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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 -
Chinese Clinical Oncology Oct 2016The pathology of biliary carcinomas is diverse with different gross and histological features in tumors arising in the different segments of the biliary system. Various... (Review)
Review
The pathology of biliary carcinomas is diverse with different gross and histological features in tumors arising in the different segments of the biliary system. Various epidemiological risk factors, varied genetic makeup, and tissue microenvironment are contributory factors. As biliary tumors have been shown to be a part of the Lynch syndrome tumor spectrum, it is plausible to speculate that DNA mismatch repair (MMR) deficiency plays a role in biliary tumors. Literature data suggest that DNA MMR deficiency indeed occurs in these tumors, albeit infrequently with the reported frequencies (weighted for sample size) of high level microsatellite instability (MSI) being 5% each for gallbladder carcinoma and carcinoma of extra-hepatic bile ducts, and 10% each for intrahepatic cholangiocarcinoma and ampullary carcinoma. Importantly, the presence of MMR deficiency in these tumors has been shown to have different implications with regard to its association with Lynch syndrome, tumor histological features, and other clinical characteristics, when compared with non-biliary tumors or among the biliary tumors from the different segments of the biliary system. Ongoing and future efforts that utilize large scale sequencing techniques and aim at detecting actionable molecular targets should emphasize a multidisciplinary approach that integrates genomic discoveries with not only functional studies but also studies of tumor pathology and the tumor's clinical and biological behavior.
Topics: Bile Duct Neoplasms; DNA Mismatch Repair; Humans; Microsatellite Instability
PubMed: 27829276
DOI: 10.21037/cco.2016.10.04 -
ESMO Open Jun 2021DNA mismatch repair system deficiency (dMMR) is found in 15% of colorectal cancers (CRCs). Two methods are used to determine dMMR, immunohistochemistry (IHC) of MMR...
BACKGROUND
DNA mismatch repair system deficiency (dMMR) is found in 15% of colorectal cancers (CRCs). Two methods are used to determine dMMR, immunohistochemistry (IHC) of MMR proteins and molecular testing of microsatellite instability (MSI). Only studies with a low number of patients have reported rates of discordance between these two methods, ranging from 1% to 10%.
MATERIALS AND METHODS
Overall, 3228 consecutive patients with CRCs from two centers were included. Molecular testing was carried out using the Pentaplex panel and IHC evaluated four (MLH1, MSH2, MSH6, and PMS2; cohort 1; n = 1085) or two MMR proteins (MLH1 and MSH2; cohort 2; n = 2143). The primary endpoint was the rate of discordance between MSI and MMR IHC tests.
RESULTS
Fifty-one discordant cases (1.6%) were initially observed. Twenty-nine out of 51 discordant cases were related to IHC misclassifications. In cohort 1, after re-reading IHC and/or carrying out new IHC, 16 discordant cases were reclassified as nondiscordant. In cohort 2, after the addition of MSH6/PMS2 IHC and re-examination, 13 were reclassified as nondiscordant. In addition, 10 misclassifications of molecular tests were identified. Finally, only 12 discordant cases (0.4%) remained: 5 were proficient MMR/MSI and 7 were dMMR/microsatellite stable.
CONCLUSIONS
Our study confirmed the high degree of concordance between MSI and MMR IHC tests. Discordant cases must be reviewed, and if needed, tests must be repeated and analyzed by an expert team.
Topics: Colorectal Neoplasms; DNA Mismatch Repair; Humans; Immunochemistry; Microsatellite Instability; Molecular Diagnostic Techniques
PubMed: 33930657
DOI: 10.1016/j.esmoop.2021.100120 -
The Journal of Pathology. Clinical... Mar 2022Mismatch repair deficiency (dMMR) is a hallmark of Lynch syndrome (LS), but its prevalence in early-onset (diagnosed under the age of 50 years) duodenal, ampullary,...
Mismatch repair deficiency (dMMR) is a hallmark of Lynch syndrome (LS), but its prevalence in early-onset (diagnosed under the age of 50 years) duodenal, ampullary, and pancreatic carcinomas (DC, AC, and PC, respectively) is largely unknown. We explored the prevalence of dMMR and the underlying molecular mechanisms in a retrospectively collected cohort of 90 early-onset carcinomas of duodenal, ampullary, and pancreatic origin. dMMR was most prevalent in early-onset DCs (47.8%); more than half of those were associated with hereditary cancer syndromes (LS or constitutional mismatch repair deficiency syndrome). All dMMR AC and PC were due to LS. Concordance of dMMR with underlying hereditary condition warrants ubiquitous dMMR testing in all early-onset DC, AC, and PC.
Topics: Brain Neoplasms; Carcinoma; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Humans; Middle Aged; Neoplastic Syndromes, Hereditary; Retrospective Studies
PubMed: 34873870
DOI: 10.1002/cjp2.252 -
International Journal of Molecular... Feb 2022Microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) is receiving more attention as a biomarker for eligibility for immune checkpoint inhibitors in... (Review)
Review
Microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) is receiving more attention as a biomarker for eligibility for immune checkpoint inhibitors in advanced diseases. However, due to high costs and resource limitations, MSI/dMMR testing is not widely performed. Some attempts are in progress to predict MSI/dMMR status through histomorphological features on H&E slides using artificial intelligence (AI) technology. In this study, the potential predictive role of this new methodology was reviewed through a systematic review. Studies up to September 2021 were searched through PubMed and Embase database searches. The design and results of each study were summarized, and the risk of bias for each study was evaluated. For colorectal cancer, AI-based systems showed excellent performance with the highest standard of 0.972; for gastric and endometrial cancers they showed a relatively low but satisfactory performance, with the highest standard of 0.81 and 0.82, respectively. However, analyzing the risk of bias, most studies were evaluated at high-risk. AI-based systems showed a high potential in predicting the MSI/dMMR status of different cancer types, and particularly of colorectal cancers. Therefore, a confirmation test should be required only for the results that are positive in the AI test.
Topics: Artificial Intelligence; Colorectal Neoplasms; DNA Mismatch Repair; Endometrial Neoplasms; Female; Humans; Microsatellite Instability
PubMed: 35269607
DOI: 10.3390/ijms23052462 -
DNA Repair Feb 2016The machinery of DNA mismatch repair enzymes is highly conserved in evolution. The process is initiated by recognition of a DNA mismatch, and validated by ATP and the... (Review)
Review
The machinery of DNA mismatch repair enzymes is highly conserved in evolution. The process is initiated by recognition of a DNA mismatch, and validated by ATP and the presence of a processivity clamp or a methylation mark. Several events in MMR promote conformational changes that lead to progression of the repair process. Here we discuss functional conformational changes in the MMR proteins and we compare the enzymes to paralogs in other systems.
Topics: Animals; Conserved Sequence; DNA Mismatch Repair; DNA Repair Enzymes; Humans; Models, Biological; Models, Molecular
PubMed: 26796427
DOI: 10.1016/j.dnarep.2015.11.012 -
Canadian Journal of Surgery. Journal... 2023It has recently been reported that mismatch repair (MMR) status and microsatellite instability (MSI) status in gastroesophageal carcinomas predict surgical,...
BACKGROUND
It has recently been reported that mismatch repair (MMR) status and microsatellite instability (MSI) status in gastroesophageal carcinomas predict surgical, chemotherapeutic and immunotherapeutic outcomes; however, there is extensive variability in the reported incidence and clinical implications of MMR/MSI status in gastroesophaegal adenocarcinomas. We characterized a Canadian surgical patient cohort with respect to MMR status, clinicopathologic correlates and anatomic tumour location.
METHODS
We investigated MMR and BRAF V600E status of gastroesophaegal adenocarcinomas in patients who underwent gastrectomy or esophagectomy with extended (D2) lymphadenectomy at a single centre between 2011 and 2019. We correlated patterns of MMR expression in the overall cohort and in anatomic location-defined subgroups with treatment response and overall survival using multivariate analysis.
RESULTS
In all, 226 cases of gastroesophaegal adenocarcinoma (63 esophageal, 98 gastroesophageal junctional and 65 gastric) were included. The MMR-deficient (dMMR) immunophenotype was found in 28 tumours (12.3%) (15 junctional [15.3%], 13 gastric [20.0%] and none of the esophageal). The majority (25 [89%]) of dMMR cases showed MLH1/PMS2 loss without concurrent BRAF V600E mutation. Two MSH2/ MSH6-deficient gastric tumours and 1 MSH6-deficient junctional tumour were detected. The pathologic response to preoperative chemotherapy was comparable in the dMMR and MMR-proficient (pMMR) cohorts. However, dMMR status was associated with significantly longer median overall survival than pMMR status (5.8 yr v. 2.4 yr, hazard ratio [HR] 1.91, 95% confidence interval [CI] 1.06-3.46), particularly in junctional tumours (4.6 yr v. 1.9 yr, HR 2.97, 95% CI 1.27-6.94).
CONCLUSION
Our study shows that MMR status has at least prognostic value, which supports the need for biomarker testing in gastroesophageal adenocarcinomas, including junctional adenocarcinomas. This highlights the clinical significance of determining the MMR status in all adenocarcinomas of the upper gastrointestinal tract. Response to induction chemotherapy, however, was not influenced by MMR status.
Topics: Humans; Proto-Oncogene Proteins B-raf; DNA Mismatch Repair; Canada; Colorectal Neoplasms; Adenocarcinoma; DNA-Binding Proteins; MutL Protein Homolog 1
PubMed: 36792128
DOI: 10.1503/cjs.017021 -
The British Journal of Radiology Nov 2020The significance of canonical DNA non-homologous end-joining (c-NHEJ) for DNA double strand break (DSB) repair has increased from lower organisms to higher eukaryotes,... (Review)
Review
The significance of canonical DNA non-homologous end-joining (c-NHEJ) for DNA double strand break (DSB) repair has increased from lower organisms to higher eukaryotes, and plays the predominant role in human cells. Ku, the c-NHEJ end-binding component, binds DSBs with high efficiency enabling c-NHEJ to be the first choice DSB repair pathway, although alternative pathways can ensue after regulated steps to remove Ku. Indeed, radiation-induced DSBs are repaired rapidly in human cells. However, an important question is the fidelity with which radiation-induced DSBs are repaired, which is essential for assessing any harmful impacts caused by radiation exposure. Indeed, is compromised fidelity a price we pay for high capacity repair. Two subpathways of c-NHEJ have been revealed; a fast process that does not require nucleases or significant chromatin changes and a slower process that necessitates resection factors, and potentially more significant chromatin changes at the DSB. Recent studies have also shown that DSBs within transcriptionally active regions are repaired by specialised mechanisms, and the response at such DSBs encompasses a process of transcriptional arrest. Here, we consider the limitations of c-NHEJ that might result in DSB misrepair. We consider the common IR-induced misrepair events and discuss how they might arise via the distinct subpathways of c-NHEJ.
Topics: Chromatin; DNA; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Mismatch Repair; G1 Phase; G2 Phase; Humans; Ku Autoantigen; Resting Phase, Cell Cycle; Transcription Termination, Genetic; Transcriptional Activation
PubMed: 31944860
DOI: 10.1259/bjr.20190966 -
Nucleic Acids Research Apr 2023In eukaryotic mismatch repair, MutS homologs recognize mismatches and recruit the MutLα endonuclease which introduces a nick in the newly replicated, error-containing...
In eukaryotic mismatch repair, MutS homologs recognize mismatches and recruit the MutLα endonuclease which introduces a nick in the newly replicated, error-containing DNA strand. The nick occurs in response to the mismatch, but at a site up to several hundred base pairs away. The MutLα nick promotes mismatch excision by an exonuclease (Exo1) or removal by the strand displacement activity of a DNA polymerase which may work in conjunction with a flap endonuclease. Models have suggested that MutL homolog endonucleases form oligomeric complexes which facilitate and are activated by strand capture mechanisms, although such models have never been explicitly tested. We present evidence that the mismatch repair MutLα endonuclease is activated by DNA-DNA associations and that it can use this property to overcome DNA torsional barriers. Using DNA ligation and pull-down experiments, we determined that the MutLα endonuclease associates two DNA duplexes. Using nuclease assays, we determined that this activity stimulates MutLα's endonuclease function. We also observe that MutLα enhances a topoisomerase without nicking the DNA itself. Our data provide a mechanistic explanation for how MutL proteins interact with DNA during mismatch repair, and how MutL homologs participate in other processes, such as recombination and trinucleotide repeat expansions.
Topics: DNA; DNA Mismatch Repair; DNA Repair; Endonucleases; MutL Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 36840719
DOI: 10.1093/nar/gkad096 -
Chromosoma Dec 2015The genome of all organisms is constantly being challenged by endogenous and exogenous sources of DNA damage. Errors like base:base mismatches or small insertions and... (Review)
Review
The genome of all organisms is constantly being challenged by endogenous and exogenous sources of DNA damage. Errors like base:base mismatches or small insertions and deletions, primarily introduced by DNA polymerases during DNA replication are repaired by an evolutionary conserved DNA mismatch repair (MMR) system. The MMR system, together with the DNA replication machinery, promote repair by an excision and resynthesis mechanism during or after DNA replication, increasing replication fidelity by up-to-three orders of magnitude. Consequently, inactivation of MMR genes results in elevated mutation rates that can lead to increased cancer susceptibility in humans. In this review, we summarize our current understanding of MMR with a focus on the different MMR protein complexes, their function and structure. We also discuss how recent findings have provided new insights in the spatio-temporal regulation and mechanism of MMR.
Topics: DNA Mismatch Repair; DNA Replication; Eukaryota; Humans
PubMed: 25862369
DOI: 10.1007/s00412-015-0514-0