Microsatellite instability (MSI) is a distinct genetic feature found in certain cancers. It occurs when specific segments of a cell’s DNA exhibit alterations in length. Understanding MSI is increasingly important in oncology, as it can significantly influence how cancer behaves and responds to treatments. This genetic signature provides valuable insights into a tumor’s biology.
Understanding Microsatellite Instability
Microsatellites are short, repetitive DNA sequences found throughout the human genome. These sequences typically consist of one to six base pairs repeated multiple times, like a stutter in the genetic code. During normal cell division, DNA replication machinery copies these sequences. The mismatch repair (MMR) system corrects errors that occur during this copying process, ensuring genetic material fidelity.
When the MMR system functions properly, it identifies and corrects mispaired bases or small insertions and deletions in the DNA. However, if the MMR system becomes deficient, these replication errors accumulate, particularly within microsatellite regions. This accumulation of uncorrected errors leads to changes in microsatellite length, termed microsatellite instability. MSI indicates the cell has lost its ability to repair DNA replication mistakes.
Testing for MSI
Determining a tumor’s MSI status involves analyzing tumor tissue for genetic alterations. Two primary methods are used: Polymerase Chain Reaction (PCR) and Immunohistochemistry (IHC). PCR testing directly measures changes in the length of specific microsatellite markers, comparing tumor DNA to normal DNA from the same patient. New or altered microsatellite fragments indicate instability.
Immunohistochemistry assesses the presence or absence of specific MMR proteins (MLH1, MSH2, MSH6, and PMS2) within tumor cells. A lack of these proteins suggests a deficient MMR system, which typically correlates with MSI. Tumors are typically classified as MSI-High (MSI-H), indicating significant instability or loss of MMR proteins, or Microsatellite Stable (MSS), indicating no instability or intact MMR. An intermediate category, MSI-Low, is also reported, where a low level of instability is detected.
MSI and Associated Cancers
Microsatellite instability is observed in various cancer types, with varying frequencies. It is particularly common in gastrointestinal and gynecological malignancies. Colorectal cancer is one of the most well-known cancers associated with MSI, with approximately 15% to 20% of cases exhibiting MSI-High status. This includes sporadic cases and those linked to Lynch syndrome.
Endometrial cancer also frequently shows MSI, with prevalence ranging from approximately 15% to 30%. Gastric cancer represents another significant group, where MSI-High is found in about 10% to 22% of cases, influencing treatment approaches. MSI can also be found in other tumor types, including small intestinal cancer and ovarian cancer.
Implications for Treatment and Outlook
Knowing a tumor’s MSI status has profound implications for cancer treatment and a patient’s prognosis. MSI-High tumors often respond favorably to specific types of systemic therapies, particularly immunotherapies known as immune checkpoint inhibitors. These drugs, such as pembrolizumab and nivolumab, enable the patient’s immune system to recognize and attack cancer cells. The high number of mutations in MSI-H tumors can lead to abnormal proteins that make cancer cells more visible targets for the immune system.
Immune checkpoint inhibitors have received approval for treating MSI-High tumors across various cancer types, regardless of their origin. In metastatic colorectal cancer, these therapies have shown sustained clinical responses. MSI status can offer insights into a patient’s outlook. MSI-High colorectal cancers, for example, are often associated with a better prognosis compared to microsatellite stable tumors, particularly in earlier stages. This information helps guide personalized treatment strategies and provides a clearer understanding of potential outcomes for patients.