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Pathologie (Heidelberg, Germany) Nov 2023Testing to detect mismatch repair deficiency (dMMR) and high-grade microsatellite instability (MSI-H) has become an integral part of the routine diagnostic workup for... (Review)
Review
Testing to detect mismatch repair deficiency (dMMR) and high-grade microsatellite instability (MSI-H) has become an integral part of the routine diagnostic workup for colorectal cancer (CRC). While MSI was initially considered to be a possible indicator of a hereditary disposition to cancer (Lynch syndrome, LS), today the prediction of the therapy response to immune checkpoint inhibitors (ICI) is in the foreground. Corresponding recommendations and testing algorithms are available for use in primary diagnosis (reviewed in: Rüschoff et al. 2021).Given the increasing importance for routine use and the expanding indication spectrum of ICI therapies for non-CRCs, such as endometrial, small intestinal, gastric, and biliary tract cancers, an updated review of dMMR/MSI testing is presented. The focus is on the challenges in the assessment of immunohistochemical stains and the value of PCR-based procedures, considering the expanded ICI indication spectrum. A practice-oriented flowchart for everyday diagnostic decision-making is provided that considers new data on the frequency and type of discordances between MMR-IHC and MSI-PCR findings, and the possible role of Next Generation Sequencing in clarifying them. Reference is made to the significance of systematic quality assurance measures (e.g., QuIP MSI portal and multicenter proficiency testing), including regular continued training and education.
Topics: Humans; DNA Mismatch Repair; Microsatellite Instability; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Multicenter Studies as Topic
PubMed: 37874379
DOI: 10.1007/s00292-023-01208-2 -
International Journal of Molecular... Oct 2022Many clinical decisions in oncology practice rely on the presence or absence of an alteration in a single genetic locus, be it a pathogenic variant in a hereditary... (Review)
Review
Many clinical decisions in oncology practice rely on the presence or absence of an alteration in a single genetic locus, be it a pathogenic variant in a hereditary cancer gene or activating mutation in a drug target. In addition, there are integrative tests that produce continuous variables and evaluate complex characteristics of the entire tumor genome. Microsatellite instability (MSI) analysis identifies tumors with the accumulation of mutations in short repetitive nucleotide sequences. This procedure is utilized in Lynch syndrome diagnostic pipelines and for the selection of patients for immunotherapy. MSI analysis is well-established for colorectal malignancies, but its applications in other cancer types lack standardization and require additional research. Homologous repair deficiency (HRD) indicates tumor sensitivity to PARP inhibitors and some cytotoxic drugs. HRD-related "genomic scars" are manifested by a characteristic pattern of allelic imbalances, accumulation of deletions with flanking homology, and specific mutation signatures. The detection of the genetic consequences of HRD is particularly sophisticated and expensive, as it involves either whole genome sequencing (WGS) or the utilization of large next-generation sequencing (NGS) panels. Tumor mutation burden (TMB) can be determined by whole exome sequencing (WES) or middle-throughput NGS multigene testing. Although TMB is regarded as an agnostic indicator of tumor sensitivity to immunotherapy, the clinical utility of this test is proven only for a few cancer types.
Topics: Humans; Microsatellite Instability; High-Throughput Nucleotide Sequencing; Medical Oncology; Mutation; Biomarkers, Tumor; Colorectal Neoplasms; Neoplasms; Genomics
PubMed: 36361916
DOI: 10.3390/ijms232113129 -
Genes May 2023Microsatellite instability (MSI) can be found in 15-20% of all colorectal cancers (CRC) and is the key feature of a defective DNA mismatch repair (MMR) system.... (Review)
Review
Microsatellite instability (MSI) can be found in 15-20% of all colorectal cancers (CRC) and is the key feature of a defective DNA mismatch repair (MMR) system. Currently, MSI has been established as a unique and pivotal biomarker in the diagnosis, prognosis, and treatment of CRC. MSI tumors display a strong lymphocytic activation and a shift toward a tumoral microenvironment restraining metastatic potential and ensuing in a high responsiveness to immunotherapy of MSI CRC. Indeed, neoplastic cells with an MMR defect overexpress several immune checkpoint proteins, such as programmed death-1 (PD-1) and programmed death-ligand 1(PD-L1), that can be pharmacologically targeted, allowing for the revival the cytotoxic immune response toward the tumor. This review aims to illustrate the role of MSI in the tumor biology of colorectal cancer, focusing on the immune interactions with the microenvironment and their therapeutic implications.
Topics: Humans; Microsatellite Instability; Prognosis; Antineoplastic Agents; Immunotherapy; Colorectal Neoplasms; Tumor Microenvironment
PubMed: 37372349
DOI: 10.3390/genes14061169 -
Journal of Cancer Research and Clinical... Dec 2019Microsatellites are widely distributed repetitive DNA motifs, accounting for approximately 3% of the genome. Due to mismatch repair system deficiency, insertion or... (Review)
Review
PURPOSE
Microsatellites are widely distributed repetitive DNA motifs, accounting for approximately 3% of the genome. Due to mismatch repair system deficiency, insertion or deletion of repetitive units often occurs, leading to microsatellite instability. In this review, we aimed to explore the relationship between MSI and biological behaviour of colorectal carcinoma, gastric carcinoma, lymphoma/leukaemia and endometrial carcinoma, as well as the application of frameshift peptide vaccines in cancer therapy.
METHODS
The relevant literature from PubMed and Baidu Xueshu were reviewed in this article. The ClinicalTrials.gov database was searched for clinical trials related to the specific topic.
RESULTS
Microsatellite instability is divided into three subtypes: high-level, low-level microsatellite instability, and stable microsatellites. The majority of tumour patients with high-level microsatellite instability often show a better efficacy and prognosis than those with low-level microsatellite instability or stable microsatellites. In coding regions, especially for genes involved in tumourigenesis, microsatellite instability often results in inactivation of proteins and contributes to tumourigenesis. Moreover, the occurrence of microsatellite instability in coding regions can also cause the generation of frameshift peptides that are thought to be unknown and novel to the individual immune system. Thus, these frameshift peptides have the potential to be biomarkers to raise tumour-specific immune responses.
CONCLUSION
MSI has the potential to become a key predictor for evaluating the degree of malignancy, efficacy and prognosis of tumours. Clinically, MSI patterns will provide more valuable information for clinicians to create optimal individualized treatment strategies based on frameshift peptides vaccines.
Topics: Animals; Carcinogenesis; Clinical Trials as Topic; DNA Mismatch Repair; Frameshift Mutation; Humans; Microsatellite Instability; Microsatellite Repeats; Neoplasms; Prognosis
PubMed: 31617076
DOI: 10.1007/s00432-019-03053-4 -
Cancer Science Mar 2023The phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed,... (Randomized Controlled Trial)
Randomized Controlled Trial
The phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite-instability-high (MSI-H)/mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE-177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n = 22; chemotherapy, n = 26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1-57.8) months with pembrolizumab and 43.9 (range 36.6-55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months-NR) with pembrolizumab versus 10.4 (95% CI 6.3-22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26-1.20). Median OS was NR (range 13.8 months-NR) versus 30.0 (14.7-NR) months (HR 0.65, 95% CI 0.27-1.55) and ORR was 50% (95% CI 28-72) versus 46% (95% CI 27-67). Grade 3/4 treatment-related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune-mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002.
Topics: Humans; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; DNA Mismatch Repair; Microsatellite Instability; Microsatellite Repeats
PubMed: 36369901
DOI: 10.1111/cas.15650 -
Annals of Oncology : Official Journal... Sep 2021
Topics: Genomic Instability; Humans; Microsatellite Instability
PubMed: 34216739
DOI: 10.1016/j.annonc.2021.06.022 -
Human Pathology Sep 2023The objective of this study was to determine if quantifying the microsatellite instability (MSI) phenotype could serve as a biomarker for clinical and immunologic...
The objective of this study was to determine if quantifying the microsatellite instability (MSI) phenotype could serve as a biomarker for clinical and immunologic features of deficient mismatch repair (dMMR) endometrial cancer (EC). Patients with EC undergoing hysterectomy whose tumors demonstrated dMMR were included. Immunohistochemistry (IHC) of mismatch repair proteins and polymerase chain reaction analysis of NR27, BAT25, BAT26, NR24, and NR21 microsatellite loci were performed on each case. The MSI phenotype was quantified by subtracting the number of nucleotides of each microsatellite in tumor tissue from the corresponding microsatellite in paired normal tissue and summing the absolute differences. This was termed marker sum (MS) and is a novel quantification. Tumor-infiltrating lymphocytes (TILs) were identified by IHC for CD3, CD4, and CD8 and quantified with digital image analysis. Tumor infiltration of lymphocytes and clinical characteristics were stratified by MS. Four hundred fifty-nine consecutive patients with dMMR EC were analyzed. MS ranged from 1 to 32. Post hoc, 2 cohorts were defined using receiver operating characteristic curves (MS less than 13 and MS greater than 12). With the exception of tumor grade, all clinical and pathologic features, all tumor characteristics, and the numbers of TILs were similar between cohorts. The MSI phenotype is highly variable in dMMR EC, and no correlation between the immune profile and the severity of the MSI phenotype was observed.
Topics: Female; Humans; Microsatellite Instability; Endometrial Neoplasms; Microsatellite Repeats; Phenotype; Immunohistochemistry; DNA Mismatch Repair; Colorectal Neoplasms
PubMed: 37245630
DOI: 10.1016/j.humpath.2023.05.011 -
Translational Research : the Journal of... Oct 2023Testing of microsatellite instability is not only used as a triage for possible Lynch syndrome, but also to predict immunotherapy treatment response. The aim of this...
Microsatellite instability in non-endometrioid ovarian epithelial tumors: a study of 400 cases comparing immunohistochemistry, PCR, and NGS based testing with mutation status of MMR genes.
Testing of microsatellite instability is not only used as a triage for possible Lynch syndrome, but also to predict immunotherapy treatment response. The aim of this study was to assess the frequency of mismatch repair deficiency (MMR-D)/microsatellite instability (MSI) in 400 cases of non-endometrioid ovarian tumors (high-grade serous, low-grade serous, mucinous and clear cell), to compare different methodological approaches of testing, and to assess the optimal approach for next generation sequencing (NGS) MSI testing. For all tumors, we evaluated immunohistochemical (IHC) expression of MMR proteins and assessed microsatellite markers by PCR-based method. Except for high-grade serous carcinoma, we correlated the findings of IHC and PCR with NGS-based MSI testing. We compared the results with somatic and germline mutation in MMR genes. Among the whole cohort, seven MMR-D cases, all clear cell carcinomas (CCC), were found. On PCR analysis, 6 cases were MSI-high and one was MSS. In all cases, mutation of an MMR gene was found; in 2 cases, the mutation was germline (Lynch syndrome). An additional 5 cases with a mutation in MMR gene(s) with MSS status and without MMR-D were identified. We further utilized sequence capture NGS for MSI testing. Employing 53 microsatellite loci provided high sensitivity and specificity. Our study shows that MSI occurs in 7% of CCC while it is rare or absent in other nonendometrioid ovarian neoplasms. Lynch syndrome was present in 2% of patients with CCC. However, some cases with MSH6 mutation can evade all testing methods, including IHC, PCR, and NGS-MSI.
Topics: Female; Humans; Microsatellite Instability; Immunohistochemistry; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Mutation; Polymerase Chain Reaction; High-Throughput Nucleotide Sequencing; Neoplasms, Glandular and Epithelial
PubMed: 37244485
DOI: 10.1016/j.trsl.2023.05.004 -
International Journal of Molecular... Nov 2023According to the Cancer Genome Atlas (TCGA), gastric cancers are classified into four molecular subtypes: Epstein-Barr virus-positive (EBV+), tumors with microsatellite... (Review)
Review
According to the Cancer Genome Atlas (TCGA), gastric cancers are classified into four molecular subtypes: Epstein-Barr virus-positive (EBV+), tumors with microsatellite instability (MSI), tumors with chromosomal instability (CIN), and genomically stable (GS) tumors. However, the gastric cancer (GC) with chromosomal instability remains insufficiently described and does not have effective markers for molecular and histological verification and diagnosis. The CIN subtype of GC is characterized by chromosomal instability, which is manifested by an increased frequency of aneuploidies and/or structural chromosomal rearrangements in tumor cells. Structural rearrangements in the CIN subtype of GC are not accidental and are commonly detected in chromosomal loci, being abnormal because of specific structural organization. The causes of CIN are still being discussed; however, according to recent data, aberrations in the gene may cause CIN development or worsen its phenotype. Clinically, patients with the CIN subtype of GC demonstrate poor survival, but receive the maximum benefit from adjuvant chemotherapy. In the review, we consider the molecular mechanisms and possible causes of chromosomal instability in GC, the common rearrangements of chromosomal loci and their impact on the development and clinical course of the disease, as well as the driver genes, their functions, and perspectives on their targeting in the CIN subtype of GC.
Topics: Humans; Stomach Neoplasms; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Chromosomal Instability; Microsatellite Instability
PubMed: 38069284
DOI: 10.3390/ijms242316961 -
Biomedica : Revista Del Instituto... May 2022Introduction: Colorectal cancer has a high incidence in the world population. Different molecular pathways, such as chromosomal instability, microsatellite instability,...
Introduction: Colorectal cancer has a high incidence in the world population. Different molecular pathways, such as chromosomal instability, microsatellite instability, and epigenetics are involved in its development. Objective: To perform molecular characterization in 44 individuals with sporadic colorectal cancer. Materials and methods: We conducted mutation analyses of the APC, KRAS, TP53 y BRAF genes using Sanger sequencing techniques; microsatellite instability was determined by capillary electrophoresis with five STR genetic markers while the methylation status of the MHL1 promotor gene was analyzed using methylation-specific PCR. Results: APC, KRAS, and TP53 genes mutation frequency was 18.1%, 25%, and 4.5%, respectively; the somatic mutations detected were located more frequently in the right colon. The frequency of microsatellite instability was 27.2% and 73.1% of the tumors had the MHL1 gene methylated while 91.6% of microsatellite instability-positive tumors had the methylated MLH1 gene. The mutation profile of microsatellite stability tumors APC, KRAS, and TP53 genes was more frequent than in the microsatellite instability-positive tumors. The methylation of the MLH1 gene was the most predominant molecular alteration. Conclusions: We identified molecular alterations in different genetic pathways of the colorectal cancer patients evaluated, which are common in the carcinogenesis of this cancer. These patients showed a different mutational profile compared to other populations. Our findings confirm the molecular heterogeneity described in the development of colorectal cancer.
Topics: Colorectal Neoplasms; Humans; Microsatellite Instability; Proto-Oncogene Proteins p21(ras); Retrospective Studies
PubMed: 35866738
DOI: 10.7705/biomedica.5957