Microsatellite instability (MSI) refers to a specific genetic alteration found in some cancers, particularly colorectal cancer. It indicates errors in short, repetitive DNA sequences within tumor cells, which arise from a compromised DNA repair system. Understanding MSI status is important as it influences both the prognosis and treatment approach for patients with colon cancer, guiding medical decisions.
Understanding Microsatellite Instability
Microsatellites are short, repetitive stretches of DNA, typically one to six base pairs in length, repeated multiple times throughout the genome. These sequences are present in thousands of locations within an organism’s DNA. While their exact length can vary between individuals, each person generally has microsatellites of a set length.
“Instability” refers to changes in the length of these repetitive DNA sequences within cancer cells, which differ from the original inherited pattern. These alterations, such as insertions or deletions of repeat units, occur at a higher rate in unstable microsatellites. This hypermutability is a hallmark of impaired DNA mismatch repair (MMR).
DNA mismatch repair (MMR) genes are responsible for correcting errors that spontaneously occur during DNA replication. The MMR system fixes single base mismatches or small insertions and deletions that escape the proofreading function of DNA polymerases. Proteins involved in MMR form a complex that binds to the mismatched DNA, excises the error, and inserts the correct sequence.
When MMR genes are deficient or not functioning properly, cells are unable to correct these replication errors, leading to an accumulation of mutations. This accumulation of errors results in the creation of new microsatellite fragments, which is the basis of microsatellite instability. MSI is a direct consequence of the loss of MMR activity, signifying that the repair system is not working normally.
Detecting Microsatellite Instability
Testing for MSI is a standard practice for individuals diagnosed with colorectal cancer. This testing helps determine the genetic stability of the tumor’s DNA. The two primary methods used to detect MSI are Polymerase Chain Reaction (PCR) and Immunohistochemistry (IHC).
PCR-based assays analyze specific microsatellite markers to identify changes in their length compared to normal tissue. If two or more markers show instability, the tumor is classified as MSI-High (MSI-H). If only one marker is unstable, it is considered MSI-Low (MSI-L), and if no instability is found, the tumor is Microsatellite Stable (MSS).
Immunohistochemistry (IHC) assesses the presence or absence of the four main MMR proteins: MLH1, MSH2, MSH6, and PMS2, in tumor tissue. A loss of expression of one or more of these proteins indicates a deficient MMR (dMMR) system, which is generally equivalent to MSI. IHC is a widely used and cost-effective technique. Both PCR and IHC methods are highly concordant.
Treatment Implications of MSI
The MSI status of a colon cancer tumor significantly influences treatment decisions and patient outcomes. MSI-High (MSI-H) tumors show a different response to conventional chemotherapy compared to Microsatellite Stable (MSS) tumors. Specifically, MSI-H colorectal cancers may show a poor response to 5-fluorouracil (5-FU) based adjuvant chemotherapy in early stages. This suggests that certain traditional chemotherapies may not be as effective for patients with MSI-H tumors.
In contrast, MSI-H tumors are highly responsive to immunotherapy, particularly immune checkpoint inhibitors such as pembrolizumab, nivolumab, and ipilimumab. These medications activate the body’s immune system to recognize and attack cancer cells. MSI-H tumors accumulate numerous DNA mutations, leading to the production of abnormal proteins called neoantigens, which make the tumor more visible to the immune system.
MSI-H tumors are often described as “immune hot” tumors because they exhibit inflammation and are infiltrated by immune cells. This immune-rich environment makes them susceptible to immune checkpoint blockade, where inhibitors “turn off” the signals cancer cells use to evade immune detection. Clinical trials have demonstrated impressive and durable responses, including complete responses, in patients with MSI-H metastatic colorectal cancer treated with these immunotherapies.
The improved prognosis associated with MSI-H colon cancers, when treated with appropriate targeted therapies, is a significant advancement. While MSI-H tumors in early stages often have a better prognosis even without adjuvant chemotherapy, immunotherapy has revolutionized the management of advanced MSI-H colorectal cancer, offering substantial benefits in progression-free and overall survival. This underscores the importance of MSI testing to guide personalized treatment strategies.
MSI and Inherited Cancer Risk
A significant connection exists between MSI-High colon cancer and inherited cancer syndromes, most notably Lynch Syndrome. Lynch Syndrome is the most common inherited cause of colon cancer, resulting from inherited mutations in DNA mismatch repair (MMR) genes, such as MLH1, MSH2, MSH6, and PMS2.
Individuals diagnosed with MSI-H colon cancer are often recommended for genetic counseling and germline testing to determine if they have Lynch Syndrome. Germline testing looks for inherited genetic changes that cause the syndrome. This process helps differentiate between sporadic MSI-H tumors (which are not inherited) and those linked to Lynch Syndrome.
A Lynch Syndrome diagnosis has substantial implications for both the patient and their family members. Patients with Lynch Syndrome have a significantly increased lifetime risk of developing other cancers, including endometrial, ovarian, gastric, small intestine, urinary tract, and pancreatic cancers. Specific screening and surveillance protocols are recommended for these individuals.
Since Lynch Syndrome is an autosomal dominant condition, there is a 50% chance that each child of an affected parent will inherit the gene mutation. This necessitates cascade testing for at-risk relatives. Genetic counseling provides families with detailed information about their cancer risks and personalized screening recommendations.