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https://www.readbyqxmd.com/read/28748347/molecular-basis-of-pediatric-brain-tumors
#1
REVIEW
Alexia Klonou, Christina Piperi, Antonios N Gargalionis, Athanasios G Papavassiliou
Brain tumors emerge as the second commonest type of pediatric solid tumors following hematologic malignancies. Genomic profiling of low- and high-grade gliomas, ependymomas and medulloblastomas has revealed chromosomal abnormalities and specific gene mutations which have been associated with aberrant activation of crucial signal transduction pathways, including mitogen-activated protein kinase, mammalian target of rapamycin and retinoblastoma tumor suppressor signaling. Furthermore, pediatric high-grade gliomas are associated with chromatin remodeling defects and somatic histone gene mutations that affect prognosis...
July 26, 2017: Neuromolecular Medicine
https://www.readbyqxmd.com/read/28747773/deciphering-mechanisms-of-acquired-t790m-mutation-after-egfr-inhibitors-for-nsclc-by-computational-simulations
#2
Bin Zou, Victor H F Lee, Lijiang Chen, Lichun Ma, Debby D Wang, Hong Yan
Metastatic non-small-cell lung cancer (NSCLC) with activating EGFR mutations responds very well to first and second generation tyrosine-kinase inhibitors (TKI) including gefitinib, erlotinib and afatinib. Unfortunately, drug resistance will eventually develop and about half of the cases are secondary to the emergence of acquired T790M somatic mutation. In this work, we prospectively recruited 68 patients with metastatic EGFR-mutated NSCLC who have developed progressive disease after first-line TKI with or without subsequent TKI and/or other systemic therapy...
July 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28747543/mutation-profile-based-methods-for-understanding-selection-forces-in-cancer-somatic-mutations-a-comparative-analysis
#3
Zhan Zhou, Yangyun Zou, Gangbiao Liu, Jingqi Zhou, Jingcheng Wu, Shimin Zhao, Zhixi Su, Xun Gu
Human genes exhibit different effects on fitness in cancer and normal cells. Here, we present an evolutionary approach to measure the selection pressure on human genes, using the well-known ratio of the nonsynonymous to synonymous substitution rate in both cancer genomes (CN/CS) and normal populations (pN/pS). A new mutation-profile-based method that adopts sample-specific mutation rate profiles instead of conventional substitution models was developed. We found that cancer-specific selection pressure is quite different from the selection pressure at the species and population levels...
July 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28747530/sequence-intrinsic-somatic-mutation-mechanisms-contribute-to-affinity-maturation-of-vrc01-class-hiv-1-broadly-neutralizing-antibodies
#4
Joyce K Hwang, Chong Wang, Zhou Du, Robin M Meyers, Thomas B Kepler, Donna Neuberg, Peter D Kwong, John R Mascola, M Gordon Joyce, Mattia Bonsignori, Barton F Haynes, Leng-Siew Yeap, Frederick W Alt
Variable regions of Ig chains provide the antigen recognition portion of B-cell receptors and derivative antibodies. Ig heavy-chain variable region exons are assembled developmentally from V, D, J gene segments. Each variable region contains three antigen-contacting complementarity-determining regions (CDRs), with CDR1 and CDR2 encoded by the V segment and CDR3 encoded by the V(D)J junction region. Antigen-stimulated germinal center (GC) B cells undergo somatic hypermutation (SHM) of V(D)J exons followed by selection for SHMs that increase antigen-binding affinity...
July 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28747472/disentangling-sources-of-variation-in-ssu-rdna-sequences-from-single-cell-analyses-of-ciliates-impact-of-copy-number-variation-and-experimental-error
#5
Chundi Wang, Tengteng Zhang, Yurui Wang, Laura A Katz, Feng Gao, Weibo Song
Small subunit ribosomal DNA (SSU rDNA) is widely used for phylogenetic inference, barcoding and other taxonomy-based analyses. Recent studies indicate that SSU rDNA of ciliates may have a high level of sequence variation within a single cell, which impacts the interpretation of rDNA-based surveys. However, sequence variation can come from a variety of sources including experimental errors, especially the mutations generated by DNA polymerase in PCR. In the present study, we explore the impact of four DNA polymerases on sequence variation and find that low-fidelity polymerases exaggerate the estimates of single-cell sequence variation...
July 26, 2017: Proceedings. Biological Sciences
https://www.readbyqxmd.com/read/28747387/molecular-characteristics-of-the-kcnj5-mutated-aldosterone-producing-adenomas
#6
Masanori Murakami, Takanobu Yoshimoto, Kazuhiko Nakabayashi, Yujiro Nakano, Takahiro Fukaishi, Kyoichiro Tsuchiya, Isao Minami, Ryotaro Bouchi, Kohji Okamura, Yasuhisa Fujii, Koshi Hashimoto, Ken-Ichiro Hata, Kazunori Kihara, Yoshihiro Ogawa
The pathophysiology of aldosterone-producing adenomas (APAs) has been investigated via genetic approaches and the pathogenic significance of a series of somatic mutations, including KCNJ5, has been uncovered. However, how the mutational status of an APA is associated with its molecular characteristics, including its transcriptome and methylome, has not been fully understood. This study was undertaken to explore the molecular characteristics of APAs, specifically focusing on APAs with KCNJ5 mutations as opposed to those without KCNJ5 mutations, by comparing their transcriptome and methylome status...
July 26, 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28746916/a-missense-mutation-in-tcn2-is-associated-with-decreased-risk-for-congenital-heart-defects-and-may-increase-cellular-uptake-of-vitamin-b12-via-megalin
#7
Peiqiang Li, Lijuan Huang, Yufang Zheng, Xuedong Pan, Rui Peng, Yueming Jiang, Richard H Finnell, Haijie Li, Bin Qiao, Hong-Yan Wang
Deregulation of folate and vitamin B12 (VB12) metabolism contributes to the risk of congenital heart defects (CHDs). Transcobalamin (TCN2) is essential for transporting VB12 from blood to cells as TCN2-bound VB12 (holo-TC) is the only form for somatic cellular uptake. In this study, we performed an association study between common polymorphisms in 46 one carbon metabolism genes and CHD in 412 CHDs and 213 controls. Only two significant association signals in coding regions were identified: FTCD c.1470C>T & TCN2 c...
July 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28746783/cd73-expression-identifies-a-subset-of-igm-antigen-experienced-cells-with-memory-attributes-that-is-t-cell-and-cd40-signaling-dependent
#8
Lucas D'Souza, Sneh Lata Gupta, Vineeta Bal, Satyajit Rath, Anna George
B cell memory was long characterized as isotype-switched, somatically mutated and germinal center (GC)-derived. However, it is now clear that the memory pool is a complex mixture that includes unswitched and unmutated cells. Further, expression of CD73, CD80 and CD273 has allowed the categorization of B cell memory into multiple subsets, with combinatorial expression of the markers increasing with GC progression, isotype-switching and acquisition of somatic mutations. We have extended these findings to determine whether these markers can be used to identify IgM memory phenotypically as arising from T-dependent versus T-independent responses...
July 26, 2017: Immunology
https://www.readbyqxmd.com/read/28744013/the-t-cell-leukemia-associated-ribosomal-rpl10-r98s-mutation-enhances-jak-stat-signaling
#9
T Girardi, S Vereecke, S O Sulima, Y Khan, L Fancello, J W Briggs, C Schwab, J O de Beeck, J Verbeeck, J Royaert, E Geerdens, C Vicente, S Bornschein, C J Harrison, J P Meijerink, J Cools, J D Dinman, K R Kampen, K De Keersmaecker
Several somatic ribosome defects have recently been discovered in cancer, yet their oncogenic mechanisms remain poorly understood. Here we investigated the pathogenic role of the recurrent R98S mutation in ribosomal protein L10 (RPL10-R98S) found in T-ALL. The JAK-STAT signaling pathway is a critical controller of cellular proliferation and survival. A proteome screen revealed overexpression of several Jak-Stat signaling proteins in engineered RPL10-R98S mouse lymphoid cells, which we confirmed in hematopoietic cells from transgenic Rpl10-R98S mice and T-ALL xenograft samples...
July 24, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28743916/analysis-of-somatic-mutations-across-the-kinome-reveals-loss-of-function-mutations-in-multiple-cancer-types
#10
Runjun D Kumar, Ron Bose
In this study we use somatic cancer mutations to identify important functional residues within sets of related genes. We focus on protein kinases, a superfamily of phosphotransferases that share homologous sequences and structural motifs and have many connections to cancer. We develop several statistical tests for identifying Significantly Mutated Positions (SMPs), which are positions in an alignment with mutations that show signs of selection. We apply our methods to 21,917 mutations that map to the alignment of human kinases and identify 23 SMPs...
July 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28743717/analysis-of-the-recovery-of-cd247-expression-in-a-pid-patient-insights-into-the-spontaneous-repair-of-defective-genes
#11
Alfonso Blázquez-Moreno, Adriana Pérez-Portilla, Miriam Agúndez-Llaca, Daniela Dukovska, Mar Valés-Gómez, Cigdem Aydogmus, Aydan Ikinciogullari, José R Regueiro, Hugh T Reyburn
Mutations in T-cell antigen receptor (TCR) subunits genes cause rare immunodeficiency diseases characterized by impaired expression of the TCR at the cell surface and selective T lymphopenia. Here detailed analyses of spontaneously arising somatic mutations that recover CD247, and so TCR expression, in a newly identified CD247 deficient patient are described. The recovery of CD247 expression in some patient T cells was associated with both reversion of the inactivating mutation and a variant with a compensating mutation that could reconstitute TCR expression, but not as efficiently as wild-type CD247...
July 25, 2017: Blood
https://www.readbyqxmd.com/read/28742274/whole-exome-sequencing-identified-genetic-variations-in-chinese-hemangioblastoma-patients
#12
Dexuan Ma, Jingyun Yang, Ying Wang, Xiang Huang, Guhong Du, Liangfu Zhou
Hemangioblastomas (HBs) are uncommon tumors characterized by the presence of inactivating alterations in the von Hippel-Lindau (VHL) gene in inherited cases and by infrequent somatic mutation in sporadic entities. We performed whole exome sequencing on 11 HB patients to further elucidate the genetics of HBs. A total of 270 somatic variations in 219 genes, of which there were 86 mutations in 67 genes, were found in sporadic HBs, and 184 mutations were found in 154 genes in familial HBs. C: G>T: A and T: A>C: G mutations are relatively common in most HB patients...
July 25, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28742097/mrtadfinder-a-network-modularity-based-approach-to-identify-topologically-associating-domains-in-multiple-resolutions
#13
Koon-Kiu Yan, Shaoke Lou, Mark Gerstein
Genome-wide proximity ligation based assays such as Hi-C have revealed that eukaryotic genomes are organized into structural units called topologically associating domains (TADs). From a visual examination of the chromosomal contact map, however, it is clear that the organization of the domains is not simple or obvious. Instead, TADs exhibit various length scales and, in many cases, a nested arrangement. Here, by exploiting the resemblance between TADs in a chromosomal contact map and densely connected modules in a network, we formulate TAD identification as a network optimization problem and propose an algorithm, MrTADFinder, to identify TADs from intra-chromosomal contact maps...
July 24, 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28741795/a-novel-molecular-mechanism-of-cellular-transformation-via-a-mutant-molecular-chaperone-in-myeloproliferative-neoplasms
#14
REVIEW
Marito Araki, Norio Komatsu
Deregulation of the cytokine-receptor signaling pathway plays a significant role in tumorigenesis. Such deregulation is frequently caused by alterations in the genes involved in the signaling pathway. At the end of 2013, recurrent somatic mutations in the calreticulin (CALR) gene that encodes a molecular chaperone were identified in a subset of patients with Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs). This review focuses on the role of CALR mutations in the oncogenic transformations observed in MPNs...
July 25, 2017: Cancer Science
https://www.readbyqxmd.com/read/28741662/molecular-breakdown-a-comprehensive-view-of-anaplastic-lymphoma-kinase-alk-rearranged-non-small-cell-lung-cancer
#15
Ka-Won Noh, Mi-Sook Lee, Seung Eun Lee, Ji-Young Song, Hyun-Tae Shin, Yu Jin Kim, Doo Yi Oh, Kyungsoo Jung, Minjung Sung, Mingi Kim, Sungbin An, Joungho Han, Young Mog Shim, Jae Ill Zo, Jhingook Kim, Woong-Yang Park, Se-Hoon Lee, Yoon-La Choi
Most anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancers (NSCLCs) show good clinical response to ALK inhibitors. However, some ALK-rearranged NSCLC patients show various primary responses with unknown reasons. Previous studies focused on the clinical aspects of ALK fusions in small cohorts, or were conducted in vitro and/or in vivo to investigate the function of ALK. One of the suggested theories describes how Echinoderm microtubule-associated protein-like 4 (EML4)-ALK variants play a role towards different sensitivities in ALK inhibitors...
July 25, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28737476/a-high-fidelity-method-for-genomic-sequencing-of-single-somatic-cells-reveals-a-very-high-mutational-burden
#16
Jan Vijg, Xiao Dong, Lei Zhang
Postzygotic mutations in somatic cells lead to genome mosaicism and can be the cause of cancer, possibly other human diseases and aging. Somatic mutations are difficult to detect in bulk tissue samples. Here, we review the available assays for measuring somatic mutations, with a focus on recent single-cell, whole genome sequencing methods. Impact statement Somatic mutations cause cancer, possibly other diseases and aging. Yet, very little is known about the frequency of such mutations in vivo, their distribution across the genome, and their possible functional consequences other than cancer...
July 2017: Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28736556/ras-signaling-inhibitors-attenuate-disease-in-adjuvant-induced-arthritis-via-targeting-pathogenic-antigen-specific-th17-type-cells
#17
Morad Zayoud, Victoria Marcu-Malina, Einav Vax, Jasmine Jacob-Hirsch, Galit Elad-Sfadia, Iris Barshack, Yoel Kloog, Itamar Goldstein
The Ras family of GTPases plays an important role in signaling nodes downstream to T cell receptor and CD28 activation, potentially lowering the threshold for T-cell receptor activation by autoantigens. Somatic mutation in NRAS or KRAS may cause a rare autoimmune disorder coupled with abnormal expansion of lymphocytes. T cells from rheumatoid arthritis (RA) patients show excessive activation of Ras/MEK/ERK pathway. The small molecule farnesylthiosalicylic acid (FTS) interferes with the interaction between Ras GTPases and their prenyl-binding chaperones to inhibit proper plasma membrane localization...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28735482/design-and-application-of-multiplex-pcr-seq-for-the-detection-of-somatic-mutations-associated-with-myeloid-malignancies
#18
Naomi Park, George Vassiliou
Targeted sequencing, in which only a selected set of genomic loci are sequenced, enables a much higher coverage of each target than what is obtained using whole genome or exome sequencing. Multiplex PCR offers a simple and affordable technique for specific capture of target regions and can be easily adapted to generate next-generation sequencing (NGS)-ready amplicons. Here we describe a multiplex PCR (MxPCR) approach for capturing 13 leukemia-associated mutation hotspots followed by MiSeq sequencing that enables robust detection of mutations with a variant allele fraction (VAF) as low as 0...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28734984/germline-versus-somatic-mutations-in-genetic-atrial-fibrillation
#19
EDITORIAL
Mark McCauley, Dawood Darbar
No abstract text is available yet for this article.
July 19, 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/28734944/triple-negative-breast-cancer-next-generation-sequencing-for-target-identification
#20
REVIEW
Jonathan D Marotti, Francine B de Abreu, Wendy A Wells, Gregory J Tsongalis
Our ability to now study disease at the most fundamental molecular level has led to a reclassification of human cancers into numerous subtypes that vary in disease progression and response to therapy. Like most solid tumors, breast cancer is a heterogeneous disease with considerable variation in histological and biological features. Triple negative breast cancer (TNBC) is a subtype of breast cancer in which estrogen receptor and progesterone receptor are not expressed, and human epidermal growth factor receptor 2 is not amplified or overexpressed...
July 19, 2017: American Journal of Pathology
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