Microsatellite instability (MSI) is an important biomarker in modern medicine, particularly in oncology. It reflects a specific genetic characteristic found in tumors, offering insights into their biological behavior. Understanding MSI helps medical professionals make informed decisions regarding diagnosis, prognosis, and therapeutic strategies for patients, guiding personalized treatment approaches.
What is Microsatellite Instability?
Microsatellites are short, repetitive DNA sequences found throughout human genome. These sequences are prone to errors during DNA replication because their repetitive nature can cause the DNA polymerase enzyme to slip. Normally, these replication errors, such as insertions or deletions of repeat units, are corrected by the body’s DNA mismatch repair (MMR) system.
Microsatellite instability occurs when the mismatch repair system is not functioning correctly. If the MMR system fails to correct these errors, the length of the microsatellite sequences can change. This accumulation of altered microsatellite lengths in tumor cells, compared to normal tissue, defines microsatellite instability. The presence of these length alterations indicates a deficiency in the cell’s ability to repair DNA errors.
Why is MSI Testing Performed?
MSI testing is performed primarily to identify specific cancer types that arise from a dysfunctional DNA mismatch repair system. This genetic signature is common in certain solid tumors, including colorectal, endometrial, gastric, and ovarian cancers. Detecting MSI helps to classify these tumors, which can influence how they are managed.
Another reason for MSI testing involves predicting how a tumor might respond to particular therapeutic approaches. Cancers with high levels of microsatellite instability often exhibit a higher number of somatic mutations, leading to the production of abnormal proteins that the immune system can recognize. This characteristic makes them more susceptible to certain immunotherapies, which work by enhancing the body’s own immune response against cancer cells.
Furthermore, MSI testing plays a role in screening for inherited cancer predisposition syndromes. A high level of microsatellite instability in a tumor can suggest the presence of an underlying inherited condition, such as Lynch syndrome. Identifying these predispositions allows for further genetic counseling and testing for the patient and their family members, potentially leading to early detection or prevention strategies for future cancers.
Types of Samples and Testing Methods
MSI testing primarily utilizes biological samples derived from the patient’s tumor. The most common sample type is formalin-fixed, paraffin-embedded (FFPE) tumor tissue, obtained from a biopsy procedure or surgical resection. In certain situations, a matched normal tissue sample, often derived from blood, is also used to compare against the tumor DNA and identify somatic changes.
Laboratory techniques employed to detect MSI involve analyzing the length variations in specific microsatellite markers. Polymerase Chain Reaction (PCR) is a widely used method where fluorescently labeled primers amplify a panel of microsatellite markers. The amplified fragments are then separated by size using capillary electrophoresis, allowing for the detection of length shifts characteristic of instability.
Next-Generation Sequencing (NGS) is another method that can assess MSI status. NGS technology simultaneously sequences many DNA fragments, providing a comprehensive view of genetic alterations across the genome, including microsatellite regions. This approach can identify MSI by analyzing changes in the number of repeat units in multiple microsatellite loci, often as part of a broader genomic profiling panel.
Understanding MSI Test Results
MSI test results are categorized into three classifications, each indicating a different genetic characteristic of the tumor. Microsatellite Instability-High (MSI-H) signifies that two or more of the analyzed microsatellite markers show length alterations. This indicates a widespread defect in the DNA mismatch repair system within the tumor cells.
Microsatellite Instability-Low (MSI-L) means that one microsatellite marker shows instability. This level of instability is not considered indicative of a widespread mismatch repair deficiency. Microsatellite Stable (MSS) indicates that none of the tested microsatellite markers show any length alterations.
Both MSI-L and MSS classifications suggest that the tumor’s DNA mismatch repair system is largely functional and effectively corrects replication errors. The distinction between MSI-L and MSS is often not clinically significant; both are frequently grouped as “microsatellite stable.” The presence of MSI-H, however, represents a distinct genetic profile with different clinical implications.
Clinical Implications of MSI Status
The MSI status of a tumor significantly influences clinical decisions and patient management strategies. For patients with certain advanced cancers, particularly colorectal and endometrial cancers, an MSI-High status can indicate eligibility for specific immunotherapy treatments. These immunotherapies, such as checkpoint inhibitors, are designed to unleash the body’s immune system to attack cancer cells. Tumors with MSI-H often have a higher tumor mutational burden, making them more responsive to these agents.
MSI-High status is also a strong indicator for potential underlying hereditary cancer syndromes. Approximately 15-20% of all colorectal cancers exhibit MSI-H, and a significant portion of these cases are associated with Lynch syndrome. Lynch syndrome is an inherited condition caused by germline mutations in mismatch repair genes, significantly increasing the risk of several cancers, including colorectal and endometrial cancers.
Identifying MSI-H in a tumor prompts further genetic testing for the patient to confirm Lynch syndrome. If confirmed, this information is then used for personalized cancer surveillance for the patient and cascade testing for family members. This proactive approach allows for early detection and preventative measures, improving outcomes for individuals at increased genetic risk.