Journal articles: 'Instabilité microsatellites'

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Collura, Ada, Jérémie H. Lefevre, Magali Svrcek, David Tougeron, Aziz Zaanan, and Alex Duval. "Instabilité des microsatellites et cancer." médecine/sciences 35, no. 6-7 (June 2019): 535–43. http://dx.doi.org/10.1051/medsci/2019093.

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L’instabilité des séquences répétées du génome (appelées microsatellites) est une conséquence de l’inactivation fonctionnelle du système de réparation des erreurs produites au cours de la réplication de l’ADN (système MMR, mismatch repair). Elle signe un phénotype tumoral fréquent appelé MSI (microsatellite instable) qui a été mis en évidence il y a un peu plus de 20 ans. Les cancers MSI sont fréquents chez l’homme, associés à de nombreuses localisations primitives (côlon, estomac, endomètre, etc.). Ils peuvent être héréditaires ou, le plus souvent, de survenue sporadique. Cet article propose une synthèse des travaux dédiés à l’étude des cancers MSI menés par des chercheurs et médecins français récompensés par le prix Jean et Madeleine Schaeverbeke de la Fondation de France. Depuis 20 ans, leur activité a grandement contribué à améliorer nos connaissances sur ce mode original de tumorigenèse, jetant les bases d’une médecine personnalisée de ces tumeurs chez l’homme, en pleine émergence aujourd’hui.

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Nshizirungu, J., M. Rui, V. Marta, P. Sónia, I. Mellouki, L. Chbani, H. Jalila, and S. Bennis. "Instabilité des microsatellites et infection par le virus d’Epstein–Barr dans les carcinomes gastriques." Revue d'Épidémiologie et de Santé Publique 68 (September 2020): S141. http://dx.doi.org/10.1016/j.respe.2020.03.084.

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Paraf, François. "Comment et quand rechercher une instabilité des microsatellites dans les cancers colorectaux en 2008 ?" Annales de Pathologie 27, no. 6 (December 2007): 433–38. http://dx.doi.org/10.1016/s0242-6498(07)71415-3.

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Fléjou, J. F., O. Lascols, N. Mourra, M. Svrcek, Y. Parc, E. Tiret, and R. Hamelin. "Expression des protéines MMR et instabilité de microsatellites dans une série consécutive de 1 555 cancers colorectaux." Annales de Pathologie 26 (November 2006): 127. http://dx.doi.org/10.1016/s0242-6498(06)78428-0.

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Borie, Claire, Martine Raphaël, Richard Hamelin, and Alex Duval. "Instabilité des microsatellites : un nouveau mécanisme de carcinogenèse associé à l’immunodépression dans les lymphomes non hodgkiniens chez l’homme." médecine/sciences 20, no. 6-7 (June 2004): 641–42. http://dx.doi.org/10.1051/medsci/2004206-7641.

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Burel-Vandenbos, F., F. Pedeutour, V. Paquis, P. Paquis, N. Cardot-Leccia, J. Haudebourg, M. C. Saint-Paul, and J. F. Michiels. "Association de deux anomalies génétiques rares dans un glioblastome à cellules géantes : un caryotype tumoral haploïde et une instabilité des microsatellites." Annales de Pathologie 26, no. 3 (June 2006): 239. http://dx.doi.org/10.1016/s0242-6498(06)77316-3.

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Yang, Guang, Ru-yi Zheng, and Zai-shun Jin. "Correlations between microsatellite instability and the biological behaviour of tumours." Journal of Cancer Research and Clinical Oncology 145, no. 12 (October 15, 2019): 2891–99. http://dx.doi.org/10.1007/s00432-019-03053-4.

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Abstract Purpose Microsatellites are widely distributed repetitive DNA motifs, accounting for approximately 3% of the genome. Due to mismatch repair system deficiency, insertion or deletion of repetitive units often occurs, leading to microsatellite instability. In this review, we aimed to explore the relationship between MSI and biological behaviour of colorectal carcinoma, gastric carcinoma, lymphoma/leukaemia and endometrial carcinoma, as well as the application of frameshift peptide vaccines in cancer therapy. Methods The relevant literature from PubMed and Baidu Xueshu were reviewed in this article. The ClinicalTrials.gov database was searched for clinical trials related to the specific topic. Results Microsatellite instability is divided into three subtypes: high-level, low-level microsatellite instability, and stable microsatellites. The majority of tumour patients with high-level microsatellite instability often show a better efficacy and prognosis than those with low-level microsatellite instability or stable microsatellites. In coding regions, especially for genes involved in tumourigenesis, microsatellite instability often results in inactivation of proteins and contributes to tumourigenesis. Moreover, the occurrence of microsatellite instability in coding regions can also cause the generation of frameshift peptides that are thought to be unknown and novel to the individual immune system. Thus, these frameshift peptides have the potential to be biomarkers to raise tumour-specific immune responses. Conclusion MSI has the potential to become a key predictor for evaluating the degree of malignancy, efficacy and prognosis of tumours. Clinically, MSI patterns will provide more valuable information for clinicians to create optimal individualized treatment strategies based on frameshift peptides vaccines.

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Gadgil, Rujuta Yashodhan, Eric J. Romer, Caitlin C. Goodman, S. Dean Rider, French J. Damewood, Joanna R. Barthelemy, Kazuo Shin-ya, Helmut Hanenberg, and Michael Leffak. "Replication stress at microsatellites causes DNA double-strand breaks and break-induced replication." Journal of Biological Chemistry 295, no. 45 (September 1, 2020): 15378–97. http://dx.doi.org/10.1074/jbc.ra120.013495.

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Short tandemly repeated DNA sequences, termed microsatellites, are abundant in the human genome. These microsatellites exhibit length instability and susceptibility to DNA double-strand breaks (DSBs) due to their tendency to form stable non-B DNA structures. Replication-dependent microsatellite DSBs are linked to genome instability signatures in human developmental diseases and cancers. To probe the causes and consequences of microsatellite DSBs, we designed a dual-fluorescence reporter system to detect DSBs at expanded (CTG/CAG)n and polypurine/polypyrimidine (Pu/Py) mirror repeat structures alongside the c-myc replication origin integrated at a single ectopic chromosomal site. Restriction cleavage near the (CTG/CAG)100 microsatellite leads to homology-directed single-strand annealing between flanking AluY elements and reporter gene deletion that can be detected by flow cytometry. However, in the absence of restriction cleavage, endogenous and exogenous replication stressors induce DSBs at the (CTG/CAG)100 and Pu/Py microsatellites. DSBs map to a narrow region at the downstream edge of the (CTG)100 lagging-strand template. (CTG/CAG)n chromosome fragility is repeat length–dependent, whereas instability at the (Pu/Py) microsatellites depends on replication polarity. Strikingly, restriction-generated DSBs and replication-dependent DSBs are not repaired by the same mechanism. Knockdown of DNA damage response proteins increases (Rad18, polymerase (Pol) η, Pol κ) or decreases (Mus81) the sensitivity of the (CTG/CAG)100 microsatellites to replication stress. Replication stress and DSBs at the ectopic (CTG/CAG)100 microsatellite lead to break-induced replication and high-frequency mutagenesis at a flanking thymidine kinase gene. Our results show that non-B structure–prone microsatellites are susceptible to replication-dependent DSBs that cause genome instability.

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Long, Dustin R., Adam Waalkes, Varun P. Panicker, Ronald J. Hause, and Stephen J. Salipante. "Identifying Optimal Loci for the Molecular Diagnosis of Microsatellite Instability." Clinical Chemistry 66, no. 10 (September 24, 2020): 1310–18. http://dx.doi.org/10.1093/clinchem/hvaa177.

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Abstract Background Microsatellite instability (MSI) predicts oncological response to checkpoint blockade immunotherapies. Although microsatellite mutation is pathognomonic for the condition, loci have unequal diagnostic value for predicting MSI within and across cancer types. Methods To better inform molecular diagnosis of MSI, we examined 9438 tumor-normal exome pairs and 901 whole genome sequence pairs from 32 different cancer types and cataloged genome-wide microsatellite instability events. Using a statistical framework, we identified microsatellite mutations that were predictive of MSI within and across cancer types. The diagnostic accuracy of different subsets of maximally informative markers was estimated computationally using a dedicated validation set. Results Twenty-five cancer types exhibited hypermutated states consistent with MSI. Recurrently mutated microsatellites associated with MSI were identifiable in 15 cancer types, but were largely specific to individual cancer types. Cancer-specific microsatellite panels of 1 to 7 loci were needed to attain ≥95% diagnostic sensitivity and specificity for 11 cancer types, and in 8 of the cancer types, 100% sensitivity and specificity were achieved. Breast cancer required 800 loci to achieve comparable performance. We were unable to identify recurrent microsatellite mutations supporting reliable MSI diagnosis in ovarian tumors. Features associated with informative microsatellites were cataloged. Conclusions Most microsatellites informative for MSI are specific to particular cancer types, requiring the use of tissue-specific loci for optimal diagnosis. Limited numbers of markers are needed to provide accurate MSI diagnosis in most tumor types, but it is challenging to diagnose breast and ovarian cancers using predefined microsatellite locus panels.

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Haiduk, Tiffany, Michael Brockmann, Christoph Schmitt, Ramona-Liza Tillmann, Monika Pieper, Jessica Lüsebrink, Oliver Schildgen, and Verena Schildgen. "Are Microsatellite Patterns Specific for Tumor Types? A Pilot Investigation." Journal of Molecular Pathology 1, no. 1 (September 4, 2020): 3–8. http://dx.doi.org/10.3390/jmp1010002.

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Microsatellite testing is an emerging field of molecular pathology, as microsatellite instability (MSI) appears to be a predictive biomarker for some cancers. Although multiple studies on microsatellites have been published, recent observations suggest that the microsatellites that define instability differ between tumor entities. This assumption is confirmed by the present study that compared different MSI assays validated for colorectal cancer. Whilst all assays deliver the same MSI/MSS status for colorectal cancers, they differ for tonsillar tumors, leading to the hypothesis that MSI patterns are tumor-type specific.

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T, Muthu Venkat, Vijayalakshmi Vijayalakshmi, and Pramila Pramila. "Significance of Microsatellite Instability in Colorectal Carcinoma- A Complete Review." Saudi Journal of Pathology and Microbiology 9, no. 03 (March 27, 2024): 71–74. http://dx.doi.org/10.36348/sjpm.2024.v09i03.003.

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The microsatellite instability (MSI-H) or mismatch repair deficient (dMMR) colorectal tumors recently have been reported that can benefit from immunotherapy, and MSI can be used as a genetic instability of a tumor detection index. Many studies have shown that there are many heterogeneous phenomena in patients with MSI tumors in terms of immunotherapy, prognosis and chemotherapy sensitivity. Here we mainly review the research results of MSI detection methods, its mechanisms, occurrence and its relationship with related tumors, aiming in such a way for brief analysis of the micro satellite instability. Microsatellites (MS) are the repeated sequences of DNA that play an important role in maintaining the tissue morphology. Any mutation of the DNA or chromosomes, lead to the instability of the microsatellites, thereby causing the microsatellite instability. There are three types of microsatellite instability (MSI). High microsatellite instability (MSI-H), low microsatellite instability (MSI-L) and microsatellite stability (MSS). Recent clinical research tends to classify MSS-L and MSS as similar. Microstaellite instability plays an important role in colorectal carcinoma. Based on different molecular mechanisms, MSI in colorectal cancer can be divided into colorectal cancer (CRC) with no obvious family genetic history and Lynch syndrome with non-polyposis with family genetic history. Lynch syndrome is an autosomal dominant disorder and syndrome caused by mutations in MMR strains, and it can also cause tumors in other parts of the colon and rectum. With the recent development of MSI detection technology and immunosuppressant in tumor therapy, researchers found that MSI-H tumors respond well to immunotherapy. There are several methods to detect the microsatellite instability. 1. Next Generation sequencing (NGS), 2. Fluoresence multiplex PCR and capillary electrophoresis. 3. Immunohistochemistry. 4. Single molecule- molecular inversion probes (SmMIP). The main mechanism of MSI includes, Slipped strand mispairing, MMR deficient.

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Wada, C., S. Shionoya, Y. Fujino, H. Tokuhiro, T. Akahoshi, T. Uchida, and H. Ohtani. "Genomic instability of microsatellite repeats and its association with the evolution of chronic myelogenous leukemia [see comments]." Blood 83, no. 12 (June 15, 1994): 3449–56. http://dx.doi.org/10.1182/blood.v83.12.3449.3449.

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Abstract Tumorigenesis has been shown to proceed through a series of genetic alterations involving protooncogenes and tumor-suppressor genes. Investigation of genomic instability of microsatellites has indicated a new mechanism for human carcinogenesis in hereditary nonpolyposis colorectal cancer and sporadic cancer and this instability has been shown to be related to inherited predisposition to cancer. This study was conducted to determine whether such microsatellite instability is associated with the evolution of chronic myelogenous leukemia (CML) to the blast crisis. Nineteen CML patients clinically progressing from the chronic phase to accelerated phase or blast crisis and 20 other patients in the CML chronic phase were studied. By polymerase chain reaction assay, DNAs for genomic instability in five separate microsatellites in chromosome arms 5q (Mfd27), 17p (Mfd41), 18q (DCC), 3p (CI3–9), and 8p (LPL) were examined. Differences in unrelated microsatellites of chronic and blastic phase DNAs in 14 of 19 patients (73.7%) were demonstrated. Somatic instability in five microsatellites, Mfd27, Mfd41, DCC, CI3–9, and LPL, was detected in 2 of 19 (10.5%), 8 of 19 (42.1%), 11 of 19 (57.9%), 4 of 17 (23.5%), and 4 of 17 (23.5%) cases. In 10 of 19 cases (52.6%), genetic instability in at least two of five microsatellites was observed and was categorized as replication error (RER+) phenotype. CML evolution cases with myeloid, lymphoid, and mixed phenotypes and the blast crisis and accelerated phase showed somatic instability in a number of microsatellites. No alterations in leukemic cells at the chronic phase could be detected in any microsatellites. These data indicate instability of microsatellites (RER+) but not familial predisposition to possibly be a late genetic event in the evolution of CML to blast crisis. In the microsatellite of the DCC gene, complicated alterations in band patterns caused by instability as well as loss of heterozygosity (LOH) were observed in 13 of 19 cases (68.4%): instability in 9 cases, instability plus LOH in 2 cases, and only LOH in 2 cases. These highly frequent alterations in microsatellites, including instability and LOH, suggesting that secondary events due possibly to loss of fidelity in replication and repair machinery may be significantly associated with CML evolution.

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Wada, C., S. Shionoya, Y. Fujino, H. Tokuhiro, T. Akahoshi, T. Uchida, and H. Ohtani. "Genomic instability of microsatellite repeats and its association with the evolution of chronic myelogenous leukemia [see comments]." Blood 83, no. 12 (June 15, 1994): 3449–56. http://dx.doi.org/10.1182/blood.v83.12.3449.bloodjournal83123449.

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Tumorigenesis has been shown to proceed through a series of genetic alterations involving protooncogenes and tumor-suppressor genes. Investigation of genomic instability of microsatellites has indicated a new mechanism for human carcinogenesis in hereditary nonpolyposis colorectal cancer and sporadic cancer and this instability has been shown to be related to inherited predisposition to cancer. This study was conducted to determine whether such microsatellite instability is associated with the evolution of chronic myelogenous leukemia (CML) to the blast crisis. Nineteen CML patients clinically progressing from the chronic phase to accelerated phase or blast crisis and 20 other patients in the CML chronic phase were studied. By polymerase chain reaction assay, DNAs for genomic instability in five separate microsatellites in chromosome arms 5q (Mfd27), 17p (Mfd41), 18q (DCC), 3p (CI3–9), and 8p (LPL) were examined. Differences in unrelated microsatellites of chronic and blastic phase DNAs in 14 of 19 patients (73.7%) were demonstrated. Somatic instability in five microsatellites, Mfd27, Mfd41, DCC, CI3–9, and LPL, was detected in 2 of 19 (10.5%), 8 of 19 (42.1%), 11 of 19 (57.9%), 4 of 17 (23.5%), and 4 of 17 (23.5%) cases. In 10 of 19 cases (52.6%), genetic instability in at least two of five microsatellites was observed and was categorized as replication error (RER+) phenotype. CML evolution cases with myeloid, lymphoid, and mixed phenotypes and the blast crisis and accelerated phase showed somatic instability in a number of microsatellites. No alterations in leukemic cells at the chronic phase could be detected in any microsatellites. These data indicate instability of microsatellites (RER+) but not familial predisposition to possibly be a late genetic event in the evolution of CML to blast crisis. In the microsatellite of the DCC gene, complicated alterations in band patterns caused by instability as well as loss of heterozygosity (LOH) were observed in 13 of 19 cases (68.4%): instability in 9 cases, instability plus LOH in 2 cases, and only LOH in 2 cases. These highly frequent alterations in microsatellites, including instability and LOH, suggesting that secondary events due possibly to loss of fidelity in replication and repair machinery may be significantly associated with CML evolution.

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Sitkovskaya, A. O., E. E. Rostorguev, S. V. Timofeeva, I. V. Mezhevova, S. Yu Filippova, T. V. Shamova, N. N. Timoshkina, and D. Yu Gvaldin. "FEATURES OF EXPRESSION OF OCT4, NANOG AND ENDOGLIN IN RENAL CELL CARCINOMAS." Crimea Journal of Experimental and Clinical Medicine 10, no. 3 (2021): 39–42. http://dx.doi.org/10.37279/2224-6444-2020-10-3-39-42.

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Glial tumors, in particular those composed of astrocytes, are the most common group of primary brain tumors. The most common glial tumor is astrocytoma. The biology of glial tumors was routinely studied on immortalized cell lines. However, multiple passages result in a loss of cellular heterogeneity. Therefore, more and more scientific laboratories in their research are beginning to use primary cell lines obtained directly from the patient’s native postoperative material. The question of the timing of the genetic stability of primary cell lines remains open. A special type of genetic instability is microsatellite instability, which affects microsatellites found throughout the genome. Microsatellites have several alleles, which are determined by changes in the number of repetitions of a motif unit. Microsatellite instability is of great importance in the oncogenesis of malignant neoplasms. The aim of this work was to study the microsatellite instability of primary cell lines of poorly differentiated glial tumors at different passages in comparison with the patient’s primary tumor material. Tumor cells of primary cultures of anaplastic astrocytoma and glioblastoma at different passages were used as material for the study. Formalin-fixed paraffin wax (FFPE) slides were used as a microsatellite control. Microsatellite analysis was performed on primary cultures of anaplastic astrocytoma and glioblastoma using the following markers: D17S250, D2S123, D5S346, NR21, NR24, NR27, BAT25, BAT26 by PCR. Microsatellite analysis has shown that primary glioblastoma cell lines are genetically more stable than primary anaplastic astrocytoma cell lines.

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Rogge, Ryan, Taylor Patterson, Alicia Navetta, and Dhruti Legare. "Abstract 2943: Investigation of microsatellite instability in RNA compared to DNA, using microsatellite targeted, anchored multiplex PCR and NGS." Cancer Research 84, no. 6_Supplement (March 22, 2024): 2943. http://dx.doi.org/10.1158/1538-7445.am2024-2943.

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Abstract MSI measurements are typically made on DNA, but it would be useful to make similar measurements from RNA or total nucleic acid inputs (TNA), so that MSI determinations could be made in parallel to interrogation of the RNA. Doing so requires characterizations of microsatellite lengths from those which are transcribed and untranscribed, because both will be detected following cDNA creation. Microsatellite instability (MSI) occurs when small unit repeats of DNA undergo incorrect replication resulting in the growth or contraction of the number of repeats in the newly synthesized DNA. This accumulation of errors at microsatellite DNA is usually mitigated by the mismatch repair (MMR) pathway which can correct these errors. MSI is of interest because it serves as a phenotypic readout of the status of the MMR machinery, and MSI status can correlate to tumor progression and response to agents that regulate these cellular mechanisms. We investigated the status of microsatellites using Anchored Multiplex PCR (AMP™) targeted panels (RUO) and compared results from TNA inputs using an AMP MSI module and both VARIANTPlex™ chemistry to interrogate DNA, and FUSIONPlex™ chemistry to interrogate both RNA + DNA. Our results indicate differences in the diversity of lengths of microsatellites present in RNA, and the resulting stability calls which would be made at those sites. Microsatellite length diversity was highly dependent on the genomic context of the microsatellite. Microsatellites located within transcripts showed increased length diversity when examining the RNA + DNA results compared to DNA alone. Microsatellites located in intergenic regions, which are unlikely to be transcribed, showed no increase in diversity of lengths when comparing the RNA + DNA results to DNA alone. While these results suggest that MSI determinations could be made from RNA or RNA + DNA NGS data, the unique behavior of microsatellites in RNA is likely to require additional investigations and unique data analysis techniques to correctly categorize microsatellites as stable or unstable. Confidential - Company Proprietary Citation Format: Ryan Rogge, Taylor Patterson, Alicia Navetta, Dhruti Legare. Investigation of microsatellite instability in RNA compared to DNA, using microsatellite targeted, anchored multiplex PCR and NGS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2943.

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Vuković Đerfi, Kristina, Anamarija Salar, Tamara Cacev, and Sanja Kapitanović. "EMAST Type of Microsatellite Instability—A Distinct Entity or Blurred Overlap between Stable and MSI Tumors." Genes 14, no. 7 (July 19, 2023): 1474. http://dx.doi.org/10.3390/genes14071474.

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Microsatellite instability (MSI) represents an accumulation of frameshifts in short tandem repeats, microsatellites, across the genome due to defective DNA mismatch repair (dMMR). MSI has been associated with distinct clinical, histological, and molecular features of tumors and has proven its prognostic and therapeutic value in different types of cancer. Recently, another type of microsatellite instability named elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) has been reported across many different tumors. EMAST tumors have been associated with chronic inflammation, higher tumor stage, and poor prognosis. Nevertheless, the clinical significance of EMAST and its relation to MSI remains unclear. It has been proposed that EMAST arises as a result of isolated MSH3 dysfunction or as a secondary event in MSI tumors. Even though previous studies have associated EMAST with MSI-low phenotype in tumors, recent studies show a certain degree of overlap between EMAST and MSI-high tumors. However, even in stable tumors, (MSS) frameshifts in microsatellites can be detected as a purely stochastic event, raising the question of whether EMAST truly represents a distinct type of microsatellite instability. Moreover, a significant fraction of patients with MSI tumors do not respond to immunotherapy and it can be speculated that in these tumors, EMAST might act as a modifying factor.

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Chen, Sophia, John Hatch, Ashley Luck, Nicole M. Nichols, Emily J. Gleason, Kathryn Martin, Kevin D. Foley, D. Scott Copeland, Sebastian Kraves, and Ezequiel Alvarez Saavedra. "Detection of DNA Microsatellites Using Multiplex Polymerase Chain Reaction Aboard the International Space Station." Gravitational and Space Research 9, no. 1 (January 1, 2021): 164–70. http://dx.doi.org/10.2478/gsr-2021-0013.

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Abstract As human exploration extends further into deep space, it is critical to understand the cellular impacts of spaceflight in order to ensure the safety of future astronauts. Extended exposure to cosmic radiation and microgravity has been shown to cause genetic damage and impair cellular DNA repair mechanisms, which together can lead to genomic instability. In particular, microsatellite instability (MSI), in which dysfunction in DNA mismatch repair (MMR) causes alterations in tandemly repeated “microsatellite” sequences, is a manifestation of genomic instability that has been associated with certain cancers. In this study, we establish the feasibility of an on-orbit multiplex polymerase chain reaction (PCR)-based assay to detect mutations in cancer-related microsatellites. Multiplex PCR was used to amplify five quasimonomorphic microsatellites in space and on Earth from both wild-type and MMR-deficient human cell lines. These data provide proof of concept of simultaneous amplification of multiple DNA sequences in space, expanding in-flight research and health-monitoring capabilities.

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Schöniger, Sandra, and Josef Rüschoff. "Mismatch Repair Deficiency and Microsatellite Instability." Encyclopedia 2, no. 3 (August 31, 2022): 1559–76. http://dx.doi.org/10.3390/encyclopedia2030106.

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Mismatch repair deficiency (MMRd) is caused by the biallelic inactivation of an MMR gene, which can be attributed either to an inherited or an acquired pathway. MMRd is characterized by the inability of cells to repair spontaneous mutations in microsatellites that occur during replication. Microsatellites are repetitive nucleotide sequences composed of one to six base pairs. Mutations in microsatellites lead to deletions or insertions of sequence units that are designated as microsatellite instability (MSI). MMRd is diagnosed by immunochemistry and is characterized by loss of nuclear immunostaining for at least one of the four MMR proteins that are routinely examined, i.e., MSH2, MSH6, MLH1 and PMS2. Available tests for MSI are PCR and next generation sequencing. MMRd and MSI predispose to tumor initiation and progression, increase tumor mutational burden as well as tumor immunogenicity, facilitate the activation of the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) immune checkpoint pathway and serve as prognostic and predictive biomarkers in solid tumors.

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Altun Tuzcu, Şadiye, İlbey Erkin Çetin, Fatih Güzel, Erdal Çetinkaya, Bekir Taşdemir, and Hüseyin Büyükbayram. "Evaluation of metabolic parameters of microsatellites stable and instable colorectal cancer patients via PET/CT." Journal of Medicine and Palliative Care 5, no. 2 (April 30, 2024): 118–22. http://dx.doi.org/10.47582/jompac.1462904.

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Aims: Microsatellite instability has been determined as an important indicator in selecting chemotherapy drugs in colorectal cancer. Within the scope of this research, we aimed to elucidate the pathology reports and determine whether the metabolic parameters detected by PET/CT differ in MSI-positive and negative patients. Methods: A total of 35 patients were analyzed retrospectively. The patient population consisted of patients who applied to the Nuclear Medicine Department with a diagnosis of colon or rectum cancer, underwent PET/CT imaging for staging purposes, and were operated on. Results: A total of 35 colon or rectum cancer patients were included in this retrospective analysis. When microsatellite instability was analyzed among the patients, it was found that female patients comprised 4 microsatellite instability-positive and 16 microsatellite instability-negative individuals. On the other hand, 5 of the males were microsatellite instability positive, and 10 were microsatellite instability negative. The mean SUVmax value was 16.4±8.2, SUVmean was 8.1±1.9, TLG was 392.4±520.8, and MTV was 26.5±25.4 in the microsatellite instability-positive individuals. On the other hand, the mean SUVmax value was 22.7±9.7, SUVmean was 5.2±2.2, TLG was 316.4±325.7, and MTV was 21.7±21.7 in the microsatellite instability-negative individuals. Conclusion: With the advancement of image analysis technology, MTV, and TLG, volumetric indexes derived from 18F-FDG PET have been proposed for risk stratification of cancer patients. Regarding the outcomes of this research, the semiquantitative and metabolic parameters obtained by PET/CT are not different in colorectal cancer cases with instable and stable microsatellites.

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Tripathi, Tanya, A. N. Srivastava, and Sharique Ahmad. "MICROSATELLITE INSTABILITY : CORELATION WITH COLORECTAL CANCER." Era's Journal of Medical Research 6, no. 2 (December 2019): 139–46. http://dx.doi.org/10.24041/ejmr2019.144.

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Buhard, Olivier, Nirosha Suraweera, Aude Lectard, Alex Duval, and Richard Hamelin. "Quasimonomorphic Mononucleotide Repeats for High-Level Microsatellite Instability Analysis." Disease Markers 20, no. 4-5 (2004): 251–57. http://dx.doi.org/10.1155/2004/159347.

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Microsatellite instability (MSI) analysis is becoming more and more important to detect sporadic primary tumors of the MSI phenotype as well as in helping to determine Hereditary Non-Polyposis Colorectal Cancer (HNPCC) cases. After some years of conflicting data due to the absence of consensus markers for the MSI phenotype, a meeting held in Bethesda to clarify the situation proposed a set of 5 microsatellites (2 mononucleotide repeats and 3 dinucleotide repeats) to determine MSI tumors. A second Bethesda consensus meeting was held at the end of 2002. It was discussed here that the 1998 microsatellite panel could underestimate high-level MSI tumors and overestimate low-level MSI tumors. Amongst the suggested changes was the exclusive use of mononucleotide repeats in place of dinucleotide repeats. We have already proposed a pentaplex MSI screening test comprising 5 quasimonomorphic mononucleotide repeats. This article compares the advantages of mono or dinucleotide repeats in determining microsatellite instability.

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Musaelyan, A. A., V. D. Nazarov, A. S. Budnikova, S. V. Lapin, S. L. Vorobyev, V. L. Emanuel, A. A. Zakharenko, and S. V. Orlov. "Clinical and morphological portrait of tumors with microsatellite instability." Advances in Molecular Oncology 8, no. 2 (July 28, 2021): 52–59. http://dx.doi.org/10.17650/2313-805x-2021-8-2-52-59.

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Background. Microsatellites are short tandem nucleotide repeats, the change in length of which plays a key roles in the pathogenesis of various malignant neoplasms. This change is called microsatellite instability. It is caused by aberrations in the genes of DNA mismatch repair system. Tumors with microsatellite instability are a special subtype regardless of location and are characterized by high sensitivity to immune checkpoint inhibitors.Objective – determination of characteristic clinical and morphological patterns of tumors of various localizations with microsatellite instability.Materials and methods. The study included 512 patients with malignant tumors of different localizations. Of these, 359 patients were diagnosed with colorectal cancer, 57 with uterine body cancer, and 57 with stomach cancer. Determination of the status of microsatellite instability was performed by a PCR-based method using 5 mononucleotide markers: BAT-25, BAT-26, NR-21, NR-24, NR-27.Results. The prevalence of microsatellite instability in colorectal cancer, uterine neoplasm and gastric cancer was 6.4; 22.8 and 1.75 %, respectively. Patients with MSI-positive colorectal cancer are characterized by yonger age (p = 0.023), right-sided localization of the tumor (p <0.0001), presence of multiple primary tumors (p = 0.0299), poorly differentiation (p = 0.0025), mucinous component (p <0.0001), tumor-infiltrating lymphocytes (p <0.0001) and Crohn-like reaction (p = 0.0006). Patients with uterine neoplasms with microsatellite instability are characterized by the presence of endometrial adenocarcinoma (p = 0.047), as well as the presence of tumor-infiltrating lymphocytes (p = 0.0022) and cribriform growth (p = 0.0011).Conclusion. A common pattern for colorectal cancer and uterine neoplasms is the presence of tumor-infiltrating lymphocytes. Certain clinical and morphological features of tumors of these localizations will more accurately identify candidates for microsatellite instability status determination for further immunotherapy.

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Powierska-Czarny, Jolanta, Danuta Miścicka-Sliwka, Jakub Czarny, Tomasz Grzybowski, Marcin Wozniak, Gerard Drewa, Włodzimierz Czechowicz, and Jan Sir. "Analysis of microsatellite instability and loss of heterozygosity in breast cancer with the use of a well characterized multiplex system." Acta Biochimica Polonica 50, no. 4 (December 31, 2003): 1195–203. http://dx.doi.org/10.18388/abp.2003_3643.

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Analysis of microsatellite instability (MI) and loss of heterozygosity (LOH) is recommended for screening patients with sporadic and hereditary malignancies. This study shows an application of a fluorescent hexaplex PCR system for microsatellite typing on A.L.F. DNA Sequencer (Pharmacia Biotech). This technique detects changes in microsatellites providing a time-efficient, reliable and accurate method for MI and LOH analyses. The Fragment Manager software was used for automated size calculation and quantitation of DNA fragments, enabling rapid and precise measurement of allelic ratios. We examined 70 breast cancer and 70 control DNA specimens, classified all the patterns of microsatellite alterations, and set up MI and LOH assessment criteria for the automated multiplex fluorescent method.

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Shrestha, Kul S., Minna M. Tuominen, and Liisa Kauppi. "Mlh1 heterozygosity and promoter methylation associates with microsatellite instability in mouse sperm." Mutagenesis 36, no. 3 (March 19, 2021): 237–44. http://dx.doi.org/10.1093/mutage/geab010.

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Abstract DNA mismatch repair (MMR) proteins play an important role in maintaining genome stability, both in somatic and in germline cells. Loss of MLH1, a central MMR protein, leads to infertility and to microsatellite instability (MSI) in spermatocytes, however, the effect of Mlh1 heterozygosity on germline genome stability remains unexplored. To test the effect of Mlh1 heterozygosity on MSI in mature sperm, we combined mouse genetics with single-molecule PCR that detects allelic changes at unstable microsatellites. We discovered 4.5% and 5.9% MSI in sperm of 4- and 12-month-old Mlh1+/− mice, respectively, and that Mlh1 promoter methylation in Mlh1+/− sperm correlated with higher MSI. No such elevated MSI was seen in non-proliferating somatic cells. Additionally, we show contrasting dynamics of deletions versus insertions at unstable microsatellites (mononucleotide repeats) in sperm.

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Pabst, T., J. Schwaller, MJ Bellomo, M. Oestreicher, D. Muhlematter, A. Tichelli, A. Tobler, and MF Fey. "Frequent clonal loss of heterozygosity but scarcity of microsatellite instability at chromosomal breakpoint cluster regions in adult leukemias." Blood 88, no. 3 (August 1, 1996): 1026–34. http://dx.doi.org/10.1182/blood.v88.3.1026.1026.

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Abstract Microsatellites are important highly polymorphic genetic markers dispersed in the human genome. Using a panel of 22 (CA)n repeat microsatellite markers mapped to recurrent breakpoint cluster regions specifically involved in leukemia, we investigated 114 adult leukemias (25 acute lymphocytic leukemia [ALL], 32 acute myeloid leukemia [AML], 36 chronic lymphocytic leukemia [CLL], and 21 chronic myeloid leukemia [CML] in chronic phase) for somatic mutations at these loci. In each patient, DNA from fresh leukemia samples was analyzed alongside normal constitutive DNA from buccal epithelium. We detected loss of heterozygosity (LOH) in 81 of 114 patients (ALL 16/25, AML 25/32, CLL 30/36, CML 10/21). Deletions were most often seen in ALL at 11q23 and 19p13; in AML at 8q22 and 11q23; in CLL at 13q14.3, 11q13, and 11q23; and in CML at 3q26. Only six deletions were reported in 74 karyotypes analyzed, whereas in these same cases, 91 LOH events were detected by microsatellites. Of 26 leukemias with a normal karyotype, 16 nevertheless showed at least one LOH by microsatellite analysis. Replication errors were found in 10 of 114 patients (8.8%). Thus, microsatellite instability is rare in leukemia in contrast to many solid tumors. Our findings suggest that in adult leukemia, LOH may be an important genetic event in addition to typical chromosomal translocations. LOH may point to the existence of tumor suppressor genes involved in leukemogenesis to a degree that has hitherto been underestimated.

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Pabst, T., J. Schwaller, MJ Bellomo, M. Oestreicher, D. Muhlematter, A. Tichelli, A. Tobler, and MF Fey. "Frequent clonal loss of heterozygosity but scarcity of microsatellite instability at chromosomal breakpoint cluster regions in adult leukemias." Blood 88, no. 3 (August 1, 1996): 1026–34. http://dx.doi.org/10.1182/blood.v88.3.1026.bloodjournal8831026.

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Microsatellites are important highly polymorphic genetic markers dispersed in the human genome. Using a panel of 22 (CA)n repeat microsatellite markers mapped to recurrent breakpoint cluster regions specifically involved in leukemia, we investigated 114 adult leukemias (25 acute lymphocytic leukemia [ALL], 32 acute myeloid leukemia [AML], 36 chronic lymphocytic leukemia [CLL], and 21 chronic myeloid leukemia [CML] in chronic phase) for somatic mutations at these loci. In each patient, DNA from fresh leukemia samples was analyzed alongside normal constitutive DNA from buccal epithelium. We detected loss of heterozygosity (LOH) in 81 of 114 patients (ALL 16/25, AML 25/32, CLL 30/36, CML 10/21). Deletions were most often seen in ALL at 11q23 and 19p13; in AML at 8q22 and 11q23; in CLL at 13q14.3, 11q13, and 11q23; and in CML at 3q26. Only six deletions were reported in 74 karyotypes analyzed, whereas in these same cases, 91 LOH events were detected by microsatellites. Of 26 leukemias with a normal karyotype, 16 nevertheless showed at least one LOH by microsatellite analysis. Replication errors were found in 10 of 114 patients (8.8%). Thus, microsatellite instability is rare in leukemia in contrast to many solid tumors. Our findings suggest that in adult leukemia, LOH may be an important genetic event in addition to typical chromosomal translocations. LOH may point to the existence of tumor suppressor genes involved in leukemogenesis to a degree that has hitherto been underestimated.

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Holt, Georgie, Christine Hayes, Rachel Phelps, Akhtar Husain, Christopher Lamb, Richard Gallon, and Neil Rajan. "P30 Microsatellite instability in cutaneous squamous cell carcinoma." British Journal of Dermatology 189, no. 1 (July 2023): e26-e26. http://dx.doi.org/10.1093/bjd/ljad174.051.

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Abstract Lynch syndrome (LS) is a hereditary cancer syndrome caused by pathogenic germline variants in genes that encode mismatch repair (MMR) proteins. LS is characterized by an increased risk of multiple cancers, including colorectal and endometrial cancer. Muir–Torre syndrome (MTS) is an allelic, phenotypic variant of LS characterized by the presence of skin tumours, including keratoacanthomas and sebaceous tumours. Recently, an association has been proposed between MTS/LS and cutaneous squamous cell carcinoma (cSCC). MTS/LS tumours demonstrate a mutation signature termed microsatellite instability (MSI) that can be used to screen sporadic tumours for underlying MTS/LS. We have previously shown that amplicon-sequencing of microsatellites can detect increased MSI in cSCC in patients with LS. In this study, we assayed a pilot cohort sporadic cSCC in the general population to further explore this potential association. DNA was extracted from cSCC samples. We used an established molecular inversion probe-based protocol to amplify informative microsatellites and sequenced these using the Illumina MiSeq platform. An MSI score was calculated for each tumour sample using a naïve Bayesian approach based on microsatellite deletion frequencies. We found that 5% (n = 1/19) of cSCCs were MSI-high (95% confidence interval 0.1–26.0), which is equivalent to estimated frequencies among unselected sporadic cSCCs in recent literature. We plan to expand our pilot cohort to include a larger series of cSCC and to also carry out somatic sequencing of MSH2, MSH6, MLH1 and PMS2 in tumours to determine if MSI status correlates with MMR gene variant status. Ultimately, this work aims to improve identification of new patients with LS presenting with cSCC and allow them to benefit equitably from preventative cancer surveillance and aspirin chemoprevention.

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Gendrel, Christiane-Gabrielle, Annick Boulet, and Marie Dutreix. "(CA/GT)_n microsatellites affect homologous recombination during yeast meiosis." Genes & Development 14, no. 10 (May 15, 2000): 1261–68. http://dx.doi.org/10.1101/gad.14.10.1261.

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One of the most common microsatellites in eukaryotes consists of tandem arrays of the dinucleotide GT. Although the study of the instability of such repetitive DNA has been extremely fruitful over the last decade, no biological function has been demonstrated for these sequences. We investigated the genetic behavior of a region of the yeast Saccharomyces cerevisiae genome containing a 39-CA/GT dinucleotide repeat sequence. When the microsatellite sequence was present at the ARG4 locus on homologous chromosomes, diploid cells undergoing meiosis generated an excess of tetrads containing a conversion of the region restricted to the region of the microsatellite close to the recombination-initiation double-strand break. Moreover, whereas the repetitive sequence had no effect on the frequency of single crossover, its presence strongly stimulated the formation of multiple crossovers. The combined data strongly suggest that numerous recombination events are restricted to the initiation side of the microsatellite as though progression of the strand exchange initiated at the ARG4 promoter locus was impaired by the repetitive sequence. This observation corroborates in vitro experiments that demonstrated that RecA-promoted strand exchange is inhibited by CA/GT dinucleotide tracts. Surprisingly, meiotic instability of the microsatellite was very high (>0.1 alterations per tetrad) in all the spores with parental and recombinant chromosomes.

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Herbreteau, Guillaume, Fabrice Airaud, Elise Pierre-Noël, Audrey Vallée, Stéphane Bézieau, Sandrine Théoleyre, Hélène Blons, Simon Garinet, and Marc Guillaume Denis. "MEM: An Algorithm for the Reliable Detection of Microsatellite Instability (MSI) on a Small NGS Panel in Colorectal Cancer." Cancers 13, no. 16 (August 20, 2021): 4203. http://dx.doi.org/10.3390/cancers13164203.

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Purpose: MEM is an NGS algorithm that uses Expectation-Maximisation to detect the presence of unstable alleles from the NGS sequences of five microsatellites (BAT-25, BAT-26, NR-21, NR-24 and NR-27). The purpose of this study was to compare the MEM algorithm with a reference PCR method (MSI-PCR) and MisMatch Repair protein immunohistochemistry (MMR-IHC). Methods: FFPE colorectal cancer samples from 146 patients were analysed in parallel by MSI-PCR and NGS using the MEM algorithm. MMR-IHC results were available for 133 samples. Serial dilutions of an MSI positive control were performed to estimate the limit of detection. Results: the MEM algorithm was able to detect unstable alleles of each microsatellite with up to a 5% allelic fraction. Of the 146 samples, 28 (19.2%) were MSI in MSI-PCR. MEM algorithm results were in perfect agreement with those of MSI-PCR, at both MSI status and individual microsatellite level (Cohen’s kappa = 1). A high level of agreement was noted between MSI-PCR/MEM algorithm results and MMR-IHC results (Cohen’s kappa = 0.931). Conclusion: the MEM algorithm can determine the MSI status of colorectal cancer samples on a small NGS panel, using only five microsatellites approved by international guidelines, and can be combined with screening for targetable mutations.

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Molenaar, Jan J., Bénédicte Gérard, Cécile Chambon-Pautas, Hélène Cavé, Michel Duval, Etienne Vilmer, and Bernard Grandchamp. "Microsatellite Instability and Frameshift Mutations in BAX and Transforming Growth Factor-β RII Genes Are Very Uncommon in Acute Lymphoblastic Leukemia In Vivo But Not in Cell Lines." Blood 92, no. 1 (July 1, 1998): 230–33. http://dx.doi.org/10.1182/blood.v92.1.230.413k17_230_233.

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Mutations in the DNA mismatch repair (MMR) system lead to an instability of simple repetitive DNA sequences involved in several cancer types. This instability is reflected in a high mutation rate of microsatellites, and recent studies in colon cancer indicate that defects in MMR result in frequent frameshift mutations in mononucleotide repeats located in the coding regions of BAX and transforming growth factor-β (TGF-β) receptor genes. Circumstantial evidence suggests that the MMR defect may be involved in some lymphoid malignancies, although several allelotype analyses have concluded on the low level of microsatellite instability in acute lymphoblastic leukemias. To further evaluate the implication of MMR defects in leukemogenesis, we have studied a series of 98 children with acute lymphoblastic leukemia and 14 leukemic cell lines using several indicators of MMR defects. Microsatellite markers were compared between blast and normal DNA from the same patients and mutations were sought in mononucleotide repeat sequences of BAX and TGF-β receptor II (TGF-β RII). The absence of microsatellite instability (MI) and the absence of mutations in the genes examined from patient's leukemic cells contrasted with the observation that half of the cell lines displayed a high degree of MI and that three of seven of these mutator cell lines harbored mutations in BAX and/or TGF-β RII. From these results we conclude that MMR defects are very uncommon in freshly isolated blasts but are likely to be selected for during the establishment of cell lines.

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de la Chapelle, Albert, and Heather Hampel. "Clinical Relevance of Microsatellite Instability in Colorectal Cancer." Journal of Clinical Oncology 28, no. 20 (July 10, 2010): 3380–87. http://dx.doi.org/10.1200/jco.2009.27.0652.

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Microsatellite instability (MSI) is a clonal change in the number of repeated DNA nucleotide units in microsatellites. It arises in tumors with deficient mismatch repair due to the inactivation of one of the four mismatch repair genes: MSH2, MLH1, MSH6, and PMS2. In order to determine the MSI status of a tumor, microdissection and polymerase chain reaction–based detection strategies are required. For practical purposes, MSI is equivalent to the loss of staining by immunohistochemistry (IHC) of one of the mismatch repair genes since both signify an abnormality in mismatch repair. Of all colorectal cancers (CRCs), 15% to 20% display MSI or abnormal IHC (often referred to as microsatellite instability [MIN] pathway). The remaining 80% to 85% of CRCs are microsatellite stable but most are characterized by chromosomal instability (CIN pathway). Almost all Lynch syndrome tumors have MSI or abnormal IHC and they account for up to one third of all MIN CRCs (3% to 5% of all CRCs). The remaining MIN tumors are sporadic as a result of somatic inactivation of the MLH1 gene caused by methylation of its promoter. Thus, the presence of a MSI/IHC abnormality prompts further investigations to diagnose Lynch syndrome, whereas its absence excludes Lynch syndrome. We recommend screening all CRC tumors for IHC or MSI. MIN tumors have a more favorable outcome than CIN tumors, and fluorouracil-based adjuvant chemotherapy does not improve the outcome of stage II or stage III MIN tumors. More data are needed to determine how best to treat patients with stage II and stage III MIN CRCs.

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Uhlig, Johannes, Michael Cecchini, Stacey Stein, Jill Lacy, and Kevin Kim. "Microsatellite instability and KRAS mutation in stage 4 CRC: Prevalence, geographic discrepancies and outcomes from the National Cancer Database." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16052-e16052. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16052.

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e16052 Background: To assess microsatellite instability (MSI) and KRAS mutation prevalence, discrepancies and their impact on outcome in AJCC stage IV colorectal adenocarcinoma (colorectal cancer; CRC). Methods: The 2010-2016 United States National Cancer Database was queried for stage IV CRC patients > 18yo and information on MSI and KRAS mutation. Microsatellite status was stratified as stable microsatellites (MSS, including low instability) and microsatellite instability high (MSI-H). KRAS status was stratified as mutation and wildtype. Prevalence and discrepancies were evaluated according to patient demographics, US geography and CRC factors. Overall survival (OS) was assessed using Cox proportional hazards models adjusting for age, gender, race, comorbidities, metastatic burden, CRC treatment, treatment center type, and year of CRC diagnosis. A priori, a statistical interaction test between microsatellite status, KRAS status and primary CRC site was planned. Results: Microsatellite/KRAS status was available for n = 10,844/n = 25,712 patients, respectively. OS was assessed in n = 5,904 patients with data on both microsatellite and KRAS status, and follow-up. Overall prevalence of MSI-H was 3.1% and KRAS mutation 42.4%. Microsatellite and KRAS status varied according to primary CR site, as presented in Table. Further variation was evident according to US-geography, with MSI-H rates ranging from 1.6% to 4.1%, and KRAS mutation rates ranging from 41.1% to 44%. On multivariable analyses, longer OS was observed in patients with KRAS wildtype versus mutation (HR = 0.91, 95% CI: 0.85-0.97 p = 0.004), MSS versus MSI-H (HR = 0.75, 95% CI: 0.62-0.9, p = 0.003), and left-sided versus right-sided CRC (HR = 0.65, 95% CI: 0.6-0.7, p < 0.001). The effect of KRAS mutation further varied with CRC site and microsatellite status (interaction p = 0.002). Conclusions: Depending on its primary site and US geography, stage IV CRC shows distinct mutational behavior. KRAS mutation, MSI-H, MSI-H and primary CRC sidedness independently affect overall survival and interact with distinct prognostic profiles. Generically classifying adenocarcinomas of different site as “CRC” might deprecate this diversity. [Table: see text]

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Amos, William. "Heterozygosity increases microsatellite mutation rate." Biology Letters 12, no. 1 (January 2016): 20150929. http://dx.doi.org/10.1098/rsbl.2015.0929.

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Whole genome sequencing of families of Arabidopsis has recently lent strong support to the heterozygote instability (HI) hypothesis that heterozygosity locally increases mutation rate. However, there is an important theoretical difference between the impact on base substitutions, where mutation rate increases in regions surrounding a heterozygous site, and the impact of HI on sequences such as microsatellites, where mutations are likely to occur at the heterozygous site itself. At microsatellite loci, HI should create a positive feedback loop, with heterozygosity and mutation rate mutually increasing each other. Direct support for HI acting on microsatellites is limited and contradictory. I therefore analysed AC microsatellites in 1163 genome sequences from the 1000 genomes project. I used the presence of rare alleles, which are likely to be very recent in origin, as a surrogate measure of mutation rate. I show that rare alleles are more likely to occur at locus-population combinations with higher heterozygosity even when all populations carry exactly the same number of alleles.

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Gao, Caihua, Xiaodong Ren, Annaliese S. Mason, Jiana Li, Wei Wang, Meili Xiao, and Donghui Fu. "Revisiting an important component of plant genomes: microsatellites." Functional Plant Biology 40, no. 7 (2013): 645. http://dx.doi.org/10.1071/fp12325.

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Microsatellites are some of the most highly variable repetitive DNA tracts in genomes. Few studies focus on whether the characteristic instability of microsatellites is linked to phenotypic effects in plants. We summarise recent data to investigate how microsatellite variations affect gene expression and hence phenotype. We discuss how the basic characteristics of microsatellites may contribute to phenotypic effects. In summary, microsatellites in plants are universal and highly mutable, they coexist and coevolve with transposable elements, and are under selective pressure. The number of motif nucleotides, the type of motif and transposon activity all contribute to the nonrandom generation and decay of microsatellites, and to conservation and distribution biases. Although microsatellites are generated by accident, they mature through responses to environmental change before final decay. This process is mediated by organism adjustment mechanisms, which maintain a balance between birth versus death and growth versus decay in microsatellites. Close relationships also exist between the physical structure, variation and functionality of microsatellites: in most plant species, sequences containing microsatellites are associated with catalytic activity and binding functions, are expressed in the membrane and organelles, and participate in the developmental and metabolic processes. Microsatellites contribute to genome structure and functional plasticity, and may be considered to promote species evolution in plants in response to environmental changes. In conclusion, the generation, loss, functionality and evolution of microsatellites can be related to plant gene expression and functional alterations. The effect of microsatellites on phenotypic variation may be as significant in plants as it is in animals.

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Srinivasan, Rajini, Nataliya Nady, Neha Arora, Laura J. Hsieh, Tomek Swigut, Geeta J. Narlikar, Mark Wossidlo, and Joanna Wysocka. "Zscan4 binds nucleosomal microsatellite DNA and protects mouse two-cell embryos from DNA damage." Science Advances 6, no. 12 (March 2020): eaaz9115. http://dx.doi.org/10.1126/sciadv.aaz9115.

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Zinc finger protein Zscan4 is selectively expressed in mouse two-cell (2C) embryos undergoing zygotic genome activation (ZGA) and in a rare subpopulation of embryonic stem cells with 2C-like features. Here, we show that Zscan4 specifically recognizes a subset of (CA)n microsatellites, repeat sequences prone to genomic instability. Zscan4-associated microsatellite regions are characterized by low nuclease sensitivity and high histone occupancy. In vitro, Zscan4 binds nucleosomes and protects them from disassembly upon torsional strain. Furthermore, Zscan4 depletion leads to elevated DNA damage in 2C mouse embryos in a transcription-dependent manner. Together, our results identify Zscan4 as a DNA sequence–dependent microsatellite binding factor and suggest a developmentally regulated mechanism, which protects fragile genomic regions from DNA damage at a time of embryogenesis associated with high transcriptional burden and genomic stress.

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Catasus, Lluis, Xavier Matias-Guiu, Pilar Machin, Gian Franco Zannoni, Giovanni Scambia, Pierluigi Benedetti-Panici, and Jaime Prat. "Frameshift mutations at coding mononucleotide repeat microsatellites in endometrial carcinoma with microsatellite instability." Cancer 88, no. 10 (May 15, 2000): 2290–97. http://dx.doi.org/10.1002/(sici)1097-0142(20000515)88:10<2290::aid-cncr13>3.0.co;2-i.

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Testolin, Raffaele, Teresa Marrazzo, Guido Cipriani, Roberta Quarta, Ignazio Verde, Maria Teresa Dettori, Marco Pancaldi, and Silviero Sansavini. "Microsatellite DNA in peach (Prunus persica L. Batsch) and its use in fingerprinting and testing the genetic origin of cultivars." Genome 43, no. 3 (June 1, 2000): 512–20. http://dx.doi.org/10.1139/g00-010.

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We isolated and sequenced 26 microsatellites from two genomic libraries of peach cultivar 'Redhaven', enriched for AC/GT and AG/CT repeats, respectively. For 17 of these microsatellites, it was possible to demonstrate Mendelian inheritance. Microsatellite polymorphism was assayed in 50 peach and nectarine cultivars. Of the 1300 PCRs carried out, all but two produced amplified products of the expected size. All microsatellites were polymorphic, showing 2-8 alleles per locus. Heterozygosity ranged from 0.04-0.74 (mean 0.47); the discrimination power (PD) ranged from 0.04-0.84 (mean 0.60). Cultivar heterozygosity varied greatly, with one cultivar ('Independence') being homozygous at all loci. The set of microsatellites discriminated all cultivars investigated, except several sport mutations, i.e., 'Dixitime' vs. 'Springcrest', 'Compact Redhaven' vs. 'Redhaven', and two pairs of cultivars, 'Venus' vs. 'Orion' and 'Elegant Lady' vs. 'Rome Star', whose pedigrees are controversial. We were able to analyze the paternity of several cultivars. In most cases, the parenthood was confirmed. The comparison of three long-living 'Redhaven' accessions supplied by different repositories did not provide any evidence of somatic instability of microsatellites. Hence, microsatellites, ranked according to their information content, are recommended as markers of choice for peach fingerprinting and suggestions are provided for interpreting band profiles and the correct sizing of alleles.Key words: genetics, molecular markers, paternity analysis, pedigree analysis, simple sequence repeat.

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Nash, G. M., M. Gimbel, J. Shia, A. T. Culliford, D. R. Nathanson, M. Ndubuisi, Y. Yamaguchi, Z. S. Zeng, F. Barany, and P. B. Paty. "Automated, Multiplex Assay for High-Frequency Microsatellite Instability in Colorectal Cancer." Journal of Clinical Oncology 21, no. 16 (August 15, 2003): 3105–12. http://dx.doi.org/10.1200/jco.2003.11.133.

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Purpose: In a series of hereditary nonpolyposis colorectal cancer (HNPCC) patients, we evaluated the sensitivities of the individual microsatellites recommended by the National Cancer Institute (NCI) consensus workshop for detection of high-frequency microsatellite instability (MSI-H). On the basis of this evaluation, we developed a three-marker assay that assigns microsatellite instability (MSI) in a multiplex polymerase chain reaction. Methods: Individual marker sensitivity was assessed in 18 HNPCC tumors. Multiplex and NCI assays were then assessed in a series of 120 patients with early-onset colon cancer. Results: The sensitivity of microsatellite markers BAT25, BAT26, D2S123, D5S346, and D17S250 for ASI in HNPCC cancers was 100%, 94%, 72%, 50%, and 50%, respectively. The three most accurate markers were combined and optimized in a multiplex assay that assigned MSI-H whenever at least two of three markers revealed ASI. In early-onset colon cancers, the prevalence of MSI-H determined by the multiplex assay and by the NCI assay was 16% and 23%, respectively. The additional MSI-H tumors and patients with MSI-H identified by the NCI assay lacked the traits characteristic of MSI-H seen in tumors and patients identified by the multiplex assay: retention of heterozygosity (NCI additional 22% v multiplex 84%; P = .003), characteristic tumor morphology (0% v 64%; P = .006), and 5-year cancer survival rate (44% v 100%; P = .0003). Conclusion: The multiplex assay identifies colon cancers with MSI-H by assessing three highly accurate microsatellite markers. This assay identifies a smaller MSI-H cohort with more homogeneous clinical features and is superior as a marker of favorable prognosis. It merits prospective evaluation as a marker of prognosis and as a screening test for HNPCC.

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Fernández-Galindo, Martha Alejandra, José Miguel Moreno-Ortiz, José Alfredo Contreras-Gutiérrez, Jesús Israel Martínez-Félix, Misael Guerrero-Valdez, and Saúl Armando Beltrán-Ontiveros. "Inestabilidad de Microsatélites como marcador biológico para la administración de Pembrolizumab." REVMEDUAS 12, no. 2 (April 1, 2022): 135–42. http://dx.doi.org/10.28960/revmeduas.2007-8013.v12.n2.008.

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Los microsatélites son secuencias cortas de ADN repetidas en tándem, distribuidas dentro del genoma, los cuales son propensos a errores en la replicación. El sistema Mismatch Repair (MMR), se encarga de identificar, señalar y reparar bases mal emparejadas, principalmente en secuencias repetitivas de ADN. La inactivación de cualquiera de los genes que codifican para las proteínas MMR puede provocar cambios en la longitud de los microsatélites causando un fenotipo hipermutable conocido como inestabilidad de microsatélites (MSI), vía de tumorigénesis bien establecida relacionada con la aparición, progresión y pronóstico de diversas neoplasias malignas. Debido a la gran cantidad de mutaciones somáticas, los tumores MSI tienen mayor sensibilidad a la inmunoterapia. La FDA ha aprobado un anticuerpo monoclonal como tratamiento para pacientes pediátricos y adultos con tumores sólidos MSI, el cual ha demostrado una actividad antitumoral sólida y duradera y un perfil de seguridad manejable contra varias neoplasias malignas avanzadas. Palabras clave: Microsatélites, marcador biológico, Pembrolizumab

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Atkin, N. B. "Microsatellite instability." Cytogenetic and Genome Research 92, no. 3-4 (2001): 177–81. http://dx.doi.org/10.1159/000056898.

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FRAYLING, I. M. "Microsatellite instability." Gut 45, no. 1 (July 1, 1999): 1–4. http://dx.doi.org/10.1136/gut.45.1.1.

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de la Chapelle, Albert. "Microsatellite Instability." New England Journal of Medicine 349, no. 3 (July 17, 2003): 209–10. http://dx.doi.org/10.1056/nejmp038099.

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Lowsky, Robert, Anthony Magliocco, Ryo Ichinohasama, Armin Reitmair, Stuart Scott, Michele Henry, Marshall E. Kadin, and John F. DeCoteau. "MSH2-deficient murine lymphomas harbor insertion/deletion mutations in the transforming growth factor beta receptor type 2 gene and display low not high frequency microsatellite instability." Blood 95, no. 5 (March 1, 2000): 1767–72. http://dx.doi.org/10.1182/blood.v95.5.1767.005k07_1767_1772.

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High-frequency microsatellite instability (MSI), defined as more than 20% unstable loci, is an inconsistent finding in hematologic malignancies; consequently, the significance of deficient DNA mismatch repair (MMR) to their pathogenesis has been questioned. To further investigate the relationship between MMR deficiency and genomic instability in hematologic malignancies, this study evaluatedMSH2−/− murine lymphomas for insertion/deletion (ID) mutations within the transforming growth factor (TGF)-beta receptor type II (TβR-II) gene and MSI at 10 neutral microsatellites. The lymphomas displayed ID mutations within short mononucleotide runs of TβR-II at a high frequency, whereas nonmalignant tissue from corresponding animals lacked mutations. Loss ofTβR-II transcripts and protein was seen in 6 of 7 murine lymphomas harboring acquired TβR-II mutations. In the analysis of paired nonmalignant and tumor DNA samples, low-frequency but not high-frequency MSI was found. Low-frequency MSI occurred in 8 of 20 lymphomas and 12 displayed microsatellite stability. MSI was even less frequent in nonmalignant tissue as only 3 of 20 samples displayed low-frequency MSI and 17 displayed stability. Evaluation of 20 single cell clones from the MSH2−/− lymphoma cell lines R25 and L15 identified high-frequency MSI in 4 and 2 clones, respectively. The remaining clones showed low-frequency MSI or stability. These findings suggest that acquired TβR-IImutations represent important inactivating events in tumor pathogenesis following MSH2 deficiency. Furthermore, for some hematolymphoid malignancies, the evaluation of cancer-associated genes for ID mutations may represent a more sensitive marker of MMR deficiency than evaluation of neutral microsatellites for high-frequency MSI.

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Ladas, Ioannis, Harvey J. Mamon, Kimmie Ng, Fangyan Yu, Ka Wai Leong, Matthew H. Kulke, and G. Mike Makgrigiorgos. "Sensitive detection of microsatellite instability in tumors and liquid biopsies using nuclease-based enrichment." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e15117-e15117. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e15117.

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e15117 Background: The role of MSI in colorectal cancer (CRC) is well characterized, and tumors are classified as MSI-High or MSI-Stable by screening specific microsatellites. MSI-H reflects mismatch repair deficiency, is predictive for CRC therapy outcome in chemotherapy and immunotherapy and has a higher 5-year survival. While tumor testing is the gold standard, a convenient approach to screen for MSI before and during cancer treatment is screening circulating DNA (liquid biopsy) using a blood draw. However, using electrophoresis or next generation sequencing for MSI detection presents challenges at low levels of MSI due to polymerase slippage (‘stutter’) that generate high false positive rates at positions of homo-polymers. We present a new approach for enrichment of altered micro-satellites prior to DNA-amplification thereby reducing stutter from wild-type alleles and facilitating detection of MSI. The method employs a double-strand-DNA-specific nuclease and overlapping oligonucleotide-probes interrogating multiple micro-satellite targets (‘NaMe-PrO’, nuclease-assisted minor-allele enrichment with probe-overlap). Following DNA denaturation, the probes form double-stranded regions with their targets, thereby guiding nuclease digestion to selected sites. Microsatellite indels create ‘bulges’ that inhibit digestion, thus subsequent amplification yields DNA with microsatellite alterations enhanced at multiple targets. Methods: We first validated the method by evaluating 5 MSI targets simultaneously, NR27, NR21, NR24, BAT25 and BAT26 using DNA from tumor biopsies and circulating-DNA from colorectal cancer patients. The technique detected microsatellite alterations down to 0.01% altered allele frequency, thus improving detection sensitivity by > 100-fold relative to current approaches. Next, a clinical study was performed. We screened microsatellites in circulating DNA from groups of early stage colon cancer patients with known MSI status in the tumor. Results: Combination of NAME-PRO with capillary electrophoresis demonstrated 100% sensitivity (10/10) and 90% specificity (9/10) in detecting MSI status in the blood, thereby opening the possibility of early cancer detection for MSI positive tumors, or for application in minimal residual disease detection. Conclusions: We anticipate application of this highly- multiplex-able method either with standard 5-plex reactions or with NGS-based detection of MSI on thousands of targets to enable sensitive detection in tumors and liquid biopsies.

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Daunay, Antoine, Alex Duval, Laura G. Baudrin, Olivier Buhard, Victor Renault, Jean-François Deleuze, and Alexandre How-Kit. "Low temperature isothermal amplification of microsatellites drastically reduces stutter artifact formation and improves microsatellite instability detection in cancer." Nucleic Acids Research 47, no. 21 (September 17, 2019): e141-e141. http://dx.doi.org/10.1093/nar/gkz811.

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Abstract Microsatellites are polymorphic short tandem repeats of 1–6 nucleotides ubiquitously present in the genome that are extensively used in living organisms as genetic markers and in oncology to detect microsatellite instability (MSI). While the standard analysis method of microsatellites is based on PCR followed by capillary electrophoresis, it generates undesirable frameshift products known as ‘stutter peaks’ caused by the polymerase slippage that can greatly complicate the analysis and interpretation of the data. Here we present an easy multiplexable approach replacing PCR that is based on low temperature isothermal amplification using recombinase polymerase amplification (LT-RPA) that drastically reduces and sometimes completely abolishes the formation of stutter artifacts, thus greatly simplifying the calling of the alleles. Using HT17, a mononucleotide DNA repeat that was previously proposed as an optimal marker to detect MSI in tumor DNA, we showed that LT-RPA improves the limit of detection of MSI compared to PCR up to four times, notably for small deletions, and simplifies the identification of the mutant alleles. It was successfully applied to clinical colorectal cancer samples and enabled detection of MSI. This easy-to-handle, rapid and cost-effective approach may deeply improve the analysis of microsatellites in several biological and clinical applications.

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GuhaMajumdar, Monica, Ethan Dawson-Baglien, and Barbara B. Sears. "Creation of a Chloroplast Microsatellite Reporter for Detection of Replication Slippage in Chlamydomonas reinhardtii." Eukaryotic Cell 7, no. 4 (February 8, 2008): 639–46. http://dx.doi.org/10.1128/ec.00447-07.

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ABSTRACT Microsatellites are composed of short tandem direct repeats; deletions or duplications of those repeats through the process of replication slippage result in microsatellite instability relative to other genomic loci. Variation in repeat number occurs so frequently that microsatellites can be used for genotyping and forensic analysis. However, an accurate assessment of the rates of change can be difficult because the presence of many repeats makes it difficult to determine whether changes have occurred through single or multiple events. The current study was undertaken to experimentally assess the rates of replication slippage that occur in vivo in the chloroplast DNA of Chlamydomonas reinhardtii. A reporter construct was created in which a stretch of AAAG repeats was inserted into a functional gene to allow changes to be observed when they occurred at the synthetic microsatellite. Restoration of the reading frame occurred through replication slippage in 15 of every million viable cells. Since only one-third of the potential insertion/deletion events would restore the reading frame, the frequency of change could be deduced to be 4.5 × 10−5. Analysis of the slippage events showed that template slippage was the primary event, resulting in deletions rather than duplications. These findings contrasted with events observed in Escherichia coli during maintenance of the plasmid, where duplications were the rule.

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Vostrukhina, Olga A., Tatyana A. Shtam, N. V. Mokhova, Aleksey V. Gulyaev, Oleg F. Chepick, and Vladislav A. Lanzov. "Microsatellite instability level and p53 gene mutations in human carcinomas of gastrointestinal tract." Ecological genetics 2, no. 4 (December 15, 2004): 22–28. http://dx.doi.org/10.17816/ecogen2422-28.

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The human carcinomas of gastrointestinal tract (GIT) are developed via "suppressor" (pJJ-dependent) or "mutator" (with deficiency in DNA mismatch repair) pathways. These pathways are known to be accompanies by variations in both clinicopathological and therapeutic characteristics. The mutator pathway manifests in genome microsatellite instability (MSI). All GIT carcinomas can be subdivided in three classes, with high (MSI-H), low (MSI-L) and zero (MSS) level of MSI. 34 DNA samples from GIT carcinomas were analyzed with 9 microsatellites and 5 exones of p53 gene in searching for correlation between the level of MSI and mutations inp53. The MSI-H carcinomas appeared to be of mutator type whereas both MSI-L and MSS were of suppressor type

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Sia, Elaine Ayres, Margaret Dominska, Lela Stefanovic, and Thomas D. Petes. "Isolation and Characterization of Point Mutations in Mismatch Repair Genes That Destabilize Microsatellites in Yeast." Molecular and Cellular Biology 21, no. 23 (December 1, 2001): 8157–67. http://dx.doi.org/10.1128/mcb.21.23.8157-8167.2001.

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ABSTRACT The stability of simple repetitive DNA sequences (microsatellites) is a sensitive indicator of the ability of a cell to repair DNA mismatches. In a genetic screen for yeast mutants with elevated microsatellite instability, we identified strains containing point mutations in the yeast mismatch repair genes, MSH2,MSH3, MLH1, and PMS1. Some of these mutations conferred phenotypes significantly different from those of null mutations in these genes. One semidominant MSH2mutation was identified. Finally we showed that strains heterozygous for null mutations of mismatch repair genes in diploid strains in yeast confer subtle defects in the repair of small DNA loops.

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Waalkes, Adam, Nahum Smith, Kelsi Penewit, Jennifer Hempelmann, Eric Q. Konnick, Ronald J. Hause, Colin C. Pritchard, and Stephen J. Salipante. "Accurate Pan-Cancer Molecular Diagnosis of Microsatellite Instability by Single-Molecule Molecular Inversion Probe Capture and High-Throughput Sequencing." Clinical Chemistry 64, no. 6 (June 1, 2018): 950–58. http://dx.doi.org/10.1373/clinchem.2017.285981.

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Abstract BACKGROUND Microsatellite instability (MSI) is an emerging actionable phenotype in oncology that informs tumor response to immune checkpoint pathway immunotherapy. However, there remains a need for MSI diagnostics that are low cost, highly accurate, and generalizable across cancer types. We developed a method for targeted high-throughput sequencing of numerous microsatellite loci with pan-cancer informativity for MSI using single-molecule molecular inversion probes (smMIPs). METHODS We designed a smMIP panel targeting 111 loci highly informative for MSI across cancers. We developed an analytical framework taking advantage of smMIP-mediated error correction to specifically and sensitively detect instability events without the need for typing matched normal material. RESULTS Using synthetic DNA mixtures, smMIPs were sensitive to at least 1% MSI-positive cells and were highly consistent across replicates. The fraction of identified unstable microsatellites discriminated tumors exhibiting MSI from those lacking MSI with high accuracy across colorectal (100% diagnostic sensitivity and specificity), prostate (100% diagnostic sensitivity and specificity), and endometrial cancers (95.8% diagnostic sensitivity and 100% specificity). MSI-PCR, the current standard-of-care molecular diagnostic for MSI, proved equally robust for colorectal tumors but evidenced multiple false-negative results in prostate (81.8% diagnostic sensitivity and 100% specificity) and endometrial (75.0% diagnostic sensitivity and 100% specificity) tumors. CONCLUSIONS smMIP capture provides an accurate, diagnostically sensitive, and economical means to diagnose MSI across cancer types without reliance on patient-matched normal material. The assay is readily scalable to large numbers of clinical samples, enables automated and quantitative analysis of microsatellite instability, and is readily standardized across clinical laboratories.

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Cossio, Silvia Liliana, Renata dos Santos Coura, Maria Cátira Bortolini, Roberto Giugliani, Patricia Ashton-Prolla, and João Carlos Prolla. "Polymorphic variation of mononucleotide microsatellites in healthy humans and its implication for microsatellite instability screening." Arquivos de Gastroenterologia 44, no. 1 (March 2007): 64–67. http://dx.doi.org/10.1590/s0004-28032007000100014.

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BACKGROUND: Colorectal cancer is the sixth most common tumor and the fifth in mortality in Brazil. Molecular markers have been associated with disease prognosis, especially in relation to therapeutic response and overall survival rates. Among these, microsatellite instability has been extensively studied. Microsatellite stability status is usually determined by comparison of normal and tumoral tissues from the same patient and instability is characterized by the difference in the PCR-amplification profile of these tissues at a given locus. Usually, a panel of five markers is used for this purpose. Two of them (BAT-25 and BAT-26) are considered monomorphic in populations of European origin. AIM: To analyse the frequency of constitutive polymorphic variation at BAT-25 and BAT-26 loci in a sample of individuals from Southern Brazil. METHODS: Two-hundred and sixteen healthy and unrelated individuals were analised to assess the frequency of allelic variation at the BAT-25 and BAT-26 loci in DNA extracted from peripheral blood. Analysis was done by polymerase chain reaction - single strand conformation polymorphism (PCR-SSCP). RESULTS: From the sample of patients studied, 7% and 6% of the patients had possible constitutive allelic variation at the BAT-25 and BAT-26 loci, respectively. CONCLUSIONS: These results indicate that significant constitutive allelic variation of these loci does occur in heterogeneous populations such as ours, and reinforce the importance of comparative studies between tumoral and corresponding normal tissue to determine microsatellite stability status and correctly identify microsatellite instability in selected populations.

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Journal articles on the topic 'Instabilité microsatellites'

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