Mismatch repair deficiency

A condition affecting DNA repair mechanisms

Mismatch Repair Deficiency
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Synonyms	N/A
Pronounce	N/A
Specialty	N/A
Symptoms	Increased risk of certain cancers
Complications	N/A
Onset	N/A
Duration	N/A
Types	N/A
Causes	Mutations in mismatch repair genes
Risks	N/A
Diagnosis	Genetic testing, Microsatellite instability testing
Differential diagnosis	N/A
Prevention	N/A
Treatment	Surveillance, surgery, chemotherapy
Medication	N/A
Prognosis	N/A
Frequency	N/A
Deaths	N/A

Mismatch Repair Deficiency (MMR-D) is a condition characterized by the inability of the DNA mismatch repair (MMR) system to correct errors that occur during DNA replication. This deficiency can lead to an accumulation of mutations, which increases the risk of developing certain types of cancer, most notably Lynch syndrome-associated cancers.

Pathophysiology

The MMR system is responsible for correcting base-base mismatches and insertion-deletion loops that occur during DNA replication. Key proteins involved in this process include MLH1, MSH2, MSH6, and PMS2. Mutations in any of these genes can lead to MMR-D. When the MMR system is deficient, errors in the DNA sequence are not corrected, leading to microsatellite instability (MSI) and an increased mutation rate.

Clinical Significance

MMR-D is most commonly associated with Lynch syndrome, an inherited condition that significantly increases the risk of colorectal cancer, endometrial cancer, and other types of cancer. Individuals with Lynch syndrome typically inherit one mutated copy of an MMR gene and acquire a second mutation in somatic cells, leading to tumor development.

Associated Cancers

- Colorectal cancer - Endometrial cancer - Ovarian cancer - Gastric cancer - Small bowel cancer - Urothelial cancer

Diagnosis

Diagnosis of MMR-D can be achieved through several methods:

• Microsatellite Instability Testing: Tumors with MMR-D often exhibit high levels of MSI, which can be detected using PCR-based assays.
• Immunohistochemistry (IHC): This method detects the presence or absence of MMR proteins in tumor tissue.
• Genetic Testing: Identifying germline mutations in MMR genes can confirm a diagnosis of Lynch syndrome.

Management

Management of MMR-D involves increased surveillance for associated cancers, prophylactic surgeries, and consideration of chemotherapeutic options. For example, patients with Lynch syndrome may undergo regular colonoscopies and consider prophylactic hysterectomy and oophorectomy.

Research and Future Directions

Research is ongoing to better understand the molecular mechanisms of MMR-D and to develop targeted therapies. Immunotherapy, particularly immune checkpoint inhibitors, has shown promise in treating MMR-D tumors due to their high mutational burden.

Also see

• Lynch syndrome
• Microsatellite instability
• DNA repair
• Colorectal cancer