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https://www.readbyqxmd.com/read/28108514/somatic-ephrin-receptor-mutations-are-associated-with-metastasis-in-primary-colorectal-cancer
#1
Lucy Mathot, Snehangshu Kundu, Viktor Ljungström, Jessica Svedlund, Lotte Moens, Tom Adlerteg, Elin Falk-Sörqvist, Verónica Rendo, Claudia Bellomo, Markus Mayrhofer, Carme Cortina, Magnus Sundström, Patrick Micke, Johan Botling, Anders Isaksson, Aristidis Moustakas, Eduard Batlle, Helgi Birgisson, Bengt Glimelius, Mats Nilsson, Tobias Sjöblom
The contribution of somatic mutations to metastasis of colorectal cancers (CRC) is currently unknown. To find mutations involved in the CRC metastatic process, we performed deep mutational analysis of 676 genes in 107 stages II-IV primary CRC, of which half had metastasized. The mutation prevalence in the ephrin (Eph) family of tyrosine kinase receptors was ten-fold higher in primary tumors of metastatic CRC than in non-metastatic cases and preferentially occurred in stage III and IV tumours. Mutational analyses in situ confirmed expression of mutant Eph receptors...
January 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/28107566/recent-advances-in-understanding-clonal-haematopoiesis-in-aplastic-anaemia
#2
REVIEW
Natasha Stanley, Timothy S Olson, Daria V Babushok
Acquired aplastic anaemia (AA) is an immune-mediated bone marrow failure disorder inextricably linked to clonal haematopoiesis. The majority of AA patients have somatic mutations and/or structural chromosomal abnormalities detected as early as at diagnosis. In contrast to other conditions linked to clonal haematopoiesis, the clonal signature of AA reflects its immune pathophysiology. The most common alterations are clonal expansions of cells lacking glycophosphotidylinositol-anchored proteins, loss of human leucocyte antigen alleles, and mutations in BCOR/BCORL1, ASXL1 and DNMT3A...
January 20, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28107452/mice-lacking-hbp1-function-are-viable-and-fertile
#3
Cassy M Spiller, Dagmar Wilhelm, David A Jans, Josephine Bowles, Peter Koopman
Fetal germ cell development is tightly regulated by the somatic cell environment, and is characterised by cell cycle states that differ between XY and XX gonads. In the testis, gonocytes enter G1/G0 arrest from 12.5 days post coitum (dpc) in mice and maintain cell cycle arrest until after birth. Failure to correctly maintain G1/G0 arrest can result in loss of germ cells or, conversely, germ cell tumours. High mobility group box containing transcription factor 1 (HBP1) is a transcription factor that was previously identified in fetal male germ cells at the time of embryonic cell cycle arrest...
2017: PloS One
https://www.readbyqxmd.com/read/28106558/validation-of-suspected-somatic-single-nucleotide-variations-in-the-brain-of-alzheimer-s-disease-patients
#4
Alberto Gomez-Ramos, Angel J Picher, Esther García, Patricia Garrido, Felix Hernandez, Eduardo Soriano, Jesús Avila
Next-generation sequencing techniques and genome-wide association study analyses have provided a huge amount of data, thereby enabling the identification of DNA variations and mutations related to disease pathogenesis. New techniques and software tools have been developed to improve the accuracy and reliability of this identification. Most of these tools have been designed to discover and validate single nucleotide variants (SNVs). However, in addition to germ-line mutations, human tissues bear genomic mosaicism, which implies that somatic events are present only in low percentages of cells within a given tissue, thereby hindering the validation of these variations using standard genetic tools...
January 19, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28104840/tumor-aneuploidy-correlates-with-markers-of-immune-evasion-and-with-reduced-response-to-immunotherapy
#5
Teresa Davoli, Hajime Uno, Eric C Wooten, Stephen J Elledge
Immunotherapies based on immune checkpoint blockade are highly effective in a subset of patients. An ongoing challenge is the identification of biomarkers that predict which patients will benefit from these therapies. Aneuploidy, also known as somatic copy number alterations (SCNAs), is widespread in cancer and is posited to drive tumorigenesis. Analyzing 12 human cancer types, we find that, for most, highly aneuploid tumors show reduced expression of markers of cytotoxic infiltrating immune cells, especially CD8(+) T cells, and increased expression of cell proliferation markers...
January 20, 2017: Science
https://www.readbyqxmd.com/read/28104796/clonal-hematopoiesis-associated-with-tet2-deficiency-accelerates-atherosclerosis-development-in-mice
#6
José J Fuster, Susan MacLauchlan, María A Zuriaga, Maya N Polackal, Allison C Ostriker, Raja Chakraborty, Chia-Ling Wu, Soichi Sano, Sujatha Muralidharan, Cristina Rius, Jacqueline Vuong, Sophia Jacob, Varsha Muralidhar, Avril A B Robertson, Matthew A Cooper, Vicente Andrés, Karen K Hirschi, Kathleen A Martin, Kenneth Walsh
Human aging is associated with an increased frequency of somatic mutations in hematopoietic cells. Several of these recurrent mutations, including those in the gene encoding the epigenetic modifier enzyme TET2, promote expansion of the mutant blood cells. This "clonal hematopoiesis" correlates with an increased risk of atherosclerotic cardiovascular disease. Here we studied the effects of the expansion of Tet2-mutant cells in atherosclerosis-prone, low-density lipoprotein receptor-deficient (Ldlr-/-) mice. We found that partial bone marrow reconstitution with Tet2-deficient cells was sufficient for their clonal expansion and led to a marked increase in atherosclerotic plaque size...
January 19, 2017: Science
https://www.readbyqxmd.com/read/28104713/multimerization-properties-of-piggymac-a-domesticated-piggybac-transposase-involved-in-programmed-genome-rearrangements
#7
Emeline Dubois, Nathalie Mathy, Vinciane Régnier, Julien Bischerour, Céline Baudry, Raphaëlle Trouslard, Mireille Bétermier
During sexual processes, the ciliate Paramecium eliminates 25-30% of germline DNA from its somatic genome. DNA elimination includes excision of ∼45 000 short, single-copy internal eliminated sequences (IESs) and depends upon PiggyMac (Pgm), a domesticated piggyBac transposase that is essential for DNA cleavage at IES ends. Pgm carries a core transposase region with a putative catalytic domain containing three conserved aspartic acids, and a downstream cysteine-rich (CR) domain. A C-terminal extension of unknown function is predicted to adopt a coiled-coil (CC) structure...
January 18, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28104537/correlation-between-classic-driver-oncogene-mutations-in-egfr-alk-or-ros1-and-22c3-pd-l1-%C3%A2-50-expression-in-lung-adenocarcinoma
#8
Deepa Rangachari, Paul A VanderLaan, Meghan Shea, Xiuning Le, Mark S Huberman, Susumu S Kobayashi, Daniel B Costa
INTRODUCTION: Targeted somatic genomic analysis (EGFR, ALK and ROS1) and PD-L1 tumor proportion score (TPS) by immunohistochemistry (IHC) are used for selection of 1(st)-line therapies in advanced lung cancer; however, the frequency of overlap of these biomarkers in routine clinical practice is poorly reported. METHODS: We retrospectively probed the first 71 lung adenocarcinoma-patient pairs from our institution analyzed for PD-L1 IHC using the clone 22C3 pharmDx kit and evaluated co-occurrence of genomic aberrations along with clinical-pathologic characteristics...
January 16, 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28104464/genetic-defects-in-pi3k%C3%AE-affect-b-cell-differentiation-and-maturation-leading-to-hypogammaglobulineamia-and-recurrent-infections
#9
Marjolein Wentink, Virgil Dalm, Arjan C Lankester, Pauline A van Schouwenburg, Liesbeth Schölvinck, Tomas Kalina, Radana Zachova, Anna Sediva, Annechien Lambeck, Ingrid Pico-Knijnenburg, Jacques J M van Dongen, Malgorzata Pac, Ewa Bernatowska, Martin van Hagen, Gertjan Driessen, Mirjam van der Burg
BACKGROUND: Mutations in PIK3CD and PIK3R1 cause activated PI3K-δ syndrome (APDS) by dysregulation of the PI3K-AKT pathway. METHODS: We studied precursor and peripheral B-cell differentiation and apoptosis via flowcytometry. Furthermore, we performed AKT-phosphorylation assays and somatic hypermutations (SHM) and class switch recombination (CSR) analysis. RESULTS: We identified 13 patients of whom 3 had new mutations in PIK3CD or PIK3R1. Patients had low total B-cell numbers with increased frequencies of transitional B cells and plasmablasts, while the precursor B-cell compartment in bone marrow was relatively normal...
January 16, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28104311/comprehensive-profiling-of-the-androgen-receptor-in-liquid-biopsies-from-castration-resistant-prostate-cancer-reveals-novel-intra-ar-structural-variation-and-splice-variant-expression-patterns
#10
Bram De Laere, Pieter-Jan van Dam, Tom Whitington, Markus Mayrhofer, Emanuela Henao Diaz, Gert Van den Eynden, Jean Vandebroek, Jurgen Del-Favero, Steven Van Laere, Luc Dirix, Henrik Grönberg, Johan Lindberg
BACKGROUND: Expression of the androgen receptor splice variant 7 (AR-V7) is associated with poor response to second-line endocrine therapy in castration-resistant prostate cancer (CRPC). However, a large fraction of nonresponding patients are AR-V7-negative. OBJECTIVE: To investigate if a comprehensive liquid biopsy-based AR profile may improve patient stratification in the context of second-line endocrine therapy. DESIGN, SETTING, AND PARTICIPANTS: Peripheral blood was collected from patients with CRPC (n=30) before initiation of a new line of systemic therapy...
January 16, 2017: European Urology
https://www.readbyqxmd.com/read/28103247/bombyx-mori-p-element-somatic-inhibitor-bmpsi-is-a-key-auxiliary-factor-for-silkworm-male-sex-determination
#11
Jun Xu, Shuqing Chen, Baosheng Zeng, Anthony A James, Anjiang Tan, Yongping Huang
Manipulation of sex determination pathways in insects provides the basis for a wide spectrum of strategies to benefit agriculture and public health. Furthermore, insects display a remarkable diversity in the genetic pathways that lead to sex differentiation. The silkworm, Bombyx mori, has been cultivated by humans as a beneficial insect for over two millennia, and more recently as a model system for studying lepidopteran genetics and development. Previous studies have identified the B. mori Fem piRNA as the primary female determining factor and BmMasc as its downstream target, while the genetic scenario for male sex determination was still unclear...
January 19, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28103133/role-of-choline-in-the-modulation-of-degenerative-processes-in-vivo-and-in-vitro-studies
#12
Tania Merinas-Amo, Inmaculada Tasset-Cuevas, Antonio M Díaz-Carretero, Ángeles Alonso-Moraga, Fernando Calahorro
The purpose of the present study was to examine the nutraceutical potential of choline as an added value to its well-known brain nutrient role. Several toxicity, antitoxicity, genotoxicity, antigenotoxicity, and longevity endpoints were checked in the somatic mutation and recombination test in in vivo Drosophila animal model. Cytotoxicity in human leukemia-60 cell line (HL-60) promyelocytic and NIH3T3 mouse fibroblast cells, proapoptotic DNA fragmentation, comet assay, methylation status, and macroautophagy (MA) activity were tested in in vitro assays...
January 19, 2017: Journal of Medicinal Food
https://www.readbyqxmd.com/read/28102343/individualised-multiplexed-circulating-tumour-dna-assays-for-monitoring-of-tumour-presence-in-patients-after-colorectal-cancer-surgery
#13
Sarah B Ng, Clarinda Chua, Matthew Ng, Anna Gan, Polly Sy Poon, Melissa Teo, Cherylin Fu, Wei Qiang Leow, Kiat Hon Lim, Alexander Chung, Si-Lin Koo, Su Pin Choo, Danliang Ho, Steve Rozen, Patrick Tan, Mark Wong, William F Burkholder, Iain Beehuat Tan
Circulating tumour DNA (ctDNA) has the potential to be a specific biomarker for the monitoring of tumours in patients with colorectal cancer (CRC). Here, our aim was to develop a personalised surveillance strategy to monitor the clinical course of CRC after surgery. We developed patient-specific ctDNA assays based on multiplexed detection of somatic mutations identified from patient primary tumours, and applied them to detect ctDNA in 44 CRC patients, analysing a total of 260 plasma samples. We found that ctDNA detection correlated with clinical events - it is detectable in pre-operative but not post-operative plasma, and also in patients with recurrent CRC...
January 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28102204/the-prevalence-of-ctnnb1-mutations-in-primary-aldosteronism-and-consequences-for-clinical-outcomes
#14
Vin-Cent Wu, Shuo-Meng Wang, Shih-Chieh Jeff Chueh, Shao-Yu Yang, Kuo-How Huang, Yen-Hung Lin, Jian-Jhong Wang, Rory Connolly, Ya-Hui Hu, Celso E Gomez-Sanchez, Kang-Yung Peng, Kwan-Dun Wu
Constitutive activation of the Wnt pathway/β-catenin signaling may be important in aldosterone-producing adenoma (APA). However, significant gaps remain in our understanding of the prevalence and clinical outcomes after adrenalectomy in APA patients harboring CTNNB1 mutations. The molecular expression of CYP11B2 and gonadal receptors in adenomas were also explored. Adenomas from 219 APA patients (95 men; 44.2%; aged 50.5 ± 11.9 years) showed a high rate of somatic mutations (n = 128, 58.4%). The majority of them harbored KCNJ5 mutations (n = 116, 52...
January 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28101802/cold-pcr-technologies-in-the-area-of-personalized-medicine-methodology-and-applications
#15
REVIEW
Florence Mauger, Alexandre How-Kit, Jörg Tost
Somatic mutations bear great promise for use as biomarkers for personalized medicine, but are often present only in low abundance in biological material and are therefore difficult to detect. Many assays for mutation analysis in cancer-related genes (hotspots) have been developed to improve diagnosis, prognosis, prediction of drug resistance, and monitoring of the response to treatment. Two major approaches have been developed: mutation-specific amplification methods and methods that enrich and detect mutations without prior knowledge on the exact location and identity of the mutation...
January 18, 2017: Molecular Diagnosis & Therapy
https://www.readbyqxmd.com/read/28101245/apobec3b-expression-in-human-leptomeninges-and-meningiomas
#16
Mahlon D Johnson, Jay E Reeder, Mary O'Connell
Nucleic acid-editing enzymes of the apolipoprotein B mRNA-editing enzyme (APOBEC) family have been associated with somatic mutation in cancer. However, the role of APOBEC catalytic subunit 3B (APOBEC3B) editing in the pathogenesis of base substitutions in meningiomas is unknown. In the present study, the expression of APOBEC3B was examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analyses in five fetal and one adult human leptomeninges and 38 meningiomas. Genomic DNA was sequenced using the Illumina Tru-Seq Cancer Panel...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28100454/gene-therapy-targeting-oligodendrocytes-provides-therapeutic-benefit-in-a-leukodystrophy-model
#17
Elena Georgiou, Kyriaki Sidiropoulou, Jan Richter, Christos Papaneophytou, Irene Sargiannidou, Alexia Kagiava, Georg von Jonquieres, Christina Christodoulou, Matthias Klugmann, Kleopas A Kleopa
Pelizaeus-Merzbacher-like disease or hypomyelinating leukodystrophy-2 is an autosomal recessively inherited leukodystrophy with childhood onset resulting from mutations in the gene encoding the gap junction protein connexin 47 (Cx47, encoded by GJC2). Cx47 is expressed specifically in oligodendrocytes and is crucial for gap junctional communication throughout the central nervous system. Previous studies confirmed that a cell autonomous loss-of-function mechanism underlies hypomyelinating leukodystrophy-2 and that transgenic oligodendrocyte-specific expression of another connexin, Cx32 (GJB1), can restore gap junctions in oligodendrocytes to achieve correction of the pathology in a disease model...
January 18, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28099595/exome-sequence-analysis-of-kaposiform-hemangioendothelioma-identification-of-putative-driver-mutations
#18
Sho Egashira, Masatoshi Jinnin, Miho Harada, Shinichi Masuguchi, Satoshi Fukushima, Hironobu Ihn
BACKGROUND: Kaposiform hemangioendothelioma is a rare, intermediate, malignant tumor. The tumor's etiology remains unknown and there are no specific treatments. OBJECTIVE: In this study, we performed exome sequencing using DNA from a Kaposiform hemangioendothelioma patient, and found putative candidates for the responsible mutations. METHOD: The genomic DNA for exome sequencing was obtained from the tumor tissue and matched normal tissue from the same individual...
November 2016: Anais Brasileiros de Dermatologia
https://www.readbyqxmd.com/read/28099461/whole-exome-sequencing-of-growing-and-non-growing-cutaneous-neurofibromas-from-a-single-patient-with-neurofibromatosis-type-1
#19
Daniel L Faden, Saurabh Asthana, Tarik Tihan, Joseph DeRisi, Michel Kliot
The growth behaviors of cutaneous neurofibromas in patients with Neurofibromatosis type 1 are highly variable. The role of the germline NF1 mutation, somatic NF1 mutation and mutations at modifying loci, are poorly understood. We performed whole exome sequencing of three growing and three non-growing neurofibromas from a single individual to assess the role of acquired somatic mutations in neurofibroma growth behavior. 1-11 mutations were identified in each sample, including two deleterious NF1 mutations. No trends were present between the types of somatic mutations identified and growth behavior...
2017: PloS One
https://www.readbyqxmd.com/read/28099272/mixed-phenotype-acute-leukemia-current-challenges-in-diagnosis-and-therapy
#20
Ofir Wolach, Richard M Stone
PURPOSE OF REVIEW: Mixed-phenotype acute leukemia (MPAL) is a rare disease that poses many diagnostic and therapeutic challenges. Patients with MPAL are considered to have poor outcomes. The difficulties in classifying this leukemia, the lack of prospectively collected data concerning therapeutic outcomes, and rare incidence result in much uncertainty as to the best approach for patients with MPAL. RECENT FINDINGS: Recent studies demonstrated that most MPALs are associated with cytogenetic abnormalities; genetic sequencing studies disclose a high frequency of somatic mutations in genes encoding epigenetic regulators, tumor suppressors, and transcription factors...
January 17, 2017: Current Opinion in Hematology
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