In oncology, cancers are increasingly defined by their genetic characteristics rather than solely by their location. One such characteristic is deficient mismatch repair, or dMMR, which describes cancer cells that have a faulty DNA repair mechanism. As cells divide, errors can occur when DNA is copied, and the mismatch repair system’s job is to correct these mistakes. When this system is broken, the cells accumulate a high number of genetic mutations, altering their behavior.
Identifying a tumor as dMMR provides specific information about its biology. This classification has direct implications for a patient’s treatment path and overall outlook. It allows for personalized medical strategies that target the vulnerabilities of these cancer cells.
The Genetic Mechanism of Mismatch Repair Deficiency
The Mismatch Repair (MMR) system acts as a DNA “spell checker,” fixing errors made during cell division. This system relies on proteins from four genes: MLH1, MSH2, MSH6, and PMS2. A deficiency in this system (dMMR) occurs when one or more of these proteins is absent or non-functional, preventing the correction of DNA mismatches.
When the MMR system fails, errors accumulate rapidly, leading to microsatellite instability (MSI). Microsatellites are repetitive DNA sequences prone to errors during replication. The inability to fix these mistakes results in microsatellites of varying lengths within tumor cells, a feature known as MSI-High (MSI-H).
The breakdown of the mismatch repair system can be sporadic, arising randomly within a tumor, which is the most common cause. The deficiency can also be hereditary, passed down through families. The most well-known condition is Lynch syndrome, a genetic disorder that increases cancer risk due to an inherited mutation in an MMR gene.
Determining dMMR Status
Two principal laboratory techniques are used to determine if a tumor has a deficient mismatch repair system. The first method is Immunohistochemistry (IHC), which uses staining to detect the four main MMR proteins in a tumor tissue sample. If one or more of these proteins—MLH1, MSH2, MSH6, and PMS2—are missing from the cancer cells, the tumor is classified as dMMR.
A second method is a molecular test using Polymerase Chain Reaction (PCR) to detect microsatellite instability (MSI). By analyzing specific DNA regions in both tumor and normal tissue, technicians check for changes in length. If many microsatellites are unstable, the tumor is designated MSI-High (MSI-H), the molecular signature of a dMMR tumor.
Cancers Commonly Exhibiting dMMR
While mismatch repair deficiency can occur in any cancer type, it is far more prevalent in certain malignancies. Colorectal and endometrial cancers are the two malignancies most frequently associated with dMMR. A significant portion of these cancers exhibit this genetic feature; for instance, approximately 20% of stage II colon cancers are dMMR. This high prevalence has made dMMR testing a standard of care for individuals diagnosed with these cancers.
Beyond the colon and endometrium, dMMR is also found in a variety of other cancers, although at a lower frequency. These include:
- Gastric (stomach)
- Ovarian
- Pancreatic
- Small intestine cancers
Less commonly, certain brain tumors and other solid tumors can also be identified as dMMR.
Therapeutic Approaches for dMMR Cancers
A tumor’s dMMR status is relevant because it unlocks a specific treatment avenue. The numerous mutations inside dMMR cancer cells lead to the production of abnormal proteins, known as neoantigens. These neoantigens are not present in healthy cells and act like flags, making the cancer cells highly visible to the body’s immune system.
This high visibility makes dMMR tumors particularly responsive to immune checkpoint inhibitors. These therapies work by “releasing the brakes” on the immune system, allowing it to recognize and destroy cancer cells more effectively. Checkpoint inhibitors like pembrolizumab and nivolumab are approved as standard treatments for dMMR cancers and can produce significant, lasting responses.
The success of immunotherapy highlights a shift in cancer treatment, where a tumor’s genetic makeup can be more important than its location. In many cases, immunotherapy has proven more effective than traditional chemotherapy for dMMR tumors. For example, studies of metastatic colorectal cancer show patients with dMMR tumors treated with immunotherapy have better outcomes than those receiving chemotherapy.
Prognosis for Patients with dMMR Cancer
The prognosis for patients with dMMR cancer can be unique. In some cases, like colon cancer, the presence of dMMR is associated with a better outcome, even before treatment. This may be due to the increased immune response these highly mutated tumors naturally provoke, which can slow their progression.
The outlook for patients with advanced dMMR cancers has been substantially improved with immunotherapy. For many, immune checkpoint inhibitors have led to durable responses and improved survival rates. The effectiveness of these treatments underscores the importance of personalized medicine, where understanding the specific molecular drivers of a cancer can lead to highly effective therapies.