Deficient Mismatch Repair (dMMR) is a genetic malfunction found in certain cancer cells that influences both the cancer’s behavior and its response to therapy. This deficiency means the cell has lost the ability to correct copying errors made during DNA replication, essentially turning off the cell’s internal “spellchecker.” Because these mistakes go unfixed, the cancer cells accumulate a vast number of genetic mutations, leading to a hypermutated state. This high mutation rate drives cancer progression but also creates a unique vulnerability that modern medicine can target.
Understanding the Mismatch Repair System
The Mismatch Repair (MMR) system is a set of proteins that function as the cell’s primary proofreading mechanism for DNA. Its job is to detect and correct small errors, such as base mismatches or tiny insertions and deletions, that occur when a cell divides and copies its genetic material. When the MMR system is working correctly, it ensures genomic stability by keeping the mutation rate low.
When one or more of the core MMR proteins (MLH1, MSH2, MSH6, or PMS2) become dysfunctional or absent, the system fails, leading to the deficient MMR (dMMR) status. This failure allows replication errors to accumulate rapidly in specific areas of the DNA called microsatellites. The resulting changes in the length of these repetitive sequences is known as high microsatellite instability (MSI-H), which is the molecular hallmark of dMMR tumors.
How dMMR Status is Determined
Determining a tumor’s dMMR status is a standard step in cancer diagnosis and involves two primary testing methods. The first is Immunohistochemistry (IHC), which uses antibodies to check for the presence or absence of the four main MMR proteins (MLH1, MSH2, MSH6, and PMS2) in a tumor tissue sample. The loss of nuclear expression of even one of these proteins indicates a dMMR tumor.
The second method is molecular testing, which directly assesses the resulting genomic instability, known as Microsatellite Instability (MSI). This is typically done using Polymerase Chain Reaction (PCR) or Next-Generation Sequencing (NGS) to compare the length of microsatellite markers in the tumor DNA versus normal DNA. If a high percentage of these markers show alterations in length, the tumor is classified as MSI-High (MSI-H), which is functionally equivalent to dMMR. The specific pattern of protein loss identified by IHC can also provide clues about a potential hereditary link.
Cancers Associated with Mismatch Repair Deficiency
While dMMR can occur in many types of solid tumors, it is most frequently observed in cancers of the digestive and reproductive systems. Approximately 15% of colorectal cancers (CRC) and up to 30% of endometrial cancers are classified as dMMR/MSI-H. It is also found in a significant proportion of gastric (stomach) cancers, often around 15% to 20%.
Testing for dMMR status is routinely recommended for all newly diagnosed colorectal and endometrial cancers due to its prevalence and treatment implications. dMMR is also found less frequently in cancers of the small bowel, ovary, and certain types of urothelial cancers.
Treatment Implications for dMMR Tumors
The dMMR status is a primary biomarker in oncology because it strongly predicts a unique, positive response to a specific class of drugs. The hypermutated state of dMMR tumors results in a high Tumor Mutational Burden (TMB), which leads to the creation of many abnormal proteins, called neoantigens, that the immune system recognizes as foreign.
These cancer cells are highly visible to the body’s immune cells, making dMMR tumors particularly susceptible to immune checkpoint inhibitor (ICI) therapy. ICIs, such as PD-1 inhibitors like pembrolizumab, function by releasing the brakes on the immune system, allowing T-cells to aggressively attack the cancer cells. This therapeutic approach has demonstrated success in dMMR cancers, with significantly higher response rates than in tumors without this deficiency.
In contrast, dMMR colorectal tumors often show a poor response to traditional chemotherapy agents. The effectiveness of immunotherapy led the U.S. Food and Drug Administration (FDA) to grant a tissue-agnostic approval for certain checkpoint inhibitors. This means the drug can be used for any unresectable or metastatic solid tumor that is found to be dMMR or MSI-H, regardless of where the cancer originated in the body.
The Hereditary Link: Lynch Syndrome
The discovery of a dMMR tumor suggests the potential presence of an underlying inherited condition called Lynch Syndrome. Lynch Syndrome is caused by a germline (inherited) mutation in one of the MMR genes, such as MLH1 or MSH2. This syndrome is responsible for a significant fraction of dMMR cancers, including a quarter of all dMMR colon cancers.
Identifying Lynch Syndrome is important because it means the patient has a high lifetime risk for multiple cancers, including colorectal, endometrial, ovarian, and gastric cancers. Patients with a dMMR tumor are typically referred for genetic counseling and germline testing to confirm or rule out the syndrome. Confirmation of Lynch Syndrome has profound implications for the patient’s medical management, leading to intensified cancer screening protocols, such as more frequent colonoscopies. It also necessitates genetic testing and counseling for their family members.