Microsatellite instability (MSI) and mismatch repair deficiency are an emerging issue in oncology and molecular pathology. Besides being associated with better clinical outcome in colon cancer, MSI also harbors the potential to predict response to chemotherapy and immunotherapy. MSI was also observed in other solid tumors, including endometrial cancer, ovarian cancer, and melanoma, besides colon cancer. Strong evidence shows that MSI is a frequent event in melanoma. However, the data on MSI prevalence, pathogenesis, and clinical consequences in melanoma are limited. Therefore, we summarize the current knowledge on MSI in melanoma and outline future perspectives and clinical implications, including its role as a prognostic and/or a predictive factor.

• MeSH
• imunoterapie metody   MeSH
• lidé MeSH
• melanom imunologie   MeSH
• mikrosatelitní nestabilita MeSH
• nádory kůže imunologie   MeSH
• oprava chybného párování bází DNA imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Immunotherapy has attracted attention as a novel treatment modality for malignant melanoma. Although the use of immunotherapy in metastatic melanoma has shown promising results, there remains a lack of predictive biomarkers indicating treatment benefit from immunotherapy. There is growing evidence suggesting that microsatellite instability (MSI) as a product of DNA mismatch repair deficiency, may be one of possible predictive markers in malignant melanoma. It has been proposed that the immunogenicity of some tumors might be determined by mutational heterogeneity and could be the key to the success of immune therapies. This is also supported by the fact that tumors with the highest amount of somatic mutations, such as malignant melanoma have showed positive results with immune checkpoint inhibitors. There are promising data regarding the association between MSI status and immunogenicity from studies with colorectal cancer, where MSI is linked to improved prognosis compared to microsatellite stable cancers. MSI in colon cancer is linked to a significant increase of immunocompetent cells responsible for the antitumor activity - CD3(+), CD8(+), CD45RO(+), and T-bet(+) lymphocytes and decrease of inhibition factors such as Foxp3, IL-6, IL-17, and TGF-β. On the other hand, taking into account the progression-dependent accumulation of somatic mutations in MSI tumors and consequent high levels of neo-antigens, the possible drug resistance of MSI tumors to traditional treatment, and the presence of inhibition checkpoints within the MSI tumors, there is a solid rationale for the use of novel therapeutic strategies such as immunotherapy in MSI melanomas. We presume that the MSI phenotype in malignant melanoma might be helpful to identify patients, who would be more likely to profit from immunotherapy than from conventional therapy.

• MeSH
• antigeny nádorové imunologie   MeSH
• imunoterapie metody   MeSH
• lidé MeSH
• melanom genetika   imunologie   terapie   MeSH
• mikrosatelitní nestabilita * MeSH
• mikrosatelitní repetice MeSH
• mutace MeSH
• nádory kůže genetika   imunologie   terapie   MeSH
• oprava DNA MeSH
• prognóza MeSH
• T-lymfocyty imunologie   MeSH
• teoretické modely MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny nádorové MeSH

The replication error (RER+) phenotype, characterized by microsatellite instability (MSI) has been recently related to mutations of genes involved in DNA mismatch repair pathway. These genetic alterations were first described in hereditary non polyposis colorectal cancer (HNPCC). We examined 44 patients with hematological malignancies (27 AML, 9 MDS, 2 CML-BP and 6 T-ALL) for evidence of MSI. Twenty seven percent of our patients showed differences for only one marker. In four cases (9.1%) MSI was observed in multiple markers and these cases were described as RER+ phenotype. Presented data suggest that this phenomenon may play a role in at least a subset of patients with hematological malignancies.

• MeSH
• dítě MeSH
• dospělí MeSH
• expanze trinukleotidových repetic MeSH
• fenotyp MeSH
• genetické markery MeSH
• hematologické nádory genetika   MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikrosatelitní repetice * MeSH
• mladiství MeSH
• mutace * MeSH
• mutační analýza DNA metody   MeSH
• oprava DNA genetika   MeSH
• předškolní dítě MeSH
• recidiva MeSH
• senioři MeSH
• ztráta heterozygozity MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• genetické markery MeSH

BACKGROUND/AIM: The prognostic role of microsatellite instability (MSI) in stage II colon cancer patients remains controversial despite the fact that it has been investigated in a number of studies. Hazard ratios differ considerably among these studies. We performed a meta-analysis to define the significance of MSI in this group of patients. MATERIALS AND METHODS: Studies indexed in PubMed presenting separate data on MSI status and survival outcomes for stage II colon cancer patients have been analyzed using fixed-effect meta-analysis of hazard ratio (HR) according to the method of Peto. RESULTS: Analysis was performed on 19 studies including 5,998 patients. A 47.3% of patients received postoperative chemotherapy and included 52.8% males and 47.2% females. Eight studies included some rectal cancer patients although this cohort was not clearly defined in 3 of these. MSI observed in 20.8% (mean) of patients (median 19.9%). HR for overall survival (OS) of MSI vs. microsatellite stable (MSS) tumors for the entire population: 0.73 (95% confidence interval (CI)=0.33-1.65); HR for disease-free survival (DFS):0.60 (95%CI=0.27-1.32). No statistical significant difference was found when studies analyzing MSI with genotyping (MG) and immunohistochemistry (IHC) were compared separately (MG vs. IHC: HR OS 0.45, 95%CI=0.10-2.05 vs. 0.95, 95%CI=0.57-1.58; HR DFS 0.51, 95%CI=0.14-1.85 vs. 0.67, 95%CI=0.26-1.70). However, numerically MSI determination with genotyping shows significantly lower hazard ratios for both DFS and OS. Separate analysis of studies describing colon cancer patients only showed HR OS 0.72 (95%CI=0.31-1.71); HR DFS 0.60 (95%CI=0.27-1.31). CONCLUSION: No significant relation was found between MSI status and OS or DFS. Routine determination of MSI status to guide postoperative management of stage II colon cancer patients cannot be recommended. New large scale high quality studies are needed to answer this question definitively, since currently analyzed studies vary considerably.

• Klíčová slova
• Colon cancer, meta-analysis, microsatellite instability, predictive factor, prognostic factor, systematic review,
• MeSH
• hodnocení výsledků zdravotní péče metody   statistika a číselné údaje   MeSH
• lidé MeSH
• mikrosatelitní nestabilita * MeSH
• nádory tračníku farmakoterapie   genetika   chirurgie   MeSH
• přežití po terapii bez příznaků nemoci MeSH
• prognóza MeSH
• proporcionální rizikové modely MeSH
• staging nádorů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• přehledy MeSH
• systematický přehled MeSH

The dysfunction of the DNA mismatch repair system results in microsatellite instability (MSI). MSI plays a central role in the development of multiple human cancers. In colon cancer, despite being associated with resistance to 5-fluorouracil treatment, MSI is a favourable prognostic marker. In gastric and endometrial cancers, its prognostic value is not so well established. Nevertheless, recognising the MSI tumours may be important for predicting the therapeutic effect of immune checkpoint inhibitors. Several gene expression signatures were trained on microarray data sets to understand the regulatory mechanisms underlying microsatellite instability in colorectal cancer. A wealth of expression data already exists in the form of microarray data sets. However, the RNA-seq has become a routine for transcriptome analysis. A new MSI gene expression signature presented here is the first to be valid across two different platforms, microarrays and RNA-seq. In the case of colon cancer, its estimated performance was (i) AUC = 0.94, 95% CI = (0.90 - 0.97) on RNA-seq and (ii) AUC = 0.95, 95% CI = (0.92 - 0.97) on microarray. The 25-gene expression signature was also validated in two independent microarray colon cancer data sets. Despite being derived from colorectal cancer, the signature maintained good performance on RNA-seq and microarray gastric cancer data sets (AUC = 0.90, 95% CI = (0.85 - 0.94) and AUC = 0.83, 95% CI = (0.69 - 0.97), respectively). Furthermore, this classifier retained high concordance even when classifying RNA-seq endometrial cancers (AUC = 0.71, 95% CI = (0.62 - 0.81). These results indicate that the new signature was able to remove the platform-specific differences while preserving the underlying biological differences between MSI/MSS phenotypes in colon cancer samples.

• MeSH
• analýza dat MeSH
• kolorektální nádory genetika   patologie   MeSH
• lidé MeSH
• mikrosatelitní nestabilita * MeSH
• mikrosatelitní repetice genetika   MeSH
• nádory žaludku genetika   patologie   MeSH
• prognóza MeSH
• regulace genové exprese u nádorů genetika   MeSH
• stanovení celkové genové exprese MeSH
• transkriptom genetika   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Microsatellite instability (MSI) is present in 15-20% of primary colorectal cancers. MSI status is assessed to detect Lynch syndrome, guide adjuvant chemotherapy, determine prognosis, and use as a companion test for checkpoint blockade inhibitors. Traditionally, MSI status is determined by immunohistochemistry or molecular methods. The Idylla™ MSI Assay is a fully automated molecular method (including automated result interpretation), using seven novel MSI biomarkers (ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A, SULF2) and not requiring matched normal tissue. In this real-world global study, 44 clinical centers performed Idylla™ testing on a total of 1301 archived colorectal cancer formalin-fixed, paraffin-embedded (FFPE) tissue sections and compared Idylla™ results against available results from routine diagnostic testing in those sites. MSI mutations detected with the Idylla™ MSI Assay were equally distributed over the seven biomarkers, and 84.48% of the MSI-high samples had ≥ 5 mutated biomarkers, while 98.25% of the microsatellite-stable samples had zero mutated biomarkers. The concordance level between the Idylla™ MSI Assay and immunohistochemistry was 96.39% (988/1025); 17/37 discordant samples were found to be concordant when a third method was used. Compared with routine molecular methods, the concordance level was 98.01% (789/805); third-method analysis found concordance for 8/16 discordant samples. The failure rate of the Idylla™ MSI Assay (0.23%; 3/1301) was lower than that of referenced immunohistochemistry (4.37%; 47/1075) or molecular assays (0.86%; 7/812). In conclusion, lower failure rates and high concordance levels were found between the Idylla™ MSI Assay and routine tests.

• Klíčová slova
• Colorectal cancer, FFPE clinical tissue samples, Idylla™ MSI assay, Microsatellite instability, Multi-center study,
• MeSH
• fixace tkání * MeSH
• fixativa MeSH
• formaldehyd MeSH
• imunohistochemie * MeSH
• kolorektální nádory chemie   genetika   patologie   MeSH
• laboratorní automatizace MeSH
• lidé MeSH
• mikrosatelitní nestabilita * MeSH
• mutace * MeSH
• mutační analýza DNA * MeSH
• nádorové biomarkery * analýza   genetika   MeSH
• prediktivní hodnota testů MeSH
• reprodukovatelnost výsledků MeSH
• zalévání tkání do parafínu * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• srovnávací studie MeSH
• Názvy látek
• fixativa MeSH
• formaldehyd MeSH
• nádorové biomarkery * MeSH

Approximately 4-5% of patients with metastatic colorectal cancer (mCRC) have mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) tumours. These tumours present challenges in the clinical practice due to variant response to fluoropyrimidine-based chemotherapy and, perhaps, also non-immunologic targeted therapies. Recently, a breakthrough in the treatment of dMMR/MSI-H mCRC has been achieved with several clinical trials showing dramatic long-term benefit of immunotherapy using checkpoint inhibitors. Nevertheless, several questions remain regarding the optimisation of immunotherapy regimens and the use of biomarkers to identify populations set to derive the greatest benefit from immunotherapy. Combination regimens and/or the use of immunotherapy as a maintenance after induction non-immunologic systemic therapy may be the way forward to improve outcomes.

• Klíčová slova
• chemotherapy, colorectal cancer, ipilimumab, mismatch repair, nivolumab, pembrolizumab,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

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.

• MeSH
• dědičné nepolypózní kolorektální nádory * genetika   patologie   MeSH
• imunohistochemie MeSH
• lidé MeSH
• mikrosatelitní nestabilita MeSH
• mutace MeSH
• nádory glandulární a epitelové * MeSH
• oprava chybného párování bází DNA genetika   MeSH
• polymerázová řetězová reakce MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Microsatellites are tandem repeats of simple polymorphic sequences randomly distributed in non-coding regions of DNA. They can be used in cancer genetics and indirect cancer diagnosis and can help unraveling the genetic basis of tumor formation and progression of cancer. Breast cancer is a complex disease in which numerous genetic alterations occur. The knowledge of specific genetic changes and their biological consequences is critical to an understanding of breast cancer tumorigenesis, screening and treatment of patients. Microsatellites can undergo two events during tumor progression. Loss of heterozygosity indicates absence of one allele in a given locus, which is associated with the loss of a corresponding genes. Microsatellite instability reflects replication errors induced by defective function of mismatch repair genes and is demonstrated with the appearance of novel, noninherited alleles in tumor cells and represents a specific pathway of tumor development. Both events serve as prognostic markers, which can be correlated with clinicopathological features and can help exploring breast cancer formation.

• MeSH
• genetické markery MeSH
• lidé MeSH
• mikrosatelitní repetice * MeSH
• nádory prsu diagnóza   genetika   MeSH
• ztráta heterozygozity MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• genetické markery MeSH

One of the most common mechanisms of immune evasion in MSI colorectal cancers (CRCs) is loss of HLA class I expression due to mutations in B2M gene which can become a negative predictor for checkpoint blockade therapy. The aim of this study was the determination of prevalence of B2M somatic mutations in MSI CRC patients and relationship between B2M mutations and lymphocytes infiltration and other clinicopathological features as well as detection of methylation changes in B2M promoter region which can be another mechanism of immune escape. In our study, 37 MSI-H and 5 MSI-L patients were selected for screening of B2M mutational and methylation status. The characterization of patients was based on standard histopathological diagnosis and TNM classification; BRAF, KRAS mutations, tumor-infiltrating lymphocytes and peritumoral lymphoid reaction were also determined. MSI analysis was performed using fragment analysis. B2M mutations were identified by Sanger sequencing, and methylation of CpG islands in promoter region was detected by methylation-specific PCR. Heterozygous mutations in the B2M gene were detected in five MSI-H patients (13.5%), while the mutation c.45_48delTTCT was determined in four patients and mutation c.276delC was found in two patients. One of these five patients was compound heterozygote harboring both mutations. Methylation of the promoter region of the B2M gene was observed in one patient with MSI-H colorectal cancer. Detection of genetic and epigenetic changes in B2M gene could be important in personalized therapy for CRC patients as these changes may be one of the mechanisms of secondary resistance of MSI positive tumors to immunotherapy.

• Klíčová slova
• Beta-2-microglobulin, Cancer immunogenicity, Colorectal cancer, Microsatellite instability, Promoter methylation,
• MeSH
• beta-2-mikroglobulin genetika   MeSH
• CpG ostrůvky MeSH
• dospělí MeSH
• down regulace MeSH
• epigeneze genetická MeSH
• kolorektální nádory genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metylace DNA * MeSH
• mikrosatelitní nestabilita * MeSH
• mutace MeSH
• promotorové oblasti (genetika) MeSH
• regulace genové exprese u nádorů MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• B2M protein, human MeSH Prohlížeč
• beta-2-mikroglobulin MeSH