Microsatellite instability (MSI) is a condition resulting from a defect in the DNA mismatch repair (MMR) system. This defect leads to a higher mutation rate and the accumulation of errors in DNA sequences called microsatellites.
Understanding Microsatellite Instability
Microsatellites are short, repetitive sequences of DNA that are prone to errors during DNA replication. The MMR system normally corrects these errors. When the MMR system is defective, these errors accumulate, resulting in MSI. This instability can alter gene function and contribute to the development of various cancers.
Causes of MSI
The MMR system can be impaired due to:
- Inherited mutations: Germline mutations in MMR genes (e.g., MLH1, MSH2, MSH6, PMS2) can cause Lynch syndrome (hereditary non-polyposis colorectal cancer or HNPCC), a condition that significantly increases the risk of several cancers.
- Acquired mutations: Somatic mutations or epigenetic silencing (e.g., methylation of the MLH1 promoter) can also disrupt MMR function. These acquired changes are more common in sporadic cancers.
Cancers Associated with MSI
MSI is frequently found in:
- Colorectal cancer: Approximately 15% of colorectal cancers exhibit MSI.
- Endometrial cancer: A significant portion of endometrial cancers demonstrates MSI.
- Gastric cancer: MSI is observed in a subset of gastric cancers.
- Other cancers: MSI can also be found in other cancers, including ovarian, small bowel, and sebaceous gland carcinomas.
Clinical Significance of MSI
The presence of MSI has significant clinical implications:
- Prognosis: In some cancers like colorectal cancer, MSI-high (MSI-H) status is associated with a better prognosis in early stages.
- Treatment response: MSI-H tumors are often highly responsive to immune checkpoint inhibitors, a type of immunotherapy. This is because the high mutation burden in MSI-H tumors leads to the production of more neoantigens, making them more visible to the immune system.
- Diagnosis: MSI testing helps identify individuals with Lynch syndrome, allowing for genetic counseling and screening for other associated cancers.
MSI Testing
MSI is typically assessed using:
- PCR-based assays: These assays examine microsatellite markers to detect variations in repeat length, indicating instability.
- Immunohistochemistry (IHC): IHC is used to detect the presence or absence of MMR proteins. Loss of MMR protein expression suggests a defect in the MMR system.
In conclusion, microsatellite instability (MSI) is a molecular phenotype indicating a deficient DNA mismatch repair system, leading to increased mutation rates and found in various cancers, impacting prognosis, treatment decisions, and identification of hereditary cancer syndromes.
