Mismatch Repair (MMR) and Microsatellite Instability (MSI) Across Cancer Types

by Jason Wasserman MD PhD FRCPC
March 26, 2026

Mismatch repair (MMR) and microsatellite instability (MSI) testing tell doctors whether a tumour’s internal DNA repair system is working properly. When that system breaks down, the cancer cells accumulate a large number of genetic errors — and those errors turn out to be exactly what makes these tumours sensitive to a powerful type of cancer drug called immunotherapy. This test also matters for a second reason: it can reveal whether the cancer developed because of an inherited condition called Lynch syndrome, which raises cancer risk for other members of your family. In 2017, a drug called pembrolizumab (Keytruda) became the first cancer treatment ever approved based purely on this one test result, regardless of which organ the cancer started in — a historic milestone in cancer medicine. Understanding what your MMR/MSI result means is an important step in making sense of your diagnosis and treatment options.

What the test looks for

Every time a cell divides, it has to copy all of its DNA. This copying process is not perfect — small errors happen regularly. Your body has a built-in repair system called the mismatch repair (MMR) system, which finds and fixes these errors before they become permanent. Think of it like a spell-checker for your genetic code.

The MMR system is made up of four proteins — MLH1, PMS2, MSH2, and MSH6 — that work together in pairs: MLH1 pairs with PMS2, and MSH2 pairs with MSH6. If one protein in a pair is lost or stops working, the whole repair function for that pair fails.

When the MMR system stops working within a cancer cell, errors accumulate across the cell’s DNA. This shows up in a very specific way: short repetitive stretches of DNA called microsatellites become unstable and change in length. When a lab test detects this pattern, the tumour is called microsatellite instability-high (MSI-H). A tumour whose MMR system has broken down is called MMR-deficient (dMMR). A tumour in which everything is working normally is called MMR-proficient (pMMR) or microsatellite-stable (MSS).

Why do these errors matter for treatment? When a tumour has accumulated many errors, it produces many abnormal proteins — called neoantigens — that appear on the surface of cancer cells. These look foreign to your immune system, so your body’s fighting cells (T cells) try to attack them. But cancers can block T cells using molecular “off switches.” Immunotherapy drugs called immune checkpoint inhibitors work by releasing those off switches, allowing T cells to attack the cancer. Tumours with dMMR/MSI-H tend to respond well to these drugs because the large number of errors gives the immune system many targets to work with.

MMR/MSI status is measured in two main ways. The first is a test called immunohistochemistry (IHC), which uses special stains to check whether the four MMR proteins are present in the tumour tissue. The second uses DNA testing — either PCR or next-generation sequencing — to examine the tumour’s DNA directly for signs of instability. Both approaches test for the same underlying problem and usually agree.

MMR and MSI by cancer type

Although dMMR/MSI-H can occur in almost any cancer, it is much more common in some cancers than others. The sections below explain where it most often appears, what it means for treatment in each cancer type, and when it may point to Lynch syndrome.

Colorectal cancer

Colorectal cancer is where MMR/MSI testing was first developed and is best understood. About 15% of colorectal cancers that have not yet spread to distant organs are dMMR/MSI-H. In cancers that have already spread (metastatic disease), the proportion drops to around 4-5%.

Of all dMMR colorectal cancers, roughly one quarter to one third are caused by Lynch syndrome. The rest are sporadic — meaning the repair system failed due to a change within the tumour itself rather than an inherited gene change. Telling these apart is important, and is explained in the Lynch syndrome section below.

For metastatic dMMR/MSI-H colorectal cancer, pembrolizumab is approved as a first-line treatment and has been shown to work better than standard chemotherapy in this group. In early-stage colorectal cancer, a dMMR result is associated with a better outlook and also affects decisions about chemotherapy after surgery. The MMR and MSI in Colorectal Cancer article on this site covers these details fully.

Endometrial cancer (cancer of the uterus lining)

Endometrial cancer has the highest rate of dMMR/MSI-H of any common cancer — about 25 to 30% of endometrial cancers are dMMR. This makes it the tumour type most frequently affected in terms of actual numbers of patients.

Most dMMR endometrial cancers are sporadic. However, Lynch syndrome is also a significant cause, and endometrial cancer is the most common Lynch syndrome-related cancer in women — the lifetime risk is 40 to 60% in some women, depending on which gene is affected. Because of this strong connection, MMR testing is now standard for all newly diagnosed cases of endometrial cancer.

Immunotherapy has transformed the treatment of advanced dMMR endometrial cancer. Pembrolizumab (Keytruda), dostarlimab (Jemperli), and durvalumab (Imfinzi) are all approved for advanced or recurrent dMMR endometrial cancer, either alone or combined with chemotherapy. A few years ago, advanced endometrial cancer had very limited treatment options; today, dMMR patients have several proven immunotherapy-based choices.

Stomach cancer and small bowel cancer

About 5-10% of stomach cancers are dMMR/MSI-H. These tumours tend to respond well to pembrolizumab, which is approved in this setting. Small bowel (small intestine) cancers have a higher rate of dMMR — around 14% — and are particularly associated with Lynch syndrome. When dMMR is found in a stomach or small bowel cancer, Lynch syndrome evaluation should be discussed.

Pancreatic cancer

Only about 1 to 2% of pancreatic cancers are dMMR/MSI-H — uncommon, but very important when it does occur. Pancreatic cancer is one of the hardest cancers to treat, and standard options are limited. For the small number of patients with dMMR pancreatic cancer, pembrolizumab can sometimes produce meaningful and lasting responses. Because dMMR is also strongly associated with Lynch syndrome in pancreatic cancer, genetic testing should always be part of the conversation when this result is found.

Ovarian cancer

About 2 to 5% of ovarian cancers overall are dMMR/MSI-H, though the rate is higher in a specific subtype called endometrioid ovarian cancer (around 10 to 15%). Lynch syndrome is a recognized cause, and a dMMR result in ovarian cancer warrants a discussion about genetic testing. Immunotherapy for dMMR ovarian cancer is supported by the pan-cancer pembrolizumab approval.

Prostate cancer

About 2 to 5% of prostate cancers are dMMR/MSI-H — more often in the most advanced, treatment-resistant form of the disease. Pembrolizumab is approved for these patients under the pan-cancer approval. Lynch syndrome is a recognized cause of some dMMR prostate cancers, and testing is now recommended as part of comprehensive molecular profiling for metastatic prostate cancer.

Bladder and urinary tract cancers

Cancers of the upper urinary tract — the kidney collecting system and the tube connecting the kidney to the bladder (ureter) — have among the strongest links to Lynch syndrome of any tumour type. Bladder cancer overall has a lower rate of dMMR, but any dMMR finding in a urinary tract cancer should prompt consideration of Lynch syndrome. Immunotherapy is already a standard part of urothelial cancer treatment; a dMMR result provides additional support for its use.

Bile duct cancer and other rare Lynch-associated cancers

Cancers of the bile ducts (called cholangiocarcinoma) have a dMMR rate of roughly 5 to 10%, and Lynch syndrome accounts for a meaningful portion of these. Brain tumours, certain skin gland tumours, and other rare cancers can also be associated with Lynch syndrome. Whenever dMMR is found in any of these less common cancer types, Lynch syndrome evaluation should be pursued. The pan-cancer pembrolizumab approval means that patients with any of these rare dMMR cancers can also be considered for immunotherapy.

Why is the test done

MMR/MSI testing serves three important purposes, and all three may apply simultaneously to the same patient.

To find out whether immunotherapy is an option

A dMMR/MSI-H result is one of the strongest predictors that a cancer will respond to immune checkpoint inhibitor drugs. Pembrolizumab is fully FDA-approved for any advanced dMMR/MSI-H solid tumour that has progressed after prior treatment — this approval covers any cancer type. In colorectal and endometrial cancer, immunotherapy is also approved in earlier treatment settings. If your cancer is dMMR/MSI-H and you have advanced disease, your oncologist will discuss whether immunotherapy is appropriate for you.

To screen for Lynch syndrome

Finding dMMR in a tumour is the standard first step in evaluating for Lynch syndrome. Lynch syndrome is one of the most common hereditary cancer syndromes — affecting about 1 in 280 people — but most cases are never diagnosed. Identifying it matters enormously because it affects your entire family: parents, siblings, and children each have a 50% chance of carrying the same inherited gene change. Those who do can take steps to catch or prevent cancers early. A dMMR result does not confirm Lynch syndrome — further testing is needed — but it means the possibility must be investigated.

To help predict the cancer’s behaviour

In some cancers, a dMMR result carries meaning beyond its role in guiding treatment. In early-stage colorectal cancer, it is generally associated with a better prognosis and affects decisions about chemotherapy after surgery. In endometrial cancer, knowing the MMR status is part of a broader molecular assessment that helps predict how the cancer is likely to behave.

How the test is performed

MMR/MSI testing is done on tumour tissue — usually from a biopsy or tissue removed during surgery. No additional procedure is usually needed; the tissue already collected for diagnosis is sufficient.

The most common first step is immunohistochemistry (IHC). A pathologist uses special stains to check whether the four MMR proteins are present in the cancer cells. Normal cells in the same tissue sample always stain positively, confirming the test worked. If any protein is absent from the cancer cells, this indicates MMR deficiency.

DNA-based testing — PCR or next-generation sequencing — checks the tumour DNA directly for instability. When a comprehensive molecular panel is ordered (as is increasingly routine in advanced cancer), MSI status is usually calculated automatically alongside all other biomarker results.

How results are reported

Depending on which test was used, your report will use one of these sets of terms:

MMR-proficient (pMMR). All four proteins are present. The repair system is intact. This corresponds to MSS (microsatellite stable) on DNA testing.
MMR-deficient (dMMR). One or more proteins are absent. The repair system has broken down. The report will specify which proteins are missing — for example, “loss of MLH1 and PMS2.” This corresponds to MSI-H on DNA testing.
MSS (microsatellite stable). The DNA shows no instability. This corresponds to pMMR.
MSI-H (microsatellite instability-high). The DNA shows significant instability. This corresponds to dMMR.
MSI-L (microsatellite instability-low). A borderline result. For most treatment decisions, this is managed the same as MSS, though your oncologist will interpret it in the full context of your results.

Some reports include both IHC and DNA testing results, particularly when one test was done to confirm or clarify the other.

What the result means

pMMR / MSS — repair system intact

A normal result means the cancer’s repair system is working. Immunotherapy based on MMR/MSI status alone is generally not recommended, as checkpoint inhibitors tend not to work in pMMR/MSS tumours. Lynch syndrome is also unlikely to be the cause of this cancer. Your treatment will be planned based on the cancer type, stage, and other test results.

dMMR / MSI-H — repair system broken down

An abnormal result has two main implications that need to be addressed together:

Immunotherapy may be an option. If your cancer is advanced or metastatic, pembrolizumab or another approved checkpoint inhibitor may be suitable for you, depending on the specific situation. Your oncologist will discuss this.
Lynch syndrome needs to be considered. Further testing is needed to find out whether your dMMR result is due to Lynch syndrome or a spontaneous, non-inherited change in the tumour. This will involve additional tumour tests and may lead to a referral to a genetic counsellor. It does not mean Lynch syndrome has been confirmed — only that it needs to be looked into.

Lynch syndrome: what it is and why it matters for your family

Lynch syndrome is a hereditary condition caused by an inherited mutation in one of the four MMR genes — MLH1, MSH2, MSH6, or PMS2. People with Lynch syndrome are born with one faulty copy of an MMR gene in every cell of their body. When the remaining healthy copy of that gene is also damaged over time, the repair system fails, and cancer can develop. This is why Lynch syndrome raises the lifetime risk of several cancers, including colorectal cancer, endometrial cancer, stomach cancer, ovarian cancer, and urinary tract cancer.

Lynch syndrome is passed through families. Each child, sibling, or parent of someone with a confirmed Lynch syndrome mutation has a 50% chance of carrying the same mutation. Those who do carry it benefit enormously from knowing that regular screening (such as more frequent colonoscopies or other monitoring, depending on the specific gene involved) can catch cancers early, when treatment is most effective.

How do you tell Lynch syndrome from a sporadic dMMR result?

This is the most important follow-up question after any dMMR result. The answer depends on which proteins are missing and what further tests show:

Loss of MLH1 and PMS2 together is the most common pattern. In most cases, this is caused by a sporadic, non-inherited change called MLH1 methylation — a chemical switch that turns off the MLH1 gene only within the tumour, not throughout the body. It is not hereditary. In colorectal cancer, finding a BRAF V600E mutation alongside this pattern is further evidence of a sporadic cause. If neither MLH1 methylation nor BRAF V600E is found, Lynch syndrome becomes more likely, and a blood test for inherited mutations is recommended.
Loss of MSH2 and MSH6 together is strongly associated with Lynch syndrome and should always prompt a genetics referral and blood (germline) testing.
Loss of MSH6 alone or PMS2 alone is also associated with Lynch syndrome and warrants genetic evaluation.

What happens if Lynch syndrome is confirmed?

If a blood test confirms an inherited MMR gene mutation, Lynch syndrome is diagnosed. For you, this means your oncology and follow-up care will be tailored to account for the elevated risk of other Lynch-associated cancers — with closer surveillance, additional screening tests, and discussions about options to lower future risk.

For your family, it means your biological relatives should be offered genetic testing. This process — called cascade testing — involves offering a blood test to your siblings, parents, and children so they can find out whether they also carry the mutation. Those who test positive can begin appropriate cancer screening before any cancer has a chance to develop undetected. This is how Lynch syndrome identification genuinely saves lives in families.

A genetic counsellor will guide you through every step of this process — explaining the findings clearly, helping you think through how to share information with family members, and addressing concerns about practical issues like insurance implications, which vary by country.

If all of this feels overwhelming on top of dealing with your own cancer diagnosis, that is completely understandable. The Lynch syndrome evaluation can generally proceed at a pace that fits your treatment timeline, and it does not need to be resolved before your cancer treatment begins.

What happens next

If your result is dMMR/MSI-H, two things will happen in parallel: your oncologist will explore whether immunotherapy is right for your situation. Your care team will begin evaluating you for Lynch syndrome. These two paths move forward together, and neither needs to wait for the other.

If your result is pMMR/MSS, immunotherapy based on MMR/MSI status is not indicated, and Lynch syndrome is unlikely to be the cause of your cancer. Your treatment will be planned based on your cancer type, stage, and other findings.

If you are unsure what your result means, or if you have received a dMMR result but have not yet had the chance to speak with your oncologist about it, asking for a clear explanation of the next steps is completely appropriate. You do not need to understand everything at once, and you do not need to navigate it alone.

Questions to ask your doctor

Was my cancer tested for MMR/MSI status, and what were the results?
If my result is dMMR/MSI-H, which proteins are missing — and does the pattern suggest Lynch syndrome or a non-inherited (sporadic) cause?
Has MLH1 methylation testing or BRAF V600E testing been done to help distinguish between Lynch syndrome and a sporadic cause?
Should I be referred to a genetic counsellor for evaluation of Lynch syndrome?
Based on my dMMR/MSI-H result, am I a candidate for pembrolizumab or another immunotherapy?
If Lynch syndrome is confirmed, what does this mean for my future follow-up?
How should I tell my family members about the possible hereditary implications, and can they be tested?
Are there clinical trials I should be aware of based on my MMR/MSI result?