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Seminars in Cancer Biology Oct 2018Colorectal cancer (CRC) is a common and lethal disease with a high therapeutic need. For most patients with metastatic CRC, chemotherapy is the only viable option.... (Review)
Review
Colorectal cancer (CRC) is a common and lethal disease with a high therapeutic need. For most patients with metastatic CRC, chemotherapy is the only viable option. Currently, immunotherapy is restricted to the particular genetic subgroup of mismatch-repair deficient (MMRd)/microsatellite instable (MSI) CRC. Anti-PD1 therapy was recently FDA-approved as a second-line treatment in this subgroup. However, in a metastatic setting, these MMRd/MSI tumors are vastly outnumbered by mismatch-repair proficient (MMRp)/microsatellite stable (MSS) tumors. These MMRp/MSS tumors do not meaningfully respond to any traditional immunotherapy approach including checkpoint blockade, adoptive cell transfer and vaccination. This resistance to immunotherapy is due to a complex tumor microenvironment that counteracts antitumor immunity through a combination of poorly antigenic tumor cells and an immunosuppressive tumor microenvironment. To find ways of overcoming immunotherapy resistance in the majority of CRC patients, it is necessary to analyze the immunological makeup in an in-depth and personalized way and in the context of their tumor genetic makeup. Flexible, biomarker-guided early-phase immunotherapy trials are needed to optimize this workflow. In this review, we detail key mechanisms for immune evasion and emerging immune biomarkers for personalized immunotherapy in CRC. Also, we present a template for biomarker-guided clinical trials that are needed to move new immunotherapy approaches closer to clinical application.
Topics: Animals; Antigens, Neoplasm; Biomarkers, Tumor; Colorectal Neoplasms; DNA Mismatch Repair; Genomics; Humans; Immunotherapy; Microsatellite Instability; Tumor Microenvironment
PubMed: 29501787
DOI: 10.1016/j.semcancer.2018.02.010 -
Journal of Molecular Biology Oct 2018DNA mismatch repair (MMR) corrects DNA base-pairing errors that occur during DNA replication. MMR catalyzes strand-specific DNA degradation and resynthesis by dynamic... (Review)
Review
DNA mismatch repair (MMR) corrects DNA base-pairing errors that occur during DNA replication. MMR catalyzes strand-specific DNA degradation and resynthesis by dynamic molecular coordination of sequential downstream pathways. The temporal and mechanistic order of molecular events is essential to insure interactions in MMR that occur over long distances on the DNA. Biophysical real-time studies of highly conserved components on mismatched DNA have shed light on the mechanics of MMR. Single-molecule imaging has visualized stochastically coordinated MMR interactions that are based on thermal fluctuation-driven motions. In this review, we describe the role of diffusivity and stochasticity in MMR beginning with mismatch recognition through strand-specific excision. We conclude with a perspective of the possible research directions that should solve the remaining questions in MMR.
Topics: Animals; Biophysical Phenomena; DNA; DNA Mismatch Repair; Diffusion; Humans; Multiprotein Complexes; Stochastic Processes; Thermodynamics
PubMed: 29792877
DOI: 10.1016/j.jmb.2018.05.032 -
European Journal of Obstetrics,... Jul 2022Infertility is associated to multiple types of different genomic instabilities and is a genetic feature of genomic instability syndromes. While the mismatch repair... (Review)
Review
Infertility is associated to multiple types of different genomic instabilities and is a genetic feature of genomic instability syndromes. While the mismatch repair machinery contributes to the maintenance of genome integrity, surprisingly its potential role in infertility is overlooked. Defects in mismatch repair mechanisms contribute to microsatellite instability and genomic instability syndromes, due to the inability to repair newly replicated DNA. This article reviews the literature to date to elucidate the contribution of microsatellite instability to genomic instability syndromes and infertility. The key findings presented reveal microsatellite instability is poorly researched in genomic instability syndromes and infertility.
Topics: DNA Mismatch Repair; Genomic Instability; Humans; Infertility; Microsatellite Instability; Microsatellite Repeats; Syndrome
PubMed: 35671666
DOI: 10.1016/j.ejogrb.2022.06.001 -
DNA Repair Feb 2016DNA mismatch repair (MMR) protects genome integrity by correcting DNA replication-associated mispairs, modulating DNA damage-induced cell cycle checkpoints and... (Review)
Review
DNA mismatch repair (MMR) protects genome integrity by correcting DNA replication-associated mispairs, modulating DNA damage-induced cell cycle checkpoints and regulating homeologous recombination. Loss of MMR function leads to cancer development. This review describes progress in understanding how MMR is carried out in the context of chromatin and how chromatin organization/compaction, epigenetic mechanisms and posttranslational modifications of MMR proteins influence and regulate MMR in eukaryotic cells.
Topics: Animals; Chromatin Assembly and Disassembly; DNA Mismatch Repair; Eukaryotic Cells; Histone Code; Humans; Models, Biological; Protein Processing, Post-Translational
PubMed: 26719139
DOI: 10.1016/j.dnarep.2015.11.021 -
Cells May 2021We describe the contribution of DNA mismatch repair (MMR) to the stability of the eukaryotic nuclear genome as determined by whole-genome sequencing. To date, wild-type... (Review)
Review
We describe the contribution of DNA mismatch repair (MMR) to the stability of the eukaryotic nuclear genome as determined by whole-genome sequencing. To date, wild-type nuclear genome mutation rates are known for over 40 eukaryotic species, while measurements in mismatch repair-defective organisms are fewer in number and are concentrated on and human tumors. Well-studied organisms include and , while less genetically tractable species include great apes and long-lived trees. A variety of techniques have been developed to gather mutation rates, either per generation or per cell division. Generational rates are described through whole-organism mutation accumulation experiments and through offspring-parent sequencing, or they have been identified by descent. Rates per somatic cell division have been estimated from cell line mutation accumulation experiments, from systemic variant allele frequencies, and from widely spaced samples with known cell divisions per unit of tissue growth. The latter methods are also used to estimate generational mutation rates for large organisms that lack dedicated germlines, such as trees and hyphal fungi. Mechanistic studies involving genetic manipulation of MMR genes prior to mutation rate determination are thus far confined to yeast, , , and one chicken cell line. A great deal of work in wild-type organisms has begun to establish a sound baseline, but far more work is needed to uncover the variety of MMR across eukaryotes. Nonetheless, the few MMR studies reported to date indicate that MMR contributes 100-fold or more to genome stability, and they have uncovered insights that would have been impossible to obtain using reporter gene assays.
Topics: Cell Nucleus; DNA Damage; DNA Mismatch Repair; DNA Mutational Analysis; Genomic Instability; Humans; Mutation Rate; Whole Genome Sequencing
PubMed: 34067668
DOI: 10.3390/cells10051224 -
International Journal of Molecular... Mar 2023There is increasing evidence in a range of cancer types that the microbiome plays a direct role in modulating the anti-cancer immune response both at the gut level and... (Review)
Review
There is increasing evidence in a range of cancer types that the microbiome plays a direct role in modulating the anti-cancer immune response both at the gut level and systemically. Differences in the gut microbiota have been shown to correlate with differences in immunotherapy responses in a range of non-gastrointestinal tract cancers. DNA mismatch repair-deficient (dMMR) colorectal cancer (CRC) is radically different to DNA mismatch repair-proficient (pMMR) CRC in clinical phenotype and in its very good responses to immunotherapy. While this has usually been thought to be due to the high mutational burden in dMMR CRC, the gut microbiome is radically different in dMMR and pMMR CRC in terms of both composition and diversity. It is probable that differences in the gut microbiota contribute to the varied responses to immunotherapy in dMMR versus pMMR CRC. Targeting the microbiome offers a way to boost the response and increase the selection of patients who might benefit from this therapy. This paper reviews the available literature on the role of the microbiome in the response to immunotherapy in dMMR and pMMR CRC, explores the potential causal relationship and discusses future directions for study in this exciting and rapidly changing field.
Topics: Humans; Gastrointestinal Microbiome; Colorectal Neoplasms; Immunotherapy; Microsatellite Repeats; DNA Mismatch Repair; Microsatellite Instability
PubMed: 36982838
DOI: 10.3390/ijms24065767 -
Asian Journal of Surgery Feb 2024Immunohistochemistry (IHC) and traditional polymerase chain reaction (PCR) are the methods of choice in clinical practice to identify the mismatch repair (MMR) and...
BACKGROUND
Immunohistochemistry (IHC) and traditional polymerase chain reaction (PCR) are the methods of choice in clinical practice to identify the mismatch repair (MMR) and microsatellite instability (MSI) status in colorectal cancer (CRC). In some previous researches, the concordance rate between two methods was different and discordance existed in about 1 %-9.7 %.
METHODS
We retrospectively reviewed 406 patients received surgical CRC resections and tests of both MMR IHC and MSI PCR from January 2019 to April 2022 in Shanghai Changzheng Hospital. The incidence of deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) CRCs, the concordance rate between two methods, and the reasons for discordant results were evaluated with clinicopathological data, immunochemical staining, whole-exome sequencing, and MLH1 methylation analysis.
RESULTS
Among 406 patients, the incidence of MSI-H CRCs was 7.88 %. Nearly a quarter of the cases under reexamination of IHC was initial misinterpreted. Besides, the concordance rate between MMR IHC and MSI PCR was 99.26 % (401 of 404) and the Kappa value was 0.945 (p < 0.001). Finally, some somatic variants of MMR and POLE genes which may explain the discordance were identified.
CONCLUSION
The incidence rate of MSI-H in Chinese patients with CRC might be relatively low owing to tumor location. Although MSI and IHC analyses are highly concordant, both MMR IHC and MSI PCR tests should be simultaneously performed and MMR IHC should be interpreted by experienced pathologists. In the future, further studies on discordant results should be carried out to improve the personalized management of CRC.
Topics: Humans; Microsatellite Instability; Colorectal Neoplasms; DNA Mismatch Repair; Retrospective Studies; China; Microsatellite Repeats
PubMed: 38185557
DOI: 10.1016/j.asjsur.2023.12.176 -
Cell Research May 2021DNA mismatch repair (MMR) relies on MutS and MutL ATPases for mismatch recognition and strand-specific nuclease recruitment to remove mispaired bases in daughter...
DNA mismatch repair (MMR) relies on MutS and MutL ATPases for mismatch recognition and strand-specific nuclease recruitment to remove mispaired bases in daughter strands. However, whether the MutS-MutL complex coordinates MMR by ATP-dependent sliding on DNA or protein-protein interactions between the mismatch and strand discrimination signal is ambiguous. Using functional MMR assays and systems preventing proteins from sliding, we show that sliding of human MutSα is required not for MMR initiation, but for final mismatch removal. MutSα recruits MutLα to form a mismatch-bound complex, which initiates MMR by nicking the daughter strand 5' to the mismatch. Exonuclease 1 (Exo1) is then recruited to the nick and conducts 5' → 3' excision. ATP-dependent MutSα dissociation from the mismatch is necessary for Exo1 to remove the mispaired base when the excision reaches the mismatch. Therefore, our study has resolved a long-standing puzzle, and provided new insights into the mechanism of MMR initiation and mispair removal.
Topics: Adenosine Triphosphatases; Base Pair Mismatch; DNA; DNA Mismatch Repair; DNA Repair; DNA-Binding Proteins; Humans; MutS DNA Mismatch-Binding Protein
PubMed: 33510387
DOI: 10.1038/s41422-021-00468-y -
Journal of Huntington's Disease 2021DNA damage repair (DDR) mechanisms have been implicated in a number of neurodegenerative diseases (both genetically determined and sporadic). Consistent with this,... (Review)
Review
DNA damage repair (DDR) mechanisms have been implicated in a number of neurodegenerative diseases (both genetically determined and sporadic). Consistent with this, recent genome-wide association studies in Huntington's disease (HD) and other trinucleotide repeat expansion diseases have highlighted genes involved in DDR mechanisms as modifiers for age of onset, rate of progression and somatic instability. At least some clinical genetic modifiers have been shown to have a role in modulating trinucleotide repeat expansion biology and could therefore provide new disease-modifying therapeutic targets. In this review, we focus on key considerations with respect to drug discovery and development using DDR mechanisms as a target for trinucleotide repeat expansion diseases. Six areas are covered with specific reference to DDR and HD: 1) Target identification and validation; 2) Candidate selection including therapeutic modality and delivery; 3) Target drug exposure with particular focus on blood-brain barrier penetration, engagement and expression of pharmacology; 4) Safety; 5) Preclinical models as predictors of therapeutic efficacy; 6) Clinical outcome measures including biomarkers.
Topics: Animals; DNA Damage; DNA Mismatch Repair; Drug Development; Drug Discovery; Humans; Huntingtin Protein; Huntington Disease; Trinucleotide Repeat Expansion
PubMed: 32925081
DOI: 10.3233/JHD-200421 -
Frontiers in Immunology 2019Around 30% of endometrial cancers (EC) are mismatch repair (MMR) deficient, mostly as a consequence of mutations acquired during tumorigenesis, but a significant...
Around 30% of endometrial cancers (EC) are mismatch repair (MMR) deficient, mostly as a consequence of mutations acquired during tumorigenesis, but a significant minority is caused by Lynch syndrome (LS). This inherited cancer predisposition syndrome primes an anti-cancer immune response, even in healthy carriers. We sought to explore the intra-tumoral immunological differences between genetically confirmed LS-associated MMR-deficient (MMRd), sporadic MMR-deficient, and MMR-proficient (MMRp) EC. Endometrial tumors from women with known LS were identified ( = 25). Comparator tumors were recruited prospectively and underwent microsatellite instability (MSI) testing, immunohistochemistry (IHC) for MMR expression and methylation testing. Those found to have hypermethylation formed the sporadic MMR-deficient group ( = 33). Those found to be mismatch repair proficient and microsatellite stable formed the MMR-proficient group ( = 35). A fully automated monoplex IHC panel was performed on sequential formalin-fixed paraffin-embedded tumor sections to identify CD3+, CD8+, CD45RO+, FoxP3+, and PD-1+ immune cells, and PD-L1 expression by tumor/immune cells. Two independent observers quantified immune marker expression at the tumor center and invasive margin. Mean and overall compartmental T-cell counts generated standard (binary: Low/High) and higher resolution (quaternary: 0-25, 25-50, 50-75, 75-100%) immune scores, which were used as explanatory features in neural network, support vector machine, and discriminant predictive modeling. Overall T-cell counts were significantly different between the three cohorts: CD3+ ( = <0.0001), CD8+ ( = <0.0001), CD45RO+ (<0.0001), FoxP3+ ( = <0.0001), and PD1+ ( = <0.0001), with LS-associated MMR-deficient tumors having highest infiltrations. There were significant differences in CD8+ ( = 0.02), CD45RO+ ( = 0.007), and PD-1+ ( = 0.005) T-cell counts at the invasive margin between LS-associated and sporadic MMR-deficient tumors, but not between sporadic MMR-deficient and MMR-proficient tumors. Predictive modeling could accurately determine MMR status based on CD8+ T-cell counts within the tumor center alone. This study shows that LS-associated and sporadic MMR-deficient EC are distinct immunological entities, which has important implications for treatment and prognosis.
Topics: Biomarkers, Tumor; CD8-Positive T-Lymphocytes; Cohort Studies; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Methylation; DNA Mismatch Repair; Endometrial Neoplasms; Female; Humans; Microsatellite Instability; Middle Aged; MutL Protein Homolog 1; Prognosis; Programmed Cell Death 1 Receptor
PubMed: 31998307
DOI: 10.3389/fimmu.2019.03023