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Clinica Chimica Acta; International... Apr 2023Drugs targeting DNA repair have developed rapidly in cancer therapy, and numerous inhibitors have already been utilized in preclinical and clinical stages. To optimize... (Review)
Review
Drugs targeting DNA repair have developed rapidly in cancer therapy, and numerous inhibitors have already been utilized in preclinical and clinical stages. To optimize the selection of patients for treatment, it is essential to discover biomarkers to anticipate chemotherapy response. The DNA mismatch repair (MMR) pathway is closely correlated with cancer susceptibility and plays an important role in the occurrence and development of cancers. Here, we give a concise introduction of the MMR genes and focus on the potential biomarkers of chemotherapeutic response and resistance. It has been clarified that the status of MMR may affect the outcome of chemotherapy. However, the specific underlying mechanisms as well as contradictory results continue to raise considerable controversy and concern. In this review, we summarize the current literature to provide a general overview.
Topics: Humans; DNA Mismatch Repair; DNA Repair; Neoplasms; Biomarkers; Drug Resistance, Neoplasm
PubMed: 37060988
DOI: 10.1016/j.cca.2023.117338 -
Revista de Gastroenterologia de Mexico... 2022A frequent task in the study of colorectal carcinomas (CRC) is to identify tumors harboring deficient DNA mismatch repair systems (dMMR), which are associated with...
INTRODUCTION AND AIMS
A frequent task in the study of colorectal carcinomas (CRC) is to identify tumors harboring deficient DNA mismatch repair systems (dMMR), which are associated with microsatellite instability. Given that there is scant information on those tumors in Mexican patients, our aim was to describe their frequency, clinical and pathologic characteristics, and results, which are necessary for future trials.
MATERIALS AND METHODS
A consecutive series of CRC patients, treated and followed at a tertiary care center was performed. The clinical and pathologic variables and the risk of hereditary or familial cancer syndrome were retrieved. The original slides and hMLH1, hPMS2, hMSH2, hMSH6 immunohistochemistry were evaluated. Tumors with an absence of at least one protein were considered dMMR. Differences were contrasted, utilizing non-parametric tests.
RESULTS
One hundred and forty-four patients were included, with a median age of 65 years. A total of 134/93% patients presented with sporadic CRC, 8/5.6% had a family history of CRC, and 2/1.4% met the diagnostic criteria for hereditary non-polyposis colon cancer, according to the Amsterdam and Bethesda criteria. dMMR tumors were found in 39 patients, distributed among the three groups. They were locally advanced (p<0.001), right-sided, had the mucinous phenotype, and harbored a Crohn's-like lymphoid reaction (all three features, p<0.04). Adjuvant or palliative chemotherapy was administered to 57 (39.6%), concomitant chemoradiotherapy to 24 (16.7%), but 63 (43.8%) patients received no additional treatment to surgery. Five-year follow-up was completed in 131 of the patients and the outcomes alive-with-disease or died-of-disease were more frequently observed in the proficient (pMMR) lesions.
CONCLUSIONS
In the present pre-FOLFOX case series, outcomes were better in dMMR CRC than in proficient lesions.
Topics: Humans; DNA Mismatch Repair; Follow-Up Studies; Colorectal Neoplasms; Microsatellite Instability; Phenotype
PubMed: 35661637
DOI: 10.1016/j.rgmxen.2022.05.017 -
DNA Repair Feb 2016The enzyme activation-induced deaminase (AID) targets the immunoglobulin loci in activated B cells and creates DNA mutations in the antigen-binding variable region and... (Review)
Review
The enzyme activation-induced deaminase (AID) targets the immunoglobulin loci in activated B cells and creates DNA mutations in the antigen-binding variable region and DNA breaks in the switch region through processes known, respectively, as somatic hypermutation and class switch recombination. AID deaminates cytosine to uracil in DNA to create a U:G mismatch. During somatic hypermutation, the MutSα complex binds to the mismatch, and the error-prone DNA polymerase η generates mutations at A and T bases. During class switch recombination, both MutSα and MutLα complexes bind to the mismatch, resulting in double-strand break formation and end-joining. This review is centered on the mechanisms of how the MMR pathway is commandeered by B cells to generate antibody diversity.
Topics: Animals; Antibodies; Base Sequence; Cytidine Deaminase; DNA Mismatch Repair; DNA-Directed DNA Polymerase; Humans; Molecular Sequence Data; Mutation; Somatic Hypermutation, Immunoglobulin
PubMed: 26719140
DOI: 10.1016/j.dnarep.2015.11.011 -
DNA Repair Sep 2020DNA mismatch repair (MMR) maintains genomic stability primarily by correcting replication errors. Defects in MMR lead to cancers and cause resistance to many... (Review)
Review
DNA mismatch repair (MMR) maintains genomic stability primarily by correcting replication errors. Defects in MMR lead to cancers and cause resistance to many chemotherapeutic drugs. Emerging evidence reveals that MMR is coupled with replication and precisely regulated in the context of chromatin; strikingly, tumors defective in MMR are highly responsive to immune checkpoint blockade therapy. As a tribute to Dr. Samuel Wilson for his many scientific contributions to the field of DNA repair and his leadership as Editor-in-Chief of the journal DNA Repair, we summarize recent developments in research on MMR at the chromatin level, its implications for tumorigenesis, and its therapeutic potential.
Topics: Carcinogenesis; Chromatin; DNA Damage; DNA Mismatch Repair; Humans; Neoplasms
PubMed: 33087261
DOI: 10.1016/j.dnarep.2020.102918 -
Journal of the National Cancer Institute Nov 2017Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations... (Review)
Review
Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations (such as BRCA1 or 2). It now appears that a clinically significant fraction of cancers have acquired DNA repair defects. DNA repair pathways operate in related networks, and cancers arising from loss of one DNA repair component typically become addicted to other repair pathways to survive and proliferate. Drug inhibition of the rescue repair pathway prevents the repair-deficient cancer cell from replicating, causing apoptosis (termed synthetic lethality). However, the selective pressure of inhibiting the rescue repair pathway can generate further mutations that confer resistance to the synthetic lethal drugs. Many such drugs currently in clinical use inhibit PARP1, a repair component to which cancers arising from inherited BRCA1 or 2 mutations become addicted. It is now clear that drugs inducing synthetic lethality may also be therapeutic in cancers with acquired DNA repair defects, which would markedly broaden their applicability beyond treatment of cancers with inherited DNA repair defects. Here we review how each DNA repair pathway can be attacked therapeutically and evaluate DNA repair components as potential drug targets to induce synthetic lethality. Clinical use of drugs targeting DNA repair will markedly increase when functional and genetic loss of repair components are consistently identified. In addition, future therapies will exploit artificial synthetic lethality, where complementary DNA repair pathways are targeted simultaneously in cancers without DNA repair defects.
Topics: Antineoplastic Agents; DNA End-Joining Repair; DNA Mismatch Repair; DNA Repair; Genes, BRCA1; Genes, BRCA2; Homologous Recombination; Humans; Molecular Targeted Therapy; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Synthetic Lethal Mutations
PubMed: 28521333
DOI: 10.1093/jnci/djx059 -
Modern Pathology : An Official Journal... Nov 2022In managing patients with solid tumors, the value of detecting the status of tumor DNA mismatch repair function is widely recognized. Mismatch repair protein... (Review)
Review
In managing patients with solid tumors, the value of detecting the status of tumor DNA mismatch repair function is widely recognized. Mismatch repair protein immunohistochemistry and molecular microsatellite instability testing constitute the two major test modalities currently in use, yet each is associated with caveats and limitations that can be consequential. Most notably, the traditional approach of defining mismatch repair protein immunohistochemistry abnormality by complete loss of staining in all tumor cells is evolving. Partial or clonal loss is becoming recognized as a manifestation of gene abnormality; in some cases, such clonal loss is associated with germline pathogenic variants. The current criteria and cutoff values for defining microsatellite instability-high are developed primarily according to colorectal tumors. Non-colorectal cases, and occasionally even colorectal tumors, that are mismatch repair-deficient by immunohistochemistry but not microsatellite instability-high by current standards are being recognized. Emerging data suggest that these immunohistochemistry abnormal / non-microsatellite instability-high cases warrant further genetic workup for Lynch syndrome detection. Whether these tumors respond to immunotherapy is a question still to be addressed. It is imperative that pathologists as well as clinicians and investigators be aware of such intricacies regarding routine immunohistochemistry and microsatellite instability testing and the results they generate. This review summarizes our current understanding of the advantages and limitations of these tests and offer our view on what constitutes the most optimal strategy in test selection and how best to utilize case context to enhance the interpretation of the test results.
Topics: Humans; Immunohistochemistry; Microsatellite Instability; Neoplastic Syndromes, Hereditary; Colorectal Neoplasms; DNA Mismatch Repair
PubMed: 35668150
DOI: 10.1038/s41379-022-01109-4 -
Journal For Immunotherapy of Cancer Jun 2022The development of cancer vaccines to induce tumor-antigen specific immune responses was sparked by the identification of antigens specific to or overexpressed in cancer... (Review)
Review
The development of cancer vaccines to induce tumor-antigen specific immune responses was sparked by the identification of antigens specific to or overexpressed in cancer cells. However, weak immunogenicity and the mutational heterogeneity in many cancers have dampened cancer vaccine successes. With increasing information about mutational landscapes of cancers, mutational neoantigens can be predicted computationally to elicit strong immune responses by CD8 +cytotoxic T cells as major mediators of anticancer immune response. Neoantigens are potentially more robust immunogens and have revived interest in cancer vaccines. Cancers with deficiency in DNA mismatch repair have an exceptionally high mutational burden, including predictable neoantigens. Lynch syndrome is the most common inherited cancer syndrome and is caused by DNA mismatch repair gene mutations. Insertion and deletion mutations in coding microsatellites that occur during DNA replication include tumorigenesis drivers. The induced shift of protein reading frame generates neoantigens that are foreign to the immune system. Mismatch repair-deficient cancers and Lynch syndrome represent a paradigm population for the development of a preventive cancer vaccine, as the mutations induced by mismatch repair deficiency are predictable, resulting in a defined set of frameshift peptide neoantigens. Furthermore, Lynch syndrome mutation carriers constitute an identifiable high-risk population. We discuss the pathogenesis of DNA mismatch repair deficient cancers, in both Lynch syndrome and sporadic microsatellite-unstable cancers. We review evidence for pre-existing immune surveillance, the three mechanisms of immune evasion that occur in cancers and assess the implications of a preventive frameshift peptide neoantigen-based vaccine. We consider both preclinical and clinical experience to date. We discuss the feasibility of a cancer preventive vaccine for Lynch syndrome carriers and review current antigen selection and delivery strategies. Finally, we propose RNA vaccines as having robust potential for immunoprevention of Lynch syndrome cancers.
Topics: Brain Neoplasms; Cancer Vaccines; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Humans; Immunotherapy; Neoplastic Syndromes, Hereditary
PubMed: 35732349
DOI: 10.1136/jitc-2021-004416 -
International Journal of Molecular... Sep 2023Approximately 20-30% of endometrial carcinomas (EC) are characterized by mismatch repair (MMR) deficiency (dMMR) or microsatellite instability (MSI), and their testing...
Approximately 20-30% of endometrial carcinomas (EC) are characterized by mismatch repair (MMR) deficiency (dMMR) or microsatellite instability (MSI), and their testing has become part of the routine diagnosis. The aim of this study was to establish and compare the MMR status using various approaches. Immunohistochemistry (IHC), PCR-based MSI, and the detection of defects in the four key MMR genes (MLH1, PMS2, MSH2, and MSH6) via methylation-specific multiplex ligation-dependent probe amplification (MLPA) and targeted next-generation sequencing (NGS) were performed. MSH3 expression was also evaluated. A set of 126 early-stage EC samples were analyzed, 53.2% of which were dMMR and 46.8% of which were proficient MMR (pMMR) as determined using IHC, whereas 69.3% were classified as microsatellite stable, while 8.8% and 21.9% were classified MSI-low (MSI-L) and MSI-high (MSI-H), respectively. In total, 44.3% of the samples showed genetic or epigenetic alterations in one or more genes; MLH1 promoter methylation was the most common event. Although acceptable concordance was observed, there were overall discrepancies between the three testing approaches, mainly associated with the dMMR group. IHC had a better correlation with MMR genomic status than the MSI status determined using PCR. Further studies are needed to establish solid conclusions regarding the best MMR assessment technique for EC.
Topics: Female; Humans; DNA Mismatch Repair; Endometrial Neoplasms; Colorectal Neoplasms; Neoplastic Syndromes, Hereditary; Microsatellite Instability
PubMed: 37833916
DOI: 10.3390/ijms241914468 -
Annual Review of Genetics 2015Three processes act in series to accurately replicate the eukaryotic nuclear genome. The major replicative DNA polymerases strongly prevent mismatch formation,... (Review)
Review
Three processes act in series to accurately replicate the eukaryotic nuclear genome. The major replicative DNA polymerases strongly prevent mismatch formation, occasional mismatches that do form are proofread during replication, and rare mismatches that escape proofreading are corrected by mismatch repair (MMR). This review focuses on MMR in light of increasing knowledge about nuclear DNA replication enzymology and the rate and specificity with which mismatches are generated during leading- and lagging-strand replication. We consider differences in MMR efficiency in relation to mismatch recognition, signaling to direct MMR to the nascent strand, mismatch removal, and the timing of MMR. These studies are refining our understanding of relationships between generating and repairing replication errors to achieve accurate replication of both DNA strands of the nuclear genome.
Topics: DNA; DNA Damage; DNA Mismatch Repair; DNA Replication; Escherichia coli; Genomic Instability; Humans; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 26436461
DOI: 10.1146/annurev-genet-112414-054722 -
Current Biology : CB Mar 2021State-of-the-art genetic and cellular studies uniquely implicate the S. cerevisiae Pms1 endonuclease (human PMS2) and ExoI as the major components that produce and/or...
State-of-the-art genetic and cellular studies uniquely implicate the S. cerevisiae Pms1 endonuclease (human PMS2) and ExoI as the major components that produce and/or maintain the strand-specific nicks that precisely direct mismatch repair.
Topics: DNA Mismatch Repair; Humans; MutL Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 33756142
DOI: 10.1016/j.cub.2021.02.001