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Chromothripsis

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https://www.readbyqxmd.com/read/28643781/recurrent-mutation-of-igf-signalling-genes-and-distinct-patterns-of-genomic-rearrangement-in-osteosarcoma
#1
Sam Behjati, Patrick S Tarpey, Kerstin Haase, Hongtao Ye, Matthew D Young, Ludmil B Alexandrov, Sarah J Farndon, Grace Collord, David C Wedge, Inigo Martincorena, Susanna L Cooke, Helen Davies, William Mifsud, Mathias Lidgren, Sancha Martin, Calli Latimer, Mark Maddison, Adam P Butler, Jon W Teague, Nischalan Pillay, Adam Shlien, Ultan McDermott, P Andrew Futreal, Daniel Baumhoer, Olga Zaikova, Bodil Bjerkehagen, Ola Myklebost, M Fernanda Amary, Roberto Tirabosco, Peter Van Loo, Michael R Stratton, Adrienne M Flanagan, Peter J Campbell
Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours...
June 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/28588432/of-simple-and-complex-genome-rearrangements-chromothripsis-chromoanasynthesis-and-chromosome-chaos
#2
EDITORIAL
Martin Poot
No abstract text is available yet for this article.
May 2017: Molecular Syndromology
https://www.readbyqxmd.com/read/28512242/a-systematic-analysis-of-oncogenic-gene-fusions-in-primary-colon-cancer
#3
Wigard P Kloosterman, Robert R J Coebergh van den Braak, Mark Pieterse, Markus J van Roosmalen, Anieta M Sieuwerts, Christina Stangl, Ronne Brunekreef, Zarina S Lalmahomed, Salo Ooft, Anne van Galen, Marcel Smid, Armel Lefebvre, Fried Zwartkruis, John W M Martens, John A Foekens, Katharina Biermann, Marco J Koudijs, Jan N M IJzermans, Emile E Voest
Genomic rearrangements that give rise to oncogenic gene fusions can offer actionable targets for cancer therapy. Here we present a systematic analysis of oncogenic gene fusions among a clinically well-characterized, prospectively collected set of 278 primary colon cancers spanning diverse tumor stages and clinical outcomes. Gene fusions and somatic genetic variations were identified in fresh frozen clinical specimens by Illumina RNA-sequencing, the STAR fusion gene detection pipeline, and GATK RNA-seq variant calling...
May 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28494505/genome-wide-analysis-of-somatic-copy-number-alterations-and-chromosomal-breakages-in-osteosarcoma
#4
Jan Smida, Hongen Xu, Yanping Zhang, Daniel Baumhoer, Sebastian Ribi, Michal Kovac, Irene von Luettichau, Stefan Bielack, Valerie B O'Leary, Christine Leib-Mösch, Dmitrij Frishman, Michaela Nathrath
Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. It is characterized by highly complex karyotypes with structural and numerical chromosomal alterations. The observed OS-specific characteristics in localization and frequencies of chromosomal breakages strongly implicate a specific set of responsible driver genes or a specific mechanism of fragility induction. In this study, a comprehensive assessment of somatic copy number alterations (SCNAs) was performed in 160 OS samples using whole-genome CytoScan High Density arrays (Affymetrix, Santa Clara, CA)...
August 15, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28357089/chromothripsis-and-progression-free-survival-in-metastatic-colorectal-cancer
#5
Elina Skuja, Dagnija Kalniete, Miki Nakazawa-Miklasevica, Zanda Daneberga, Arnis Abolins, Gunta Purkalne, Edvins Miklasevics
Metastatic dissemination of the primary tumor is the major cause of death in colorectal cancer (CRC) patients. Multiple chromosomal breaks and chromothripsis, a phenomenon involving multiple chromosomal fragmentations occurring in a single catastrophic event, are associated with cancer genesis, progression and developing of metastases. The aim of this study was to evaluate the effect of chromothripsis and total breakpoint count (breakpoint instability index) on progression-free survival (PFS). A total of 19 patients with metastatic CRC (mCRC) receiving FOLFOX first-line palliative chemotherapy between August, 2011 and October, 2012 were selected for this study...
February 2017: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/28342454/fate-of-micronuclei-and-micronucleated-cells
#6
REVIEW
Henning Hintzsche, Ulrike Hemmann, Albrecht Poth, Dietmar Utesch, Jasmin Lott, Helga Stopper
The present review describes available evidence about the fate of micronuclei and micronucleated cells. Micronuclei are small, extranuclear chromatin bodies surrounded by a nuclear envelope. The mechanisms underlying the formation of micronuclei are well understood but not much is known about the potential fate of micronuclei and micronucleated cells. Many studies with different experimental approaches addressed the various aspects of the post-mitotic fate of micronuclei and micronucleated cells. These studies are reviewed here considering four basic possibilities for potential fates of micronuclei: degradation of the micronucleus or the micronucleated cell, reincorporation into the main nucleus, extrusion from the cell, and persistence in the cytoplasm...
January 2017: Mutation Research
https://www.readbyqxmd.com/read/28260531/defining-the-diverse-spectrum-of-inversions-complex-structural-variation-and-chromothripsis-in-the-morbid-human%C3%A2-genome
#7
Ryan L Collins, Harrison Brand, Claire E Redin, Carrie Hanscom, Caroline Antolik, Matthew R Stone, Joseph T Glessner, Tamara Mason, Giulia Pregno, Naghmeh Dorrani, Giorgia Mandrile, Daniela Giachino, Danielle Perrin, Cole Walsh, Michelle Cipicchio, Maura Costello, Alexei Stortchevoi, Joon-Yong An, Benjamin B Currall, Catarina M Seabra, Ashok Ragavendran, Lauren Margolin, Julian A Martinez-Agosto, Diane Lucente, Brynn Levy, Stephan J Sanders, Ronald J Wapner, Fabiola Quintero-Rivera, Wigard Kloosterman, Michael E Talkowski
BACKGROUND: Structural variation (SV) influences genome organization and contributes to human disease. However, the complete mutational spectrum of SV has not been routinely captured in disease association studies. RESULTS: We sequenced 689 participants with autism spectrum disorder (ASD) and other developmental abnormalities to construct a genome-wide map of large SV. Using long-insert jumping libraries at 105X mean physical coverage and linked-read whole-genome sequencing from 10X Genomics, we document seven major SV classes at ~5 kb SV resolution...
March 6, 2017: Genome Biology
https://www.readbyqxmd.com/read/28244221/genomic-rearrangements-induced-by-unscheduled-dna-double-strand-breaks-in-somatic-mammalian-cells
#8
REVIEW
Ayeong So, Tangui Le Guen, Bernard S Lopez, Josée Guirouilh-Barbat
DNA double-strand breaks (DSBs) are highly toxic lesions that can lead to profound genome rearrangements and/or cell death. DSBs routinely occur in genomes due to endogenous or exogenous stresses. Efficient repair systems, canonical non-homologous end-joining and homologous recombination, exist in the cell and not only ensure the maintenance of genome integrity but also, via specific programmed DNA double-strand breaks, permit its diversity and plasticity. However, these repair systems need to be tightly controlled because they can also generate genomic rearrangements...
February 28, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28235956/genomic-complexity-and-targeted-genes-in-anaplastic-thyroid-cancer-cell-lines
#9
Eleanor Louise Woodward, Andrea Biloglav, Naveen Ravi, Minjun Yang, Lars Ekblad, Johan Wennerberg, Kajsa Paulsson
Anaplastic thyroid cancer (ATC) is a highly malignant disease with very short median survival times. Few studies have addressed the underlying somatic mutations, and the genomic landscape of ATC thus remains largely unknown. In the present study, we have ascertained copy number aberrations, gene fusions, gene expression patterns, and mutations in early-passage cells from ten newly established ATC cell lines using single nucleotide polymorphism (SNP) array analysis, RNA-sequencing and whole exome sequencing...
February 24, 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28212808/next-generation-repeat-free-fish-probes-for-dna-amplification-in-glioblastoma-in-vivo-improving-patient-selection-to-mdm2-targeted-inhibitors
#10
Matteo Brunelli, Albino Eccher, Luca Cima, Tobia Trippini, Serena Pedron, Marco Chilosi, Mattia Barbareschi, Aldo Scarpa, Giampietro Pinna, Giulio Cabrini, Sara Pilotto, Luisa Carbognin, Emilio Bria, Giampaolo Tortora, Adele Fioravanzo, Nicola Schiavo, Mario Meglio, Teodoro Sava, Laura Belli, Guido Martignoni, Claudio Ghimenton
A next-generation FISH probe mapping to the MDM2 locus-specific region has recently been designed. The level of MDM2 gene amplification (high versus low) may allow selection of patients for cancer treatment with MDM2 inhibitors and may predict their responsiveness. We investigated the spectrum of MDM2 gene alterations using the new probes in vivo after visualizing single neoplastic cells in situ from a series of glioblastomas. Signals from next-generation repeat-free FISH interphase probes were identified in tissue microarrays that included 3 spots for each of the 48 cases...
January 2017: Cancer Genetics
https://www.readbyqxmd.com/read/28196983/genomic-profiling-of-acute-lymphoblastic-leukemia-in-ataxia-telangiectasia-patients-reveals-tight-link-between-atm-mutations-and-chromothripsis
#11
M Ratnaparkhe, M Hlevnjak, T Kolb, A Jauch, K K Maass, F Devens, A Rode, V Hovestadt, A Korshunov, A Pastorczak, W Mlynarski, S Sungalee, J Korbel, J Hoell, U Fischer, T Milde, C Kramm, M Nathrath, K Chrzanowska, E Tausch, M Takagi, T Taga, S Constantini, J Loeffen, J Meijerink, S Zielen, G Gohring, B Schlegelberger, E Maass, R Siebert, J Kunz, A E Kulozik, B Worst, D T Jones, S M Pfister, M Zapatka, P Lichter, A Ernst
Recent developments in sequencing technologies led to the discovery of a novel form of genomic instability, termed chromothripsis. This catastrophic genomic event, involved in tumorigenesis, is characterized by tens to hundreds of simultaneously acquired locally clustered rearrangements on one chromosome. We hypothesized that leukemias developing in individuals with Ataxia Telangiectasia, who are born with two mutated copies of the ATM gene, an essential guardian of genome stability, would show a higher prevalence of chromothripsis due to the associated defect in DNA double-strand break repair...
March 14, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28153049/longitudinal-analysis-of-treatment-induced-genomic-alterations-in-gliomas
#12
E Zeynep Erson-Omay, Octavian Henegariu, S Bülent Omay, Akdes Serin Harmancı, Mark W Youngblood, Ketu Mishra-Gorur, Jie Li, Koray Özduman, Geneive Carrión-Grant, Victoria E Clark, Caner Çağlar, Mehmet Bakırcıoğlu, M Necmettin Pamir, Viviane Tabar, Alexander O Vortmeyer, Kaya Bilguvar, Katsuhito Yasuno, Lisa M DeAngelis, Joachim M Baehring, Jennifer Moliterno, Murat Günel
BACKGROUND: Glioblastoma multiforme (GBM) constitutes nearly half of all malignant brain tumors and has a median survival of 15 months. The standard treatment for these lesions includes maximal resection, radiotherapy, and chemotherapy; however, individual tumors display immense variability in their response to these approaches. Genomic techniques such as whole-exome sequencing (WES) provide an opportunity to understand the molecular basis of this variability. METHODS: Here, we report WES-guided treatment of a patient with a primary GBM and two subsequent recurrences, demonstrating the dynamic nature of treatment-induced molecular changes and their implications for clinical decision-making...
February 2, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28126037/molecular-dissection-of-germline-chromothripsis-in-a-developmental-context-using-patient-derived-ips-cells
#13
Sjors Middelkamp, Sebastiaan van Heesch, A Koen Braat, Joep de Ligt, Maarten van Iterson, Marieke Simonis, Markus J van Roosmalen, Martijn J E Kelder, Evelien Kruisselbrink, Ron Hochstenbach, Nienke E Verbeek, Elly F Ippel, Youri Adolfs, R Jeroen Pasterkamp, Wigard P Kloosterman, Ewart W Kuijk, Edwin Cuppen
BACKGROUND: Germline chromothripsis causes complex genomic rearrangements that are likely to affect multiple genes and their regulatory contexts. The contribution of individual rearrangements and affected genes to the phenotypes of patients with complex germline genomic rearrangements is generally unknown. METHODS: To dissect the impact of germline chromothripsis in a relevant developmental context, we performed trio-based RNA expression analysis on blood cells, induced pluripotent stem cells (iPSCs), and iPSC-derived neuronal cells from a patient with de novo germline chromothripsis and both healthy parents...
January 26, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28125801/genome-wide-copy-number-aberrations-and-her2-and-fgfr1-alterations-in-primary-breast-cancer-by-molecular-inversion-probe-microarray
#14
Hui Chen, Rajesh R Singh, Xinyan Lu, Lei Huo, Hui Yao, Kenneth Aldape, Ronald Abraham, Shumaila Virani, Meenakshi Mehrotra, Bal Mukund Mishra, Alex Bousamra, Constance Albarracin, Yun Wu, Sinchita Roy-Chowdhuri, Rashmi Kanagal-Shamanna, Mark J Routbort, L Jeffrey Medeiros, Keyur P Patel, Russell Broaddus, Aysegul Sahin, Rajyalakshmi Luthra
Breast cancer remains the second leading cause of cancer-related death in women despite stratification based on standard hormonal receptor (HR) and HER2 testing. Additional prognostic markers are needed to improve breast cancer treatment. Chromothripsis, a catastrophic genome rearrangement, has been described recently in various cancer genomes and affects cancer progression and prognosis. However, little is known about chromothripsis in breast cancer. To identify novel prognostic biomarkers in breast cancer, we used molecular inversion probe (MIP) microarray to explore genome-wide copy number aberrations (CNA) and breast cancer-related gene alterations in DNA extracted from formalin-fixed paraffin-embedded tissue...
February 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28119329/marker-chromosomes-can-arise-from-chromothripsis-and-predict-adverse-prognosis-in-acute-myeloid-leukemia
#15
Tilmann Bochtler, Martin Granzow, Friedrich Stölzel, Christina Kunz, Brigitte Mohr, Mutlu Kartal-Kaess, Katrin Hinderhofer, Christoph E Heilig, Michael Kramer, Christian Thiede, Volker Endris, Martina Kirchner, Albrecht Stenzinger, Axel Benner, Martin Bornhäuser, Gerhard Ehninger, Anthony D Ho, Anna Jauch, Alwin Krämer
Metaphase karyotyping is an established diagnostic standard in acute myeloid leukemia (AML) for risk stratification. One of the cytogenetic findings in AML is structurally highly abnormal marker chromosomes. In this study, we have assessed frequency, cytogenetic characteristics, prognostic impact, and underlying biological origin of marker chromosomes. Given their inherent gross structural chromosomal damage, we speculated that they may arise from chromothripsis, a recently described phenomenon of chromosome fragmentation in a single catastrophic event...
March 9, 2017: Blood
https://www.readbyqxmd.com/read/28099951/complex-x-chromosomal-rearrangements-in-two-women-with-ovarian-dysfunction-implications-of-chromothripsis-chromoanasynthesis-dependent-and-independent-origins-of-complex-genomic-alterations
#16
Erina Suzuki, Hirohito Shima, Machiko Toki, Kunihiko Hanew, Keiko Matsubara, Hiroki Kurahashi, Satoshi Narumi, Tsutomu Ogata, Tsutomu Kamimaki, Maki Fukami
Our current understanding of the phenotypic consequences and the molecular basis of germline complex chromosomal rearrangements remains fragmentary. Here, we report the clinical and molecular characteristics of 2 women with germline complex X-chromosomal rearrangements. Patient 1 presented with nonsyndromic ovarian dysfunction and hyperthyroidism; patient 2 exhibited various Turner syndrome- associated symptoms including ovarian dysfunction, short stature, and autoimmune hypothyroidism. The genomic abnormalities of the patients were characterized by array-based comparative genomic hybridization, high-resolution karyotyping, microsatellite genotyping, X-inactivation analysis, and bisulfite sequencing...
2016: Cytogenetic and Genome Research
https://www.readbyqxmd.com/read/28096526/telomeres-in-cancer-tumour-suppression-and-genome-instability
#17
REVIEW
John Maciejowski, Titia de Lange
The shortening of human telomeres has two opposing effects during cancer development. On the one hand, telomere shortening can exert a tumour-suppressive effect through the proliferation arrest induced by activating the kinases ATM and ATR at unprotected chromosome ends. On the other hand, loss of telomere protection can lead to telomere crisis, which is a state of extensive genome instability that can promote cancer progression. Recent data, reviewed here, provide new evidence for the telomere tumour suppressor pathway and has revealed that telomere crisis can induce numerous cancer-relevant changes, including chromothripsis, kataegis and tetraploidization...
March 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28056863/growth-progression-and-chromosome-instability-of-neuroblastoma-a-new-scenario-of-tumorigenesis
#18
Gian Paolo Tonini
BACKGROUND: Neuroblastoma is a pediatric cancer with a low survival rate of patients with metastatic stage 4 disease. Tumor aggressiveness and progression have been associated with structural copy number variations (CNVs) that are observed in malignant cells. In contrast, localized Neuroblastomas, which are associated with a low number of structural CNVs but frequent numerical CNVs, are less aggressive, and patients have good outcomes. Finally, whole-genome and whole-exome sequencing of Neuroblastoma tissues have shown few damaging mutations in these tumors...
January 5, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28045556/generalized-hultman-numbers-and-cycle-structures-of-breakpoint-graphs
#19
Nikita Alexeev, Anna Pologova, Max A Alekseyev
Genome rearrangements can be modeled as k-breaks, which break a genome at k positions and glue the resulting fragments in a new order. In particular, reversals, translocations, fusions, and fissions are modeled as 2-breaks, and transpositions are modeled as 3-breaks. Although k-break rearrangements for [Formula: see text] have not been observed in evolution, they are used in cancer genomics to model chromothripsis, a catastrophic event of multiple breakages happening simultaneously in a genome. It is known that the k-break distance between two genomes (i...
February 2017: Journal of Computational Biology: a Journal of Computational Molecular Cell Biology
https://www.readbyqxmd.com/read/28008180/y-chromothripsis
#20
Emily M Hatch
Micronucleation of missegregated chromatin can lead to substantial chromosome rearrangements via chromothripsis. However, the molecular details of micronucleus-based chromothripsis are still unclear. Now, an elegant system that specifically induces missegregation of the Y chromosome provides insight into this process, including a role for non-homologous end joining.
December 23, 2016: Nature Cell Biology
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