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Journal of Clinical Pathology Feb 2023DNA mismatch repair complex is involved in the maintenance of DNA stability. In the recent years, a plethora of technical approaches for microsatellite instability (MSI)... (Review)
Review
DNA mismatch repair complex is involved in the maintenance of DNA stability. In the recent years, a plethora of technical approaches for microsatellite instability (MSI) analysis emerged. Here, we review the results of our MSI status evaluation by adopting a customised workflow on microfluidic system obtained in 4 years of diagnostic routine practice. Data from MSI status were retrieved from our institutional archive covering the period from January 2017 to December 2021. Microfluidic analysis was carried out on microfluidic platform. Results were inspected with a proprietary software. Overall, microsatellite stability (MSS) and MSI-high (MSI-H) profile was detected in n=423/458 (92.36%) and n=35/458 (7.64%) patients with metastatic CRC (mCRC), respectively. In addition, n=78/86 (90.70%) and n=8/86 (9.30%) patients without CRC showed an MSS and MSI-H profile. This review highlights the suitability of microfluidic approach in patients with cancer for MSI testing.
Topics: Humans; Microsatellite Instability; Colorectal Neoplasms; Microsatellite Repeats; DNA Mismatch Repair
PubMed: 35545354
DOI: 10.1136/jclinpath-2022-208203 -
Der Pathologe May 2019After introduction of the Bethesda microsatellite test panel demonstration of microsatellite instability (MSI) and/or loss of mismatch repair proteins (MMRD) was... (Review)
Review
After introduction of the Bethesda microsatellite test panel demonstration of microsatellite instability (MSI) and/or loss of mismatch repair proteins (MMRD) was primarily used as a marker for cancer predisposition of Lynch syndrome (LS, previous: HNPCC). Nowadays MSI/MMRD has become an important biomarker to predict therapy response to checkpoint immunotherapies. MSI can be determined either by polymerase chain reaction (PCR)-based technologies with or without specification of fragment sizes or next generation sequencing (NGS) methods. Depending on the individual tumor entities, these test methods are used differently. Currently, MSI/MMRD is a tumor biomarker which covers a broad spectrum of indications in tumor pathology, especially in colorectal, endometrial and gastric cancer. In advanced carcinomas, MSI is an established predictor of therapy response to checkpoint-directed immunotherapies.
Topics: Biomarkers, Tumor; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Humans; Microsatellite Instability
PubMed: 31119365
DOI: 10.1007/s00292-019-0610-7 -
ESMO Open Feb 2022Microsatellite instability (MSI) testing and tumor mutational burden (TMB) are genomic biomarkers used to identify patients who are likely to benefit from immune...
INTRODUCTION
Microsatellite instability (MSI) testing and tumor mutational burden (TMB) are genomic biomarkers used to identify patients who are likely to benefit from immune checkpoint inhibitors. Pembrolizumab was recently approved by the Food and Drug Administration for use in TMB-high (TMB-H) tumors, regardless of histology, based on KEYNOTE-158. The primary objective of this retrospective study was real-world applicability and use of immunotherapy in TMB/MSI-high patients to lend credence to and refine this biomarker.
METHODS
Charts of patients with advanced solid tumors who had MSI/TMB status determined by next generation sequencing (NGS) (FoundationOne CDx) were reviewed. Demographics, diagnosis, treatment history, and overall response rate (ORR) were abstracted. Progression-free survival (PFS) was determined from Kaplan-Meier curves. PFS1 (chemotherapy PFS) and PFS2 (immunotherapy PFS) were determined for patients who received immunotherapy after progressing on chemotherapy. The median PFS2/PFS1 ratio was recorded.
RESULTS
MSI-high or TMB-H [≥20 mutations per megabase (mut/MB)] was detected in 157 adults with a total of 27 distinct tumor histologies. Median turnaround time for NGS was 73 days. ORR for most recent chemotherapy was 34.4%. ORR for immunotherapy was 55.9%. Median PFS for patients who received chemotherapy versus immunotherapy was 6.75 months (95% confidence interval, 3.9-10.9 months) and 24.2 months (95% confidence interval, 9.6 months to not reached), respectively (P = 0.042). Median PFS2/PFS1 ratio was 4.7 in favor of immunotherapy.
CONCLUSION
This real-world study reinforces the use of TMB as a predictive biomarker. Barriers exist to the timely implementation of NGS-based biomarkers and more data are needed to raise awareness about the clinical utility of TMB. Clinicians should consider treating TMB-H patients with immunotherapy regardless of their histology.
Topics: Adult; Biomarkers, Tumor; Humans; Immunotherapy; Microsatellite Instability; Neoplasms; Retrospective Studies
PubMed: 34953399
DOI: 10.1016/j.esmoop.2021.100336 -
Genes, Chromosomes & Cancer Jun 2022The mismatch repair system is a major pathway that functions in the maintenance of genomic integrity. It is involved in mitotic and meiotic recombination, apoptosis,... (Review)
Review
The mismatch repair system is a major pathway that functions in the maintenance of genomic integrity. It is involved in mitotic and meiotic recombination, apoptosis, immunoglobulin gene rearrangement, somatic hypermutation, and other processes. Deficiencies in mismatch repair give rise to hypermutability and the phenomenon called microsatellite instability. Detection of deficient mismatch repair function or microsatellite instability is used diagnostically, predictively, and prognostically. Specifically, deficient mismatch repair function is used for screening of Lynch syndrome, determining patients who are likely to respond to immune checkpoint inhibition, and to contributes to an understanding of which cancer patients may pursue a more aggressive clinical course. Microsatellite instability can be evaluated directly by polymerase chain reaction (PCR) or indirectly by assessment of mismatch repair protein expression using immunohistochemistry (IHC), and mismatch repair function using next-generation sequencing assays which evaluates homopolymer indels. In this article, we provide a concise practical review on mismatch repair deficiency (MMR-d)/microsatellite instability (MSI), focusing on clinical testing, different testing methods, interpretation of findings, the predictive, and prognostic utility of MSI.
Topics: Brain Neoplasms; Colorectal Neoplasms; DNA Mismatch Repair; Humans; Microsatellite Instability; Neoplastic Syndromes, Hereditary
PubMed: 34837268
DOI: 10.1002/gcc.23015 -
Polish Journal of Pathology : Official... Sep 2015Although often viewed as a single disease, colorectal cancer more accurately represents a constellation of heterogeneous subtypes that result from different combinations... (Review)
Review
Although often viewed as a single disease, colorectal cancer more accurately represents a constellation of heterogeneous subtypes that result from different combinations of genetic events and epigenetic alterations. Chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) have been identified as the three major molecular characteristics, which interact with other significant mutations, such as mutations in the KRAS and BRAF genes. High-level MSI (MSI-H) is of eminent clinical importance. It is the seminal molecular feature for the identification of individuals with Lynch syndrome, but it may also occur in sporadic cancers with CIMP phenotype, which arise from serrated precursor lesions. MSI-H status is a marker of favorable prognosis and may be used for outcome prediction, that is, molecular grading. Among others, mucinous and medullary histology, signet-ring cell differentiation, and a marked anti-tumoral immune response are histological features suggesting MSI. Universal tumor testing is recommended and may be performed using immunohistochemistry (mismatch repair protein expression) or molecular analysis, as has recently been recommended by an international task force. In this review, we consider in detail the molecular pathogenesis of colorectal cancer, focusing on the diagnosis of MSI in both hereditary and sporadic tumors.
Topics: Colorectal Neoplasms; Humans; Microsatellite Instability
PubMed: 26619098
DOI: 10.5114/pjp.2015.54953 -
Biophysical Chemistry Jun 2017Microsatellites are short, tandemly repeated DNA motifs of 1-6 nucleotides, also termed simple sequence repeats (SRSs) or short tandem repeats (STRs). Collectively,... (Review)
Review
Microsatellites are short, tandemly repeated DNA motifs of 1-6 nucleotides, also termed simple sequence repeats (SRSs) or short tandem repeats (STRs). Collectively, these repeats comprise approximately 3% of the human genome Subramanian et al. (2003), Lander and Lander (2001) [1,2], and represent a large reservoir of loci highly prone to mutations Sun et al. (2012), Ellegren (2004) [3,4] that contribute to human evolution and disease. Microsatellites are known to stall and reverse replication forks in model systems Pelletier et al. (2003), Samadashwily et al. (1997), Kerrest et al. (2009) [5-7], and are hotspots of chromosomal double strand breaks (DSBs). We briefly review the relationship of these repeated sequences to replication stalling and genome instability, and present recent data on the impact of replication stress on DNA fragility at microsatellites in vivo.
Topics: DNA Breaks, Double-Stranded; DNA Replication; Humans; Microsatellite Instability; Microsatellite Repeats
PubMed: 27914716
DOI: 10.1016/j.bpc.2016.11.007 -
International Journal of Gynecological... Mar 2023The Cancer Genome Atlas (TCGA) endometrial cancer data expanded our knowledge about the role of different immunotherapeutic approaches based on molecular subtypes.... (Review)
Review
The Cancer Genome Atlas (TCGA) endometrial cancer data expanded our knowledge about the role of different immunotherapeutic approaches based on molecular subtypes. Immune checkpoint inhibitors demonstrated distinct antitumor activities as monotherapy or in combination. In microsatellite unstable (microsatellite instability-high) endometrial cancer, immunotherapy with immune checkpoint inhibitors showed promising single agent activity in recurrent settings. Different strategies are needed to enhance the response or reverse resistance to immune checkpoint inhibitors, or both, in microsatellite instability-high endometrial cancer. On the other hand, single immune checkpoint inhibitors showed underwhelming efficacy in microsatellite stable endometrial cancer but this was significantly improved using a combination approach. Furthermore, studies are also needed to improve response along with ensuring safety and tolerability in microsatellite stable endometrial cancer. This review summarizes the current indications of immunotherapy for the treatment of advanced and recurrent endometrial cancer. We also outline potential future strategies for an immunotherapy based combination approach in endometrial cancer to combat resistance or enhance response to immune checkpoint inhibitors, or both.
Topics: Humans; Female; Immune Checkpoint Inhibitors; Microsatellite Instability; Endometrial Neoplasms; Immunotherapy; Microsatellite Repeats
PubMed: 36878570
DOI: 10.1136/ijgc-2022-003675 -
Asia-Pacific Journal of Clinical... Dec 2010Approximately 20 percent of right-sided colon cancers and 5 percent of left-sided colon and rectal cancers have a deficient DNA mismatch repair system. This results in... (Review)
Review
Approximately 20 percent of right-sided colon cancers and 5 percent of left-sided colon and rectal cancers have a deficient DNA mismatch repair system. This results in the widespread accumulation of mutations to nucleotide repeats, some of which occur within the coding regions of cancer-related genes such as TGFβRII and BAX. A standardized definition for microsatellite instability (MSI) based on the presence of deletions to mononucleotide repeats is gaining widespread acceptance in both research and the clinic. Colorectal cancer (CRC) with MSI are characterized histologically by an abundance of tumor-infiltrating lymphocytes, poor differentiation and a signet ring or mucinous phenotype. In younger patients these tumors usually develop along the chromosomal instability pathway, in which case the mismatch repair genes are inactivated by germline mutation, somatic mutation and loss of heterozygosity. In older patients MSI CRC usually develops against a background of widespread hypermethylation that includes methylation-induced silencing of the mismatch repair gene MLH1. The overall biological and clinical phenotype of MSI CRC that arise in these two pathways is likely to be different and may account for some of the discordant results reported in the literature relating to the clinical properties of these tumors. The available evidence indicates that MSI is unlikely to be a clinically useful marker for the prognostic stratification of early-stage CRC. The predictive value of MSI for response to 5-fluorouracil-based chemotherapy remains controversial, while for other agents the predictive value is difficult to assess because they are used in combination regimens. The MSI phenotype is being actively investigated for novel therapeutic approaches based on the principle of synthetic lethality. Finally, the MSI status of CRC is an extremely useful marker for population-based screening programs that aim to identify individuals and families with the hereditary cancer condition known as Lynch syndrome.
Topics: Colorectal Neoplasms; Humans; Microsatellite Instability
PubMed: 21114775
DOI: 10.1111/j.1743-7563.2010.01335.x -
Journal of B.U.ON. : Official Journal... 2021
Topics: Humans; Microsatellite Instability; Thyroid Neoplasms
PubMed: 34268987
DOI: No ID Found -
Expert Reviews in Molecular Medicine Sep 2022Roughly 3% of the human genome consists of microsatellites or tracts of short tandem repeats (STRs). These STRs are often unstable, undergoing high-frequency expansions... (Review)
Review
Roughly 3% of the human genome consists of microsatellites or tracts of short tandem repeats (STRs). These STRs are often unstable, undergoing high-frequency expansions (increases) or contractions (decreases) in the number of repeat units. Some microsatellite instability (MSI) is seen at multiple STRs within a single cell and is associated with certain types of cancer. A second form of MSI is characterised by expansion of a single gene-specific STR and such expansions are responsible for a group of 40+ human genetic disorders known as the repeat expansion diseases (REDs). While the mismatch repair (MMR) pathway prevents genome-wide MSI, emerging evidence suggests that some MMR factors are directly involved in generating expansions in the REDs. Thus, MMR suppresses some forms of expansion while some MMR factors promote expansion in other contexts. This review will cover what is known about the paradoxical effect of MMR on microsatellite expansion in mammalian cells.
Topics: Animals; DNA Mismatch Repair; Genomic Instability; Humans; Mammals; Microsatellite Instability; Microsatellite Repeats
PubMed: 36059110
DOI: 10.1017/erm.2022.16