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somatic mutations

Philip H Iffland, Peter B Crino
PURPOSE OF REVIEW: There has been rapid progress in defining novel causative gene variants responsible for a large spectrum of human epilepsy syndromes and subtypes. Of particular interest is the discovery that somatic mutations, for example, noninherited mutations occurring in neuroglial progenitor cells during embryonic brain development, are highly linked to malformations of cortical development (MCD) such as focal cortical dysplasia (FCD) type II and hemimegalencephaly. RECENT FINDINGS: Somatic gene variants have been identified in genes encoding regulatory proteins within the mechanistic target of rapamycin (mTOR) signaling cascade and have thus comprised the group classified as mTORopathies...
February 11, 2019: Current Opinion in Neurology
Samantha X Y Wang, Bing M Zhang, Heather A Wakelee, Michael Z Koontz, MingGui Pan, Maximilian Diehn, Christian A Kunder, Joel W Neal
The mesenchymal-to-epithelial transition (MET) gene is altered and becomes a driver mutation in up to 5% of non-small-cell lung cancer (NSCLC). We report our institutional experience treating patients with MET exon 14 skipping (METex14) mutations, including responses to the MET inhibitors crizotinib and cabozantinib. We identified cases of NSCLC with METex14 mutations using an institutionally developed or commercial next-generation sequencing assay. We assessed patient and disease characteristics by retrospective chart review...
February 12, 2019: Anti-cancer Drugs
Ping Luo, Yulian Ding, Xiujuan Lei, Fang-Xiang Wu
With the advances in high-throughput technologies, millions of somatic mutations have been reported in the past decade. Identifying driver genes with oncogenic mutations from these data is a critical and challenging problem. Many computational methods have been proposed to predict driver genes. Among them, machine learning-based methods usually train a classifier with representations that concatenate various types of features extracted from different kinds of data. Although successful, simply concatenating different types of features may not be the best way to fuse these data...
2019: Frontiers in Genetics
Nicole A McNeer, John Philip, Heather Geiger, Rhonda E Ries, Vincent-Philippe Lavallée, Michael Walsh, Minita Shah, Kanika Arora, Anne-Katrin Emde, Nicolas Robine, Todd A Alonzo, E Anders Kolb, Alan S Gamis, Malcolm Smith, Daniela Se Gerhard, Jaime Guidry-Auvil, Soheil Meshinchi, Alex Kentsis
Acute myeloid leukemias (AML) are characterized by mutations of tumor suppressor and oncogenes, involving distinct genes in adults and children. While certain mutations have been associated with the increased risk of AML relapse, the genomic landscape of primary chemotherapy-resistant AML is not well defined. As part of the TARGET initiative, we performed whole-genome DNA and transcriptome RNA and miRNA sequencing analysis of pediatric AML with failure of induction chemotherapy. We identified at least three genetic groups of patients with induction failure, including those with NUP98 rearrangements, somatic mutations of WT1 in the absence of apparent NUP98 mutations, and additional recurrent variants including those in KMT2C and MLLT10...
February 13, 2019: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Marcela Nunes Rosa, Adriane Feijó Evangelista, Letícia Ferro Leal, Cristina Mendes De Oliveira, Viviane Aline Oliveira Silva, Carla Carolina Munari, Fernanda Franco Munari, Graziela De Macêdo Matsushita, Ricardo Dos Reis, Carlos Eduardo Andrade, Cristiano de Pádua Souza, Rui Manuel Reis
Cervical cancer is the fourth most common cancer in women. Although cure rates are high for early stage disease, clinical outcomes for advanced, metastatic, or recurrent disease remain poor. To change this panorama, a deeper understanding of cervical cancer biology and novel study models are needed. Immortalized human cancer cell lines such as HeLa constitute crucial scientific tools, but there are few other cervical cancer cell lines available, limiting our understanding of a disease known for its molecular heterogeneity...
February 13, 2019: Scientific Reports
Guillermo Garcia-Manero, Yasmin Abaza, Koichi Takahashi, Bruno C Medeiros, Martha Arellano, Samer K Khaled, Mrinal Patnaik, Olatoyosi Odenike, Hamid Sayar, Mohan Tummala, Prapti Patel, Lori Maness-Harris, Robert Stuart, Elie Traer, Kasra Karamlou, Abdulraheem Yacoub, Richard Ghalie, Ruben Giorgino, Ehab Atallah
Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity in acute myeloid leukemia (AML), has shown synergistic antitumor activity when combined with azacitidine. This single-group, multicenter phase 2 study assessed the safety and efficacy of pracinostat combined with azacitidine in patients who were at least 65 years old with newly diagnosed AML and who were ineligible for standard induction chemotherapy. Patients received pracinostat 60 mg/d, 3 d/wk, for 3 consecutive weeks, plus azacitidine 75 mg/m2 daily for 7 days in a 28-day cycle...
February 26, 2019: Blood Advances
Claire Oget, Charlotte Allain, David Portes, Gilles Foucras, Alessandra Stella, Jean-Michel Astruc, Julien Sarry, Gwenola Tosser-Klopp, Rachel Rupp
BACKGROUND: The identification of loci associated with resistance to mastitis or of the causative mutations may be helpful in breeding programs for dairy sheep as it is for cattle worldwide. Seven genomic regions that control milk somatic cell counts, an indirect indicator of udder infection, have already been identified in sheep (Spanish Churra, French Lacaune and Italian Sardinian-Lacaune backcross populations). In this study, we used a 960 custom-designed ovine single nucleotide polymorphism (SNP) chip in Lacaune and Manech Tête Rousse dairy sheep to validate these seven genomic regions associated with mastitis...
February 13, 2019: Genetics, Selection, Evolution: GSE
Igor B Rogozin, Abiel Roche-Lima, Artem G Lada, Frida Belinky, Ivan A Sidorenko, Galina V Glazko, Vladimir N Babenko, David N Cooper, Youri I Pavlov
Cancer genomes accumulate nucleotide sequence variations that number in the tens of thousands per genome. A prominent fraction of these mutations is thought to arise as a consequence of the off-target activity of DNA/RNA editing cytosine deaminases. These enzymes, collectively called activation induced deaminase (AID)/APOBECs, deaminate cytosines located within defined DNA sequence contexts. The resulting changes of the original C:G pair in these contexts (mutational signatures) provide indirect evidence for the participation of specific cytosine deaminases in a given cancer type...
February 12, 2019: Cancers
Peter Valent, Wolfgang Kern, Gregor Hoermann, Jelena D Milosevic Feenstra, Karl Sotlar, Michael Pfeilstöcker, Ulrich Germing, Wolfgang R Sperr, Andreas Reiter, Dominik Wolf, Michel Arock, Torsten Haferlach, Hans-Peter Horny
The development of leukemia is a step-wise process that is associated with molecular diversification and clonal selection of neoplastic stem cells. Depending on the number and combinations of lesions, one or more sub-clones expand/s after a variable latency period. Initial stages may develop early in life or later in adulthood and include premalignant (indolent) stages and the malignant phase, defined by an acute leukemia. We recently proposed a cancer model in which the earliest somatic lesions are often age-related early mutations detectable in apparently healthy individuals and where additional oncogenic mutations will lead to the development of an overt neoplasm that is usually a preleukemic condition such as a myelodysplastic syndrome...
February 12, 2019: International Journal of Molecular Sciences
Bernhard Schermer, Thomas Benzing
The emergence of genome editing technologies can be regarded as one of the most groundbreaking revolutions in the history of science. Modern genome editing allows the introduction of precise mutations into the genome of virtually all cells and organisms without leaving any additional trace. Undoubtedly, genome editing with CRISPR/Cas9, often casually referred to as "genetic scissors", will revolutionize medical research and development. However, at the same time it creates a great need for ethical considerations as it might hold risks for both people and the environment that cannot yet be fully assessed...
February 2019: Deutsche Medizinische Wochenschrift
Takashi Yoshida, Tatsuya Yamaguchi, Shinya Maekawa, Shinichi Takano, Toru Kuno, Keisuke Tanaka, Fumihiko Iwamoto, Yuya Tsukui, Shoji Kobayashi, Yukiko Asakawa, Hiroko Shindo, Mitsuharu Fukasawa, Yasuhiro Nakayama, Taisuke Inoue, Tomoyoshi Uetake, Masahiko Ohtaka, Tadashi Sato, Kunio Mochizuki, Nobuyuki Enomoto
BACKGROUND AND AIMS: The recent advancement of next-generation sequencing (NGS) has enabled the identification of cancer-related somatic aberrations in advanced gastric cancer. However, these remain unclear in early gastric cancers, especially in intramucosal gastric cancers. PATIENTS AND METHODS: Thirty-one well-differentiated (tub1) intramucosal gastric cancers obtained by endoscopic submucosal dissection (ESD) from 29 patients were analyzed. After precise collection of tumors and non-tumors from formalin-fixed paraffin-embedded tissues using laser-captured microdissection (LCM), target sequencing analysis of 50 cancer-related genes was performed using an Ion-Proton sequencer...
February 11, 2019: Gastric Cancer
Libin Yan, Yangjun Zhang, Beichen Ding, Hui Zhou, Weimin Yao, Hua Xu
Background: Histone lysine methyltransferases (HMTs), a category of enzymes, play essential roles in regulating transcription, cellular differentiation, and chromatin construction. The genomic landscape and clinical significance of HMTs in renal cell carcinoma (RCC) remain uncovered. Methods: We conducted an integrative analysis of 50 HMTs in RCC and discovered the internal relations among copy number alterations (CNAs), expressive abundance, mutations, and clinical outcome...
2019: PeerJ
Helen M McRae, Alexandra L Garnham, Yifang Hu, Matthew T Witkowski, Mark A Corbett, Mathew P Dixon, Rose E May, Bilal N Sheikh, William Chiang, Andrew J Kueh, Tan A Nguyen, Kevin Man, Renee Gloury, Brandon J Aubrey, Antonia Policheni, Ladina Di Rago, Warren S Alexander, Daniel H D Gray, Andreas Strasser, Edwin D Hawkins, Stephen Wilcox, Jozef Gécz, Axel Kallies, Matthew P McCormack, Gordon K Smyth, Anne K Voss, Tim Thomas
Somatically acquired mutations in PHF6 ( plant homeodomain finger 6 ) frequently occur in hematopoietic malignancies and often coincide with ectopic expression of TLX3 However, there is yet no functional evidence to demonstrate whether these mutations contribute to tumorigenesis. Similarly, the role of PHF6 in hematopoiesis is unknown. We report here that Phf6 deletion in mice resulted in a reduced number of hematopoietic stem cells, an increased number of hematopoietic progenitor cells, and an increased proportion of cycling stem and progenitor cells...
February 12, 2019: Blood
Sonia Coni, Laura Di Magno, Silvia Maria Serrao, Yuta Kanamori, Enzo Agostinelli, Gianluca Canettieri
Hedgehog (Hh) signaling is a critical developmental regulator and its aberrant activation,due to somatic or germline mutations of genes encoding pathway components, causes Basal CellCarcinoma (BCC) and medulloblastoma (MB). A growing effort has been devoted at theidentification of druggable vulnerabilities of the Hedgehog signaling, leading to the identificationof various compounds with variable efficacy and/or safety. Emerging evidence shows that anaberrant polyamine metabolism is a hallmark of Hh-dependent tumors and that itspharmacological inhibition elicits relevant therapeutic effects in clinical or preclinical models ofBCC and MB...
February 11, 2019: Cells
Maria Florencia Martinez, Maria Vanesa Romano, Alfredo Pedro Martinez, Abel González, Carolina Muchnik, Fernando Miguel Stengel, Luis Daniel Mazzuoccolo, Pablo Javier Azurmendi
Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCC), mainly caused by PTCH1 gene mutations. Our current study aimed to establish (1) PTCH1 germinal and somatic mutational status, (2) component and Hedgehog (HH) pathway targets gene expression patterns, and (3) profile variations according to the genetic background in BCC and normal surrounding skin (NSS). We collected 23 blood and 20 BCC patient samples and analyzed the PTCH1 gene using bidirectional sequencing and multiplex ligation-dependent probe amplification...
February 11, 2019: Cells
Frédéric Anglès, Darren M Hutt, William E Balch
Understanding the role of the epigenome in protein misfolding diseases remains a challenge in light of genetic diversity found in the world-wide population revealed by human genome sequencing efforts and the highly variable response of the disease population to therapeutics. An ever-growing body of evidence has shown that histone deacetylase (HDAC) inhibitors (HDACi) can have significant benefit in correcting protein misfolding diseases that occur in response to both familial and somatic mutation. Cystic fibrosis (CF) is a familial autosomal recessive disease, caused by genetic diversity in the CF transmembrane conductance regulator (CFTR) gene, a cAMP-dependent chloride channel expressed at the apical plasma membrane of epithelial cells in multiple tissues...
February 7, 2019: Human Molecular Genetics
Antonio Marcondes Lerario, Kazutaka Nanba, Amy R Blinder, Sachiko Suematsu, Masao Omura, Tetsuo Nishikawa, Thomas J Giordano, William Rainey, Tobias Else
Somatic variants in genes that regulate intracellular ion homeostasis have been identified in aldosterone-producing adenomas (APA). Although the mechanisms leading to an increased aldosterone production in APA cells has been well studied, the molecular events that cause cell proliferation and tumor formation are poorly understood. In the present study, we have performed whole exome sequencing (WES) to characterize the landscape of somatic alterations in a homogeneous series of APA with pathogenic KCNJ5 variants...
February 1, 2019: Endocrine-related Cancer
Kazuyoshi Yanagihara, Takanori Kubo, Keichiro Mihara, Takeshi Kuwata, Atsushi Ochiai, Toshio Seyama, Hiroshi Yokozaki
OBJECTIVES: Peritoneal dissemination (PD) is an important cause of morbidity and mortality among patients with pancreatic ductal adenocarcinoma (PDAC). We sought to develop and characterized a novel PD mouse model by using a previously established PDAC cell line TCC-Pan2. METHODS: TCC-Pan2 cell line was characterized for growth rate, tumor markers, histology, and somatic mutations. TCC-Pan2 cells were implanted orthotopically to produce PD. TCC-Pan2 cells from these metastatic foci were expanded in vitro and then implanted orthotopically in mice...
February 8, 2019: Pancreas
Garima Tanwar, Rituraj Purohit
Aurora A is a mitotic serine/threonine kinase protein that is a proposed target of the first-line anticancer drug design. It has been found to be overexpressed in many human cancer cells, including hematological, breast, and colorectal. Here, we focus on a particular somatic mutant S155R of Aurora kinase A protein, whose activity decreases because of loss of interaction with a TPX2 protein that results in ectopic expression of the Aurora kinase A protein, which contributes chromosome instability, centrosome amplification, and oncogenic transformation...
February 11, 2019: Journal of Cellular Biochemistry
Dane Cheasley, Na Li, Simone M Rowley, Kenneth Elder, G Bruce Mann, Sherene Loi, Peter Savas, David L Goode, Tanjina Kader, Magnus Zethoven, Tim Semple, Stephen B Fox, Jia-Min Pang, David Byrne, Lisa Devereux, Carolyn Nickson, Pietro Procopio, Grant Lee, Siobhan Hughes, Hugo Saunders, Kenji M Fujihara, Keilly Kuykhoven, Jacquie Connaughton, Paul A James, Kylie L Gorringe, Ian G Campbell
Breast cancer (BC) diagnosed after a negative mammogram but prior to the next screening episode is termed an "interval breast cancer" (IBC). Understanding the molecular differences between IBC and screen-detected breast cancers (SDBC) could improve mammographic screening and management options. Therefore, we assessed both germline and somatic genomic aberrations in a prospective cohort. Utilizing the Lifepool cohort of >54,000 women attending mammographic screening programs, 930 BC cases with screening status were identified (726 SDBC and 204 IBC)...
February 11, 2019: Journal of Pathology
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