Abstract
The mismatch repair (MMR) system has a key role in supporting the DNA polymerase proofreading function and in maintaining genome stability. Alterations in the MMR genes are driving events of tumorigenesis, tumor progression, and resistance to therapy. These genetic scars may occur in either hereditary or sporadic settings, with different frequencies across tumor types. Appropriate characterization of the MMR status is a crucial task in oncologic pathology because it allows for both the tailored clinical management of cancer patients and surveillance of individuals at risk. The currently available MMR testing methods have specific strengths and weaknesses, and their application across different tumor types would require a tailored approach. This article highlights the indications and challenges in MMR status assessment for molecular pathologists, focusing on the possible strategies to overcome analytical and pre-analytical issues.
Highlights
DNA mismatch repair (MMR) is a highly conserved system aimed at recognizing and repairing single-base mismatches that evaded polymerase proofreading activity [1]
Four key proteins belong to the MMR, namely mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), and postmeiotic segregation increased 2 (PMS2)
IHC and microsatellite instability (MSI) real-time PCR (RT-PCR) are routinely used in the clinical settings, a recent report on immunotherapy in metastatic colorectal cancer has shown that approximately 10% of the patients enrolled in immunotherapy trials experienced failure in the therapy due to false-positive dMMR or MSI RT-PCR results assessed by local laboratories [49]
Summary
DNA mismatch repair (MMR) is a highly conserved system aimed at recognizing and repairing single-base mismatches that evaded polymerase proofreading activity [1]. Neoplasms with MMR dysfunctions are prone to have a hypermutator phenotype that frequently results in microsatellite instability (MSI) [6] This condition is defined by the detection of alternate-sized microsatellite tandem repeats, which are small DNA motifs that are distributed throughout the genome [7,8,9]. MSI is frequent in endometrial and colorectal cancers, but exceedingly rare in breast, prostate, and ovarian cancer [17,18,19,20,21] For this reason, the harmonization of MMR clinical testing strategies is a goal to be achieved for next-generation pathologists [22,23,24]. Completion of strict laboratory procedures, regular quality controls, cutting-edge infrastructure maintenance, and periodic training programs are required
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