Correct errors that occur during DNA replication.
A highly conserved DNA repair mechanism through which the erroneous insertion and deletion and the misincorporation of bases during DNA replication and recombination are recognized and corrected to ensure genomic integrity.
When mismatch repair (MMR) is defective accumulation of mutations occur that inactivate key cellular functions resulting in malignant transformation.
The loss of activity of MMR proteins translates into an accumulation of DNA replication errors characterized by a high frequency of frameshift mutations in microsatellite DNA, referred to as microsatellite instability (MSI).
Tumors deficient in mismatch repair proteins are unable to repair mismatches that occur during DNA repair.
MMR-D may be sporadic or inherited as part of Lynch syndrome, mostly arising as a consequence of germline in mutations in one of the MMR genes.
Tumors with a deficiency in mismatch repair have a high level of mutations, and mutations lead to novel changes in the amino acid sequence.
Microsatellites are prone to DNA replication errors, which usually are repaired in normal cells.
In cells with defective DNA mismatch repair gene errors accumulate, leading to somatic microsatellite polymorphisms, or MSI.
MSI has been observed in many types of cancer but is most prevalent in Colorectal, endometrial, and gastric cancers.
If the new sequence has not been seen by a person’s immune system it functions as a foreign sequence, a neo antigen.
Neo antigens are recognized by the immune system and tends to be key drivers behind robust immune responses and tumors with MMR-D have a lot of neoantigens because they have a lot of mutations.
As a result of this deficiency to repair mutations accumulate and the more mutations the higher the probability that a tumor will create neoantigens that the immune system can target.
Mismatchrepair deficinet tumors are identified by immunohistological stains showing deficient or missing mismatch repair proteins -MLH1, MSH2, MSH^, or PmS2 or by a polymerase chain reaction based test.
Associated with at least half the cases of HNPCC referred to as the Lynch syndrome.
The mismatch repair (MMR) system is a complex cellular and somatic mechanism that identifies and corrects DNA errors during cell division and prevents mutagenesis.
Deficient mismatch repair is also termed of microsatellite instability-high (MSH-high).
MSI-H status is caused by shift resulting from the accumulation of errors in repetitive DNA sequences.
Epigenetic modification can lead to silencing of the same genes and can account for 15 to 20% of sporadic colorectal cancers.
MSI present in 15-20% of colorectal tumors, and in 4-6% of metastatic colorectal tumors.
Epigenetic modification leads to hypermethylation of the promotor region of MLH1 in 70% of cases.
The 4 MMR genes most commonly tested are: MLH1, MSH2,MSH6,andPMS2.
Testing can be performed by immunohistochemistry or PCR.
MSI status is prognostic.
MSI-high tumors have been shown to have improved prognosis and longer overall survival in stage II and stage III disease and in the metastatic setting of colorectal cancer.
Conflicting data exists as to whether patients with stage II MSI-high colon cancer may benefit from adjuvant chemo therapy.
MMR-Deficiency rate is approximally 10%-20% and stage I, II, III colorectal cancer and 4% in stage IV colorectal cancer.
Pembrolizumab approved was for the treatment of adult and pediatric patients with any unresectable or metastatic solid tumor that displays mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) and who have progressed after previous treatment and have no satisfactory alternatives.
Pembrolizumab and nivolumab approved specifically for patients with MSI-H or dMMR colorectal cancer (CRC) that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.