A MMRd tumor is a tumor that is mismatch repair deficient, meaning its cells lack the ability to properly fix errors that occur when DNA is copied.
Understanding Mismatch Repair (MMR) and MMRd
Our bodies have sophisticated systems for ensuring DNA is copied accurately during cell division. One of these systems is called DNA mismatch repair (MMR). MMR acts like a proofreader, scanning newly synthesized DNA for errors – mismatched base pairs – and correcting them.
When the MMR system isn't working correctly, due to genetic mutations or other factors, the cells become mismatch repair deficient (MMRd). This means they can no longer effectively correct these DNA copying errors.
Consequences of MMRd in Tumors
The inability to correct these errors has several consequences:
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Microsatellite Instability (MSI): MMRd often leads to microsatellite instability (MSI). Microsatellites are short, repetitive DNA sequences. Because MMR isn't working, these sequences become unstable, accumulating insertions or deletions.
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Accumulation of Mutations: The lack of MMR allows mutations to accumulate rapidly in the tumor's DNA. This increased mutation rate can drive cancer development and progression.
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Potential for Increased Immunogenicity: The high number of mutations in MMRd tumors can lead to the production of novel proteins (neoantigens) that the immune system recognizes as foreign. This can make MMRd tumors more susceptible to immunotherapy.
Clinical Significance
Identifying MMRd tumors is clinically important for several reasons:
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Diagnostic Marker: MMRd can be a diagnostic marker for certain types of cancer, such as colorectal cancer, endometrial cancer, and others.
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Prognostic Indicator: In some cancers, MMRd status may be associated with a better or worse prognosis.
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Predictive Biomarker for Immunotherapy: MMRd tumors are often highly responsive to immune checkpoint inhibitors, a type of immunotherapy. Testing for MMRd status helps determine whether a patient is likely to benefit from this treatment.
How MMRd is Determined
MMRd status is typically determined using one or more of the following methods:
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Immunohistochemistry (IHC): IHC is used to detect the presence or absence of MMR proteins (e.g., MLH1, MSH2, MSH6, PMS2) in tumor cells. If one or more of these proteins are absent, it suggests that the MMR system is deficient.
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Microsatellite Instability (MSI) Testing: MSI testing assesses the stability of microsatellite sequences in the tumor's DNA compared to normal tissue. High levels of MSI (MSI-H) indicate MMR deficiency.
