Overview
Microsatellite instability and mismatch repair deficiency represent a molecular condition caused by the loss of normal DNA mismatch repair function. Microsatellite instability reflects genetic hypermutability that occurs when mismatch repair proteins fail to correct replication errors. Deficient mismatch repair results from inactivation or loss of key proteins, including MLH1, MSH2, MSH6, and PMS2, with MLH1 and MSH2 accounting for the majority of cases. The presence of MSI serves as phenotypic evidence of impaired mismatch repair and is most commonly associated with colorectal cancer, particularly tumors of the right colon, but is also important in endometrial, gastric, and other malignancies.
Symptoms
MSI or dMMR itself does not cause specific symptoms. Clinical manifestations depend on the underlying malignancy. Patients may present with symptoms related to colorectal, endometrial, gastric, ovarian, pancreatic, or other cancers where MSI or dMMR is involved. These may include altered bowel habits, abdominal pain, unexplained weight loss, abnormal uterine bleeding, or anemia. In many cases, MSI or dMMR is detected during tumor evaluation rather than based on clinical symptoms alone.
Causes
MSI or dMMR occurs due to the loss of function of the DNA mismatch repair system. This system normally corrects base pair mismatches during DNA replication. Inactivation of mismatch repair genes leads to the accumulation of mutations, particularly in microsatellite regions. Deficiency may arise from germline mutations, as seen in Lynch syndrome, or from sporadic causes such as MLH1 promoter methylation. The resulting genetic instability contributes to tumor development and progression, while also producing a high mutational burden within affected tumors.
Risk Factors
Risk factors include a personal or family history of colorectal or endometrial cancer, early onset malignancy, and tumors with specific histological features such as poor differentiation, mucinous components, and prominent tumor-infiltrating lymphocytes. MSI and dMMR are also associated with reduced metastatic potential in certain cancers. Testing is indicated across a wide range of malignancies, including colorectal, endometrial, gastric, small intestinal, ovarian, biliary, pancreatic, and brain tumors. Inadequate tumor tissue, tumor heterogeneity, and technical limitations may influence test accuracy.
Prevention
There are no direct preventive measures for MSI or dMMR development, as these are driven by genetic and epigenetic alterations. Prevention in a clinical context focuses on early identification and appropriate testing. Accurate sample collection using tumor tissue, blood, or formalin-fixed paraffin-embedded samples is essential. Detection through immunohistochemistry, PCR-based methods, or next-generation sequencing guides prognosis, identifies Lynch syndrome, and supports personalized treatment decisions. Early recognition of MSI or dMMR status enables optimal use of immunotherapy, improves risk stratification, and supports effective cancer management strategies.
