What Does Microsatellite Instability (MSI) Mean?

Microsatellites are short, repeating stretches of DNA. They are scattered throughout our genes. Cells normally fix small copying errors that happen in them. Microsatellite instability, or MSI, means those errors are not being repaired. They have built up inside the tumor's DNA.

When many errors build up, a tumor is called MSI-high. This tells doctors two useful things. First, MSI-high tumors tend to respond unusually well to immunotherapy. This is a class of drugs called checkpoint inhibitors. The result can open up a treatment path that would not otherwise be considered. Second, MSI-high status can be a clue. It may mean an inherited condition, most often Lynch syndrome, runs in the family. This may prompt genetic counseling for you and your relatives.

MSI is caused by a breakdown in the mismatch repair system. This is the cellular machinery that fixes small DNA errors. A tumor described as "deficient mismatch repair," or dMMR, is the same underlying finding. It is just measured with a different test. dMMR testing uses immunohistochemistry to look for missing repair proteins. MSI testing looks at the DNA repeats themselves. Reports may use either term. For treatment purposes, doctors treat them as the same thing.

In 2017, pembrolizumab became the first cancer drug approved by the FDA based purely on a biomarker. That biomarker was MSI-H or dMMR status. It did not matter which organ the cancer started in. This was the FDA's first tissue-agnostic approval. The same drug could be used for MSI-high colorectal cancer, endometrial cancer, stomach cancer, or more than a dozen other cancer types. The only requirement was the biomarker itself.

In the trials behind this approval, roughly 40% of people with MSI-H or dMMR advanced cancers responded to treatment. Most of those responses lasted six months or longer. Since then, more MSI-targeted treatment options have followed.

MSI-high status does not guarantee a response to immunotherapy. It raises the odds substantially. But not everyone with this result benefits. It also does not replace other biomarker testing. Your cancer may have other relevant results, such as PD-L1 or specific driver mutations. These factor into the same treatment decision. And an MSI-high result is not, by itself, a genetic test for Lynch syndrome. It is a signal. It prompts your team to discuss whether formal genetic testing makes sense.

MSI testing does not require immediate action on its own. But the result is worth discussing promptly. It can open up treatment options, particularly if standard chemotherapy has not worked or is not a good fit.

• Is my tumor MSI-high or dMMR, or was neither found?
• Does this open up immunotherapy as an option for me?
• Should I or my family members consider genetic counseling or testing for Lynch syndrome?
• How does this result fit with any other biomarker testing I've had?

If your MSI-high or dMMR result prompts a genetic counseling referral, the process is usually straightforward. A genetic counselor reviews your personal and family cancer history, explains what a positive or negative test might mean, and orders a blood or saliva test looking directly at the genes involved in Lynch syndrome. If a mutation is found, your close relatives can then be offered testing for that same specific change, which is far simpler and cheaper than broad testing without a known starting point. Finding Lynch syndrome also means earlier and more frequent screening for colon and other related cancers going forward, for you and affected relatives.

An MSI-high result found in your tumor doesn't automatically mean you carry Lynch syndrome; sporadic, non-inherited MSI-high tumors happen too, especially in older adults, through a different mechanism unrelated to inherited genes. Only formal genetic testing can tell the two apart. If genetic testing does confirm Lynch syndrome, your first-degree relatives, parents, siblings, and children, each have roughly a 50% chance of carrying the same mutation, and are typically offered testing and earlier screening themselves once your result is known.

• FDA — Pembrolizumab first tissue/site-agnostic approval for MSI-H/dMMR solid tumors