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https://www.readbyqxmd.com/read/28611940/involvement-of-chromatin-remodeling-genes-and-the-rho-gtpases-rhob-and-cdc42-in-ovarian-clear-cell-carcinoma
#1
Nicolai Skovbjerg Arildsen, Jenny-Maria Jönsson, Katarina Bartuma, Anna Ebbesson, Sofia Westbom-Fremer, Anna Måsbäck, Susanne Malander, Mef Nilbert, Ingrid A Hedenfalk
OBJECTIVE: Ovarian clear cell carcinomas (OCCCs) constitute a rare ovarian cancer subtype with distinct clinical features, but may nonetheless be difficult to distinguish morphologically from other subtypes. There is limited knowledge of genetic events driving OCCC tumorigenesis beyond ARID1A, which is reportedly mutated in 30-50% of OCCCs. We aimed to further characterize OCCCs by combined global transcriptional profiling and targeted deep sequencing of a panel of well-established cancer genes...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28608921/whole-exome-sequencing-reveals-critical-genes-underlying-metastasis-in-esophageal-squamous-cell-carcinoma
#2
Wei Dai, Josephine Mun Yee Ko, Sheyne Sta Ana Choi, Zhouyou Yu, Luwen Ning, Hong Zheng, Vinod Gopalan, Kin Tak Chan, Nikki Pui-Yue Lee, Kwok Wah Chan, Simon Ying-Kit Law, Alfred King-Yin Lam, Maria Li Lung
Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers due to a high frequency of metastasis. However, little is known about the genomic landscape of metastatic ESCC. To identify the genetic alterations that underlie ESCC metastasis, whole-exome sequencing (WES) was performed for 41 primary tumors and 15 lymph nodes (LNs) with metastatic ESCC. Eleven cases included matched primary tumors, synchronous LN metastases and non-neoplastic mucosa. Approximately 50-76% of the mutations identified in primary tumors appeared in the synchronous LN metastases...
June 13, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28601352/comprehensive-genomic-characterization-of-upper-tract-urothelial-carcinoma
#3
Tyler J Moss, Yuan Qi, Liu Xi, Bo Peng, Tae-Beom Kim, Nader E Ezzedine, Maribel E Mosqueda, Charles C Guo, Bogdan A Czerniak, Michael Ittmann, David A Wheeler, Seth P Lerner, Surena F Matin
BACKGROUND: Upper urinary tract urothelial cancer (UTUC) may have unique etiologic and genomic factors compared to bladder cancer. OBJECTIVE: To characterize the genomic landscape of UTUC and provide insights into its biology using comprehensive integrated genomic analyses. DESIGN, SETTING, AND PARTICIPANTS: We collected 31 untreated snap-frozen UTUC samples from two institutions and carried out whole-exome sequencing (WES) of DNA, RNA sequencing (RNAseq), and protein analysis...
June 7, 2017: European Urology
https://www.readbyqxmd.com/read/28590022/on-the-significance-of-craniosynostosis-in-a-case-of-kabuki-syndrome-with-a-concomitant-kmt2d-mutation-and-3-2%C3%A2-mbp-de-novo-10q22-3q23-1-deletion
#4
Alexandra Topa, Lena Samuelsson, Lovisa Lovmar, Göran Stenman, Lars Kölby
Craniosynostosis has rarely been described in patients with Kabuki syndrome. We report here a boy with facial asymmetry due to combined premature synostosis of the right coronal and sagittal sutures as well as several symptoms reminiscent of Kabuki syndrome (KS). Our case supports previous observations and suggests that craniosynostosis is a part of the KS phenotype. The uniqueness of our case is the sporadic co-occurrence of two genetic disorders, that is, a de novo frameshift variant in the KMT2D gene and a de novo 3...
June 7, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28582546/the-contribution-of-homology-arms-to-nuclease-assisted-genome-engineering
#5
Oliver Baker, Sarah Tsurkan, Jun Fu, Barbara Klink, Andreas Rump, Mandy Obst, Andrea Kranz, Evelin Schröck, Konstantinos Anastassiadis, A Francis Stewart
Designer nucleases like CRISPR/Cas9 enable fluent site-directed damage or small mutations in many genomes. Strategies for their use to achieve more complex tasks like regional exchanges for gene humanization or the establishment of conditional alleles are still emerging. To optimize Cas9-assisted targeting, we measured the relationship between targeting frequency and homology length in targeting constructs using a hypoxanthine-guanine phosphoribosyl-transferase assay in mouse embryonic stem cells. Targeting frequency with supercoiled plasmids improved steeply up to 2 kb total homology and continued to increase with even longer homology arms, thereby implying that Cas9-assisted targeting efficiencies can be improved using homology arms of 1 kb or greater...
June 5, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28552796/epigenetic-modifications-in-poorly-differentiated-and-anaplastic-thyroid-cancer
#6
REVIEW
Thanyawat Sasanakietkul, Timothy D Murtha, Mahsa Javid, Reju Korah, Tobias Carling
Well-differentiated thyroid cancer accounts for the majority of endocrine malignancies and, in general, has an excellent prognosis. In contrast, the less common poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are two of the most aggressive human malignancies. Recently, there has been an increased focus on the epigenetic alterations underlying thyroid carcinogenesis, including those that drive PDTC and ATC. Dysregulated epigenetic candidates identified include the Aurora group, KMT2D, PTEN, RASSF1A, multiple non-coding RNAs (ncRNA), and the SWI/SNF chromatin-remodeling complex...
May 25, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28506208/a-strategy-to-apply-quantitative-epistasis-analysis-on-developmental-traits
#7
Marta K Labocha, Wang Yuan, Boanerges Aleman-Meza, Weiwei Zhong
BACKGROUND: Genetic interactions are keys to understand complex traits and evolution. Epistasis analysis is an effective method to map genetic interactions. Large-scale quantitative epistasis analysis has been well established for single cells. However, there is a substantial lack of such studies in multicellular organisms and their complex phenotypes such as development. Here we present a method to extend quantitative epistasis analysis to developmental traits. METHODS: In the nematode Caenorhabditis elegans, we applied RNA interference on mutants to inactivate two genes, used an imaging system to quantitatively measure phenotypes, and developed a set of statistical methods to extract genetic interactions from phenotypic measurement...
May 15, 2017: BMC Genetics
https://www.readbyqxmd.com/read/28486103/tackling-resistance-to-pi3k-inhibition-by-targeting-the-epigenome
#8
Shany Koren, Mohamed Bentires-Alj
Phosphoinositide-3-kinase (PI3K) pathway inhibitors have emerged as promising therapeutic agents for estrogen receptor (ERα)-positive breast cancers. However, incipient resistance limits the clinical benefit. Toska and colleagues identified that the epigenetic regulator KMT2D enhances ERα activity in BYL719-treated PIK3CA mutant breast cancer, leading to a rationale for targeting the epigenome and PI3K signaling.
May 8, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28483418/mll3-and-mll4-facilitate-enhancer-rna-synthesis-and-transcription-from-promoters-independently-of-h3k4-monomethylation
#9
Kristel M Dorighi, Tomek Swigut, Telmo Henriques, Natarajan V Bhanu, Benjamin S Scruggs, Nataliya Nady, Christopher D Still, Benjamin A Garcia, Karen Adelman, Joanna Wysocka
Monomethylation of histone H3 at lysine 4 (H3K4me1) and acetylation of histone H3 at lysine 27 (H3K27ac) are correlated with transcriptionally engaged enhancer elements, but the functional impact of these modifications on enhancer activity is not well understood. Here we used CRISPR/Cas9 genome editing to separate catalytic activity-dependent and independent functions of Mll3 (Kmt2c) and Mll4 (Kmt2d, Mll2), the major enhancer H3K4 monomethyltransferases. Loss of H3K4me1 from enhancers in Mll3/4 catalytically deficient cells causes partial reduction of H3K27ac, but has surprisingly minor effects on transcription from either enhancers or promoters...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28475860/charge-and-kabuki-syndromes-gene-specific-dna-methylation-signatures-identify-epigenetic-mechanisms-linking-these-clinically-overlapping-conditions
#10
Darci T Butcher, Cheryl Cytrynbaum, Andrei L Turinsky, Michelle T Siu, Michal Inbar-Feigenberg, Roberto Mendoza-Londono, David Chitayat, Susan Walker, Jerry Machado, Oana Caluseriu, Lucie Dupuis, Daria Grafodatskaya, William Reardon, Brigitte Gilbert-Dussardier, Alain Verloes, Frederic Bilan, Jeff M Milunsky, Raveen Basran, Blake Papsin, Tracy L Stockley, Stephen W Scherer, Sanaa Choufani, Michael Brudno, Rosanna Weksberg
Epigenetic dysregulation has emerged as a recurring mechanism in the etiology of neurodevelopmental disorders. Two such disorders, CHARGE and Kabuki syndromes, result from loss of function mutations in chromodomain helicase DNA-binding protein 7 (CHD7(LOF)) and lysine (K) methyltransferase 2D (KMT2D(LOF)), respectively. Although these two syndromes are clinically distinct, there is significant phenotypic overlap. We therefore expected that epigenetically driven developmental pathways regulated by CHD7 and KMT2D would overlap and that DNA methylation (DNAm) alterations downstream of the mutations in these genes would identify common target genes, elucidating a mechanistic link between these two conditions, as well as specific target genes for each disorder...
May 4, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28471124/multiplex-genomic-test-of-mutation-and-fusion-genes-in-small-biopsy-specimen-of-lung-cancer
#11
Fumihiro Oshita, Rika Kasajima, Yohei Miyagi
We evaluated multiple oncogenic mutations and fusion genes in small specimen obtained by bronchoscopy. Eight patients with lung cancer were recruited, 3 small cell lung cancer, 3 non-small cell lung cancer, 1 adenocarcinoma and 1 squamous cell carcinoma. A median value of extracted RNA and DNA amounts from specimen was 1573 ng (range 367.5 to 8900) and 6700 ng (range 550 to 68000 ng), respectively. We applied amplicon sequencing panels that cover exon regions of 41 genes related to lung tumorigenesis as well as total 61 major variants of ALK, ROS, RET or NTRK1 fusion transcripts...
July 2016: Journal of Experimental Therapeutics & Oncology
https://www.readbyqxmd.com/read/28440294/next-generation-dna-sequencing-identifies-novel-gene-variants-and-pathways-involved-in-specific-language-impairment
#12
Xiaowei Sylvia Chen, Rose H Reader, Alexander Hoischen, Joris A Veltman, Nuala H Simpson, Clyde Francks, Dianne F Newbury, Simon E Fisher
A significant proportion of children have unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. Developmental language disorders are highly heritable with substantial societal impact. Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. We performed whole-exome sequencing of 43 unrelated probands affected by severe specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to shed new light on aetiology...
April 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28404210/characteristics-of-epilepsy-in-patients-with-kabuki-syndrome-with-kmt2d-mutations
#13
Naoko Kurahashi, Noriko Miyake, Seiji Mizuno, Eriko Koshimizu, Hirokazu Kurahashi, Keitaro Yamada, Jun Natsume, Yusuke Aoki, Miho Nakamura, Hiroko Taniai, Yuki Maki, Chihiro Abe-Hatano, Naomichi Matsumoto, Koichi Maruyama
BACKGROUND: The characteristics of epilepsy in patients with Kabuki syndrome with KMT2D mutations (KABUK1) have not yet been well documented. This is the first review to explore this. MATERIALS & METHODS: We enrolled 14 patients with KABUK1, whose median age was 13.6years (range=4.1-21.3years). Their medical records from October 1981 to May 2016 were retrospectively analyzed. RESULTS: Epilepsy was present in 5 (36%) patients. Four of these patients presented with nonsense mutations and one with missense mutations...
April 9, 2017: Brain & Development
https://www.readbyqxmd.com/read/28389907/targeted-next-generation-sequencing-identified-novel-mutations-in-triple-negative-myeloproliferative-neoplasms
#14
Yu-Cheng Chang, Huan-Chau Lin, Yi-Hao Chiang, Caleb Gon-Shen Chen, Ling Huang, Wei-Ting Wang, Chun-Chia Cheng, Johnson Lin, Yi-Fang Chang, Ming-Chih Chang, Ruey-Kuen Hsieh, Shu-Jen Chen, Ken-Hong Lim, Yuan-Yeh Kuo
Mutations in JAK2, MPL and CALR genes have been identified in the majority of myeloproliferative neoplasm (MPN) patients, and patients negative for these three mutations are the so-called triple-negative (TN) MPN. In this study, we examined the mutational profiles of 16 triple-negative MPN patients including 7 essential thrombocythemia (ET), 1 primary myelofibrosis and 8 polycythemia vera (PV). Targeted next-generation sequencing was performed using the ACTOnco Comprehensive Cancer Panel (Ion AmpliSeq Comprehensive Cancer Panel, Life Technologies) to target all coding exons of 409 cancer-related genes...
May 2017: Medical Oncology
https://www.readbyqxmd.com/read/28375985/distinct-functions-of-histone-h3-lysine-4-methyltransferases-in-normal-and-malignant-hematopoiesis
#15
Weiwei Yang, Patricia Ernst
PURPOSE OF REVIEW: Histone H3, lysine 4 (H3K4) methylation is one chromatin modification that defines distinct regulatory states of euchromatin. Mammals express six main histone methyltransferase (HMT) enzymes that modify H3K4 by monomethylation, dimethylation or trimethylation. Recent studies examine roles of some of these HMTs and their cofactors in hematopoiesis and leukemia. We discuss these emerging studies together with prior embryonic stem data, revealing how these enzymes function...
July 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28363912/pi3k-signaling-regulates-er-activity-via-kmt2d-in-er-breast-cancer
#16
(no author information available yet)
Targeting PI3Kα enhances KMT2D methyltransferase activity to promote ER-mediated transcription.
May 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28336670/pi3k-pathway-regulates-er-dependent-transcription-in-breast-cancer-through-the-epigenetic-regulator-kmt2d
#17
Eneda Toska, Hatice U Osmanbeyoglu, Pau Castel, Carmen Chan, Ronald C Hendrickson, Moshe Elkabets, Maura N Dickler, Maurizio Scaltriti, Christina S Leslie, Scott A Armstrong, José Baselga
Activating mutations in PIK3CA, the gene encoding phosphoinositide-(3)-kinase α (PI3Kα), are frequently found in estrogen receptor (ER)-positive breast cancer. PI3Kα inhibitors, now in late-stage clinical development, elicit a robust compensatory increase in ER-dependent transcription that limits therapeutic efficacy. We investigated the chromatin-based mechanisms leading to the activation of ER upon PI3Kα inhibition. We found that PI3Kα inhibition mediates an open chromatin state at the ER target loci in breast cancer models and clinical samples...
March 24, 2017: Science
https://www.readbyqxmd.com/read/28329645/frequent-somatic-mutations-of-chromatin-remodeling-genes-in-metastatic-cutaneous-squamous-cell-carcinoma
#18
Amanda Ewart Toland
Exome and targeted sequencing studies have identified potential driver mutations for a variety of tumor types. Cutaneous squamous cell carcinoma (cSCC) is one of the most highly mutated cancers but is typically correlated with high survival rates and low rates of metastasis. Nevertheless, metastatic cSCC is a significant health threat; up to 8800 individuals are estimated to die yearly from this disease. As it is difficult to predict which cSCCs are more likely to metastasize, and because there are no targeted therapies specifically designated for metastatic cSCC, we performed exome and targeted sequencing of 18 metastatic and 10 primary cSCCs to identify mutations with potential therapeutic benefit...
September 15, 2016: Dermatology Online Journal
https://www.readbyqxmd.com/read/28302137/mutations-of-crebbp-and-socs1-are-independent-prognostic-factors-in-diffuse-large-b-cell-lymphoma-mutational-analysis-of-the-sakk-38-07-prospective-clinical-trial-cohort
#19
Darius Juskevicius, David Jucker, Dirk Klingbiel, Christoph Mamot, Stephan Dirnhofer, Alexandar Tzankov
BACKGROUND/PURPOSE: Recently, the mutational background of diffuse large B cell lymphoma (DLBCL) has been revealed, identifying specific genetic events that drive lymphomagenesis. However, the prognostic value of these mutations remains to be determined. Prognostic biomarkers in DLBCL are urgently needed, since the current clinical parameter-based factors (e.g., International Prognostic Index (IPI)) are insufficient, particularly in identifying patients with poor prognosis who might benefit from alternative treatments...
March 17, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28295206/molecular-clinical-and-neuropsychological-study-in-31-patients-with-kabuki-syndrome-and-kmt2d-mutations
#20
N Lehman, A C Mazery, A Visier, C Baumann, D Lachesnais, Y Capri, A Toutain, S Odent, M Mikaty, C Goizet, E Taupiac, M L Jacquemont, E Sanchez, E Schaefer, V Gatinois, L Faivre, D Minot, H Kayirangwa, K-H L Q Sang, N Boddaert, S Bayard, D Lacombe, S Moutton, I Touitou, M Rio, J Amiel, S Lyonnet, D Sanlaville, M C Picot, D Geneviève
Kabuki syndrome (KS-OMIM 147920) is a rare developmental disease characterized by the association of multiple congenital anomalies and intellectual disability. This study aimed to investigate intellectual performance in children with KS and link the performance to several clinical features and molecular data. We recruited 31 children with KMT2D mutations who were 6 to 16 years old. They all completed the Weschler Intelligence Scale for Children, fourth edition. We calculated all indexes: the Full Scale Intellectual Quotient (FSIQ), Verbal Comprehension Index (VCI), Perceptive Reasoning Index (PRI), Processing Speed Index (PSI), and Working Memory Index (WMI)...
March 14, 2017: Clinical Genetics
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