scholarly journals Mismatch Repair Deficiency in Colorectal Adenocarcinoma: Clinical, Pathological and Prognostic Features, a Single Center’s Experience of 1002 Cases

2021 ◽  
Author(s):  
Fatma Yildirim ◽  
Murat Sezak ◽  
Tayfun Yoldas ◽  
Bulent Karabulut ◽  
Basak Doganavsargil
Keyword(s):  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Tumor Infiltrating Lymphocytes ◽  
Clinicopathological Features ◽  
Prognostic Features ◽  
Mucinous Component ◽  
Significant Difference ◽  
Mmr Deficiency ◽  
High Level

Background and Study Aims: Microsatellite instability pathway caused by loss of DNA “Mismatch Repair genes” (MMR) is responsible of Lynch Syndrome-related tumors and 10-15% of sporadical colorectal cancers. Although MSI-test is regarded as the golden standard for detection of “Lynch Syndrome-related tumors”, there are increasing evidence on similar analytic sensitivity of immunohistochemical evaluations. Patinets and Metods: We retrospectively evaluated 1002 colorectal tumors for loss of DNA MMR protein (MLH1, PMS2, MSH2, MSH6) immunohistochemically. The results were correlated with clinicopathological features and high level-microsatellite instability (MSI-H) related histological parameters. Results: MMR protein expression loss was observed in 9.8% of the cases. MLH1-PMS2 loss (53.2%) was the most common loss followed by MSH2-MSH6 (31.6%), isolated PMS2 loss (12%), and isolated MSH6 loss (2%). MMR deficiency was more frequent under 50 years-old (p<0.0001), in right colon tumors (p<0.0001), poorly differentiated tumors (p<0.0001), tumors with tumor infiltrating lymphocytes (p<0.0001), mucinous component (p=0.001), and medullary component (p<0.0001). Also MMR deficiency was less frequent in tumor with tumor budding (p<0.0001) and dirty necrosis (p<0.0001). The 5 years-survival rate was 55.7%. No significant correlation was found with MMR deficiency and survival. Conclusions: MMR deficiency was observed in 9.8% of the cases with distinct clinicopathological features. The results were consistent with previous studies. Unlike the literature, we did not find any statistically significant difference between MMR deficiency and prognosis.

scholarly journals Does mismatch repair (MMR) deficiency have prognostic significance in low-risk endometrioid endometrial cancers?

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e17122-e17122
Author(s):  
Soyoun Rachel Kim ◽  
Annick Pina ◽  
Arianne Albert ◽  
Jessica N. McAlpine ◽  
Robert Wolber ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Prognostic Significance ◽  
Cox Proportional Hazards Model ◽  
Low Risk ◽  
Recurrence Rates ◽  
Significant Difference ◽  
Stage Ia ◽  
Endometrial Cancers ◽  
Mmr Deficiency

e17122 Background: Mismatch repair (MMR) deficiency is observed in 25-30% of all endometrial cancers. This can be detected by the absence of MMR protein staining on immunohistochemistry (IHC), and is used in many jurisdictions as a screen for an inherited mutation in one of the MMR genes (Lynch Syndrome). Only 10% of women with MMR deficiency (MMRd) have Lynch syndrome, but MMRd may still have prognostic significance. The objective of this study was to compare clinical outcomes between MMR deficient and proficient low-risk endometrioid endometrial cancers (stage IA, grade 1/2). Methods: This was a retrospective population-based cohort study of all low-risk endometrial cancers from Vancouver Coastal Health authority region from 2011 to 2016 that were assessed for MMR deficiency (MMRd). Primary outcome measures were recurrence rates expressed per person-years (py), progression free survival (PFS) and overall survival (OS) calculated using Kaplan-Meier method and log-rank tests. Cox proportional hazards model estimated the association between MMRd and recurrence and death after adjustment for covariates, expressed as hazard ratios (HR). Results: There were 475 low-risk patients, including 131 MMRd (27.6%) and 345 MMRp (proficient) patients. Women with MMRd tumors had higher recurrence rates (3.53p100py vs 1.21p100py) and worse PFS (p = 0.0082) compared to women with MMRp tumors. After adjustment for age, LVSI status, adjuvant therapy, and post-operative grade, MMRd status remained associated with a higher risk of recurrence (HR 2.99, 95% CI 1.27-7.04). There was no significant difference in OS between MMR groups (HR 1.38, 95% CI 0.57-3.33). Conclusions: In low-risk stage IA grade 1 or 2 endometrioid endometrial cancers, MMR deficiency is associated with a higher recurrence rate than in MMR proficient cases, after adjustment for covariates, implying that MMR deficiency reflects a different biology in endometrial cancer.

scholarly journals Mismatch Repair Protein Deficiency/Microsatellite Instability Is Rare in Cholangiocarcinomas and Associated With Distinctive Morphologies

2019 ◽  
Vol 153 (5) ◽  
pp. 598-604 ◽  
Author(s):  
Jennifer Y Ju ◽  
Megan E Dibbern ◽  
Mani S Mahadevan ◽  
Jinbo Fan ◽  
Paul R Kunk ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Repair Protein ◽  
Signet Ring ◽  
The Us ◽  
History Of ◽  
Mmr Deficiency ◽  
Pattern Of Invasion ◽  
Mismatch Repair Protein

Abstract Objectives Although germline mutations of mismatch repair (MMR) genes (Lynch syndrome) are not typically associated with cholangiocarcinomas, the US Food and Drug Administration recently approved the use of pembrolizumab in patients with advanced solid tumors at all sites that show MMR deficiency or associated high microsatellite instability. Methods We analyzed 96 cases of intra- and extrahepatic cholangiocarcinomas for morphology using H&E and for MMR status using immunohistochemical staining. We submitted any results with MMR loss for microsatellite instability testing. Results We found that 6% of samples showed MMR deficiency. The best predictive factor was a nontypical infiltrating pattern of invasion (P &lt; .0001). No patients with MMR deficiency had a history of a cancer typically associated with Lynch syndrome. Conclusions Solid, mucinous, or signet-ring appearance of a cholangiocarcinoma should prompt MMR testing for immunotherapy options but should not necessarily raise concern about Lynch syndrome.

scholarly journals Prevalence of Lynch syndrome among patients with upper urinary tract carcinoma in a Japanese hospital-based population

2019 ◽  
Vol 50 (1) ◽  
pp. 80-88 ◽  
Author(s):  
Tetsuya Ito ◽  
Koji Kono ◽  
Hidetaka Eguchi ◽  
Yasushi Okazaki ◽  
Gou Yamamoto ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Urothelial Carcinoma ◽  
Mismatch Repair ◽  
Upper Urinary Tract ◽  
Screening Methods ◽  
Cancer History ◽  
High Level ◽  
Urinary Tract Urothelial Carcinoma

Abstract Background The prevalence of Lynch syndrome and the use of universal tumor screening to identify Lynch syndrome among unselected patients with upper urinary tract urothelial carcinoma, which is associated with Lynch syndrome, have not been closely investigated yet. Methods A total of 166 tumors from 164 upper urinary tract urothelial carcinoma patients were tested for microsatellite instability and expression of mismatch repair proteins (MLH1, MHS2, MSH6 and PMS2) by immunohistochemistry. Genetic testing was performed for patients suspected of having Lynch syndrome. Clinicopathological factors, including familial and personal cancer history associated with mismatch repair deficiency, were evaluated. Results The frequency of high-level microsatellite instability and loss of at least one mismatch repair protein was 2.4% (4/164); the microsatellite instability and immunohistochemistry results showed complete concordance. Of these four patients, three were genetically proven to have Lynch syndrome, while the remaining one was highly suggestive for Lynch syndrome based on their personal cancer history. Univariate analysis showed that age&lt;70 years (P = 0.04), ureter as the tumor location (P = 0.052), previous history/synchronous diagnosis of colorectal cancer (P &lt; 0.01) and fulfillment of the criteria per the revised Bethesda guideline (P &lt; 0.01) tended to be or were significantly associated with high-level microsatellite instability/mismatch repair loss. Conclusions The prevalence of Lynch syndrome among unselected upper urinary tract urothelial carcinoma patients was at least 1.8% in our study population. The screening efficacies of the microsatellite instability test and immunohistochemistry appear equivalent. Universal tumor screening may be a valid approach; however, selective screening methods that consider factors associated with mismatch repair loss/high-level microsatellite instability tumors require further investigation.

scholarly journals Mutational signature profiling classifies subtypes of clinically different mismatch repair deficient tumors with a differential immunogenic response potential

2021 ◽  
Author(s):  
Mar Giner-Calabuig ◽  
Seila De Leon ◽  
Julian Wang ◽  
Tara D Fehlmann ◽  
Chinedu Ukaegbu ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Molecular Characterization ◽  
Mutational Signatures ◽  
Mmr Deficiency ◽  
High Level ◽  
Sporadic Tumors ◽  
Generation Sequencing ◽  
Immunogenic Response

ABSTRACTBackgroundMismatch repair (MMR) deficiency is the hallmark of tumors from Lynch syndrome (LS), sporadic MLH1 hypermethylated, and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterization to identify novel features that can impact tumor behavior and clinical management.MethodsWe tested 105 MMR-deficient colorectal cancer tumors (25 LS, 35 LLS, and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load.Results78% of tumors showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumors. 22% of tumors showed weaker features of MMR deficiency, 73% lost MSH2/MSH6 expression and included half of LS and LLS tumors. Remarkably, 9% of all tumors lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumors that show the strongest contribution of MMR-deficient tumors.ConclusionsNext-generation sequencing approaches allow for a granular molecular characterization of MMR-deficient tumors, which can be essential to properly diagnose and treat patients with these tumors in the setting of personalized medicine.

scholarly journals The Frequency of DNA Mismatch Repair Deficiency Is Very Low in Surgically Resected Lung Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Naoki Yanagawa ◽  
Noriyuki Yamada ◽  
Ryo Sugimoto ◽  
Mitsumasa Osakabe ◽  
Noriyuki Uesugi ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Protein Expression ◽  
Microsatellite Instability ◽  
Cell Carcinoma ◽  
Mismatch Repair ◽  
Squamous Cell ◽  
Lung Carcinoma ◽  
The Other ◽  
Dna Mismatch ◽  
Mmr Deficiency

IntroductionDNA mismatch repair (MMR) deficiency leads to changes in the length of nucleotide repeat sequences of tumor DNA. In that situation, DNA replicational errors occur and accumulate during DNA replication. As a result, this mechanism frequently affects the coding regions of oncogenes and tumor suppressor genes and causes carcinogenesis. Recently, DNA MMR deficiency has been recognized as a predictive biomarker for immunotherapy. The aim of this study is to examine the frequency of DNA MMR deficiency and clinicopathological characteristics in surgically resected lung carcinoma (LC) and their correlation.MethodsA total of 1153 LCs were examined. Tissue microarrays were constructed. The status of MMR deficiency was evaluated by immunohistochemical analysis of MMR protein expression (hMLH1, hMSH2, hMSH6, and hPMS2). Microsatellite instability analysis, BRAF mutation, and MLH1 methylation analysis were performed for cases that showed MMR deficiency.ResultsOnly 2 of the 1153 cases (0.17%) showed a loss of hMLH1/hPMS2 protein expression. They also had high levels of microsatellite instability (MSI-H), had neither MLH1 promoter methylation nor BRAF mutation, and were male smokers. Histopathologically, one was a squamous cell carcinoma, and the other was combined small cell carcinoma with squamous cell carcinoma. Regarding PD-L1 protein expression, one had high expression, and the other had none.ConclusionThe frequency of MMR deficiency was very low in LC. However, our two cases were non-adenocarcinoma and differed from previous studies. Because of its very low frequency, MMR deficiency is not a practical biomarker to predict the effect of immune checkpoint inhibitors in LC.

Microsatellite Instability, Mismatch Repair Deficiency, and BRAF Mutation in Treatment-Resistant Germ Cell Tumors

2009 ◽  
Vol 27 (13) ◽  
pp. 2129-2136 ◽  
Author(s):  
Friedemann Honecker ◽  
Hendrik Wermann ◽  
Frank Mayer ◽  
Ad J.M. Gillis ◽  
Hans Stoop ◽  
...  
Keyword(s):  
Germ Cell ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Braf Mutation ◽  
Cisplatin Resistance ◽  
Germ Cell Tumors ◽  
Braf V600e ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Mmr Deficiency

Purpose Mismatch repair (MMR) deficiency and microsatellite instability (MSI) are associated with cisplatin resistance in human germ cell tumors (GCTs). BRAF mutation (V600E) is found in MSI colorectal cancers. The role of RAS/RAF pathway mutations in GCT treatment response is unknown. Patients and Methods Two patient cohorts were investigated: 100 control GCTs (50 seminomas and 50 nonseminomas) and 35 cisplatin-based chemotherapy-resistant GCTs. MMR proteins were analyzed by immunohistochemistry, and eight microsatellite loci were examined for MSI. Tumors were assessed for specific BRAF and KRAS mutations. Results Resistant tumors showed a higher incidence of MSI than controls: 26% versus 0% in two or more loci (P < .0001). All resistant tumors were wild-type KRAS, and two controls (2%) contained a KRAS mutation. There was a significantly higher incidence of BRAF V600E mutation in resistant tumors compared with controls: 26% versus 1% (P < .0001). BRAF mutations were highly correlated with MSI (P = .006), and MSI and mutated BRAF were correlated with weak or absent staining for hMLH1 (P = .017 and P = .008). Low or absent staining of hMLH1 was correlated with promoter hypermethylation (P < .001). Tumors lacking expression of hMLH1 or MSH6 were significantly more frequent in resistant GCTs than in controls (P = .001 and 0.0036, respectively). Within the subgroup of resistant tumors, patients with MSI showed a trend to longer progression-free survival (P = .068). Conclusion We report for the first time a correlation between a gene mutation—BRAF V600E—and cisplatin resistance in nonseminomatous GCTs. Furthermore, a correlation between MMR deficiency, MSI, and treatment failure is confirmed.

Idylla MSI test as a new tool for microsatellite instability detection in sebaceous tumours and keratoacanthomas

2021 ◽  
pp. jclinpath-2021-207606
Author(s):  
Loëtitia Favre ◽  
Ruiqian Chen ◽  
Yaëlle Bellahsen-Harrar ◽  
Nicolas Ortonne ◽  
Anaïs Pujals
Keyword(s):  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Sensitivity And Specificity ◽  
Molecular Techniques ◽  
Molecular Methods ◽  
Specific Method ◽  
Skin Tumours ◽  
Automated Method ◽  
Mmr Deficiency ◽  
Mmr Proteins

AimSebaceous tumours and keratoacanthomas can be associated with mismatch repair (MMR) deficiency and thus microsatellite instability (MSI). In such tumours, MSI phenotype could be an argument to search for an underlying Muir-Torre syndrome (MTS). MTS has been recognised as a variant of Lynch syndrome, characterised by a deficiency of the MMR proteins. In Lynch syndrome, the sensitivity and specificity of the techniques used to detect MSI is well described, which is not the case for skin tumours. In our hands, immunohistochemistry is a sensitive and specific method to detect MMR deficiency in those tumours. Contrasting with tumours of Lynch spectrum, sensitivity and specificity of molecular methods has not been extensively studied. This study aimed at evaluating two molecular methods to detect MSI phenotype in MTS associated tumours: a commonly used pentaplex PCR using Bethesda markers and the fully automated method using the Idylla MSI assay.MethodsA comparison between PCR, and Idylla was performed on 39 DNA extracted from cutaneous tumours. Immunohistochemistry was used as the gold standard to calculate sensitivity and specificity of both molecular techniques.ResultsConcordant results were found in 32 cases (82%) with pentaplex PCR and in 36 cases (92%) with Idylla. The sensitivity of pentaplex PCR to detect MSI phenotype was 76% whereas Idylla sensitivity was 90%.ConclusionIdylla is more performant than PCR, for the detection of MSI in MTS-associated tumours and is a reliable additional technique to help detecting MTS in these tumours.

scholarly journals Understanding Inherited Risk in Unselected Newly Diagnosed Patients With Endometrial Cancer

2019 ◽  
pp. 1-15
Author(s):  
Karen A. Cadoo ◽  
Diana L. Mandelker ◽  
Semanti Mukherjee ◽  
Carolyn Stewart ◽  
Deborah DeLair ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Next Generation Sequencing ◽  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Cancer Predisposition ◽  
Next Generation ◽  
Germline Variants ◽  
Predisposition Genes ◽  
Generation Sequencing

PURPOSE Mutations in DNA mismatch repair genes and PTEN, diagnostic of Lynch and Cowden syndromes, respectively, represent the only established inherited predisposition genes in endometrial cancer to date. The prevalence of other cancer predisposition genes remains unclear. We determined the prevalence of pathogenic germline variants in unselected patients with endometrial cancer scheduled for surgical consultation. PATIENTS AND METHODS Patients prospectively consented (April 2016 to May 2017) to an institutional review board–approved protocol of tumor-normal sequencing via a custom next-generation sequencing panel—the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets—that yielded germline results for more than 75 cancer predisposition genes. Tumors were assessed for microsatellite instability. Per institutional standards, all tumors underwent Lynch syndrome screening via immunohistochemistry (IHC) for mismatch repair proteins. RESULTS Of 156 patients who consented to germline genetic testing, 118 (76%) had stage I disease. In 104 patients (67%), tumors were endometrioid, and 60 (58%) of those tumors were grade 1. Twenty-four pathogenic germline variants were identified in 22 patients (14%): seven (4.5%) had highly penetrant cancer syndromes and 15 (9.6%) had variants in low-penetrance, moderate-penetrance, or recessive genes. Of these, five (21%) were in Lynch syndrome genes (two MSH6, two PMS2, and one MLH1). All five tumors had concordant IHC staining; two (40%) were definitively microsatellite instability–high by next-generation sequencing. One patient had a known BRCA1 mutation, and one had an SMARCA4 deletion. The remaining 17 variants (71%) were incremental findings in low- and moderate-penetrance variants or genes associated with recessive disease. CONCLUSION In unselected patients with predominantly low-risk, early-stage endometrial cancer, germline multigene panel testing identified cancer predisposition gene variants in 14%. This finding may have implications for future cancer screening and risk-reduction recommendations. Universal IHC screening for Lynch syndrome successfully identifies the majority (71%) of high-penetrance germline mutations.

Tumor site discordance in mismatch repair deficiency in synchronous endometrial and ovarian cancers

2020 ◽  
Vol 30 (12) ◽  
pp. 1951-1958
Author(s):  
Soyoun Rachel Kim ◽  
Alicia Tone ◽  
Raymond Kim ◽  
Matthew Cesari ◽  
Blaise Clarke ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Ovarian Tumor ◽  
Tumor Site ◽  
Mismatch Repair Deficiency ◽  
Ovarian Cancers ◽  
Repair Deficiency ◽  
Endometrial Tumor ◽  
Germline Testing

ObjectivesFor synchronous endometrial and ovarian cancers, most centers rely on mismatch repair testing of the endometrial cancer to identify Lynch syndrome, and neglect the ovarian tumor site completely. We examined the mismatch repair immunohistochemistry and microsatellite instability results from the endometrium and ovary to assess discordance between the tumor sites and between tests.Methods30 women with newly diagnosed synchronous endometrial and ovarian cancer were prospectively recruited from three cancer centers in Ontario, Canada. Both tumor sites were assessed for mismatch repair deficiency by immunohistochemistry and microsatellite instability test; discordance in results between tumor sites and discordance between test results at each site was examined. Cases with discordant results had tumors sequenced with a targeted panel in order to reconcile the findings. All women underwent mismatch repair gene germline testing.ResultsOf 30 patients, 11 (37%) were mismatch repair deficient or microsatellite instable at either tumor site, with 5 (17%) testing positive for Lynch syndrome. Mismatch repair immunohistochemistry expression was discordant between endometrial and ovarian tumor sites in 2 of 27 patients (7%) while microsatellite instability results were discordant in 2 of 25 patients (8%). Relying on immunohistochemistry or microsatellite instability alone on the endometrial tumor would have missed one and three cases of Lynch syndrome, respectively. One patient with Lynch syndrome with a PMS2 pathogenic variant was not detected by either immunohistochemistry or microsatellite instability testing. The rate of discordance between immunohistochemistry and microsatellite instability test was 3.8% in the ovary and 12% in the endometrium.ConclusionsThere was discordance in immunohistochemistry and microsatellite instability results between tumor sites and between tests within each site. Endometrial tumor testing with mismatch repair immunohistochemistry performed well, but missed one case of Lynch syndrome. Given the high incidence of Lynch syndrome (17%), consideration may be given to germline testing in all patients with synchronous endometrial and ovarian cancers.

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