Microsatellite Instability-High (MSI-H) describes a specific genetic feature found in some cancer cells. It indicates that the tumor has an unusually high number of mutations in particular sections of its DNA. This instability means the cancer cells are fundamentally different from normal cells, and this difference can be measured as a biomarker. Identifying a tumor’s MSI status has become a foundational step in personalized oncology, directly influencing how doctors approach treatment.
The Role of Microsatellites and DNA Repair
The foundation of MSI-H involves small, repetitive DNA sequences called microsatellites. These sequences consist of short segments of one to six DNA bases repeated multiple times throughout the genome, acting like genetic stuttering. Due to this repetitive structure, microsatellite regions are particularly prone to errors, such as base insertions or deletions, when a cell divides and copies its DNA.
Cells use the Mismatch Repair (MMR) system, a sophisticated quality control mechanism, to maintain genetic integrity. The MMR system involves a group of proteins, including MLH1, MSH2, MSH6, and PMS2, that scan newly synthesized DNA for errors. When the genes producing these MMR proteins are mutated or inactivated, the repair system fails, resulting in deficient MMR (dMMR).
The failure of the MMR system allows errors in the microsatellites to accumulate unchecked, defining the MSI-H status. These tumors become hyper-mutated, rapidly accumulating changes in their DNA with every cell division. This accumulation of errors leads to a state of widespread genetic instability, giving the cancer a unique molecular signature.
Determining MSI Status: Testing and Classification
Determining a tumor’s MSI status is a practical diagnostic step performed on a sample of the tumor tissue. The two most widely used methods are Polymerase Chain Reaction (PCR) analysis and Immunohistochemistry (IHC). PCR testing directly measures the length of specific microsatellite sequences in tumor DNA compared to normal DNA; significant differences indicate instability.
IHC testing identifies the presence or absence of the four main Mismatch Repair proteins (MLH1, MSH2, MSH6, and PMS2) within the tumor cells. The absence of one or more of these proteins confirms a deficient MMR system, which is biologically equivalent to MSI-H status. Both methods yield similar results, but IHC is often used as a first-line screen due to its relative speed and accessibility.
Tumors are classified into three categories based on test results. Microsatellite Instability-High (MSI-H) means a high percentage (typically 30% or more) of microsatellites are unstable, or MMR proteins are absent. Microsatellite Stable (MSS) tumors show no instability, while Microsatellite Instability-Low (MSI-L) tumors show only a small degree of instability. Clinically, MSI-L tumors are generally grouped with MSS tumors, leaving MSI-H as the primary category of interest.
Clinical Implications for Treatment
The MSI-H status is highly significant in clinical practice because it predicts how a tumor will respond to specific therapies. The massive number of genetic errors in MSI-H tumors leads to the production of many abnormal proteins, called neoantigens, on the surface of the cancer cells. These numerous, foreign-looking neoantigens make the tumor highly visible to the body’s immune system.
This high visibility makes MSI-H tumors exceptionally responsive to immune checkpoint inhibitors, a type of immunotherapy. These drugs work by releasing the natural “brakes” on the immune system, allowing the patient’s own T-cells to recognize and attack the highly mutated cancer cells. MSI-H status was the first biomarker approved by the FDA as a tissue-agnostic indicator for immunotherapy, meaning the treatment is effective regardless of the cancer’s origin.
In advanced or metastatic disease, response rates to immune checkpoint inhibitors are significantly higher in MSI-H tumors than in MSS tumors. For some early-stage cancers, particularly colorectal cancer, MSI-H status often indicates a more favorable prognosis following surgery alone. Conversely, MSI-H tumors in stage II colorectal cancer gain little benefit from traditional chemotherapy like 5-fluorouracil, leading to recommendations that this treatment be avoided.
MSI-H and Hereditary Cancer Syndromes
While MSI-H status can arise spontaneously within a tumor, it is also strongly linked to a common inherited condition called Lynch Syndrome. Lynch Syndrome is caused by an inherited, or germline, mutation in one of the MMR genes. When a person inherits one defective copy of an MMR gene, their cells are predisposed to MMR failure, leading to the development of MSI-H tumors at a younger age and across multiple organs.
The presence of an MSI-H tumor, particularly in common locations like the colon or endometrium, is a strong signal that Lynch Syndrome may be present. Studies show that a significant percentage of patients with MSI-H tumors will test positive for a germline mutation indicative of Lynch Syndrome. The association is now considered so strong that finding an MSI-H tumor should prompt further germline genetic testing, regardless of the cancer type or family history.
Identifying Lynch Syndrome has profound implications that extend beyond the individual’s current cancer treatment. It allows for increased cancer surveillance for the patient, including screening for other associated cancers like gastric or ovarian cancer. Crucially, it also enables genetic counseling and testing for family members who may have inherited the same gene mutation, allowing them to take proactive measures to manage their own cancer risk.