What is Mismatch Repair (MMR)?
Mismatch Repair (MMR) is a critical cellular process responsible for the correction of DNA replication errors. These errors include base-base mismatches and insertion-deletion loops that arise during DNA replication and recombination. The MMR system plays a crucial role in maintaining genetic stability by preventing mutations from becoming permanent.
How Does MMR Work?
The primary components of the MMR system are a set of proteins that identify and repair mismatched DNA. The key proteins involved are
MutS and
MutL homologs, which recognize and initiate repair of the mismatches. After the mismatch is detected, the incorrect DNA segment is excised, and the gap is filled with the correct sequence using the undamaged strand as a template.
MMR and Cancer
Deficiencies in the MMR system are strongly associated with the development of cancer. When the MMR system fails, the mutation rate in the genome increases, leading to genomic instability. This instability can drive oncogenesis by allowing the accumulation of mutations in
oncogenes and
tumor suppressor genes.
Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
One of the most well-known associations between MMR deficiency and cancer is
Hereditary Nonpolyposis Colorectal Cancer (HNPCC), also known as
Lynch Syndrome. This inherited condition is caused by germline mutations in MMR genes such as
MLH1,
MSH2,
MSH6, and
PMS2. Individuals with Lynch Syndrome have a significantly increased risk of developing colorectal cancer and other types of cancer.
MMR Deficiency and Sporadic Cancers
MMR deficiencies are not limited to hereditary cancers. Sporadic cancers can also exhibit MMR deficiencies. For example, somatic hypermethylation of the
MLH1 promoter can lead to MMR deficiency in sporadic colorectal cancers. This epigenetic alteration silences the MLH1 gene, reducing the MMR capability of the cell.
Microsatellite Instability (MSI)
A hallmark of MMR deficiency is
microsatellite instability (MSI), which is the presence of length variations in microsatellite regions of the genome. MSI is a diagnostic marker for identifying tumors with MMR defects. High levels of MSI (MSI-H) are often observed in cancers associated with Lynch Syndrome and other MMR-deficient cancers.
Implications for Treatment
Understanding the MMR status of a tumor can have significant implications for treatment. Tumors with MMR deficiencies, particularly those with MSI-H, are more likely to respond to
immune checkpoint inhibitors like
pembrolizumab and
nivolumab. These therapies enhance the immune system's ability to recognize and attack cancer cells, which is particularly effective in tumors with high mutational loads.
Screening and Genetic Testing
Given the importance of MMR in cancer, screening for MMR deficiencies is crucial, especially in patients with a family history of cancer. Genetic testing can identify mutations in MMR genes, allowing for early detection and preventive measures. Such testing is a cornerstone of managing Lynch Syndrome and can guide treatment decisions in sporadic cancers exhibiting MMR deficiencies.Conclusion
Mismatch Repair is a vital system that maintains genomic integrity by correcting DNA replication errors. Deficiencies in MMR are closely linked to the development of various cancers, both hereditary and sporadic. Understanding MMR mechanisms and their implications can aid in the diagnosis, treatment, and prevention of cancer, providing personalized therapeutic options and improving patient outcomes.
