in short, repetitive DNA sequences, acting as a unique genetic signature. Understanding a tumor’s MSI-High status provides medical professionals with valuable information about how the cancer might behave. This insight helps guide decisions regarding a patient’s care and treatment pathways.
The Genetic Cause of MSI-High
The underlying reason for MSI-High involves specific segments of DNA known as microsatellites. These are short, repetitive stretches of DNA, typically 1 to 6 base pairs long, repeated multiple times throughout the genome. Mistakes can occur when DNA copies itself during cell division.
A specialized cellular system, called the Mismatch Repair (MMR) system, functions like a “DNA spell-checker” to detect and correct these errors. The MMR system involves several proteins, including MLH1, MSH2, MSH6, and PMS2, which work together to maintain genomic stability. If this MMR system is not working correctly, often described as “deficient mismatch repair” (dMMR), errors accumulate in the DNA.
When errors build up within microsatellite regions, they cause changes in the length of these repetitive sequences. This accumulation defines microsatellite instability. A “High” designation means a significant number of these regions exhibit instability, indicating a widespread failure in the tumor cell’s DNA repair mechanisms.
Cancers Associated with MSI-High
MSI-High is commonly identified in several cancer types, accounting for approximately 15% of all colorectal cancers. It is also frequently observed in endometrial (uterine) and gastric (stomach) cancers. MSI-High can also occur in other solid tumors, including small bowel, ovarian, and certain brain cancers.
A significant connection exists between MSI-High status and Lynch syndrome, a hereditary condition that increases an individual’s lifetime risk of various cancers. Lynch syndrome is caused by an inherited alteration in one of the MMR genes (MLH1, MSH2, MSH6, or PMS2). This inherited predisposition accounts for 3% to 5% of all MSI-High colorectal cancers.
It is important to differentiate between MSI-High linked to Lynch syndrome and “sporadic” MSI-High. Sporadic cases, which are more common, arise from changes only within tumor cells and are not inherited. Many sporadic MSI-High colorectal cancers, for example, result from an epigenetic change inactivating the MLH1 gene. This distinction is important because hereditary MSI-High may suggest genetic counseling and testing for family members to assess their cancer risk.
How MSI-High Status is Determined
Determining a tumor’s MSI-High status typically involves specific laboratory tests on tumor tissue samples. One common method is Immunohistochemistry (IHC), which examines the presence or absence of Mismatch Repair (MMR) proteins within cancer cells. If one or more MMR proteins (MLH1, MSH2, MSH6, PMS2) are missing, it indicates a deficient MMR system (dMMR). A dMMR finding by IHC is generally considered equivalent to MSI-High status.
Another primary method is Polymerase Chain Reaction (PCR), a DNA-based test that measures the lengths of specific microsatellite regions. DNA is extracted from both tumor cells and a patient’s normal cells for comparison. If the microsatellite lengths in the tumor DNA differ significantly from the normal DNA, it indicates instability. MSI-High is typically diagnosed when instability is detected in two or more of the specific microsatellite markers.
Next-Generation Sequencing (NGS) offers a comprehensive approach to detecting MSI-High. This advanced technology analyzes thousands of microsatellite loci simultaneously, providing a broader view of genomic instability. NGS can also identify other genetic alterations within the tumor, offering a more complete genetic profile. These methods help pinpoint whether a tumor possesses the MSI-High signature.
Treatment Guided by MSI-High Status
An MSI-High diagnosis holds significance for cancer treatment due to the unique biological characteristics of these tumors. The high number of DNA errors in MSI-High tumors leads to the creation of many abnormal proteins, known as neoantigens. These neoantigens make cancer cells appear “foreign” and recognizable to the immune system. This heightened visibility makes MSI-High tumors susceptible to certain types of immunotherapy.
Immune checkpoint inhibitors, such as PD-1/PD-L1 inhibitors, are a class of immunotherapy effective against MSI-High cancers. These drugs work by “releasing the brakes” on the immune system’s T-cells, allowing them to recognize and attack cancer cells more effectively. The increased neoantigen burden in MSI-High tumors often leads to a robust immune response when these checkpoints are disinhibited.
The recognition of MSI-High as a predictive biomarker led to a landmark moment in cancer treatment. In 2017, the U.S. Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab, an immune checkpoint inhibitor, for use in any advanced solid tumor with MSI-High status, regardless of its origin. This was a significant shift, moving beyond site-specific cancer treatments to those guided by a tumor’s genetic features. In contrast, MSI-High tumors often respond less favorably to certain traditional chemotherapies, such as 5-fluorouracil (5-FU) based regimens, which highlights the importance of MSI testing in guiding treatment.