A biomarker is a measurable indicator of a biological state or process within the body. These indicators provide insights into normal biological processes, disease progression, or the body’s response to treatment. Microsatellite instability (MSI) is a specific genetic alteration found within tumor cells. It functions as an important biomarker in oncology, guiding both diagnosis and therapeutic strategies.
What is Microsatellite Instability?
Microsatellites are short, repetitive DNA sequences found throughout the human genome. During DNA replication, errors can occur within these regions, leading to insertions or deletions of base pairs. Normally, a specialized cellular system called the DNA mismatch repair (MMR) system identifies and corrects these errors.
The MMR system involves proteins like MLH1, MSH2, MSH6, and PMS2, which maintain genomic integrity. Microsatellite instability arises from defects or non-functional mutations in one or more of these MMR genes. When the MMR system is impaired, replication errors accumulate in microsatellite regions, causing their length to become unstable in tumor cells compared to normal cells.
Tumors are categorized by the extent of these changes. Tumors with many unstable microsatellites are classified as MSI-High (MSI-H). If only a few markers show instability, the tumor is MSI-Low (MSI-L). Tumors without detectable changes are Microsatellite Stable (MSS).
The Clinical Significance of MSI
Microsatellite instability serves as both a prognostic and a predictive biomarker in cancer care. As a prognostic marker, MSI-High status indicates a more favorable outcome in certain early-stage cancers, such as stage II colorectal cancer. It is associated with a lower risk of recurrence without adjuvant chemotherapy.
MSI’s role as a predictive marker is notable in guiding therapeutic decisions. Tumors with MSI-High status respond favorably to specific systemic therapies, especially immune checkpoint inhibitors. This responsiveness is due to MSI-H tumors generating numerous abnormal proteins that can be recognized by the immune system.
MSI-High status also has implications for hereditary cancer syndromes. MSI is a characteristic feature of Lynch syndrome, an inherited condition caused by germline mutations in MMR genes. Identifying MSI in a tumor often prompts further genetic testing for Lynch syndrome, which can inform cancer screening strategies for the patient and their family members.
Detecting MSI
Identifying microsatellite instability in tumor samples involves laboratory techniques that assess the DNA mismatch repair system. One common approach is Polymerase Chain Reaction (PCR)-based assays. These analyze the length of specific microsatellite markers. DNA is extracted from both tumor and normal tissue, and PCR amplifies these regions. Comparing the amplified fragments reveals shifts in length if MSI is present.
Another widely used method is Immunohistochemistry (IHC). IHC detects the presence or absence of the four main MMR proteins (MLH1, MSH2, MSH6, and PMS2) within tumor cells. If one or more of these proteins are missing, it indicates a deficient MMR system, strongly correlated with MSI-High status.
Next-generation sequencing (NGS) is an evolving method for MSI detection, offering comprehensive genomic profiling. NGS can directly identify somatic mutations in MMR genes or assess the overall mutational burden, including alterations in microsatellite regions. This technique provides a quantitative measure of MSI, potentially offering more detailed information about the tumor’s genetic landscape.
MSI and Cancer Treatment
A patient’s microsatellite instability status influences their treatment options, particularly regarding immunotherapy. Tumors classified as MSI-High or mismatch repair deficient (dMMR) exhibit many somatic mutations. These lead to the production of abnormal proteins called neoantigens, which the immune system recognizes as foreign. This makes MSI-H/dMMR tumors highly susceptible to immune attack.
Immune checkpoint inhibitors, a class of immunotherapy drugs, work by blocking proteins that suppress the immune response, such as PD-1 or PD-L1. By lifting this “brake,” these drugs allow the body’s T-cells to more effectively target and destroy cancer cells. The high neoantigen load in MSI-H tumors makes them responsive to this therapy, often leading to durable responses.
This strong correlation led to the “tumor-agnostic” or “pan-cancer” approval of certain immune checkpoint inhibitors for any solid tumor that is MSI-High or dMMR, regardless of its origin. For example, patients with advanced MSI-H colorectal cancer or endometrial cancer may receive pembrolizumab, a PD-1 inhibitor, as a standard treatment option.
Cancers Where MSI is Relevant
Microsatellite instability testing is routinely performed and clinically significant across several cancer types. Colorectal cancer is where MSI was first extensively studied, with approximately 15% of all colorectal cancers exhibiting MSI-High status. Here, MSI testing guides decisions regarding adjuvant chemotherapy for early-stage disease and determines eligibility for immunotherapy in advanced stages.
Endometrial cancer frequently displays MSI, with around 20% to 30% of cases being MSI-High. MSI testing in endometrial cancer identifies patients who may benefit from immune checkpoint inhibitors, especially in recurrent or advanced settings. It also helps screen for underlying Lynch syndrome.
Gastric cancer shows MSI in about 10% to 20% of cases, primarily in the intestinal subtype. MSI-High gastric cancers are associated with distinct molecular features and a different clinical course, making MSI status a predictor of response to immunotherapy. Small bowel cancer, though less common, also has a notable proportion of MSI-High tumors, often linked to Lynch syndrome, where MSI testing guides both genetic counseling and treatment selection.