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Microsatellite instability

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https://www.readbyqxmd.com/read/29334683/epigenetic-silencing-of-the-mlh1-promoter-in-relation-to-the-development-of-gastric-cancer-and-its-use-as-a-biomarker-for-patients-with-microsatellite-instability-a-systematic-analysis
#1
Guimei Hu, Lijun Qin, Xinjun Zhang, Guoliang Ye, Tao Huang
BACKGROUND/AIMS: Human mutL homolog 1 (MLH1) promoter methylation was reported in gastric cancer (GC). This study determined the clinicopathological, prognostic, and diagnostic effects of MLH1 promoter methylation in GC. METHODS: The combined odds ratio (OR) or hazard ratio (HR) and their corresponding 95% confidence intervals (95% CI) were calculated. The pooled sensitivity, specificity, and area under the curve (AUC) were analyzed. RESULTS: A total of 4654 GC patients and 3669 non-malignant controls were identified in this systematic analysis...
January 15, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29329588/accuracy-of-four-mononucleotide-repeat-markers-for-the-identification-of-dna-mismatch-repair-deficiency-in-solid-tumors
#2
Yuko Takehara, Takeshi Nagasaka, Akihiro Nyuya, Tomoko Haruma, Junko Haraga, Yoshiko Mori, Keiichiro Nakamura, Toshiyoshi Fujiwara, C Richard Boland, Ajay Goel
BACKGROUND: To screen tumors with microsatellite instability (MSI) arising due to DNA mismatch repair deficiency (dMMR), a panel of five quasi-monomorphic mononucleotide-repeat markers amplified in a multiplex PCR (Pentaplex) are commonly used. In spite of its several strengths, the pentaplex assay is not robust at detecting the loss of MSH6-deficiency (dMSH6). In order to overcome this challenge, we designed this study to develop and optimize a panel of four quasi-monomorphic mononucleotide-repeat markers (Tetraplex) for identifying solid tumors with dMMR, especially dMSH6...
January 12, 2018: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29329208/advances-in-molecular-profiling-and-categorisation-of-pancreatic-adenocarcinoma-and-the-implications-for-therapy
#3
REVIEW
Rille Pihlak, Jamie M J Weaver, Juan W Valle, Mairéad G McNamara
Pancreatic ductal adenocarcinoma (PDAC) continues to be a disease with poor outcomes and short-lived treatment responses. New information is emerging from genome sequencing identifying potential subgroups based on somatic and germline mutations. A variety of different mutations and mutational signatures have been identified; the driver mutation in around 93% of PDAC is KRAS, with other recorded alterations being SMAD4 and CDKN2A. Mutations in the deoxyribonucleic acid (DNA) damage repair pathway have also been investigated in PDAC and multiple clinical trials are ongoing with DNA-damaging agents...
January 12, 2018: Cancers
https://www.readbyqxmd.com/read/29327160/differences-in-histological-features-and-pd-l1-expression-between-sporadic-microsatellite-instability-and-lynch-syndrome-associated-disease-in-japanese-patients-with-colorectal-cancer
#4
Rin Yamada, Tatsuro Yamaguchi, Takeru Iijima, Rika Wakaume, Misato Takao, Koichi Koizumi, Tsunekazu Hishima, Shin-Ichiro Horiguchi
BACKGROUND: The field of immunotherapy has recently focused on cancers with microsatellite instability (MSI). These cancers include both Lynch-syndrome-associated tumors, which are caused by mismatch repair (MMR) germline mutations, and sporadic MSI tumors, which are mainly attributed to MLH1 promoter methylation. The present study aimed to clarify differences in the histological and PD-L1 expression profiles between these two types of MSI cancers in Japanese patients. METHODS: Among 908 cases of colorectal cancer treated via surgical resection from 2008 to 2014, we identified 64 MSI cancers, including 36 sporadic MSI and 28 Lynch-syndrome-associated cancers, using a BRAF V600E mutation analysis and MLH1 methylation analysis...
January 11, 2018: International Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29320758/polymerase-epsilon-mutations-and-concomitant-%C3%AE-2-microglobulin-mutations-in-cancer
#5
Ioannis A Voutsadakis
Mutations in the exonuclease domain of polymerase epsilon (POLE), an enzyme of DNA synthesis, are involved in a newly described syndrome of colorectal polyposis and cancer, and have been associated with a high mutation burden with or without microsatellite instability (MSI) phenotype. The exonuclease domain of POLE executes a proofreading function that decreases the mutation rate during DNA replication by an estimated of one to two orders. The high mutation burden resulting from its loss of function could create a load of neo-antigens that would put the neoplastic cells in severe disadvantage of an immune attack if properly presented to the immune system...
January 7, 2018: Gene
https://www.readbyqxmd.com/read/29315503/the-clinical-implications-of-immunogenomics-in-colorectal-cancer-a-path-for-precision-medicine
#6
REVIEW
Jenny M Riley, Ashley W Cross, Chrystal M Paulos, Mark P Rubinstein, John Wrangle, E Ramsay Camp
Colorectal cancer (CRC) remains the third most common malignancy and the second-leading cause of cancer-related deaths in the United States. Large multi-omic databases, such as The Cancer Genome Atlas and the International Colorectal Cancer Subtyping Consortium, have identified distinct molecular subtypes related to anatomy. The identification of genomic alterations in CRC is now critical because of the recent success and US Food and Drug Administration approval of pembrolizumab and nivolumab for microsatellite-instable tumors...
January 9, 2018: Cancer
https://www.readbyqxmd.com/read/29306042/associations-between-molecular-classifications-of-colorectal-cancer-and-patient-survival-a-systematic-review
#7
REVIEW
Elizabeth Alwers, Min Jia, Matthias Kloor, Hendrik Bläker, Hermann Brenner, Michael Hoffmeister
BACKGROUND & AIMS: Colorectal cancer (CRC) is a heterogeneous disease with different mechanisms of pathogenesis. Classification systems have been proposed based on molecular features of tumors, but none are used in clinical practice. We performed a systematic review of studies on the associations between molecular classifications of CRC and patient survival. METHODS: We searched the PubMed, Embase, Cochrane, and Web of Science databases for combinations of terms related to CRC, molecular markers, subtype classifications, and survival (overall survival, disease-specific survival, disease-free survival)...
January 3, 2018: Clinical Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/29305587/consensus-molecular-subtypes-of-colorectal-cancer-are-recapitulated-in-in-vitro-and-in-vivo-models
#8
Janneke F Linnekamp, Sander R van Hooff, Pramudita R Prasetyanti, Raju Kandimalla, Joyce Y Buikhuisen, Evelyn Fessler, Prashanthi Ramesh, Kelly A S T Lee, Grehor G W Bochove, Johan H de Jong, Kate Cameron, Ronald van Leersum, Hans M Rodermond, Marek Franitza, Peter Nürnberg, Laura R Mangiapane, Xin Wang, Hans Clevers, Louis Vermeulen, Giorgio Stassi, Jan Paul Medema
Colorectal cancer (CRC) is a highly heterogeneous disease both from a molecular and clinical perspective. Several distinct molecular entities, such as microsatellite instability (MSI), have been defined that make up biologically distinct subgroups with their own clinical course. Recent data indicated that CRC can be best segregated into four groups called consensus molecular subtypes (CMS1-4), each of which has a unique biology and gene expression pattern. In order to develop improved, subtype-specific therapies and to gain insight into the molecular wiring and origin of these subtypes, reliable models are needed...
January 5, 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29303062/the-role-of-microsatellite-instability-in-positive-margin-gastric-cancer-patients
#9
Karol Polom, Daniele Marrelli, Elizabeth C Smyth, Costantino Voglino, Giandomenico Roviello, Valeria Pascale, Julian Varas, Carla Vindigni, Franco Roviello
PURPOSE: A positive resection margin (RM+) is acknowledged as a poor prognostic factor after gastrectomy. Microsatellite instability (MSI-H) gastric cancer has been identified as a subgroup of gastric cancer that may be associated with an improved prognosis. The aim of the study was an analysis of MSI status on patients with margin involvement after gastrectomy and examination of the association between MSI, margin status, and survival outcomes. METHODS: From a large prospectively annotated surgical database we collected clinicopathological and survival data on patients who had undergone a potentially curative resection for gastric cancer...
January 1, 2018: Surgical Innovation
https://www.readbyqxmd.com/read/29302048/diagnostic-challenges-in-a-child-with-early-onset-desmoplastic-medulloblastoma-and-homozygous-variants-in-msh2-and-msh6
#10
Julia Taeubner, Katharina Wimmer, Martine Muleris, Olivier Lascols, Chrystelle Colas, Christine Fauth, Triantafyllia Brozou, Joerg Felsberg, Jasmin Riemer, Michael Gombert, Sebastian Ginzel, Jessica I Hoell, Arndt Borkhardt, Michaela Kuhlen
Constitutional mismatch repair deficiency (CMMRD) is an autosomal recessively inherited childhood cancer susceptibility syndrome caused by biallelic germline mutations in one of the mismatch repair (MMR) genes. The spectrum of CMMRD-associated tumours is very broad and many CMMRD patients additionally display signposting non-neoplastic features, most frequently café-au-lait macules and other pigmentation alterations. We report on a 13-month-old girl suspected of having CMMRD due to a desmoplastic medulloblastoma and a striking skin pigmentation that included multiple café-au-lait macules, hypopigmented areas and Mongolian spots...
January 4, 2018: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/29301504/nine-primary-malignant-neoplasms-involving-the-esophagus-stomach-colon-rectum-prostate-and-external-ear-canal-without-microsatellite-instability-a-case-report
#11
Keiichi Arakawa, Keisuke Hata, Yoko Yamamoto, Takeshi Nishikawa, Toshiaki Tanaka, Tomomichi Kiyomatsu, Kazushige Kawai, Hiroaki Nozawa, Masafumi Yoshida, Hiroshi Fukuhara, Mitsuhiro Fujishiro, Teppei Morikawa, Tatsuya Yamasoba, Kazuhiko Koike, Masashi Fukayama, Toshiaki Watanabe
BACKGROUND: Although cases of multiple primary malignant neoplasms are increasing, reports of more than three or four primary metachronous malignant neoplasms are extremely rare. Moreover, very few publications have provided a genetic mutational analysis or have evaluated risk factors associated with such neoplasms. We present an extremely rare case of nine primary malignant lesions in a man who was successfully treated. We also report on microsatellite stability status, analyze risk factors, and discuss the relevant literature...
January 4, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29296220/sequencing-of-lynch-syndrome-tumors-reveals-the-importance-of-epigenetic-alterations
#12
Noora Porkka, Satu Valo, Taina T Nieminen, Alisa Olkinuora, Satu Mäki-Nevala, Samuli Eldfors, Päivi Peltomäki
Genomic instability and epigenetic aberrations are important classifiers of human tumors, yet, their interrelations are poorly understood. We used Lynch syndrome (LS) to address such relationships. Forty-five tumors (11 colorectal adenomas, 18 colorectal carcinomas, and 16 ovarian carcinomas) were profiled for CpG Island Methylator Phenotype (CIMP) and somatic mutations. All tumors showed high-degree microsatellite instability. Panel sequencing of 578 cancer-relevant genes revealed the average number of 1433, 1124, and 657 non-synonymous somatic mutations per colorectal adenoma, colorectal carcinoma, and ovarian carcinoma, respectively...
December 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/29296022/targeting-immune-checkpoints-potentiates-immunoediting-and-changes-the-dynamics-of-tumor-evolution
#13
Mirjana Efremova, Dietmar Rieder, Victoria Klepsch, Pornpimol Charoentong, Francesca Finotello, Hubert Hackl, Natascha Hermann-Kleiter, Martin Löwer, Gottfried Baier, Anne Krogsdam, Zlatko Trajanoski
The cancer immunoediting hypothesis postulates a dual role of the immune system: protecting the host by eliminating tumor cells, and shaping the tumor by editing its genome. Here, we elucidate the impact of evolutionary and immune-related forces on editing the tumor in a mouse model for hypermutated and microsatellite-instable colorectal cancer. Analyses of wild-type and immunodeficient RAG1 knockout mice transplanted with MC38 cells reveal that upregulation of checkpoint molecules and infiltration by Tregs are the major tumor escape mechanisms...
January 2, 2018: Nature Communications
https://www.readbyqxmd.com/read/29287922/gynaecological-neoplasms-in-common-familial-syndromes-lynch-and-hboc
#14
REVIEW
Carla Bartosch, Blaise Clarke, Tjalling Bosse
Recognising hereditary predisposition in a cancer patient has implications both for the patient and the patient's kindred. For the latter, cascade germline testing can reassure those not-at-risk family members while carriers can be enrolled in cancer screening and prevention programs that are medically effective and economically sustainable for health care systems. Furthermore, in many of these syndromes, ramifications of molecular phenotypes are increasing, and it is now emerging that, in addition, they convey prognostic and predictive information...
December 26, 2017: Pathology
https://www.readbyqxmd.com/read/29284010/safety-and-antitumor-activity-of-the-anti-pd-1-antibody-pembrolizumab-in-patients-with-advanced-colorectal-carcinoma
#15
Bert H O'Neil, John M Wallmark, David Lorente, Elena Elez, Judith Raimbourg, Carlos Gomez-Roca, Samuel Ejadi, Sarina A Piha-Paul, Mark N Stein, Albiruni R Abdul Razak, Katia Dotti, Armando Santoro, Roger B Cohen, Marlena Gould, Sanatan Saraf, Karen Stein, Sae-Won Han
BACKGROUND: Colorectal cancers (CRCs) expressing programmed death ligand 1 (PD-L1) have poor prognosis. In the multicohort KEYNOTE-028 trial, the anti-PD-1 antibody pembrolizumab was evaluated in 20 PD-L1-positive advanced solid tumors. Herein, we report results for the advanced CRC cohort. METHODS: Patients with advanced, treatment-resistant PD-L1-positive carcinoma of the colon or rectum were enrolled, regardless of microsatellite instability (MSI) status. Pembrolizumab 10 mg/kg was administered every 2 weeks for up to 2 years or until disease progression/unacceptable toxicity...
2017: PloS One
https://www.readbyqxmd.com/read/29277635/a-novel-and-reliable-method-to-detect-microsatellite-instability-in-colorectal-cancer-by-next-generation-sequencing
#16
Lizhen Zhu, Yanqin Huang, Xuefeng Fang, Chenglin Liu, Wanglong Deng, Chenhan Zhong, Jinghong Xu, Dong Xu, Ying Yuan
Two types of molecular tests have been established to assess the deficiency of DNA mismatch repair (MMR) system: microsatellite instability (MSI) and immunohistochemical (IHC) analysis. We have developed a reliable method to analyze the MSI status by next-generation sequencing (NGS) based on read count distribution. A total of 91 patients with primary colorectal cancer were recruited. These patients included 54 cases with the loss of expression of any MMR protein in IHC suggesting deficient MMR (dMMR), and 37 cases of colorectal cancer with staining of all four MMR proteins in IHC, suggesting proficient MMR (pMMR) in postoperative sample...
December 19, 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/29242316/colorectal-cancer-consensus-molecular-subtypes-translated-to-preclinical-models-uncover-potentially-targetable-cancer-cell-dependencies
#17
Anita Sveen, Jarle Bruun, Peter W Eide, Ina A Eilertsen, Lorena Ramirez, Astrid Murumägi, Mariliina A Arjama, Stine A Danielsen, Kushtrim Kryeziu, Elena Elez, Josep Tabernero, Justin Guinney, Hector G Palmer, Arild Nesbakken, Olli Kallioniemi, Rodrigo Dienstmann, Ragnhild A Lothe
PURPOSE: Response to standard oncological treatment is limited in colorectal cancer (CRC). The gene expression-based consensus molecular subtypes (CMS) provide a new paradigm for stratified treatment and drug repurposing, however, drug discovery is currently limited by the lack of translation of CMS to preclinical models. EXPERIMENTAL DESIGN: We analyzed CMS in primary CRCs, cell lines and patient-derived xenografts (PDXs). For classification of preclinical models, we developed an optimized classifier enriched for cancer cell-intrinsic gene expression signals, and performed high-throughput in vitro drug screening (n=459 drugs) to analyze subtype-specific drug sensitivities...
December 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29241727/simple-classifiers-for-molecular-subtypes-of-colorectal-cancer
#18
Woo Gyeong Kim, Joo Yeon Kim, Do Youn Park
BACKGROUND AND STUDY AIM: Colorectal cancer (CRC) is a heterogeneous disease entity with a diverse biological pathogenesis. This study aims to validate the two studies published in 2013 which established a separate CRC molecular subtype classification by utilizing a rapidly accessible miniclassifier, and verify a simplified version thereof. PATIENTS AND METHODS: Participants diagnosed with CRC (n = 568) were subtyped in three classifications for characteristic, and prognostic purposes...
December 11, 2017: Arab Journal of Gastroenterology: the Official Publication of the Pan-Arab Association of Gastroenterology
https://www.readbyqxmd.com/read/29239195/-immunotherapy-of-colorectal-and-anal-carcinoma
#19
J Tomášek, I Kiss
BACKGROUND: The lower part of the digestive tract includes the large intestine, rectum and anus. Treatment algorithms of cancers in these localities have significant differences in both early and advanced stages. The vast majority of metastatic cases are incurable. A few years ago, it was generally accepted that gastrointestinal tumors are poorly immunogenic and modern immunotherapy would not work in gastrointestinal cancers. The breakthrough has become the recognition of the mismatch repair system (MMR) that affects the microsatellite instability (MSI) and its role in the development of colorectal carcinoma (CRC)...
2017: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
https://www.readbyqxmd.com/read/29233671/endoscopic-detection-rate-of-sessile-serrated-lesions-in-lynch-syndrome-patients-is-comparable-to-an-age-and-gender-matched-control-population-case-control-study-with-expert-pathology-review
#20
Jasper L A Vleugels, Husna Sahin, Yark Hazewinkel, Lianne Koens, Jose G van den Berg, Monique E van Leerdam, Evelien Dekker
BACKGROUND: Carcinogenesis in Lynch syndrome involves fast progression of adenomas to colorectal cancer (CRC) due to microsatellite instability. The role of sessile serrated lesions (SSLs) and the serrated neoplasia pathway in these patients is unknown. The aim of this matched case-control study was to compare endoscopic detection rates and distribution of SSLs in Lynch syndrome patients to a matched control population. METHODS: We collected data of Lynch syndrome patients with a proven germline mutation who underwent colonoscopy between January 2011 and April 2016 in 2 tertiary referral hospitals...
December 9, 2017: Gastrointestinal Endoscopy
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