Thematische Bibliographien / Microsatellites instability

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Auswahl der wissenschaftlichen Literatur zum Thema „Microsatellites instability“

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Veröffentlicht am 25. Mai 2024

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Zeitschriftenartikel zum Thema "Microsatellites instability"

Wada, C., S. Shionoya, Y. Fujino, H. Tokuhiro, T. Akahoshi, T. Uchida und H. Ohtani. „Genomic instability of microsatellite repeats and its association with the evolution of chronic myelogenous leukemia [see comments]“. Blood 83, Nr. 12 (15.06.1994): 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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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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Gadgil, Rujuta Yashodhan, Eric J. Romer, Caitlin C. Goodman, S. Dean Rider, French J. Damewood, Joanna R. Barthelemy, Kazuo Shin-ya, Helmut Hanenberg und Michael Leffak. „Replication stress at microsatellites causes DNA double-strand breaks and break-induced replication“. Journal of Biological Chemistry 295, Nr. 45 (01.09.2020): 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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Yang, Guang, Ru-yi Zheng und Zai-shun Jin. „Correlations between microsatellite instability and the biological behaviour of tumours“. Journal of Cancer Research and Clinical Oncology 145, Nr. 12 (15.10.2019): 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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Haiduk, Tiffany, Michael Brockmann, Christoph Schmitt, Ramona-Liza Tillmann, Monika Pieper, Jessica Lüsebrink, Oliver Schildgen und Verena Schildgen. „Are Microsatellite Patterns Specific for Tumor Types? A Pilot Investigation“. Journal of Molecular Pathology 1, Nr. 1 (04.09.2020): 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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Schöniger, Sandra, und Josef Rüschoff. „Mismatch Repair Deficiency and Microsatellite Instability“. Encyclopedia 2, Nr. 3 (31.08.2022): 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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Long, Dustin R., Adam Waalkes, Varun P. Panicker, Ronald J. Hause und Stephen J. Salipante. „Identifying Optimal Loci for the Molecular Diagnosis of Microsatellite Instability“. Clinical Chemistry 66, Nr. 10 (24.09.2020): 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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T, Muthu Venkat, Vijayalakshmi Vijayalakshmi und Pramila Pramila. „Significance of Microsatellite Instability in Colorectal Carcinoma- A Complete Review“. Saudi Journal of Pathology and Microbiology 9, Nr. 03 (27.03.2024): 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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Chen, Sophia, John Hatch, Ashley Luck, Nicole M. Nichols, Emily J. Gleason, Kathryn Martin, Kevin D. Foley, D. Scott Copeland, Sebastian Kraves und Ezequiel Alvarez Saavedra. „Detection of DNA Microsatellites Using Multiplex Polymerase Chain Reaction Aboard the International Space Station“. Gravitational and Space Research 9, Nr. 1 (01.01.2021): 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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Rogge, Ryan, Taylor Patterson, Alicia Navetta und Dhruti Legare. „Abstract 2943: Investigation of microsatellite instability in RNA compared to DNA, using microsatellite targeted, anchored multiplex PCR and NGS“. Cancer Research 84, Nr. 6_Supplement (22.03.2024): 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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Dissertationen zum Thema "Microsatellites instability"

Bodo, Sahra. „Induction d'un processus d'instabilité des microsatellites du génome dans des modèles murin et cellulaire : intérêt physiopathologique et clinique“. Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066565/document.

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L'inactivation du système MMR (mismatch repair) favorise un processus oncogénique d'instabilité des microsatellites du génome (MSI). Au cours de ma thèse, j'ai étudié d'une part le rôle de l'azathioprine (Aza) dans l'induction de tumeurs MSI chez la souris. Des études épidémiologiques avaient rapporté une corrélation entre l'émergence de cancers MSI tardifs chez l'homme, et la prise au long cours de cet immunosuppresseur dont la cytotoxicité in vitro est médiée par l'activité MMR. Dans une étude dose-réponse, j'ai observé l'émergence de rares lymphomes MSI de survenue tardive chez la souris de génotype sauvage traitée par l'Aza, mais pas par la ciclosporine (autre immunosuppresseur utilisé en comparaison). Ces résultats permettent d'établir in vivo que l'Aza est un facteur de risque pour l'émergence de tumeurs MSI lors d'une exposition prolongée. D'autre part, je me suis intéressée au syndrome CMMRD (constitutional MMR deficiency), une prédisposition majeure et rare, aux cancers MSI. Les patients atteints étant porteurs de mutations germinales bialléliques d'un gène MMR, le diagnostic repose sur le génotypage constitutionnel, une méthode non-contributive quand un variant de signification inconnue est détecté (30% patients). Dans ce contexte, j'ai développé une méthode d'aide au dépistage de ce syndrome chez les sujets à risque, l'hypothèse étant que 2 caractéristiques fonctionnelles des cellules tumorales MMR-déficientes, le phénotype MSI et la tolérance aux agents génotoxiques tels que l'Aza, pouvaient être objectivées dans les tissus sains des patients CMMRD. Mes travaux proposent un test diagnostique sensible et spécifique qui répond aux limites de l'analyse génétique
Inactivation of the MMR (mismatch repair) system promotes the oncogenic process of microsatellite instability (MSI). During my PhD, I firstly investigated the role of azathioprine (Aza) in the induction of MSI tumors in mice. Epidemiological studies reported a correlation between the occurrence of late MSI cancers in humans and long-term treatment with this immunosuppressant whose cytotoxicity was shown in vitro to be mediated by MMR activity. Using a dose-response study, I observed the occurrence of rare late-onset MSI lymphomas in wild-type mice treated with Aza, but not with ciclosporin (another immunosuppressant used for comparison). These results established in vivo that long-term Aza exposure is a risk factor for the emergence of MSI tumors. Secondly, I was interested in the CMMRD syndrome (constitutional MMR deficiency), a major and rare predisposition to MSI cancers. Since CMMRD patients are carriers of biallelic germline mutations of a MMR gene, diagnosis is based on constitutional genotyping, a method that was found non-contributory when a variant of unknown significance is detected (30% patients). In this context, I developed a complementary approach for the detection of this syndrome in at-risk patients, based on the hypothesis that two functional features of MMR-deficient tumor cells, i.e. the MSI phenotype and the tolerance to genotoxic agents such as Aza, can be demonstrated in non-neoplastic tissues of CMMRD patients. We provided a sensitive and specific method that may constitute a valuable tool when diagnosis of CMMRD could not be confirmed by genetic testing

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Wright, C. M. „The prognostic significance of microsatellite instability in sporadic stage C colorectal cancer“. Thesis, The University of Sydney, 2008. https://hdl.handle.net/2123/28955.

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Identification and understanding of the molecular events involved in colorectal cancer (CRC) pathogenesis should lead to better comprehension of the disease process, hopefully leading to better prognostic stratification, and as a result more targeted treatment regimens and improved patient outcomes. A sub group of sporadic CRC exhibit microsatellite instability (MSI). MSI is seen when the fidelity of DNA replication is impaired. Cancers may be categorized as MSI-high (MSI-H), MSI-low (MSI-L), or microsatellite stable (MSS), according to the degree of MSI exhibited. This research project was designed to analyse the association between MSI—H and MSI-L, clinicopathological features and survival in an unselected group of patients with sporadic Australian Clinicopathological Stage (ACPS) C / American Joint Committee on Cancer (AJCC) stage III CRC, i.e. patients with lymph node metastases at the time of surgical resection of their cancer. The criteria used to determine MSI, specifically the type and number of microsatellite markers used, were also reviewed. 255 patients who underwent resection for sporadic ACPS stage C CRC were studied; none of these patients received chemotherapy. Archival normal and tumour DNA were extracted and amplified by polymerase chain reaction using a radioactive-labelling technique and a panel of internationally recognised microsatellite markers. MSI-H was defined as instability in 2 40% of 7 markers, MSI-L as instability at > 0% but < 40% of 11 markers, and M88 as no instability. Twenty one MSI-H and 33 MSI-L CRC were identified. Significant results included that MSI-H tumours are more commonly right sided (p < 0.00001); larger (p 5 0.0005); more likely to be high grade (p = 0.049); and, after adjustment for age, sex and other pathology variables, associated with improved survival (p = 0.015). No difference was found between the biological characteristics of MSI-L and MSS CRC. MSI-L CRC showed a trend towards poorer cancer-specific survival than MSS CRC but this difference did not reach statistical significance. Although dependent on the number and type of microsatellites used, similar trends in the results were seen when different criteria were used to determine MSI. This study has contributed to the rapidly expanding literature on CRC carcinogenesis and, at the time completed, was one of the first to show an association between MSI-H and improved survival in clinicopathological stage C CRC patients who had not received chemotherapy. It supports the view that identification of MSI status in patients with sporadic ACPS C / AJCC stage III tumours may help stratify patients according to prognosis and should be considered in therapeutic decision making and future trials of adjuvant therapy. However to accurately determine the clinical usefulness of MSI more precise standardisation of the definition and methodologies used to identify M81 is required.

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Greene, Malorie. „Étude des conséquences génomiques et fonctionnelles de l'instabilité des microsatellites dans le cancer colorectal“. Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066592/document.

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L’instabilité des séquences répétées microsatellites du génome (courtes répétitions en tandem d’un à cinq nucléotides) est une conséquence de l’inactivation du système MMR (MisMatch Repair), en charge de la réparation des erreurs produites au cours de la réplication de l’ADN. Cette instabilité est associée à un processus de transformation cellulaire original, observé chez l’homme dans des pathologies tumorales fréquentes, nommées MSI (pour Microsatellite Instability). Les localisations primaires les plus fréquentes de ces tumeurs sont le côlon, l’endomètre et l’estomac. Elles peuvent avoir une origine héréditaire (prédisposition familiale ; syndrome de Lynch et apparentés), mais sont dans la majorité des cas de survenue sporadique. La transformation des cellules MMR-déficientes s’observe dans le contexte de l’accumulation de nombreuses mutations somatiques dans l’ADN tumoral. Certaines ont un caractère oncogénique en favorisant la troncature et la perte de fonction de gènes suppresseurs de tumeur ou apparentés, impliqués dans des voies de signalisations diverses et qui contiennent des microsatellites codants (mutations indels d’une à deux paires de base, décalant le cadre de lecture, fréquemment rapportées dans ces tumeurs). Les travaux présentés dans le cadre de mon doctorat visent à mieux comprendre le rôle de l’instabilité microsatellitaire dans la tumorigenèse MSI. Ils s’inscrivent dans le contexte du décryptage et de l’analyse des données de séquençage d’exome de 47 cancers colorectaux primitifs MSI. Dans le contexte d’un niveau élevé d’instabilité génomique caractérisant ces tumeurs, la mise au point par mon laboratoire d’accueil de modèles probabilistes a permis de dresser une liste restreinte de gènes, remarquables par le fait qu’ils sont affectés par des mutations somatiques dont les fréquences sont exceptionnellement élevées ou basses dans l’ADN tumoral. Sous l’hypothèse que de tels évènements somatiques affectent des gènes clés de la tumorigenèse MSI colique, j’ai focalisé mes recherches sur les gènes dont les altérations sont peu fréquentes. Brièvement, j’ai pu démontrer le caractère délétère d’un petit nombre d’altérations microsatellitaires codantes dont la survenue semble soumise à une pression de sélection négative (N=13). Mes résultats indiquent que ces mutations semblent fragiliser le phénotype tumoral des cellules dans lesquelles elles surviennent, la perte de fonction des gènes qu’elles affectent conduisant à diverses conséquences délétères en fonction du gène candidat (e.g. sensibilisation à la mort cellulaire, perte des capacités proliférative et migratoire, ralentissement de la croissance tumorale). Ces résultats rapportent pour la première fois et à grande échelle, la sélection négative de mutations dans des tumeurs à forte instabilité génomique MSI. Ils ouvrent de nouvelles voies pour la compréhension de ce mode particulier de transformation cellulaire, et sont potentiellement d’intérêt pour la mise au point de thérapies personnalisées pour les patients
Since the discovery of a link between mismatch repair (MMR) deficiency and cancer, microsatellite instability (MSI) is thought as a process underlying cell transformation and tumour progression and invasion. MSI tumours are a subset of frequent human neoplasms, both inherited and sporadic, associated with several primary locations (colon, stomach, endometrium…). In MMR-deficient cells, MSI generates hundreds of frameshift mutations in genes (MSI Target Genes, MSI-TGs) containing coding microsatellite sequences (e.g. -1/+1 bp, insertions/deletions, i.e. indels). Some of these mutations affect genes with a role in human carcinogenesis and are thus expected to promote the MSI-driven tumorigenic process. During my PhD, I aimed to decipher the role of MSI in colon tumorigenesis. I exploited exome-sequencing data available in my lab that were generated from the analysis of a series of 47 human MSI primary colorectal cancer (CRC). Through biostatistics analysis and mathematical models that we designed to interpret mutation rates in the context of the high background for instability characterizing MSI in CRC, we identified a few microsatellites containing genes coding mutations that were negatively selected in MSI colon tumours (N=13). Under the hypothesis that these events may have a negative impact in colon tumorigenesis, I demonstrated that the silencing of these MSI target genes (siRNA/shRNA) was deleterious for MSI cancer cells using in vitro and in vivo models (impairment of proliferation and/or migration and/or response to chemotherapy and/or tumour growth) (Jonchère*, Marisa*, Greene* et al., submitted)

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Micelli, Lupinacci Renato. „Caractérisation anatomo-clinique et phénotypique des adénocarcinomes canalaires du pancréas avec instabilité des microsatellites“. Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066311/document.

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L’adénocarcinome canalaire du pancréas (ACP) est un problème majeur de santé publique. L’ACP se développe principalement à partir de deux lésions précurseurs : les néoplasies intra-épithéliales pancréatiques et les tumeurs intracanalaires papillaires et mucineuses du pancréas (TIPMP). Les mécanismes moléculaires sous-tendant l’oncogenèse pancréatique sont nombreux. Nous avons étudié le mécanisme de cancérogenèse MSI (MicroSatellite Instability) où il existe une déficience dans le système de réparation des erreurs de réplication de l’ADN ou système MMR (Mismatch Repair). Ce mécanisme de cancérogenèse original est caractérisé par une instabilité génétique de l’ADN affectant les séquences répétées microsatellites du génome. Le phénotype MSI a été décrit dans le syndrome de Lynch (SL), dans lequel il existe une mutation germinale d’un des gènes du système MMR (MLH1, MSH2, MSH6 et PMS2). L’intérêt de l’étude des cancers MSI s’est accru de façon considérable avec le développement des immunothérapies dirigées contre les checkpoints immunitaires (ICK), en particulier PD-1/PD-L1. Nous avons confirmé que la fréquence du phénotype MSI se situe entre 1-2%. Nous avons montré que l’immunohistochimie est la méthode de screening plus adaptée pour l’identification de l’ACP MSI en comparaison avec les techniques de biologie moléculaire. Le phénotype MSI a été plus fréquemment observé dans un contexte de TIPMP. Les cas MSI identifiés présentaient des caractéristiques biologiques évocatrices du SL. Egalement, nos résultats confirment la présence d’un processus de carcinogenèse MSI immunogénique, mais suggèrent des évènements somatiques spécifiques à l’organe d’origine du cancer. Par ailleurs, les ACP MSI étaient caractérisés par un infiltrat inflammatoire riche en lymphocytes cytotoxiques T CD8+ et surexprimaient l’ICK PD-L1 permettant de supposer une probable réponse clinique de l’ACP MSI à l’immunothérapie anti-PD1/PD-L1
Pancreatic ductal adenocarcinoma (PDAC) is a major health problem in France and around the world. PDAC is developed mainly from two precursor lesions: pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm (IPMN). There are several molecular mechanisms underlying pancreatic oncogenesis. Particularly, we were interested in the MSI (MicroSatellite Instability) which is due to a defective DNA Mismatch Repair (MMR) system, which normally functions to recognize and repair erroneous insertions, deletions, and mis-incorporation of bases that can arise during DNA replication and recombination. The MSI phenotype was first described in the familial cancer condition known as Lynch syndrome (LS), where the MMR genes MLH1, MSH2, MSH6 or PMS2 harbor germline mutations. Interest in MSI tumors has recently increased after studies have highlighted the concomitant expression of multiple active immune checkpoint (ICK) markers including PD-1 and PD-L1 and the role of the MSI status to predict clinical benefit from immune checkpoint blockade. A Our results indicate that the MSI phenotype occurs in PDAC with a frequency of 1-2%. Our data showed that IHC using antibodies against the four MMR proteins was more sensitive for the assessment of MSI status than PCR-based methods. In addition, we demonstrate for the first time a statistically significant positive association between MSI and IPMNs in PDAC. MSI PDAC, including IPMN, are unlikely to be sporadic since they display molecular features that are usually observed in LS-related neoplasms. Also, our results highlight that an MSI-driven immunogenic pathway to cancer is active in MSI PDACs but suggest that MSI-driven somatic events may be tissue-specific. We observed a stronger lymphocytic tumor infiltration by activated TCD8 cells in MSI PDAC compared to MSS PDAC and found a positive association between PD-L1 expression and MSI status, suggesting that MSI PDAC could be responsive to ICK blockade therapy

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Cohen, Romain. „Caractérisation phénotypique et clinique des cancers colorectaux métastatiques avec instabilité des microsatellites Clinical and molecular characterization of hereditary and sporadic metastatic colorectal cancer harbouring microsatellite instability/DNA mismatch repair deficiency Association of primary resistance to immune checkpoint inhibitors in metastatic colorectal cancer with misdiagnosis of microsatellite instability or mismatch repair deficiency status“. Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS313.

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L’instabilité des microsatellites (MSI) est un phénotype tumoral dû à une déficience héréditaire ou acquise du système de réparation des mésappariements de l’ADN (MMR : mismatch repair). Le phénotype MSI est retrouvé dans 5% des cancers colorectaux métastatiques (CCRm) et est un facteur prédictif positif majeur de l’efficacité des inhibiteurs de checkpoints immunitaires (ICKi). L’objectif de mon travail a été de caractériser sur le plan clinique et moléculaire les CCRm MSI, d’en évaluer les modalités diagnostiques et d’évaluer la réponse aux ICKi. Dans un 1er travail, je montre que l’histoire naturelle clinique des CCRm MSI diffère selon le mécanisme sporadique ou héréditaire de la déficience MMR (Cohen et al., Eur J Cancer 2017). Dans un 2e travail, je montre que près de 10% des CCRm détectés comme MSI/MMR-déficients en vie réelle correspondent à des faux positifs des analyses immunohistochimiques et/ou de PCR, et que ces faux positifs sont responsables de la majorité des cas de résistance primaire aux ICKi observés dans les essais cliniques (Cohen*, Hain* et al., JAMA Oncol. 2018). Après une revue de la littérature concernant le phénotype MSI, son impact dans le cadre du CCR et des ICKi, je présente les résultats des travaux développés durant ce doctorat, avant de proposer différentes perspectives à l’ère de l’immunothérapie des cancers MSI
Microsatellite instability (MSI) is a tumor phenotype linked to somatic or germline inactivating alterations of DNA mismatch repair (MMR) genes. MSI is observed in approximately 5% of metastatic colorectal cancers (mCRC) and has recently emerged as a major positive predictive biomarker for the efficacy of immune checkpoint inhibitors (ICKi) amongst mCRC patients. The objectives of my work was to clinically and molecularly characterize MSI mCRC, to evaluate the accuracy of MSI screening methods and the response to immunotherapy in the context of ICKi clinical trials. Fist, I show that sporadic and inherited MSI mCRC display distinct natural history (Cohen et al., Eur J Cancer 2017). In a second work, I show that MSI testing in routine practice is associated with almost 10% of false positives due to misinterpration of IHC and PCR assays. Moreover, these false-positives are the main cause of mCRC primary resistance to ICKi observed in clinical trials (Cohen*, Hain* et al., JAMA Oncol. 2018). After summarizing the literature concerning MSI, its consequences on CRC and immunotherapy, I present the results of the nosologic and diagnostic works developed during this doctoral thesis. Then I will go on perspectives in the context of MSI cancer

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El-Murr, Nizar. „Étude de l'impact des microARNs sur la carcinogenèse des cancers colorectaux instables sur les séquences répétées microsatellites du génome“. Phd thesis, Université Pierre et Marie Curie - Paris VI, 2014. http://tel.archives-ouvertes.fr/tel-00990895.

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La progression tumorale MSI (Microsatellite Instable) est un processus multi-étapes résultant de mutations générées par un processus d'instabilité génétique qui affecte en majorité les motifs répétés en tandem de l'ADN (microsatellites). Ces mutations contribuent à l'oncogenèse lorsqu'elles perturbent la fonction d'oncogènes ou de gènes suppresseurs de tumeurs. Le trait phénotypique MSI est consécutif à l'inactivation du système de réparation des mésappariements de l'ADN (système MMR). Dans ce travail, je me suis intéressé au rôle des microARNs dans l'oncogenèse MSI. Les microARNs régulent l'expression de nombreux gènes pouvant avoir un rôle clé dans le cancer. J'ai donc fait l'hypothèse d'un rôle de ces microARNs lors des différentes étapes du processus tumorigénique MSI. Tout d'abord nous avons mis en évidence une surexpression du miR-155 (ciblant les principales protéines MMR) au niveau de la muqueuse colique non transformée des malades atteints d'une Maladie Inflammatoire Chronique Intestinale, qui pourrait constituer un évènement pré-tumoral favorisant l'émergence de clones MMR-déficients (notion d'effet de champs). Dans une deuxième partie, nous avons pu identifier la première mutation somatique touchant un microARN. Il s'agit du miR-3613 dont la répétition microsatellite est entièrement localisée dans le miR mature. L'instabilité au niveau de ce miR conduit à des changements de séquence à l'extrémité 3' du miR (notion d'IsomiRs). Les isomiRs produits ont un répertoire de cibles qui pour certaines sont communes à la forme sauvage et pour d'autres spécifiques à chacun des variants.

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Boulagnon-Rombi, Camille. „Etude du récepteur d’endocytose LRP1 dans les adénocarcinomes coliques : caractéristiques cliniques, pathologiques et moléculaires associées et valeur pronostique“. Thesis, Reims, 2017. http://www.theses.fr/2017REIMM203/document.

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LRP1 (low-density lipoprotein receptor–related protein 1), un récepteur endocytaire multifonctionnel, a récemment été identifié comme pivot d’un réseau de biomarqueurs pour la prédiction pronostique de plusieurs types de cancers. Son rôle dans le cancer du côlon n'a pas été caractérisé. Notre travail porte sur l’étude de la relation entre expression de LRP1 et cancer du côlon.L'expression de l'ARNm LRP1 a été déterminée dans des échantillons d'adénocarcinome et de muqueuses coliques appariées, ainsi que dans les cellules stromales et tumorales obtenues après microdissection laser. Les associations clinicopathologiques et moléculaires ont été étudiées par immunohistochimie dans une série de cancer colique (n = 307). La présence de méthylation ou mutation du gène LRP1 et l'expression de miR-205 ont été évaluées et comparées aux niveaux d'expression de LRP1.L’ARNm de LRP1 est sous exprimé dans les cellules d'adénocarcinome colique par rapport à la muqueuse colique par rapport aux cellules stromales. La faible expression immunohistochimique de LRP1 dans les adénocarcinomes était associée à un âge plus élevé, à localisation droite, une perte d'expression de CDX2, une expression d'Annexine A10, un statut CIMP-H, MSI-H et BRAFV600E muté. Cette faible expression était associée à un mauvais pronostic, en particulier chez les patients de stade IV. Les mutations du gène LRP1 entrainaient une sous-expression de LRP1. L’expression était peu modifiée par miR-205. Le promoteur de LRP1 n'était jamais méthylé.La perte d'expression de LRP1 est associée à un profil clinico-pathologique et moléculaire particulier et à un un mauvais pronostic dans les cancers du côlon
LRP1 (low-density lipoprotein receptor–related protein 1), a multifunctional endocytic receptor, has recently been identified as a hub in a biomarker network for multi-cancer clinical outcome prediction. Its role in côlon cancer has not been characterized. Here, we investigate the relationship between LRP1 and colon cancer.LRP1 mRNA expression was determined in colon adenocarcinoma and paired colon mucosa samples, and in stromal and tumoral cells obtained after laser capture microdissection. The clinical potential was further investigated by immunohistochemistry in a population-based colon cancer series (n = 307). LRP1 methylation, mutation and miR-205 expression were evaluated and compared to LRP1 expression levels.LRP1 mRNA levels are significantly decreased in colon adenocarcinoma cells compared to colon mucosa and stromal cells. Low LRP1 immunohistochemical expression in adenocarcinomas was associated with higher age, right-sided tumor, loss of CDX2 expression, Annexin A10 expression, CIMP-H, MSI-H and BRAFV600E mutation. Low LRP1 expression correlates with poor clinical outcome, especially in stage IV patients. LRP1 expression was downregulated by LRP1 mutation. LRP1 expression was slightly modified by miR-205 expression. LRP1 promoter was never methylated.Loss of LRP1 expression is associated with peculiar clinocopathological and molecular characteristics and with worse colon cancer outcomes

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Vaysse-Zinkhöfer, Wilhelm. „Mécanismes de réparations d’une cassure double-brin et résection au sein d’un microsatellite humain“. Electronic Thesis or Diss., Sorbonne université, 2021. http://www.theses.fr/2021SORUS477.

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Les microsatellites sont des répétitions en tandem d’un motif compris entre une et neuf paires de bases. Ces répétitions retrouvées dans tous les organismes de façon ubiquitaire, sont particulièrement abondantes dans les organismes eucaryotes. Toutes ces répétitions sont capables de former des structures secondaires in vitro et possiblement in vivo. Certains microsatellites sont enclins à une expansion, conduisant à de nombreuses maladies neurodégénératives chez l’homme telle que la dystrophie myotonique de type 1 (DM1), maladie neurodégénérative la plus fréquemment transmise. L’apparition et la sévérité des symptômes sont positivement corrélée avec le nombre de répétitions, localisées dans le 3’UTR du gène DMPK. Dans des travaux précédents du laboratoire, une TALE nucléase (TALEN) a été élaborée dans le but d’introduire une cassure double-brin au sein d’un microsatellite (CTG)n provenant d’un patient DM1. La compréhension des mécanismes conduisant à la contraction des répétitions chez la levure est nécessaire si l’on souhaite en comprendre les mécanismes chez l’homme. Ainsi, des expériences ont été menées dans des cellules dont les systèmes de réparation des CDB ont été altérés, montrant que RAD51, POL32 et DNL4 n’étaient pas nécessaires à la réparation des CDB au sein des microsatellites. Seul RAD50 et RAD52 semblent nécessaires, indiquant que la cellule répare les CDB dans les régions répétées par single-strand annealing. L’objectif de cette thèse a été d’étudier le rôle de plusieurs gènes (MRE11, EXO1, SGS1, DNA2, SAE2, RIF1 et RIF2), impliqués dans la résection et la réparation d’une unique CDB au sein d’une région répétée CTG, chez la levure
Microsatellites are tandem repeats of a motif between one and nine base pairs. These repeats are found ubiquitously in all organisms and are particularly abundant in eukaryotic organisms. All these repeats are capable of forming secondary structures in vitro and possibly in vivo. Some microsatellites are prone to expansion, leading to many neurodegenerative diseases in humans such as myotonic dystrophy type 1 (DM1), the most frequently transmitted neurodegenerative disease. The onset and severity of symptoms are positively correlated with the number of repeats located in the 3'UTR of the DMPK gene. In previous work in the laboratory, a TALE nuclease (TALEN) was developed to introduce a double-strand break into a microsatellite (GTC)n from a DM1 patient. Understanding the mechanisms leading to repeat contraction in yeast is necessary to understand the mechanisms in humans. Thus, experiments were conducted in cells with altered CBD repair systems showing that RAD51, POL32 and DNL4 were not required for CBD repair within microsatellites. Only RAD50 and RAD52 appear to be required, indicating that the cell repairs CBDs in repeated regions by single-strand annealing. The objective of this thesis was to study the role of several genes (MRE11, EXO1, SGS1, DNA2, SAE2, RIF1 and RIF2), involved in the resection and repair of a single CBD within a CTG repeat region, in yeast

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Palassin, Pascale. „Etude du rôle du corégulateur transcriptionnel RIP140 dans le contrôle de l'instabilité microsatellitaire des cancers colorectaux héréditaires“. Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT054/document.

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Le corégulateur transcriptionnel RIP140 est un facteur ubiquitaire majeur impliqué dans la régulation de nombreux processus physiopathologiques, qui possède la capacité d’être un coactivateur ou un corépresseur des voies de signalisation selon son recrutement sur les gènes cible. Des résultats du laboratoire ont montré que RIP140 est un facteur de bon pronostic de la tumorigenèse intestinale sporadique. Ce travail s’intéresse à l’implication de ce facteur de transcription dans les cancers colorectaux familiaux et, plus particulièrement, en lien avec le syndrome de Lynch (LS). Le syndrome de Lynch est une prédisposition héréditaire aux cancers, majoritairement colorectaux, caractérisés par un défaut du système de réparation des mésappariements de l’ADN (Mismatch Repair, MMR), dû à une première mutation germinale d’un des gènes de ce système. La perte de fonctionnalité MMR est responsable du phénotype d’instabilité microsatellitaire (MSI). Cependant, il existe des formes familiales de cancers colorectaux, avec MSI, où il n’est pas retrouvé d’atteinte germinale ou somatique de l’un des gènes du système MMR. Ce sont les syndromes apparentés au syndrome de Lynch (Lynch Like Syndrome, LLS) dont la prise en charge est identique à celle du LS. L’utilisation de modèles murins et de lignées cellulaires colorectales, présentant des modulations d’expression de RIP140 ont permis de mettre en évidence l’effet positif de ce corégulateur sur la régulation transcriptionnelle de l’expression des gènes du système MMR, MSH2 et MSH6. La validité fonctionnelle de cette régulation a été explorée par des analyses d’instabilité microsatellitaire et de sensibilité à différentes molécules cytotoxiques. Des cohortes de tumeurs ont permis de confirmer la corrélation d’expression entre RIP140 et les gènes MSH2 et MSH6 chez les patients. En outre, la régulation de l’expression par RIP140 d’une polymérase translésionnelle particulière, la polymérase Polκ, a été étudiée. Cette polymérase assure la réplication des séquences microsatellitaires du génome. Nous avons démontré que RIP140 stimule l’expression du gène POLK dans nos modèles cellulaires et que son expression est corrélée à celle de RIP140 au sein des tumeurs colorectales humaines. Enfin, par séquençage de différentes lignées cellulaires, nous avons mis en évidence une mutation de RIP140 qui entraîne un décalage du cadre de lecture et génère une protéine tronquée avec perte de deux domaines répresseurs de la protéine. Un séquençage à très haut débit nous a permis de rechercher cette mutation parmi des échantillons de tumeurs colorectales avec MSI. Cette mutation est retrouvée dans 19% des tumeurs, notamment LLS (16,2%), où elle est associée à une moins bonne survie globale. Elle affecte les propriétés antiprolifératives et transrépressives de RIP140 ainsi que les régulations positives des gènes MSH2, MSH6 et POLK. Le développement d’un outil anticorps spécifique de cette mutation serait extrêmement utile pour suivre l’expression de la forme mutée au sein des tumeurs et des premiers essais ont été réalisés en ce sens. En conclusion de ce travail, RIP140 contrôle l’expression de gènes majeurs impliqués dans le maintien de l’intégrité du génome et une mutation de ce corégulateur transcriptionnel pourrait être responsable de l’instabilité microsatellitaire de certaines tumeurs où des altérations des gènes MMR ne sont pas retrouvées. Des études cliniques sur des cohortes plus conséquentes seront nécessaires pour valider son intérêt en tant que marqueur utilisable dans la prise en charge des patients
The transcriptional coregulator RIP140 is an ubiquitous cofactor playing a major role in the regulation of many physiopathological processes. It can either act as a coactivator or as a corepressor of signaling pathways depending on its recruitment on target genes. It has been shown that RIP140 is a good prognostic marker in sporadic intestinal tumorigenesis. This work focuses on its role in familial colorectal cancers and particularly in relation to the Lynch syndrome (LS). Lynch syndrome is a hereditary cancer predisposition, mostly colorectal, characterized by a defect in the Mismatch Repair (MMR) system, due to a first germline mutation of one gene of this system. Loss of MMR function induces a microsatellite instability (MSI) phenotype. However, there are some MSI familial colorectal cancers, where neither germinal nor somatic alteration of one MMR gene is found. They are referred to as Lynch like Syndrome (LLS) and their overall management is identical to that of LS. Murine models and colorectal cell lines, harboring modulations of RIP140 expression, allowed us to demonstrate the positive transcriptional regulation of the MMR genes, MSH2 and MSH6 by RIP140. Functional validation of this regulation was explored by microsatellite instability and sensitivity to various cytotoxic drugs analyses. A positive correlation has been confirmed between RIP140 and MSH2 and MSH6 gene expression in a cohort of 396 patients. Moreover, the transcriptional regulation by RIP140 of a specialized translesional DNA polymerase, the Polκ polymerase, has been investigated. Polκ ensures microsatellite sequences replication. We have demonstrated that RIP140 positively stimulates the expression of the POLK gene in our cell models and which appears correlated with that of RIP140 in human colorectal tumors. Finally, by sequencing different cell lines, we found a frameshift mutation of RIP140, generating a truncated protein with loss of the last two repression domains. High-throughput sequencing allowed us to look for this mutation in patient MSI colorectal tumor samples. This mutation was found in 19% of these tumors, especially LLS (16,2%), where it has been associated with lower overall survival. This mutation affects the antiproliferative and transrepressive properties of RIP140, as well as the positive regulation of the MSH2, MSH6 and POLK gene. Development of a specific antibody for this mutation would be extremely useful in following the expression of this mutated form within tumors and first tests have been already carried out. In conclusion, RIP140 controls expression of major genes involved in genome integrity maintenance and a mutation of this transcriptional coregulator could be responsible for microsatellite instability of some tumors where alterations of MMR genes are not found. Clinical studies on larger cohorts will be necessary to validate its interest as a marker usable in patient management

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Warusavitarne, Janindra. „Analysis of the factors that influence the biological behaviour and response to chemotherapy in sporadic colorectal carcinomas with microsatellite instability“. Thesis, The University of Sydney, 2005. https://hdl.handle.net/2123/27920.

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High frequency microsatellite instability (MSI—H) is an alternate pathway of colorectal carcinogenesis and is present in approximately 15% of all sporadic colorectal cancers. These tumours are predominantly located in the right colon, occur mainly in the elderly and have a better prognosis than microsatellite stable (MSS) CRCs. In addition they are usually of mucinous type histology, tend to be locally invasive, metastasise less and are of larger size than MSS CRCs. The mismatch repair (MMR) genes hMLHl is most commonly mutated or methylated in sporadic colorectal cancers with MSI-H. Several other gene mutations occur as a result of the defective mismatch repair genes and mutations in a 10 x A repeat region of the TGFBRII gene occurs in approximately 90% of MSI-H CRCs. TGFB is an important tumour suppressor and TGFB signalling is impaired in the absence of TGFBRH. Several studies have shown that restoring TGFB signalling in MSI-H CRC results in reduced tumorigenicity suggesting that the lack of TGFB signalling may be responsible for the increased tumorigenicity seen in these CRCs. In breast and pancreatic cancer TGFB signalling has been associated with an increased metastatic rate and it is postulated that the lack of TGFB signalling in MSI-H CRC is associated with the reduced metastatic rate seen in these tumours when compared with MSS CRCS.

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Bücher zum Thema "Microsatellites instability"

Millar, Anna L. Frequency estimation of endometrial cancer associated with microsatellite instability and mismatch repair gene defects. Ottawa: National Library of Canada, 1999.

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Gryfe, Robert. Colorectal cancer microsatellite instability. 2001.

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Umar, A. Lynch Syndrome (HNPCC) and Microsatellite Instability. Ios Pr Inc, 2004.

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Umar, A. Lynch Syndrome (HNPCC) and Microsatellite Instability Analysis Guidelines, Part 2. IOS Press, 2006.

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Leahy, Dermot T. Clinicopathological significance of p53, bcl-2 and microsatellite instability in colorectal carcinoma. 1998.

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Curran, Bernie. Microsatellite instability and loss of heterozygosity distinguish two phenotypes in colorectal carcinoma and identity a subgroup with poor prognosis. 1996.

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Tumor microsatellite instability, mismatch repair deficiency and response to chemotherapy: A molecular reanalysis of randomized adjuvant chemotherapy trials in colon cancer. Ottawa: National Library of Canada, 2001.

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Buchteile zum Thema "Microsatellites instability"

Patel, Nisha R., Michael L. Wong, Anthony E. Dragun, Stephan Mose, Bernadine R. Donahue, Jay S. Cooper, Filip T. Troicki et al. „Microsatellite Instability“. In Encyclopedia of Radiation Oncology, 502. Berlin, Heidelberg: Springer Berlin Heidelberg, 2013. http://dx.doi.org/10.1007/978-3-540-85516-3_211.

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Ahlquist, Terje C., und Ragnhild A. Lothe. „Microsatellite Instability“. In Encyclopedia of Cancer, 1–5. Berlin, Heidelberg: Springer Berlin Heidelberg, 2015. http://dx.doi.org/10.1007/978-3-642-27841-9_3731-2.

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Ahlquist, Terje C., und Ragnhild A. Lothe. „Microsatellite Instability“. In Encyclopedia of Cancer, 2842–45. Berlin, Heidelberg: Springer Berlin Heidelberg, 2015. http://dx.doi.org/10.1007/978-3-662-46875-3_3731.

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Ahlquist, Terje, und Ragnhild A. Lothe. „Microsatellite Instability“. In Encyclopedia of Cancer, 2305–8. Berlin, Heidelberg: Springer Berlin Heidelberg, 2011. http://dx.doi.org/10.1007/978-3-642-16483-5_3731.

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Prasad, Meena A., und Barbara Jung. „Microsatellite Instability and Intestinal Tumorigenesis“. In Intestinal Tumorigenesis, 29–53. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-19986-3_2.

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Li, Jinhong, und Fan Lin. „Lower Gastrointestinal Tract and Microsatellite Instability“. In Handbook of Practical Immunohistochemistry, 423–33. New York, NY: Springer New York, 2011. http://dx.doi.org/10.1007/978-1-4419-8062-5_25.

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Chen, Guoli, Jianhong Li, Zongming Eric Chen, Jinhong Li und Fan Lin. „Lower Gastrointestinal Tract and Microsatellite Instability (MSI)“. In Handbook of Practical Immunohistochemistry, 701–14. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-83328-2_29.

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Elfimova, Natalia, Wafa Amer und Margarete Odenthal. „Analysis of Microsatellite Instability by Microfluidic-Based Electrophoresis“. In Methods in Molecular Biology, 287–96. Totowa, NJ: Humana Press, 2012. http://dx.doi.org/10.1007/978-1-62703-029-8_25.

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Viana-Pereira, Marta, Chris Jones und Rui Manuel Reis. „Pediatric High-Grade Glioma: Role of Microsatellite Instability“. In Pediatric Cancer, Volume 3, 205–10. Dordrecht: Springer Netherlands, 2012. http://dx.doi.org/10.1007/978-94-007-4528-5_22.

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Liu, Yuqing, Weiwen Wang, Chuan-Xian Ren und Dao-Qing Dai. „MetaCon: Meta Contrastive Learning for Microsatellite Instability Detection“. In Medical Image Computing and Computer Assisted Intervention – MICCAI 2021, 267–76. Cham: Springer International Publishing, 2021. http://dx.doi.org/10.1007/978-3-030-87237-3_26.

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Konferenzberichte zum Thema "Microsatellites instability"

Pirini, Francesca, Luigi Pasini, Sara Ravaioli, Gianluca Tedaldi, Emanuela Scarpi, Giorgia Marisi, Chiara Molinari, Daniele Calistri, Alessandro Passardi und Paola Ulivi. „Abstract 5296: Instability of non standard microsatellites in metastatic colorectal cancer patients treated with a bevacizumab based chemotherapy“. In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-5296.

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Singh, Sukhi, Janez Kokosar, Jan Otonicar und Luka Ausec. „179 Profiling microsatellite instability using RNA sequencing data“. In SITC 38th Annual Meeting (SITC 2023) Abstracts. BMJ Publishing Group Ltd, 2023. http://dx.doi.org/10.1136/jitc-2023-sitc2023.0179.

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Paulose, Assoc Prof Roopa, Prof Roopa Paulose, Divya Ail, Shital Biradar und K. Sundaram. „PTU-054 Microsatellite instability in stage II colorectal carcinoma“. In British Society of Gastroenterology, Annual General Meeting, 4–7 June 2018, Abstracts. BMJ Publishing Group Ltd and British Society of Gastroenterology, 2018. http://dx.doi.org/10.1136/gutjnl-2018-bsgabstracts.395.

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KIM, Jee Hung, Chang-gon Kim, Joong Bae Ahn, MinKyu Jung, Seung Hoon Beom, Joo Hoon Kim, Soo Jin Heo und Sang Joon Shin. „Abstract 808: Microsatellite instability in metastatic colorectal cancer (mCRC)“. In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-808.

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Samara, Katerina D., Eirini Neofytou, Nikolaos Tzanakis, Alexandros D. Karatzanis, Dimitra Papandrinopoulou, Nikolaos Siafakas und Eleni G. Tzortzaki. „Perforin Expression In COPD Patients With Microsatellite DNA Instability“. In American Thoracic Society 2010 International Conference, May 14-19, 2010 • New Orleans. American Thoracic Society, 2010. http://dx.doi.org/10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a3879.

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Bond, Catherine E., Aarti Umapathy, Ron L. Buttenshaw, Leesa Wockner, Barbara A. Leggett und Vicki LJ Whitehall. „Abstract 106: Chromosomal instability inBRAFmutant, microsatellite stable colorectal cancers“. In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-106.

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Wang, Huilin, Jiang Zhu, Guanbiao Liang, Yongyong Wang, Jianji Guo, Min Zheng, Qin Fu und Weiwei Shi. „Abstract 4316: Frequent microsatellite instability in Chinese solid tumor patients“. In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-4316.

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Sussman, Daniel A., Shivali Berera, Peter Hosein, Feng Miao, Tulay Koru-Sengul, Jacob McCauley, Erin Kobetz-Kerman, Olveen Carrasquillo und Maria T. Abreu. „Abstract B45: Microsatellite instability among disenfranchised minority colorectal cancer patients“. In Abstracts: Sixth AACR Conference: The Science of Cancer Health Disparities; December 6–9, 2013; Atlanta, GA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7755.disp13-b45.

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Abbas, Basman F., Ahmed S. Abood, Ghufran H. Abed, Nidhal A. Mohammad und Alaa D. Kadhim. „BAT26 marker as detector of microsatellite instability in breast tumors“. In 1ST SAMARRA INTERNATIONAL CONFERENCE FOR PURE AND APPLIED SCIENCES (SICPS2021): SICPS2021. AIP Publishing, 2022. http://dx.doi.org/10.1063/5.0121227.

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Kurata, K., M. Kubo, H. Mori, H. Kawaji, Y. Motoyama, L. Kuroki, M. Yamada, K. Kaneshiro, M. Kai und M. Nakamura. „Abstract P1-06-11: Microsatellite instability in triple negative breast cancers“. In Abstracts: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, Texas. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-p1-06-11.

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Berichte der Organisationen zum Thema "Microsatellites instability"

Baranovskaya, Svetlana. Microsatellite and Chromosomal Instability in Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, Juli 2004. http://dx.doi.org/10.21236/ada430384.

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Baranovskaya, Svetlana. Microsatellite and Chromosomal Instability in Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, Juli 2003. http://dx.doi.org/10.21236/ada418690.

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Michelmore, Richard, Eviatar Nevo, Abraham Korol und Tzion Fahima. Genetic Diversity at Resistance Gene Clusters in Wild Populations of Lactuca. United States Department of Agriculture, Februar 2000. http://dx.doi.org/10.32747/2000.7573075.bard.

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Genetic resistance is often the least expensive, most effective, and ecologically-sound method of disease control. It is becoming apparent that plant genomes contain large numbers of disease resistance genes. However, the numbers of different resistance specificities within a genepool and the genetic mechanisms generating diversity are poorly understood. Our objectives were to characterize diversity in clusters of resistance genes in wild progenitors of cultivated lettuce in Israel and California in comparison to diversity within cultivated lettuce, and to determine the extent of gene flow, recombination, and genetic instability in generating variation within clusters of resistance genes. Genetic diversity of resistance genes was analyzed in wild and cultivated germplasm using molecular markers derived from lettuce resistance gene sequences of the NBS-LRR type that mapped to the major cluster if resistance genes in lettuce (Sicard et al. 1999). Three molecular markers, one microsatellite marker and two SCAR markers that amplified LRR- encoding regions, were developed from sequences of resistance gene homologs at the Dm3 cluster (RGC2s) in lettuce. Variation for these markers was assessed in germplasm including 74 genotypes of cultivated lettuce, L. saliva and 71 accessions of the three wild Lactuca spp., L. serriola, L. saligna and L. virosa that represent the major species in the sexually accessible genepool for lettuce. Diversity was also studied within and between natural populations of L. serriola from Israel and California. Large numbers of haplotypes were detected indicating the presence of numerous resistance genes in wild species. We documented a variety of genetic events occurring at clusters of resistance genes for the second objective (Sicard et al., 1999; Woo el al., in prep; Kuang et al., in prepb). The diversity of resistance genes in haplotypes provided evidence for gene duplication and unequal crossing over during the evolution of this cluster of resistance genes. Comparison of nine resistance genes in cv. Diana identified 22 gene conversion and five intergenic recombinations. We cloned and sequenced a 700 bp region from the middle of RGC2 genes from six genotypes, two each from L. saliva, L. serriola, and L. saligna . We have identified over 60 unique RGC2 sequences. Phylogenetic analysis surprisingly demonstrated much greater similarity between than within genotypes. This led to the realization that resistance genes are evolving much slower than had previously been assumed and to a new model as to how resistance genes are evolving (Michelmore and Meyers, 1998). The genetic structure of L. serriola was studied using 319 AFLP markers (Kuang et al., in prepa). Forty-one populations from Turkey, Armenia, Israel, and California as well as seven European countries were examined. AFLP marker data showed that the Turkish and Armenian populations were the most polymorphic populations and the European populations were the least. The Davis, CA population, a recent post-Columbian colonization, showed medium genetic diversity and was genetically close to the Turkish populations. Our results suggest that Turkey - Armenia may be the center of origin and diversity of L. serriola and may therefore have the greatest diversity of resistance genes. Our characterization of the diversity of resistance genes and the genetic mechanisms generating it will allow informed exploration, in situ and ex situ conservation, and utilization of germplasm resources for disease control. The results of this project provide the basis for our future research work, which will lead to a detailed understanding of the evolution of resistance genes in plants.

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