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María Abáigar, Cristina Robledo, Rocío Benito, Fernando Ramos, María Díez-Campelo, Lourdes Hermosín, Javier Sánchez-Del-Real, Jose M Alonso, Rebeca Cuello, Marta Megido, Juan N Rodríguez, Guillermo Martín-Núñez, Carlos Aguilar, Manuel Vargas, Ana A Martín, Juan L García, Alexander Kohlmann, M Consuelo Del Cañizo, Jesús M Hernández-Rivas
To explore novel genetic abnormalities occurring in myelodysplastic syndromes (MDS) through an integrative study combining array-based comparative genomic hybridization (aCGH) and next-generation sequencing (NGS) in a series of MDS and MDS/myeloproliferative neoplasms (MPN) patients. 301 patients diagnosed with MDS (n = 240) or MDS/MPN (n = 61) were studied at the time of diagnosis. A genome-wide analysis of DNA copy number abnormalities was performed. In addition, a mutational analysis of DNMT3A, TET2, RUNX1, TP53 and BCOR genes was performed by NGS in selected cases...
2016: PloS One
Cody W Lewis, Roy M Golsteyn
We have examined the relationship between checkpoint adaptation (mitosis with damaged DNA) and micronuclei. Micronuclei in cancer cells are linked to genomic change, and may induce chromothripsis (chromosome shattering). We measured the cytotoxicity of the cancer drug cisplatin in M059K (glioma fibroblasts, IC50 15 μM). Nearly 100% of M059K cells were positive for histone γH2AX staining after 48 h treatment with a cytotoxic concentration of cisplatin. The proportion of micronucleated cells, as confirmed by microscopy using DAPI and lamin A/C staining, increased from 24% to 48%, and the total micronuclei in surviving cells accumulated over time...
September 16, 2016: Cell Cycle
Clemens Brunner, Bettina Brunner-Herglotz, Andrea Ziegler, Christian Frech, Gabriele Amann, Ruth Ladenstein, Inge M Ambros, Peter F Ambros
INTRODUCTION: Tumor touch imprints (TTIs) are routinely used for the molecular diagnosis of neuroblastomas by interphase fluorescence in-situ hybridization (I-FISH). However, in order to facilitate a comprehensive, up-to-date molecular diagnosis of neuroblastomas and to identify new markers to refine risk and therapy stratification methods, whole genome approaches are needed. We examined the applicability of an ultra-high density SNP array platform that identifies copy number changes of varying sizes down to a few exons for the detection of genomic changes in tumor DNA extracted from TTIs...
2016: PloS One
Mariona Terradas, Marta Martín, Anna Genescà
Micronuclei (MN) have generally been considered a consequence of DNA damage and, as such, have been used as markers of exposure to genotoxic agents. However, advances in DNA sequencing methods and the development of high-resolution microscopy with which to analyse chromosome dynamics in live cells have been fundamental in building a more refined view of the existing links between DNA damage and micronuclei. Here, we review recent progress indicating that defects of micronuclei affect basic nuclear functions, such as DNA repair and replication, generating massive damage in the chromatin of the MN...
November 2016: Archives of Toxicology
H Y Yamada, G Kumar, Y Zhang, E Rubin, S Lightfoot, W Dai, C V Rao
Mitotic error-mediated chromosome instability (CIN) can lead to aneuploidy, chromothripsis, DNA damage and/or whole chromosome gain/loss. CIN may prompt rapid accumulation of mutations and genomic alterations. Thus, CIN can promote carcinogenesis. This CIN process results from a mutation in certain genes or environmental challenge such as smoking, and is highly prevalent in various cancers, including lung cancer. A better understanding of the effects of CIN on carcinogenesis will lead to novel methods for cancer prevention and treatment...
2016: Oncogenesis
Robert C Rennert, Reid R Hoshide, Jason W Signorelli, Deirdre Amaro, Jayson A Sack, Cameron W Brennan, Clark C Chen
The authors report an unusual case of a widely metastatic glioblastoma. DNA copy number microarray profile of the resected specimen revealed complex rearrangements found throughout chromosome 6, a phenomenon known as chromothripsis. Such chromothripsis pattern was not observed in 50 nonmetastatic glioblastoma specimens analyzed. Analysis of the 1000+ gliomas profiled by The Cancer Genome Atlas (TCGA) data set revealed one case of chromosome 6 chromothripsis resembling the case described here. This TCGA patient died within 6 months of undergoing tumor resection...
July 22, 2016: Journal of Neurosurgery
Eleanor M Gregson, Jan Bornschein, Rebecca C Fitzgerald
Barrett's oesophagus (BE) is the premalignant condition associated with the development of oesophageal adenocarcinoma (OAC). Diagnostically, p53 immunohistochemistry remains the only biomarker recommended clinically to aid histopathological diagnosis. The emerging mutational profile of BE is one of highly heterogeneous lesions at the genomic level with many mutations already occurring in non-dysplastic tissue. As well as point mutations, larger scale copy-number changes appear to have a key role in the progression to OAC and clinically applicable assays for the reliable detection of aneuploidy will be important to incorporate into future clinical management of patients...
August 9, 2016: British Journal of Cancer
Jonathan C Gullett, Iya Y Znoyko, Daynna J Wolff, Cynthia A Schandl
No abstract text is available yet for this article.
June 23, 2016: Clinical Genitourinary Cancer
Nina Habermann, Balca R Mardin, Sergei Yakneen, Jan O Korbel
Characterizing genomic structural variations (SVs) in the human genome remains challenging, and there is a growing interest to understand somatic SVs occurring in cancer, a disease of the genome. A havoc-causing SV process known as chromothripsis scars the genome when localized chromosome shattering and repair occur in a one-off catastrophe. Recent efforts led to the development of a set of conceptual criteria for the inference of chromothripsis events in cancer genomes and to the development of experimental model systems for studying this striking DNA alteration process in vitro...
July 2016: Comptes Rendus Biologies
H Parker, M J J Rose-Zerilli, M Larrayoz, R Clifford, J Edelmann, S Blakemore, J Gibson, J Wang, V Ljungström, T K Wojdacz, T Chaplin, A Roghanian, Z Davis, A Parker, E Tausch, S Ntoufa, S Ramos, P Robbe, R Alsolami, A J Steele, G Packham, A E Rodríguez-Vicente, L Brown, F McNicholl, F Forconi, A Pettitt, P Hillmen, M Dyer, M S Cragg, C Chelala, C C Oakes, R Rosenquist, K Stamatopoulos, S Stilgenbauer, S Knight, A Schuh, D G Oscier, J C Strefford
Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumours including haematological malignancies. Using high-resolution single nucleotide polymorphism (SNP) arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukaemia (CLL) patients. Further validation in two independent cohorts showed that SETD2 deletions were associated with loss of TP53, genomic complexity and chromothripsis...
June 10, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Jen-Chieh Lee, Tzu-Pin Lu, Chun A Changou, Cher-Wei Liang, Hsien-Neng Huang, Alexandra Lauria, Hsuan-Ying Huang, Chin-Yao Lin, Ying-Cheng Chiang, Ben Davidson, Ming-Chieh Lin, Kuan-Ting Kuo
Müllerian adenosarcomas are malignant gynecologic neoplasms. Advanced staging and sarcomatous overgrowth predict poor prognosis. Because the genomic landscape remains poorly understood, we conducted this study to characterize the genomewide copy number variations in adenosarcomas. Sixteen tumors, including eight with and eight without sarcomatous overgrowth, were subjected to a molecular inversion probe array analysis. Copy number variations, particularly losses, were significantly higher in cases with sarcomatous overgrowth...
September 2016: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Javier Del Rey, Mónica Santos, Antonio González-Meneses, Montserrat Milà, Carme Fuster
Complex chromosome rearrangements (CCRs) are unusual structural chromosome alterations found in humans, and to date only a few have been characterized molecularly. New mechanisms, such as chromothripsis, have been proposed to explain the presence of the CCRs in cancer cells and in patients with congenital disorders and/or mental retardation. The aim of the present study was the molecular characterization of a constitutional CCR in a girl with multiple congenital disorders and intellectual disability in order to determine the genotype-phenotype relation and to clarify whether the CCR could have been caused by chromosomal catastrophic events...
2016: Cytogenetic and Genome Research
Albert Stuart Reece, Gary Kenneth Hulse
The recent demonstration that massive scale chromosomal shattering or pulverization can occur abruptly due to errors induced by interference with the microtubule machinery of the mitotic spindle followed by haphazard chromosomal annealing, together with sophisticated insights from epigenetics, provide profound mechanistic insights into some of the most perplexing classical observations of addiction medicine, including cancerogenesis, the younger and aggressive onset of addiction-related carcinogenesis, the heritability of addictive neurocircuitry and cancers, and foetal malformations...
July 2016: Mutation Research
Jian Yang, Jixiang Liu, Liang Ouyang, Yi Chen, Bo Liu, Haoyang Cai
Chromothripsis is a recently observed phenomenon in cancer cells in which one or several chromosomes shatter into pieces with subsequent inaccurate reassembly and clonal propagation. This type of event generates a potentially vast number of mutations within a relatively short-time period, and has been considered as a new paradigm in cancer development. Despite recent advances, much work is still required to better understand the molecular mechanisms of this phenomenon, and thus an easy-to-use tool is in urgent need for automatically detecting and annotating chromothripsis...
July 8, 2016: Nucleic Acids Research
Veronica Ortega, Alka Chaubey, Christina Mendiola, William Ehman, Kumari Vadlamudi, Barbara Dupont, Gopalrao Velagaleti
Genomic instability is a well-known hallmark of cancer. Recent genome sequencing studies have led to the identification of novel phenomena called chromothripsis and chromoanasynthesis in which complex genomic rearrangements are thought to be derived from a single catastrophic event rather than by several incremental steps. A new term chromoanagenesis or chromosomal rebirth was coined recently to group these two one-step catastrophic events together. These phenomena suggest an evolutionary modality for cancer cells to circumvent individual mutational events with one simultaneous shattering of chromosomes resulting in the random reassembling of segmented genetic material to form complex derivative chromosomes...
April 2016: Neoplasia: An International Journal for Oncology Research
Francesca Menghi, Koichiro Inaki, XingYi Woo, Pooja A Kumar, Krzysztof R Grzeda, Ankit Malhotra, Vinod Yadav, Hyunsoo Kim, Eladio J Marquez, Duygu Ucar, Phung T Shreckengast, Joel P Wagner, George MacIntyre, Krishna R Murthy Karuturi, Ralph Scully, James Keck, Jeffrey H Chuang, Edison T Liu
Next-generation sequencing studies have revealed genome-wide structural variation patterns in cancer, such as chromothripsis and chromoplexy, that do not engage a single discernable driver mutation, and whose clinical relevance is unclear. We devised a robust genomic metric able to identify cancers with a chromotype called tandem duplicator phenotype (TDP) characterized by frequent and distributed tandem duplications (TDs). Enriched only in triple-negative breast cancer (TNBC) and in ovarian, endometrial, and liver cancers, TDP tumors conjointly exhibit tumor protein p53 (TP53) mutations, disruption of breast cancer 1 (BRCA1), and increased expression of DNA replication genes pointing at rereplication in a defective checkpoint environment as a plausible causal mechanism...
April 26, 2016: Proceedings of the National Academy of Sciences of the United States of America
Zuzana Storchová, Wigard P Kloosterman
Human genomes are continuously subjected to mutations, which can drive genetic diseases and cancer. An intriguing recent finding has been the discovery of chromothripsis, a spectacular and complex form of chromosome rearrangement that can occur in the genomes of cancer cells and patients with congenital diseases. Chromothripsis has been described in a large array of human cancers and various types of chromothripsis have appeared, which differ in complexity and genomic hallmarks. From the combined genomic data a consensus hypothesis has been inferred, involving aberrant DNA replication and chromosome shattering as the underlying processes explaining chromothripsis...
June 2016: Current Opinion in Cell Biology
Martin Poot
No abstract text is available yet for this article.
February 2016: Molecular Syndromology
Martin Poot
No abstract text is available yet for this article.
February 2016: Molecular Syndromology
Denise M Schütze, Oscar Krijgsman, Peter J F Snijders, Bauke Ylstra, Joachim Weischenfeldt, Balca R Mardin, Adrian M Stütz, Jan O Korbel, Johan P de Winter, Chris J L M Meijer, Wim G V Quint, Leontien Bosch, Saskia M Wilting, Renske D M Steenbergen
High-risk human papillomavirus (hrHPV) types induce immortalization of primary human epithelial cells. Previously we demonstrated that immortalization of human foreskin keratinocytes (HFKs) is HPV type dependent, as reflected by the presence or absence of a crisis period before reaching immortality. This study determined how the immortalization capacity of ten hrHPV types relates to DNA damage induction and overall genomic instability in HFKs.Twenty five cell cultures obtained by transduction of ten hrHPV types (i...
March 14, 2016: Oncotarget
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