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Chromothripsis

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https://www.readbyqxmd.com/read/29351848/a-distinct-class-of-genome-rearrangements-driven-by-heterologous-recombination
#1
Ana María León-Ortiz, Stephanie Panier, Grzegorz Sarek, Jean-Baptiste Vannier, Harshil Patel, Peter J Campbell, Simon J Boulton
Erroneous DNA repair by heterologous recombination (Ht-REC) is a potential threat to genome stability, but evidence supporting its prevalence is lacking. Here we demonstrate that recombination is possible between heterologous sequences and that it is a source of chromosomal alterations in mitotic and meiotic cells. Mechanistically, we find that the RTEL1 and HIM-6/BLM helicases and the BRCA1 homolog BRC-1 counteract Ht-REC in Caenorhabditis elegans, whereas mismatch repair does not. Instead, MSH-2/6 drives Ht-REC events in rtel-1 and brc-1 mutants and excessive crossovers in rtel-1 mutant meioses...
January 18, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29345169/a-case-of-diffuse-large-b-cell-lymphoma-with-myc-gene-cluster-amplification-related-to-chromothripsis
#2
Minoru Kojima, Joaquim Carreras, Yara Yukie Kikuti, Masashi Miyaoka, Tomoki Kikuchi, Jun Amaki, Ai Sato, Daisuke Ogiya, Kiyoshi Ando, Naoya Nakamura
No abstract text is available yet for this article.
January 18, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29321523/integrative-genomic-and-transcriptomic-analysis-of-leiomyosarcoma
#3
Priya Chudasama, Sadaf S Mughal, Mathijs A Sanders, Daniel Hübschmann, Inn Chung, Katharina I Deeg, Siao-Han Wong, Sophie Rabe, Mario Hlevnjak, Marc Zapatka, Aurélie Ernst, Kortine Kleinheinz, Matthias Schlesner, Lina Sieverling, Barbara Klink, Evelin Schröck, Remco M Hoogenboezem, Bernd Kasper, Christoph E Heilig, Gerlinde Egerer, Stephan Wolf, Christof von Kalle, Roland Eils, Albrecht Stenzinger, Wilko Weichert, Hanno Glimm, Stefan Gröschel, Hans-Georg Kopp, Georg Omlor, Burkhard Lehner, Sebastian Bauer, Simon Schimmack, Alexis Ulrich, Gunhild Mechtersheimer, Karsten Rippe, Benedikt Brors, Barbara Hutter, Marcus Renner, Peter Hohenberger, Claudia Scholl, Stefan Fröhling
Leiomyosarcoma (LMS) is an aggressive mesenchymal malignancy with few therapeutic options. The mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, are largely unknown. Here we show, using whole-exome and transcriptome sequencing, that LMS tumors are characterized by substantial mutational heterogeneity, near-universal inactivation of TP53 and RB1, widespread DNA copy number alterations including chromothripsis, and frequent whole-genome duplication. Furthermore, we detect alternative telomere lengthening in 78% of cases and identify recurrent alterations in telomere maintenance genes such as ATRX, RBL2, and SP100, providing insight into the genetic basis of this mechanism...
January 10, 2018: Nature Communications
https://www.readbyqxmd.com/read/29249819/chromothripsis-in-acute-myeloid-leukemia-biological-features-and-impact-on-survival
#4
M C Fontana, G Marconi, J D M Feenstra, E Fonzi, C Papayannidis, A G L di Rorá, A Padella, V Solli, E Franchini, E Ottaviani, A Ferrari, C Baldazzi, N Testoni, I Iacobucci, S Soverini, T Haferlach, V Guadagnuolo, L Semerad, M Doubek, M Steurer, Z Racil, S Paolini, M Manfrini, M Cavo, G Simonetti, R Kralovics, G Martinelli
Chromothripsis is a one-step genome-shattering catastrophe resulting from disruption of one or few chromosomes in multiple fragments and consequent random rejoining and repair. This study define incidence of chromothripsis in 395 newly-diagnosed adult acute myeloid leukemia (AML) patients from three institutions, its impact on survival and its genomic background. SNP 6.0 or CytoscanHD Array (Affymetrix®) were performed on all samples. We detected chromothripsis with a custom algorithm in 26/395 patients. Patients harboring chromothripsis had higher age (P=0...
December 18, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29186385/identifying-simultaneous-rearrangements-in-cancer-genomes
#5
Layla Oesper, Simone Dantas, Benjamin J Raphael
Motivation: The traditional view of cancer evolution states that a cancer genome accumulates a sequential ordering of mutations over a long period of time. However, in recent years it has been suggested that a cancer genome may instead undergo a one-time catastrophic event, such as chromothripsis, where a large number of mutations instead occur simultaneously. A number of potential signatures of chromothripsis have been proposed. In this work we provide a rigorous formulation and analysis of the "ability to walk the derivative chromosome" signature originally proposed by Korbel and Campbell (2013)...
November 27, 2017: Bioinformatics
https://www.readbyqxmd.com/read/29180669/myc-containing-amplicons-in-acute-myeloid-leukemia-genomic-structures-evolution-and-transcriptional-consequences
#6
A ĹAbbate, D Tolomeo, I Cifola, M Severgnini, A Turchiano, B Augello, G Squeo, P D Addabbo, D Traversa, G Daniele, A Lonoce, M Pafundi, M Carella, O Palumbo, A Dolnik, D Muehlematter, J Schoumans, N Van Roy, G De Bellis, G Martinelli, G Merla, L Bullinger, C Haferlach, C T Storlazzi
Double minutes (dmin), homogeneously staining regions, and ring chromosomes are vehicles of gene amplification in cancer. The underlying mechanism leading to their formation as well as their structure and function in acute myeloid leukemia (AML) remain mysterious. We combined a range of high-resolution genomic methods to investigate the architecture and expression pattern of amplicons involving chromosome band 8q24 in 23 cases of AML (AML-amp). This revealed that different MYC-dmin architectures can coexist within the same leukemic cell population, indicating a step-wise evolution rather than a single event origin, such as through chromothripsis...
November 28, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29177911/mechanisms-of-sustained-neutrophilia-in-patient-whim-09-cured-of-whim-syndrome-by-chromothripsis
#7
Qian Liu, Zhanzhuo Li, Alexander Y Yang, Ji-Liang Gao, Daniel S Velez, Elena J Cho, David H McDermott, Philip M Murphy
WHIM-09 is the first patient described with WHIM syndrome, an autosomal dominant form of neutropenia related to bone marrow retention of neutrophils. Originally diagnosed incorrectly with autoimmune neutropenia, the patient underwent splenectomy at age 9, but the absolute neutrophil count (ANC) did not rise. Subsequently, she was spontaneously cured by chromothripsis (chromosome shattering), which deleted the disease allele CXCR4 R334X , and 163 other genes, on chromosome 2 in a single hematopoietic stem cell (HSC)...
November 24, 2017: Journal of Clinical Immunology
https://www.readbyqxmd.com/read/29153091/detection-of-complex-genomic-signatures-associated-with-risk-in-plasma-cell-disorders
#8
Nadine K Berry, Amanda Dixon-McIver, Rodney J Scott, Philip Rowlings, Anoop K Enjeti
Plasma cell disorders (PCD) range from benign to highly malignant disease. The ability to detect risk-stratifying aberrations based on cytogenetic and molecular genetic assays plays an increasing role in therapeutic decision making. In this study, 58 patients were chosen for screening by comparative genomic hybridisation microarray (aCGH) to identify the new high-risk prognostic markers of chromothripsis and chromoanasynthesis. All patients had an unequivocal clinical diagnosis of a plasma cell disorder (plasma cell myeloma (PCM)(n = 51) or monoclonal gammopathy of undetermined significance (MGUS)(n = 7)) and an abnormal FISH result...
December 2017: Cancer Genetics
https://www.readbyqxmd.com/read/29113112/g2-m-phase-checkpoint-adaptation-and-micronuclei-formation-as-mechanisms-that-contribute-to-genomic-instability-in-human-cells
#9
REVIEW
Danî Kalsbeek, Roy M Golsteyn
One of the most common characteristics of cancer cells is genomic instability. Recent research has revealed that G2/M-phase checkpoint adaptation-entering mitosis with damaged DNA-contributes to genomic changes in experimental models. When cancer cells are treated with pharmacological concentrations of genotoxic agents, they undergo checkpoint adaptation; however, a small number of cells are able to survive and accumulate micronuclei. These micronuclei harbour damaged DNA, and are able to replicate and reincorporate their DNA into the main nucleus...
November 6, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29109544/mapping-and-phasing-of-structural-variation-in-patient-genomes-using-nanopore-sequencing
#10
Mircea Cretu Stancu, Markus J van Roosmalen, Ivo Renkens, Marleen M Nieboer, Sjors Middelkamp, Joep de Ligt, Giulia Pregno, Daniela Giachino, Giorgia Mandrile, Jose Espejo Valle-Inclan, Jerome Korzelius, Ewart de Bruijn, Edwin Cuppen, Michael E Talkowski, Tobias Marschall, Jeroen de Ridder, Wigard P Kloosterman
Despite improvements in genomics technology, the detection of structural variants (SVs) from short-read sequencing still poses challenges, particularly for complex variation. Here we analyse the genomes of two patients with congenital abnormalities using the MinION nanopore sequencer and a novel computational pipeline-NanoSV. We demonstrate that nanopore long reads are superior to short reads with regard to detection of de novo chromothripsis rearrangements. The long reads also enable efficient phasing of genetic variations, which we leveraged to determine the parental origin of all de novo chromothripsis breakpoints and to resolve the structure of these complex rearrangements...
November 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/29079594/chromothripsis-is-linked-to-tp53-alteration-cell-cycle-impairment-and-dismal-outcome-in-acute-myeloid-leukemia-with-complex-karyotype
#11
Frank G Rücker, Anna Dolnik, Tamara J Blätte, Veronica Teleanu, Aurélie Ernst, Felicitas Thol, Michael Heuser, Arnold Ganser, Hartmut Döhner, Konstanze Döhner, Lars Bullinger
No abstract text is available yet for this article.
October 27, 2017: Haematologica
https://www.readbyqxmd.com/read/29073611/genomic-characterization-of-chromosomal-insertions-insights-into-the-mechanisms-underlying-chromothripsis
#12
Takema Kato, Yuya Ouchi, Hidehito Inagaki, Yoshio Makita, Seiji Mizuno, Mitsuharu Kajita, Toshiro Ikeda, Kazuhiro Takeuchi, Hiroki Kurahashi
Chromosomal insertions are rare structural rearrangements, and the molecular mechanisms underlying their origin are unknown. In this study, we used whole genome sequencing to analyze breakpoints and junction sequences in 4 patients with chromosomal insertions. Our analysis revealed that none of the 4 cases involved a simple insertion mediated by a 3-chromosomal breakage and rejoining events. The inserted fragments consisted of multiple pieces derived from a localized genomic region, which were shuffled and rejoined in a disorderly fashion with variable copy number alterations...
October 27, 2017: Cytogenetic and Genome Research
https://www.readbyqxmd.com/read/29063805/telomere-length-in-poor-risk-chronic-lymphocytic-leukemia-associations-with-disease-characteristics-and-outcome
#13
Daniela Steinbrecher, Billy Michael Chelliah Jebaraj, Christof Schneider, Jennifer Edelmann, Florence Cymbalista, Véronique Leblond, Alain Delmer, Stefan Ibach, Eugen Tausch, Annika Scheffold, Johannes Bloehdorn, Michael Hallek, Peter Dreger, Hartmut Döhner, Stephan Stilgenbauer
Telomere length in chronic lymphocytic leukemia (CLL) is described as an independent prognostic factor based largely on previously untreated patients from chemotherapy based trials. Here, we studied telomere length associations in high-risk, relapsed/refractory CLL treated with alemtuzumab in the CLL2O study (n = 110) of German and French CLL study groups. Telomere length (median 3.28 kb, range 2.52-7.24 kb) was relatively short, since 84.4% of patients had 17p- which is generally associated with short telomeres...
October 24, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29020724/chromothripsis-in-treatment-resistance-in-multiple-myeloma
#14
Kyoung Joo Lee, Ki Hong Lee, Kyong-Ah Yoon, Ji Yeon Sohn, Eunyoung Lee, Hyewon Lee, Hyeon-Seok Eom, Sun-Young Kong
Multiple myeloma (MM) is a malignant disease caused by an abnormal proliferation of plasma cells, of which the prognostic factors include chromosomal abnormality, β-2 microglobulin, and albumin. Recently, the term chromothripsis has emerged, which is the massive but highly localized chromosomal rearrangement in response to a one-step catastrophic event. Many studies have shown an association of chromothripsis with the prognosis in several cancers; however, few studies have investigated it in MM. Here, we studied the association between chromothripsis-like patterns and treatment resistance or prognosis...
September 2017: Genomics & Informatics
https://www.readbyqxmd.com/read/28990704/epithelioid-glioblastomas-stratify-into-established-diagnostic-subsets-upon-integrated-molecular-analysis
#15
Andrey Korshunov, Lukas Chavez, Tanvi Sharma, Marina Ryzhova, Daniel Schrimpf, Damian Stichel, David Capper, Dominik Sturm, Marcel Kool, Antje Habel, Bette K Kleinschmidt-DeMasters, Marc Rosenblum, Oksana Absalyamova, Andrey Golanov, Peter Lichter, Stefan M Pfister, David T W Jones, Arie Perry, Andreas von Deimling
Epithelioid glioblastoma (eGBM) is a newly defined and rare GBM variant in the current WHO 2016 classification. BRAF V600E mutation is overrepresented in these tumors and there is known some morphological overlap with anaplastic epithelioid PXA (ePXA). In order to further elucidate this diagnostic category, we molecularly characterized 64 pediatric and adult examples initially diagnosed as "eGBM". Tumors were analyzed using array based methylation and direct sequencing of the BRAF and TERT genes. Our results demonstrated considerable molecular and clinical heterogeneity among eGBM cohort...
October 9, 2017: Brain Pathology
https://www.readbyqxmd.com/read/28975018/comprehensive-genomic-profiling-of-a-rare-thyroid-follicular-dendritic-cell-sarcoma
#16
Jaime I Davila, Jason S Starr, Steven Attia, Chen Wang, Ryan A Knudson, Brian M Necela, Vivekananda Sarangi, Zhifu Sun, Yingxue Ren, John D Casler, David M Menke, Gavin R Oliver, Richard W Joseph, John A Copland, Alexander S Parker, Jean-Pierre A Kocher, E Aubrey Thompson, Robert C Smallridge, Yan W Asmann
We previously reported an extremely rare case of follicular dendritic cell sarcoma (FDCS) presented as a thyroid mass. Given the rarity of this disease, there are no personalized and molecularly targeted treatment options due to the lack of knowledge in the genomic makeup of the tumor. A 44-year-old white woman was diagnosed with an extranodal FDCS in thyroid. The patient underwent a total thyroidectomy, central compartment dissection, parathyroid re-implantation, and adjuvant radiation therapy. Tumor DNA sequencing of 236 genes by FoundationOne panel found truncating mutations in PTEN and missense mutations in RET and TP53...
July 3, 2017: Rare Tumors
https://www.readbyqxmd.com/read/28902524/molecular-cytogenetic-characterization-identified-the-murine-b-cell-lymphoma-cell-line-a-20-as-a-model-for-sporadic-burkitt-s-lymphoma
#17
Karolina Guja, Thomas Liehr, Martina Rincic, Nadezda Kosyakova, Shaymaa S Hussein Azawi
Here, we report the first molecular cytogenetic characterization of the BALB/cAnN mouse derived B-cell non-Hodgkin lymphoma (B-cell NHL) cell lines A-20. Even though previously used as a model for testing of, for example, dexametason, up to present, no data in the genetic properties of A-20 were available. The present study closed this gap and provides evidence that A-20 is a model for B-cell NHL subgroup sporadic Burkitt's lymphoma. C-myc oncogene is involved in a translocation and copy number alterations as gain of murine 14q material could be observed...
November 2017: Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society
https://www.readbyqxmd.com/read/28899600/rebuilding-chromosomes-after-catastrophe-emerging-mechanisms-of-chromothripsis
#18
REVIEW
Peter Ly, Don W Cleveland
Cancer genome sequencing has identified chromothripsis, a complex class of structural genomic rearrangements involving the apparent shattering of an individual chromosome into tens to hundreds of fragments. An initial error during mitosis, producing either chromosome mis-segregation into a micronucleus or chromatin bridge interconnecting two daughter cells, can trigger the catastrophic pulverization of the spatially isolated chromosome. The resultant chromosomal fragments are religated in random order by DNA double-strand break repair during the subsequent interphase...
December 2017: Trends in Cell Biology
https://www.readbyqxmd.com/read/28898877/identification-of-small-and-non-small-cell-lung-cancer-markers-in-peripheral-blood-using-cytokinesis-blocked-micronucleus-and-spectral-karyotyping-assays
#19
Randa A El-Zein, Shereen Abdel-Rahman, Kyle J Santee, Robert Yu, Sanjay Shete
Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer. There is an urgent need to develop tools to identify individuals at high risk of developing SCLC. We have previously reported that the cytokinesis-blocked micronucleus (CBMN) assay is a strong predictor of non-small cell lung cancer (NSCLC). Here, we investigate the sensitivity of the CBMN endpoints as predictors of SCLC risk. We conducted the CBMN assay on SCLC patients (n = 216), NSCLC patients (n = 173), and healthy controls (n = 204)...
2017: Cytogenetic and Genome Research
https://www.readbyqxmd.com/read/28811336/catastrophic-unbalanced-genome-rearrangements-cause-somatic-loss-of-berry-color-in-grapevine
#20
Pablo Carbonell-Bejerano, Carolina Royo, Rafael Torres-Pérez, Jérôme Grimplet, Lucie Fernandez, José Manuel Franco-Zorrilla, Diego Lijavetzky, Elisa Baroja, Juana Martínez, Enrique García-Escudero, Javier Ibáñez, José Miguel Martínez-Zapater
Grape (Vitis vinifera) color somatic variants that can be used to develop new grapevine cultivars occasionally appear associated with deletion events of uncertain origin. To understand the mutational mechanisms generating somatic structural variation in grapevine, we compared the Tempranillo Blanco (TB) white berry somatic variant with its black berry ancestor, Tempranillo Tinto. Whole-genome sequencing uncovered a catastrophic genome rearrangement in TB that caused the hemizygous deletion of 313 genes, including the loss of the functional copy for the MYB transcription factors required for anthocyanin pigmentation in the berry skin...
October 2017: Plant Physiology
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