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Amir Torshizi Esfahani, Seyed Yoosef Seyedna, Ehsan Nazemalhosseini Mojarad, Ahmad Majd, Hamid Asadzadeh Aghdaei
BACKGROUND: Microsatellite instability (MSI) is a prognostic marker in colorectal cancer (CRC). The biological significance of MSI-low (MSI-L) phenotype and its differences with microsatellite stable (MSS) phenotype remains unclear. The aim of this study is indicating the role of mononucleotide repeat in identifying MSI-L and revealing the association of MSI-L with elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) and oncologic outcome in CRC patients. METHODS: MSI and EMAST status were analyzed using three quasimonomorphic panel (BAT-25, BAT-26, and NR-27) and five tetranucleotide repeats (D20S82, D20S85, D9S242, D8S321, and MYCL1), respectively, by capillary electrophoresis method without the need to fluorescent primers...
December 13, 2018: Journal of Cellular Physiology
Taiki Mori, Yasushi Hamaya, Takahiro Uotani, Mihoko Yamade, Moriya Iwaizumi, Takahisa Furuta, Hiroaki Miyajima, Satoshi Osawa, Ken Sugimoto
Pancreatic ductal adenocarcinoma (PDAC) prognosis remains poor even after complete resection owing to no valuable biomarkers for recurrence and chemosensitivity. Tumors not expressing MSH3 show elevated microsatellite alterations at selected tetranucleotide repeats (EMAST). EMAST reportedly occurs in several tumors. In colorectal cancer (CRC), EMAST was reportedly correlated with 5-fluorouracil (5-FU) sensitivity. However, EMAST prevalence in PDAC and its significance as a prognostic biomarker are unknown. This study aimed to investigate EMAST prevalence in PDAC and the associations between EMAST and pathological factors, EMAST and prognosis, and EMAST and MSH3 expression via immunohistochemistry (IHC)...
2018: PloS One
Nitya Bhaskaran, Jennifer Luu, Scott T Kelley, Mohammad W Khan, Priyadarshini Mamindla, Kathleen L McGuire
Elevated Microsatellite Alterations at Selected Tetranucleotide repeats (EMAST) occur in up to 60% of colorectal cancers and may associate with aggressive and advanced disease in patients. Although EMAST occurs in many cancer types, current understanding is limited due to the lack of an animal model. Reported here is the design and implementation of an algorithm for detecting EMAST repeats in mice. This algorithm incorporates properties of known human EMAST sequences to identify repeat sequences in animal genomes and was able to identify EMAST-like sequences in the mouse...
September 13, 2018: Scientific Reports
Minoru Koi, Yoshiki Okita, John M Carethers
It has been recently reported that the population of Fusobacterium , particularly Fusobacterium nucleatum ( Fn ), is overrepresented in colorectal cancers and adenomas. The promoting effects of Fn infection on adenoma and/or carcinoma formation have been shown in ApcMin/+ mice. Characteristics of Fn -associated CRC were identified through studies using human CRC cohorts, and include right-sided colon location, CpG island methylation phenotype-high (CIMP-H), high level of microsatellite instability (MSI-H), and poor patient prognosis...
2018: Journal of the anus, rectum and colon
Tai-Chuan Kuan, Pei-Ching Lin, Shung-Haur Yang, Chun-Chi Lin, Yuan-Tzu Lan, Hung-Hsin Lin, Wen-Yi Liang, Wei-Shone Chen, Jen-Kou Lin, Jeng-Kai Jiang, Shih-Ching Chang
Recent studies suggest that aberrant DNA methylation might occur early and commonly in colorectal tumorigenesis. In 111 normal subjects, the mean LINE-1 methylation level of peripheral blood was 81.0 ± 5.7%. Of 143 colorectal cancer (CRC) patients, the mean level of LINE-1 methylation was 60.5 ± 12.5%. We defined below 60% as cut-off value of LINE-1 hypomethylation, and 93 cases (65.0%) had LINE-1 hypomethylation in the tumor tissue. LINE-1 hypomethylation was not associated with any other clinical features...
2018: PloS One
Minoru Koi, Stephanie S Tseng-Rogenski, John M Carethers
Microsatellite alterations within genomic DNA frameshift as a result of defective DNA mismatch repair (MMR). About 15% of sporadic colorectal cancers (CRCs) manifest hypermethylation of the DNA MMR gene MLH1 , resulting in mono- and di-nucleotide frameshifts to classify it as microsatellite instability-high (MSI-H) and hypermutated, and due to frameshifts at coding microsatellites generating neo-antigens, produce a robust protective immune response that can be enhanced with immune checkpoint blockade. More commonly, approximately 50% of sporadic non-MSI-H CRCs demonstrate frameshifts at di- and tetra-nucleotide microsatellites to classify it as MSI-low/elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) as a result of functional somatic inactivation of the DNA MMR protein MSH3 via a nuclear-to-cytosolic displacement...
January 15, 2018: World Journal of Gastrointestinal Oncology
John M Carethers
Microsatellite instability (MSI) refers to the biochemical detection of frameshifted microsatellite sequences from genomic DNA. Genesis of MSI is due to defective DNA mismatch repair (MMR) that fails to correct post DNA replicative slippage mistakes at microsatellites. Most of the estimated 100,000 genomic microsatellites are non-coding; however, ~150-300 microsatellites are coding such that, when frameshifted during the pathogenesis of an MSI tumor, can generate immunogenic neopeptide antigens that limit the growth of tumor and prolong patient survival...
February 2017: Current Colorectal Cancer Reports
H S Lee, K U Park, D-W Kim, M H Lhn, W H Kim, A N Seo, H E Chang, S K Nam, S Y Lee, H-K Oh, S-B Kang
PURPOSE: Recently, a different type of microsatellite instability (MSI) instability designated 'elevated microsatellite alterations at selected tetranucleotide repeats' (EMAST) has been reported in several neoplasms, but its clinical implications remain unclear. We aimed to determine the relationships among EMAST, MSI and clinicopathologic characteristics, including oncologic outcomes, in colorectal cancer (CRC). MATERIALS AND METHODS: We evaluated 100 sporadic CRC cases subjected to surgery using five markers (MYCL1, D9S242, D20S85, D8S321, and D20S82) for EMAST and the Bethesda panel for MSI status...
2016: Current Molecular Medicine
Ronja Adam, Isabel Spier, Bixiao Zhao, Michael Kloth, Jonathan Marquez, Inga Hinrichsen, Jutta Kirfel, Aylar Tafazzoli, Sukanya Horpaopan, Siegfried Uhlhaas, Dietlinde Stienen, Nicolaus Friedrichs, Janine Altmüller, Andreas Laner, Stefanie Holzapfel, Sophia Peters, Katrin Kayser, Holger Thiele, Elke Holinski-Feder, Giancarlo Marra, Glen Kristiansen, Markus M Nöthen, Reinhard Büttner, Gabriela Möslein, Regina C Betz, Angela Brieger, Richard P Lifton, Stefan Aretz
In ∼30% of families affected by colorectal adenomatous polyposis, no germline mutations have been identified in the previously implicated genes APC, MUTYH, POLE, POLD1, and NTHL1, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, we performed exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis. We identified two unrelated individuals with differing compound-heterozygous loss-of-function (LoF) germline mutations in the mismatch-repair gene MSH3...
August 4, 2016: American Journal of Human Genetics
Kjetil Søreide, Martin M Watson, Dordi Lea, Oddmund Nordgård, Jon Arne Søreide, Hanne R Hagland
BACKGROUND: More accurate predictive and prognostic biomarkers for patients with colorectal cancer (CRC) primaries or colorectal liver metastasis (CLM) are needed. Outside clinical trials, the translational integration of emerging pathways and novel techniques should facilitate exploration of biomarkers for improved staging and prognosis. METHODS: An observational study exploring predictive and prognostic biomarkers in a population-based, consecutive cohort of surgically treated colorectal cancers and resected colorectal liver metastases...
June 29, 2016: Journal of Translational Medicine
Martin M Watson, Dordi Lea, Emma Rewcastle, Hanne R Hagland, Kjetil Søreide
Microsatellite instability (MSI) is associated with better prognosis in colorectal cancer (CRC). Elevated microsatellite alterations at selected tetranucleotides (EMAST) is a less-understood form of MSI. Here, we aim to investigate the role of EMAST in CRC±MSI related to clinical and tumor-specific characteristics. A consecutive, population-based series of stage I-III colorectal cancers were investigated for MSI and EMAST using PCR primers for 10 microsatellite markers. Of 151 patients included, 33 (21.8%) had MSI and 35 (23...
July 2016: Cancer Medicine
Yasushi Hamaya, Carla Guarinos, Stephanie S Tseng-Rogenski, Moriya Iwaizumi, Ritabrata Das, Rodrigo Jover, Antoni Castells, Xavier Llor, Montserrat Andreu, John M Carethers
Elevated Microsatellite Alterations at Selected Tetranucleotide repeats (EMAST) is a genetic signature found in up to 60% of colorectal cancers (CRCs) that is caused by somatic dysfunction of the DNA mismatch repair (MMR) protein hMSH3. We have previously shown in vitro that recognition of 5-fluorouracil (5-FU) within DNA and subsequent cytotoxicity was most effective when both hMutSα (hMSH2-hMSH6 heterodimer) and hMutSβ (hMSH2-hMSH3 heterodimer) MMR complexes were present, compared to hMutSα > hMutSβ alone...
2015: PloS One
Sabine Venderbosch, Shannon van Lent-van Vliet, Anton F J de Haan, Marjolijn J Ligtenberg, Monique Goossens, Cornelis J A Punt, Miriam Koopman, Iris D Nagtegaal
PURPOSE: To determine the frequency and prognostic value of elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) in metastatic colorectal cancer (mCRC) patients in relation to microsatellite instability (MSI) status and MSH3 protein expression. MATERIAL AND METHODS: The frequency of EMAST was evaluated in mCRC patients with MSI tumors and microsatellite stable (MSS) tumors. A literature overview was performed to compare the frequency of EMAST in our study with existing data...
2015: PloS One
John M Carethers, Minoru Koi, Stephanie S Tseng-Rogenski
DNA mismatch repair (MMR) function is critical for correcting errors coincident with polymerase-driven DNA replication, and its proteins are frequent targets for inactivation (germline or somatic), generating a hypermutable tumor that drives cancer progression. The biomarker for defective DNA MMR is microsatellite instability-high (MSI-H), observed in ~15% of colorectal cancers, and defined by mono- and dinucleotide microsatellite frameshift mutations. MSI-H is highly correlated with loss of MMR protein expression, is commonly diploid, is often located in the right side of the colon, prognosticates good patient outcome, and predicts poor efficacy with 5-fluorouracil treatment...
March 31, 2015: Genes
Emma L Friesen, Deborah G Theodoros, Trevor G Russell
BACKGROUND: Usability is an emerging domain of outcomes measurement in assistive technology provision. Currently, no questionnaires exist to test the usability of mobile shower commodes (MSCs) used by adults with spinal cord injury (SCI). OBJECTIVE: To describe the development, construction, and initial content validation of an electronic questionnaire to test mobile shower commode usability for this population. METHODS: The questionnaire was constructed using a mixed-methods approach in 5 phases: determining user preferences for the questionnaire's format, developing an item bank of usability indicators from the literature and judgement of experts, constructing a preliminary questionnaire, assessing content validity with a panel of experts, and constructing the final questionnaire...
2015: Topics in Spinal Cord Injury Rehabilitation
Stephanie S Tseng-Rogenski, Yasushi Hamaya, Daniel Y Choi, John M Carethers
BACKGROUND & AIMS: Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is the most common DNA mismatch repair defect in colorectal cancers, observed in approximately 60% of specimens. This acquired genotype correlates with metastasis and poor outcomes for patients, and is associated with intra-epithelial inflammation and heterogeneous nuclear levels of the mismatch repair protein hMSH3. Inflammation and accompanying oxidative stress can cause hMSH3 to change its intracellular location, but little is known about the source of oxidative stress in cancer cells...
March 2015: Gastroenterology
M M C Watson, M Berg, K Søreide
Elevated microsatellite alterations at selected tetranucleotides (EMAST), a variation of microsatellite instability (MSI), has been reported in a variety of malignancies (e.g., neoplasias of the lung, head and neck, colorectal region, skin, urinary tract and reproductive organs). EMAST is more prominent at organ sites with potential external exposure to carcinogens (e.g., head, neck, lung, urinary bladder and colon), although the specific molecular mechanisms leading to EMAST remain elusive. Because it is often associated with advanced stages of malignancy, EMAST may be a consequence of rapid cell proliferation and increased mutagenesis...
August 26, 2014: British Journal of Cancer
Hiromasa Arai, Koji Okudela, Hisashi Oshiro, Noriko Komitsu, Hideaki Mitsui, Teppei Nishii, Masahiro Tsuboi, Akinori Nozawa, Yasuharu Noishiki, Kenichi Ohashi, Kenji Inui, Munetaka Masuda
The present study evaluated the potential clinicopathologic significance of elevated microsatellite alteration at selected tetra-nucleotide (EMAST) in non-small cell lung cancer (NSCLC). Sixty-five NSCLCs (19 squamous cell carcinomas, 39 adenocarcinomas, one adenosquamous cell carcinoma, and 6 large cell carcinomas) were examined for EMAST in the ten selected tetra-nucleotide markers. Traditional microsatellite instability (MSI) in the five mono- or di-nucleotide markers of the Bethesda panel was also examined, and compared with EMAST...
2013: International Journal of Clinical and Experimental Pathology
Stephanie S Tseng-Rogenski, Heekyung Chung, Maike B Wilk, Shuai Zhang, Moriya Iwaizumi, John M Carethers
BACKGROUND: Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is a genetic signature observed in 60% of sporadic colorectal cancers (CRCs). Unlike microsatellite unstable CRCs where hypermethylation of the DNA mismatch repair (MMR) gene hMLH1's promoter is causal, the precise cause of EMAST is not clearly defined but points towards hMSH3 deficiency. AIM: To examine if hMSH3 deficiency causes EMAST, and to explore mechanisms for its deficiency...
2012: PloS One
Christoph Campregher, Gerald Schmid, Franziska Ferk, Siegfried Knasmüller, Vineeta Khare, Benedikt Kortüm, Kyle Dammann, Michaela Lang, Theresa Scharl, Andreas Spittler, Andres I Roig, Jerry W Shay, Christopher Gerner, Christoph Gasche
BACKGROUND/AIM: Elevated microsatellite instability at selected tetranucleotide repeats (EMAST) is a genetic signature in certain cases of sporadic colorectal cancer and has been linked to MSH3-deficiency. It is currently controversial whether EMAST is associated with oncogenic properties in humans, specifically as cancer development in Msh3-deficient mice is not enhanced. However, a mutator phenotype is different between species as the genetic positions of repetitive sequences are not conserved...
2012: PloS One
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