Mismatch repair deficiency (dMMR) describes a condition where the body’s natural system for correcting specific errors during DNA replication is faulty. The mismatch repair system acts like a spell-checker, diligently scanning for typos that occur when new copies are made. In individuals with dMMR, this spell-checker is not working correctly, leading to an accumulation of uncorrected errors in the genetic code. This genetic instability can have significant consequences for cellular function and overall health.
The Role of the Mismatch Repair System
Every time a cell divides, its entire DNA must be accurately copied. During this complex process, the machinery that duplicates DNA can occasionally make small mistakes, known as mismatches or insertion-deletion loops, where an incorrect base pair is added or a small segment is inadvertently skipped or repeated. The mismatch repair (MMR) system is designed to detect and fix these errors, preserving the integrity of our genome. This system acts as a quality control team, patrolling newly synthesized DNA strands to identify and correct replication errors.
The MMR system involves a team of proteins that identify and repair mismatched DNA bases or small insertions/deletions. Key members of this repair team include the proteins MLH1, MSH2, MSH6, and PMS2. These proteins often work in pairs; for instance, MSH2 partners with MSH6 to recognize errors, while MLH1 forms a complex with PMS2 to coordinate the repair process. Their combined effort ensures DNA replication proceeds with high fidelity, preventing the accumulation of mutations that could disrupt normal cell function.
Causes of Mismatch Repair Deficiency
Mismatch repair deficiency can arise from two distinct pathways: it can be inherited or develop spontaneously within a tumor.
One primary cause is hereditary, resulting from a germline mutation in one of the MMR genes, such as MLH1, MSH2, MSH6, or PMS2. This means an individual is born with a non-working copy of an MMR gene, which significantly increases their lifetime risk of developing certain cancers. This inherited condition is known as Lynch syndrome, a common hereditary cancer syndrome. Since the mutation is present in every cell of the body, it can be passed down to future generations.
Alternatively, dMMR can be acquired, arising spontaneously within a tumor cell. This occurs when an MMR gene becomes “silenced” through a process called promoter hypermethylation. Chemical tags attach to the gene’s promoter region, effectively switching off the gene and preventing the production of its corresponding protein. This acquired form of dMMR is confined to the tumor and cannot be transmitted to offspring.
Identifying Mismatch Repair Deficiency
Detecting mismatch repair deficiency in tumor tissue is a routine part of modern cancer diagnostics, guiding treatment decisions and identifying individuals who may benefit from further genetic evaluation. Two common laboratory tests are used to identify dMMR, each providing a different but complementary view of the system’s function.
One widely used method is Immunohistochemistry (IHC), a staining technique that visualizes the presence or absence of the MMR proteins (MLH1, MSH2, MSH6, PMS2) within tumor cells. If a tumor lacks the expression of one or more of these proteins, it indicates that the underlying gene is not functioning properly.
Another important test is Microsatellite Instability (MSI) analysis, which examines short, repetitive DNA sequences called microsatellites. These segments are prone to changes in length during DNA replication, and a functional MMR system corrects these alterations. When the MMR system is deficient, these errors accumulate, causing the microsatellites to become unstable and change in length. A tumor displaying a high level of these length variations is classified as “MSI-High” (MSI-H).
Health Implications and Treatment Approaches
The accumulation of unrepaired DNA errors due to mismatch repair deficiency significantly increases the risk of developing certain cancers. Cells with dMMR are prone to accumulating mutations throughout their genome, which can drive uncontrolled cell growth and tumor formation. The most commonly associated cancers include colorectal, endometrial, stomach, ovarian, and small intestine cancers.
While dMMR increases cancer risk, it also creates a unique vulnerability in cancer cells that can be exploited for treatment. The high number of mutations in dMMR tumors leads to the production of many abnormal proteins, known as neoantigens, on the surface of the cancer cells. These neoantigens act as distinctive flags, making the tumor highly recognizable to the body’s immune system.
This characteristic makes dMMR cancers responsive to a class of drugs called immunotherapy, specifically immune checkpoint inhibitors. These drugs work by “unleashing” the body’s own immune cells, T-cells, that may have been held back by the tumor’s immune evasion mechanisms. By blocking these inhibitory checkpoints, immunotherapy allows the immune system to more effectively identify and attack the dMMR cancer cells, leading to durable responses in many patients.