Abstract
Microsatellite instability (MSI) is a genomic alteration in which microsatellites, usually of one to four nucleotide repeats, accumulate mutations corresponding to deletions/insertions of a few nucleotides. The MSI phenotype has been extensively characterized in colorectal cancer and is due to a deficiency of the DNA mismatch repair system. MSI has recently been shown to be present in most types of cancer with variable frequencies (from <1 to 30%). It correlates positively to survival outcome and predicts the response to immune checkpoint blockade therapy. The different methods developed for MSI detection in cancer require taking into consideration two critical parameters which influence method performance. First, the microsatellite markers used should be chosen carefully to ensure they are highly sensitive and specific for MSI detection. Second, the analytical method used should be highly resolute to allow clear identification of MSI and of the mutant allele genotype, and should present the lowest limit of detection possible for application in samples with low mutant allele frequency. In this review, we describe all the different molecular and computational methods developed to date for the detection of MSI in cancer, how they have evolved and improved over the years, and their advantages and drawbacks.
Highlights
Microsatellite instability (MSI/MSI-H) is characterized by the accumulation of mutations in microsatellites, which are continuous repetitions of 1–9 nucleotides
3% of MSI colorectal cancers arise in the context of an inherited syndrome called Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Lynch syndrome, in which a constitutional mutation of an mismatch repair system (MMR) gene leads to an increased risk of cancer incidence requiring specific management [10,11,12]
Several computational approaches based on whole genome sequencing (WGS), whole exome sequencing (WES), and targeted gene sequencing (TGS) data have been used to detect MSI, taking into account the difficulties of microsatellite sequences including management of stutter peak formation induced by PCR amplification during next-generation sequencing (NGS) library preparation, sequencing errors induced by homopolymers, and the shortcomings of sequencing read length which limits the length of the microsatellites analyzed (Figure 3)
Summary
Microsatellite instability (MSI/MSI-H) is characterized by the accumulation of mutations (insertions or deletions of a few nucleotides) in microsatellites ( known as short tandem repeats), which are continuous repetitions of 1–9 nucleotides. The MMR system comprises at least ten proteins including MLH1, MSH2, MSH6, and PMS2, which are the most frequent mutated or epimutated (MLH1) genes in cancer [1,2,3,4,5,6]. MSI has been described and extensively characterized in colorectal cancer in which 15–20% of tumors present the MSI phenotype which is correlated with better patient survival [7,8,9]. 3% of MSI colorectal cancers arise in the context of an inherited syndrome called Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Lynch syndrome, in which a constitutional mutation of an MMR gene leads to an increased risk of cancer incidence requiring specific management [10,11,12].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
