Mismatch repair deficiency (dMMR)

What it is

Mismatch repair deficiency (dMMR) is a tumour biomarker showing loss of DNA repair function, seen in about 15% of colorectal cancers. The key practical point is that dMMR can help identify possible Lynch syndrome and can predict benefit from immune checkpoint inhibitors in several cancers. It means the tumour's mismatch repair system, which normally corrects DNA copying errors, is not working properly. When this system fails, mutations accumulate, especially in repetitive DNA regions called microsatellites. That often leads to microsatellite instability, especially MSI-high (MSI-H), although dMMR and MSI are related but not perfectly identical test results.

The main mismatch repair proteins assessed in clinical practice are MLH1, PMS2, MSH2, and MSH6. Loss of one or more of these proteins on tumour testing suggests dMMR. In colorectal and endometrial cancers, dMMR testing is commonly used both for treatment planning and to decide whether a patient should be evaluated for Lynch syndrome, an inherited cancer predisposition condition. In India, many tertiary cancer centres and molecular pathology labs now include MMR testing in standard work-up for selected colorectal, endometrial, and other solid tumours.

How it works

During normal cell division, DNA polymerase can make small mistakes such as base mismatches or insertion-deletion loops. The mismatch repair system detects and fixes these errors. Two major protein complexes are involved:

Protein group	Main proteins	Role
Mismatch recognition	MSH2, MSH6, MSH3	Detect DNA mismatches
Repair coordination	MLH1, PMS2	Help remove and repair the faulty DNA segment

If one of these pathways is disrupted, the cell cannot reliably repair replication errors. Over time, the tumour accumulates many mutations. This can create abnormal proteins, called neoantigens, that make the cancer more visible to the immune system. That is one reason dMMR tumours may respond better to PD-1 or related immunotherapy than mismatch repair-proficient tumours.

dMMR can happen for different reasons:

1. Germline mutation, as in Lynch syndrome.
2. Somatic mutation, meaning changes only in the tumour.
3. Epigenetic silencing, especially MLH1 promoter hypermethylation.

This distinction matters. A dMMR result does not automatically mean a person has Lynch syndrome. Many dMMR tumours are sporadic rather than inherited.

Evidence and uses

dMMR is most established in colorectal cancer and endometrial cancer, but it is also relevant in gastric, small bowel, ovarian, prostate, and other solid tumours. The prevalence varies by tumour type. Educational NHS genomics material notes MSI is found in around 30% of endometrial cancers and 15% of colon and stomach adenocarcinomas.

Clinically, dMMR is used for two main reasons:

Use	Why it matters
Lynch syndrome screening	May indicate an inherited defect in MLH1, MSH2, MSH6, or PMS2, or EPCAM-related silencing of MSH2
Treatment selection	dMMR/MSI-H status can support use of immune checkpoint inhibitors in eligible cancers

In colorectal cancer, universal or broad testing of newly diagnosed tumours is widely recommended in many health systems because it improves detection of Lynch syndrome. In endometrial cancer, routine testing is also increasingly used for the same reason. If MLH1/PMS2 loss is found, further tumour testing for MLH1 promoter methylation is often done because methylation usually points to a sporadic tumour rather than Lynch syndrome.

For treatment, dMMR has become an important predictive biomarker for immunotherapy. Studies in advanced solid tumours showed that dMMR/MSI-H cancers can have meaningful responses to PD-1 blockade across tumour types. More recently, a small but influential 2022 study in locally advanced dMMR rectal cancer reported a complete clinical response in all 12 treated patients after dostarlimab, though follow-up and broader confirmation remain important.

Still, dMMR is not a guarantee of response. Some dMMR tumours do not respond to immunotherapy, and some treatment decisions also depend on stage, prior therapy, performance status, and local regulatory approval. In India, access may depend on tumour type, hospital protocols, and drug availability.

Diagnosis / how it's measured

dMMR is usually assessed on tumour tissue, not blood, although blood-based assays are being studied. The two main approaches are:

Test	What it looks for	Typical interpretation
Immunohistochemistry (IHC)	Presence or absence of MLH1, PMS2, MSH2, MSH6 proteins	Loss of one or more proteins suggests dMMR
Microsatellite instability (MSI) testing	Instability in selected microsatellite regions by PCR or NGS	MSI-H usually supports dMMR biology

IHC is often the first test because it is widely available and gives clues to which gene may be affected. Common patterns include:

1. MLH1 and PMS2 loss: often due to MLH1 abnormality or MLH1 promoter methylation.
2. MSH2 and MSH6 loss: often suggests MSH2 abnormality.
3. MSH6 loss alone: may suggest MSH6 abnormality.
4. PMS2 loss alone: may suggest PMS2 abnormality.

Results can occasionally be discordant. A tumour may appear dMMR by IHC but not clearly MSI-H, or vice versa. This can happen because of technical issues, tumour heterogeneity, or specific underlying mutations. When results are unclear, pathologists may repeat testing or use an alternative method such as next-generation sequencing.

A positive dMMR result often leads to the next step rather than being the final answer. That next step may include genetic counselling, germline testing for Lynch syndrome, or additional tumour testing such as MLH1 methylation or BRAF analysis, depending on the cancer type and local protocol.

When to see a clinician

Patients should discuss dMMR results with their oncologist, pathologist, or a cancer genetics specialist if:

• a tumour report shows loss of MLH1, PMS2, MSH2, or MSH6;
• the report says dMMR, MSI-H, or abnormal MMR IHC;
• there is colorectal, endometrial, ovarian, gastric, or other Lynch-associated cancer in the family;
• cancer occurred at a younger-than-expected age; or
• immunotherapy is being considered.

If Lynch syndrome is suspected, relatives may also need counselling and, in some cases, cascade testing. That can affect future cancer screening plans for the patient and family.

Limitations and open questions

dMMR is a useful biomarker, but it has limits. It does not by itself diagnose Lynch syndrome, predict prognosis in every cancer, or guarantee benefit from immunotherapy. Interpretation depends on tumour type, test method, and clinical context.

Evidence is strongest in colorectal and endometrial cancers, with growing but less mature evidence in some other tumours. Research is also ongoing on why some dMMR cancers resist immunotherapy despite having many mutations. Another open question is how best to integrate dMMR with other biomarkers such as tumour mutational burden, PD-L1, and broader genomic profiling.

In practice, dMMR should be read as part of a full pathology and oncology assessment, not as a stand-alone result.