Mismatch Repair (MMR) and Microsatellite Instability (MSI) in Prostate Cancer

Section Editor: Trevor Flood MD FRCPC
May 27, 2026

Mismatch repair (MMR) and microsatellite instability (MSI) testing tell your doctor whether the DNA repair system inside a prostate cancer is working normally or has broken down. When that repair system fails, cancer cells accumulate many genetic errors, and those errors can make them sensitive to a type of treatment called immunotherapy. The same test result can also reveal whether the cancer developed because of an inherited condition called Lynch syndrome, which raises cancer risk for biological relatives. Although MMR deficiency is uncommon in prostate cancer, finding it matters a great deal because it opens a treatment option that would otherwise not be considered.

This article explains what MMR and MSI testing look for, why it is done in prostate cancer, how the test is performed, how results are reported, and what a result means for treatment and for your family.

What the test looks for

Every cell in the body contains DNA, the genetic code that controls how cells grow and divide. Each time a cell copies its DNA to make a new cell, small errors called mismatches can occur. Cells have a built-in repair system, mismatch repair (MMR), whose job is to find and fix these errors before they cause problems.

The MMR system consists of several proteins that work together. The four most important are MLH1, PMS2, MSH2, and MSH6. These proteins work in pairs: MLH1 pairs with PMS2, and MSH2 pairs with MSH6. If any one protein in a pair is lost or stops working, the repair system for that pair fails. When that happens, DNA copying errors begin to accumulate inside the cancer cells. Over time, these errors pile up in regions of DNA called microsatellites, which are short, repetitive sequences scattered throughout the genome. When microsatellites accumulate enough errors to become unstable, the tumor is described as having microsatellite instability.

A prostate cancer with a broken MMR system is called MMR-deficient (dMMR), and the same tumor tested a different way is described as microsatellite instability-high (MSI-H). A prostate cancer with a normally working MMR system is called MMR-proficient (pMMR), also described as microsatellite stable (MSS). The terms dMMR and MSI-H describe the same underlying problem, as do pMMR and MSS; they come from two different testing methods, explained below.

How common is dMMR/MSI-H in prostate cancer?

Mismatch repair deficiency is uncommon in prostate cancer. Across all prostate cancers, only about 1 to 3% are MMR-deficient (dMMR) or microsatellite instability-high (MSI-H), the state in which the tumor’s DNA repair system has broken down. The proportion is somewhat higher in advanced and metastatic prostate cancer, where studies have found dMMR/MSI-H in roughly 3 to 5% of cases. Metastatic means the cancer has spread beyond the prostate to other parts of the body, such as the bones or lymph nodes.

Although these percentages are small, MMR testing in prostate cancer is still important. A dMMR/MSI-H result identifies a group of patients whose treatment options are meaningfully different from the large majority, and it can also be the first sign of an inherited cancer syndrome. Certain features make a dMMR result somewhat more likely, including a high tumor grade and unusual microscopic appearances such as a ductal or other non-standard pattern, although dMMR can occur in ordinary-looking prostate cancers as well.

Why the test is done

MMR and MSI testing in prostate cancer is performed for two main reasons. Both relate to what happens when the DNA repair system inside the cancer has broken down, a state called MMR-deficient (dMMR) or microsatellite instability-high (MSI-H).

To determine whether immunotherapy is an option

When a prostate cancer is MMR-deficient (dMMR/MSI-H), it accumulates a very large number of mutations, which are changes in the DNA sequence. These mutations cause abnormal proteins to appear on the surface of the cancer cells, making the cells look foreign to the immune system. The immune system can then recognize and attack the cancer, but its attack is often blocked by molecular brakes called immune checkpoints. Drugs called immune checkpoint inhibitors, a form of immunotherapy, work by releasing those brakes so the immune system can destroy the cancer. Pembrolizumab (Keytruda) is approved for any solid tumor that is dMMR/MSI-H and has progressed after prior treatment, including prostate cancer. A dMMR/MSI-H result therefore identifies a treatment option that would not otherwise be considered for prostate cancer, since immunotherapy is not effective in MMR-proficient prostate cancers.

To identify Lynch syndrome

An MMR-deficient (dMMR) result can be the first clue that prostate cancer has developed because of Lynch syndrome, an inherited condition that raises the lifetime risk of several cancers. Identifying Lynch syndrome matters not only for the patient’s own future cancer surveillance but for biological relatives, who may carry the same inherited risk. Because of this hereditary dimension, a dMMR result in prostate cancer often leads to additional testing and a referral to a genetic counselor, as explained in the sections below.

How the test is performed

There are two main methods for testing MMR and MSI status, each measuring the same underlying problem in a different way. The goal of both is to determine whether the cancer’s DNA repair system is intact (MMR-proficient) or broken (MMR-deficient).

Immunohistochemistry (IHC)

Immunohistochemistry (IHC) uses specially designed proteins called antibodies to stain for the four MMR proteins, MLH1, PMS2, MSH2, and MSH6, in a thin slice of tumor tissue. Under the microscope, a pathologist can see whether each protein is present (retained) or absent (lost) in the cancer cells. Normal cells surrounding the tumor act as a built-in control, because they should always show staining. IHC is quick, inexpensive, and widely available.

Microsatellite instability (MSI) testing by PCR or next-generation sequencing

PCR-based MSI testing directly measures the lengths of microsatellite sequences (the short, repetitive stretches of DNA described earlier) in tumor DNA and compares them with normal DNA from the same patient. If the lengths differ, the tumor is classified as microsatellite instability-high (MSI-H). If they match, the tumor is microsatellite stable (MSS). MSI status can also be assessed by next-generation sequencing (NGS), a technique that reads large amounts of tumor DNA at once. In advanced prostate cancer, NGS panels are increasingly used, and MSI status is often calculated automatically alongside other biomarker results, including BRCA and other DNA repair genes.

IHC and DNA-based MSI testing agree in most cases. When they disagree, or when one result is uncertain, the other method is often performed to confirm the finding.

How results are reported

Your pathology report will describe the result using one of two sets of terms, depending on which test was used. Both sets describe whether the cancer’s DNA repair system is working (proficient) or broken (deficient).

If immunohistochemistry (IHC) was performed, the report describes the staining result for each of the four MMR proteins and then gives an overall result:

MMR-proficient (pMMR) — All four proteins (MLH1, PMS2, MSH2, and MSH6) are present in the tumor cells. The DNA repair system is intact. This corresponds to microsatellite stable (MSS) on DNA-based testing.
MMR-deficient (dMMR) — One or more proteins are absent from the tumor cells. The DNA repair system is not working properly. The report will specify which protein or proteins are missing, for example “loss of MSH2 and MSH6.” This corresponds to microsatellite instability-high (MSI-H) on DNA-based testing.

If DNA-based MSI testing (PCR or next-generation sequencing) was performed, the report describes the result as:

MSS (microsatellite stable) — The tumor’s microsatellite sequences are stable. This corresponds to MMR-proficient (pMMR).
MSI-H (microsatellite instability-high) — The tumor’s microsatellite sequences show significant instability. This corresponds to MMR-deficient (dMMR).

Most reports use one set of terms or the other, though some include both.

What the result means

MMR-proficient (pMMR) / MSS

This is the result for the large majority of prostate cancers, approximately 97 to 99%. It means the cancer’s DNA repair system is working normally. Immunotherapy that depends on MMR status, such as the immune checkpoint inhibitor pembrolizumab, is not expected to work in an MMR-proficient cancer, so treatment is guided by other features of the cancer, such as grade, stage, and the results of other biomarker tests. A pMMR result also makes Lynch syndrome an unlikely cause of the cancer, although it does not completely rule it out in rare situations.

MMR-deficient (dMMR) / MSI-H

This uncommon result, found in only about 1 to 3% of prostate cancers, means the cancer’s DNA repair system has broken down. A dMMR/MSI-H result has two main implications. First, it identifies a cancer that may respond to immunotherapy with an immune checkpoint inhibitor, a treatment option not otherwise used in prostate cancer. Second, it raises the possibility of Lynch syndrome, the inherited condition described in the next section, and usually prompts further testing and a referral to a genetic counselor. The pathology report will specify which MMR proteins are missing, and that pattern provides the first clue about whether the deficiency is inherited.

Which proteins are lost, and why it matters

When the immunohistochemistry result shows MMR deficiency, the pattern of which proteins are missing offers clues about the cause:

Loss of MSH2 and MSH6 together — When MSH2 is lost, its partner MSH6 is usually lost as well. This pattern is strongly associated with Lynch syndrome and should prompt genetic counseling and germline testing. In prostate cancer, dMMR is more often associated with this MSH2/MSH6 pattern than is the case in colorectal cancer.
Loss of MSH6 alone — Isolated loss of MSH6 is more strongly associated with Lynch syndrome than with a non-inherited cause, although it can occasionally occur on its own.
Loss of PMS2 alone — Isolated PMS2 loss is associated with Lynch syndrome caused by an inherited PMS2 gene change, though it can also occur in a non-inherited way.
Loss of MLH1 and PMS2 together — When MLH1 is lost, its partner PMS2 is usually lost as well. In colorectal and endometrial cancer this pattern is most often non-inherited, but in prostate cancer a non-inherited cause is less well established, and germline testing is still generally recommended.

Lynch syndrome: what it is and why it matters

Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is an inherited condition caused by a germline mutation in one of the MMR genes (most commonly MLH1, MSH2, MSH6, or PMS2). A germline mutation is a change in the DNA that was present from conception and is carried in every cell of the body, including the cells that can be passed to children. A person with Lynch syndrome has an elevated lifetime risk of several cancers, most commonly colorectal and endometrial cancer, and also including stomach, ovarian, urinary tract, and other cancers.

The link between Lynch syndrome and prostate cancer is now well recognized. Men with Lynch syndrome have a modestly increased risk of developing prostate cancer compared with the general population, and prostate cancers that arise in men with Lynch syndrome are more often MMR-deficient (dMMR). When prostate cancer is found to be dMMR and the pattern of protein loss suggests an inherited cause, germline testing is recommended. Germline testing is a blood or saliva test that looks for inherited mutations in the MMR genes.

What a Lynch syndrome diagnosis means for you

If germline testing confirms Lynch syndrome, this information will shape ongoing care beyond the prostate cancer itself. Your care team will discuss an intensified surveillance schedule to catch any future Lynch-associated cancers early, which may include colonoscopy and other screening, and you will be counseled about the other cancer types associated with the condition.

What it means for your family

Each biological child, sibling, and parent of a person with confirmed Lynch syndrome has a 50% chance of carrying the same inherited mutation. The process of testing relatives once a hereditary mutation has been identified is called cascade testing. Relatives who test positive can begin earlier and more frequent screening for Lynch-associated cancers, which substantially lowers their risk of developing an advanced cancer. A genetic counselor can help coordinate this process and guide conversations with family members. It is important to understand that Lynch syndrome raises cancer risk but does not make cancer certain; many people with Lynch syndrome live long, healthy lives when they follow appropriate screening.

Treatment implications of dMMR/MSI-H in prostate cancer

For the small number of prostate cancers that are MMR-deficient (dMMR) or microsatellite instability-high (MSI-H), the result can change the treatment options available, particularly in advanced disease.

Pembrolizumab (Keytruda), an immune checkpoint inhibitor, is approved for any unresectable or metastatic solid tumor that is dMMR/MSI-H and has progressed after prior treatment. This is known as a tumor-agnostic approval, meaning eligibility is based on the biomarker result rather than on where the cancer started. For a man with metastatic prostate cancer that has stopped responding to standard treatments, a dMMR/MSI-H result therefore opens the door to immunotherapy, an option that is not used for MMR-proficient prostate cancer. Reported response rates to pembrolizumab in dMMR/MSI-H prostate cancer vary across studies but indicate that a meaningful subset of these patients benefit, and some responses are durable.

MMR status is one part of a broader molecular profile in advanced prostate cancer. Many patients also have testing for BRCA1, BRCA2, and other DNA repair genes, which can identify eligibility for different targeted treatments. Your oncologist will consider the full set of results together when discussing treatment options. Immunotherapy for dMMR/MSI-H prostate cancer is most relevant in the advanced or metastatic setting; its role in earlier-stage prostate cancer is still being studied.

What happens next

The steps that follow an MMR/MSI result depend on whether the cancer is MMR-proficient or MMR-deficient.

If the result is pMMR/MSS, the cancer’s DNA repair system is intact. MMR-based immunotherapy is generally not indicated, and treatment planning proceeds based on the grade, stage, and other features of the cancer, including the results of other biomarker tests.
If the result is dMMR/MSI-H, the cancer’s DNA repair system is broken. The care team may order additional testing to clarify the cause, and if the cancer is advanced or metastatic, immunotherapy with an immune checkpoint inhibitor will likely be discussed as a treatment option. A referral to a genetic counselor is usually arranged to evaluate for Lynch syndrome.
If germline testing confirms Lynch syndrome, you will be connected with a genetic counseling team for guidance on your own ongoing cancer surveillance and to help arrange testing for biological relatives.

If you are waiting for results, or have received a result you do not yet fully understand, it is entirely appropriate to ask your oncologist or pathologist to explain what was found and what it means for your situation.

Questions to ask your doctor

Was my prostate cancer tested for MMR or MSI status, and what was the result?
If my cancer is MMR-deficient, which proteins are missing, and what does that pattern suggest about the cause?
Does my MMR/MSI result make me a candidate for immunotherapy, and at what stage of disease would that apply?
Was my tumor tested by immunohistochemistry, by DNA-based MSI testing, or both?
Should I be referred to a genetic counselor to evaluate for Lynch syndrome?
If Lynch syndrome is confirmed, what additional cancer screening would I need?
Should my family members be tested for Lynch syndrome?
Was my cancer also tested for BRCA or other DNA repair gene changes, and how do those results fit with my MMR result?
Are there clinical trials I should be aware of based on my MMR/MSI result?

The information on this page is intended for general informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the guidance of your physician or other qualified health provider with any questions you may have regarding your medical condition.