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      Patterns of somatic structural variation in human cancer genomes

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          Abstract

          A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes 17 . Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types 8 . Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions—as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2–7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and—in liver cancer—frequently activate the telomerase gene TERT. A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.

          Abstract

          Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

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          Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations.

          Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Chromatin organization is a major influence on regional mutation rates in human cancer cells.

            Cancer genome sequencing provides the first direct information on how mutation rates vary across the human genome in somatic cells. Testing diverse genetic and epigenetic features, here we show that mutation rates in cancer genomes are strikingly related to chromatin organization. Indeed, at the megabase scale, a single feature—levels of the heterochromatin-associated histone modification H3K9me3—can account for more than 40% of mutation-rate variation, and a combination of features can account for more than 55%. The strong association between mutation rates and chromatin organization is upheld in samples from different tissues and for different mutation types. This suggests that the arrangement of the genome into heterochromatin- and euchromatin-like domains is a dominant influence on regional mutation-rate variation in human somatic cells.
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              A Microhomology-Mediated Break-Induced Replication Model for the Origin of Human Copy Number Variation

              Chromosome structural changes with nonrecurrent endpoints associated with genomic disorders offer windows into the mechanism of origin of copy number variation (CNV). A recent report of nonrecurrent duplications associated with Pelizaeus-Merzbacher disease identified three distinctive characteristics. First, the majority of events can be seen to be complex, showing discontinuous duplications mixed with deletions, inverted duplications, and triplications. Second, junctions at endpoints show microhomology of 2–5 base pairs (bp). Third, endpoints occur near pre-existing low copy repeats (LCRs). Using these observations and evidence from DNA repair in other organisms, we derive a model of microhomology-mediated break-induced replication (MMBIR) for the origin of CNV and, ultimately, of LCRs. We propose that breakage of replication forks in stressed cells that are deficient in homologous recombination induces an aberrant repair process with features of break-induced replication (BIR). Under these circumstances, single-strand 3′ tails from broken replication forks will anneal with microhomology on any single-stranded DNA nearby, priming low-processivity polymerization with multiple template switches generating complex rearrangements, and eventual re-establishment of processive replication.
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                Author and article information

                Contributors
                joachim.weischenfeldt@bric.ku.dk
                rameen_beroukhim@dfci.harvard.edu
                pc8@sanger.ac.uk
                Journal
                Nature
                Nature
                Nature
                Nature Publishing Group UK (London )
                0028-0836
                1476-4687
                5 February 2020
                5 February 2020
                2020
                : 578
                : 7793
                : 112-121
                Affiliations
                [1 ]ISNI 0000 0004 0606 5382, GRID grid.10306.34, Cancer Genome Project, , Wellcome Trust Sanger Institute, ; Hinxton, UK
                [2 ]Totient Inc, Cambridge, MA USA
                [3 ]GRID grid.66859.34, The Broad Institute of Harvard and MIT, ; Cambridge, MA USA
                [4 ]ISNI 000000041936754X, GRID grid.38142.3c, Bioinformatics and Integrative Genomics, , Harvard University, ; Cambridge, MA USA
                [5 ]ISNI 0000 0001 2106 9910, GRID grid.65499.37, Department of Cancer Biology, , Dana-Farber Cancer Institute, ; Boston, MA USA
                [6 ]ISNI 000000041936877X, GRID grid.5386.8, Weill Cornell Medical College, ; New York, NY USA
                [7 ]ISNI 0000 0004 0495 846X, GRID grid.4709.a, European Molecular Biology Laboratory, , Genome Biology Unit, ; Heidelberg, Germany
                [8 ]ISNI 0000 0004 1936 9473, GRID grid.253264.4, Department of Molecular Biology, Rosenstiel Basic Medical Sciences Research Center, , Brandeis University, ; Waltham, MA USA
                [9 ]GRID grid.429884.b, New York Genome Center, ; New York, NY USA
                [11 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, Biotech Research & Innovation Centre (BRIC), The Finsen Laboratory, Rigshospitalet, , University of Copenhagen, ; Copenhagen, Denmark
                [12 ]ISNI 0000000121885934, GRID grid.5335.0, Department of Haematology, , University of Cambridge, ; Cambridge, UK
                [15 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, University of Texas MD Anderson Cancer Center, ; Houston, TX USA
                [16 ]ISNI 0000000109410645, GRID grid.11794.3a, Department of Zoology, Genetics and Physical Anthropology, , University of Santiago de Compostela, ; Santiago de Compostela, Spain
                [17 ]ISNI 0000000109410645, GRID grid.11794.3a, Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS), , University of Santiago de Compostela, ; Santiago de Compostela, Spain
                [18 ]ISNI 0000 0001 2097 6738, GRID grid.6312.6, The Biomedical Research Centre (CINBIO), , University of Vigo, ; Vigo, Spain
                [19 ]ISNI 0000000121885934, GRID grid.5335.0, Transmissible Cancer Group, Department of Veterinary Medicine, , University of Cambridge, ; Cambridge, UK
                [20 ]ISNI 0000 0004 0626 690X, GRID grid.419890.d, Computational Biology Program, , Ontario Institute for Cancer Research, ; Toronto, Ontario Canada
                [21 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Medical Biophysics, , University of Toronto, ; Toronto, Ontario Canada
                [22 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Pharmacology, , University of Toronto, ; Toronto, Ontario Canada
                [23 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, University of California Los Angeles, ; Los Angeles, CA USA
                [24 ]ISNI 0000000403978434, GRID grid.1055.1, Peter MacCallum Cancer Centre, ; Melbourne, Victoria Australia
                [25 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Sir Peter MacCallum Department of Oncology, , University of Melbourne, ; Melbourne, Victoria Australia
                [26 ]ISNI 0000 0001 0328 4908, GRID grid.5253.1, National Center for Tumor Diseases (NCT) Heidelberg, ; Heidelberg, Germany
                [27 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Division of Applied Bioinformatics, , German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [28 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, German Cancer Consortium (DKTK), , German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [29 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Johns Hopkins School of Medicine, ; Baltimore, MD USA
                [30 ]ISNI 0000 0001 2182 2255, GRID grid.28046.38, Faculty of Medicine, Department of Biochemistry, , Microbiology and Immunology, University of Ottawa, ; Ottawa, Ontario Canada
                [31 ]ISNI 0000000121885934, GRID grid.5335.0, Centre for Molecular Science Informatics, Department of Chemistry, , University of Cambridge, ; Cambridge, UK
                [32 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Biomedical Informatics, , Harvard Medical School, ; Boston, MA USA
                [33 ]ISNI 000000041936754X, GRID grid.38142.3c, Ludwig Center, , Harvard Medical School, ; Boston, MA USA
                [34 ]ISNI 0000 0004 0387 1602, GRID grid.10097.3f, Barcelona Supercomputing Center (BSC), ; Barcelona, Spain
                [35 ]ISNI 0000000121885934, GRID grid.5335.0, Cancer Research UK Cambridge Institute, , University of Cambridge, ; Cambridge, UK
                [36 ]ISNI 0000000121885934, GRID grid.5335.0, University of Cambridge, ; Cambridge, UK
                [37 ]Sidra Medicine, Doha, Qatar
                [38 ]ISNI 0000 0004 0387 1602, GRID grid.10097.3f, Barcelona Supercomputing Center (BSC), ; Barcelona, Spain
                [39 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, , The University of Queensland, ; Brisbane, Queensland Australia
                [40 ]ISNI 0000 0004 1937 0503, GRID grid.22098.31, The Azrieli Faculty of Medicine, , Bar-Ilan University, ; Safed, Israel
                [41 ]ISNI 0000 0001 2097 5006, GRID grid.16750.35, Department of Computer Science, , Princeton University, ; Princeton, NJ USA
                [42 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Computer Science, , Yale University, ; New Haven, CT USA
                [43 ]ISNI 0000000419368710, GRID grid.47100.32, Program in Computational Biology and Bioinformatics, , Yale University, ; New Haven, CT USA
                [44 ]ISNI 0000 0001 2110 5790, GRID grid.280664.e, Genome Integrity and Structural Biology Laboratory, , National Institute of Environmental Health Sciences (NIEHS), ; Durham, NC USA
                [45 ]ISNI 0000 0001 0740 6917, GRID grid.205975.c, Biomolecular Engineering Department, , University of California, Santa Cruz, ; Santa Cruz, CA USA
                [46 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Massachusetts General Hospital Center for Cancer Research, ; Charlestown, MA USA
                [47 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Heidelberg Center for Personalized Oncology (DKFZ-HIPO), , German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [48 ]Hopp Children’s Cancer Center (KiTZ), Heidelberg, Germany
                [49 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Pediatric Glioma Research Group, , German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [50 ]ISNI 0000 0001 2292 0500, GRID grid.37172.30, Korea Advanced Institute of Science and Technology, ; Daejeon, South Korea
                [51 ]ISNI 0000 0004 0555 3608, GRID grid.454320.4, Skolkovo Institute of Science and Technology, ; Moscow, Russia
                [52 ]ISNI 0000 0004 0619 6198, GRID grid.435025.5, A. A. Kharkevich Institute of Information Transmission Problems, ; Moscow, Russia
                [53 ]Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
                [54 ]ISNI 0000 0001 2110 5790, GRID grid.280664.e, Integrative Bioinformatics Support Group, , National Institute of Environmental Health Sciences (NIEHS), ; Durham, NC USA
                [55 ]ISNI 0000 0001 0302 820X, GRID grid.412484.f, Center For Medical Innovation, , Seoul National University Hospital, ; Seoul, South Korea
                [56 ]ISNI 0000 0001 0302 820X, GRID grid.412484.f, Department of Internal Medicine, , Seoul National University Hospital, ; Seoul, South Korea
                [57 ]ISNI 000000041936754X, GRID grid.38142.3c, Division of Genetics and Genomics, , Harvard Medical School, ; Boston, MA USA
                [58 ]ISNI 0000 0004 0378 8438, GRID grid.2515.3, Boston Children’s Hospital, ; Boston, MA USA
                [59 ]ISNI 0000 0001 0721 1626, GRID grid.11914.3c, School of Medicine/School of Mathematics and Statistics, , University of St Andrews, ; St Andrews, UK
                [60 ]ISNI 000000041936877X, GRID grid.5386.8, Department of Physiology and Biophysics, , Weill Cornell Medicine, ; New York, NY USA
                [61 ]ISNI 000000041936877X, GRID grid.5386.8, Institute for Computational Biomedicine, , Weill Cornell Medicine, ; New York, NY USA
                [62 ]ISNI 000000041936877X, GRID grid.5386.8, Englander Institute for Precision Medicine, , Weill Cornell Medicine, ; New York, NY USA
                [63 ]ISNI 0000 0001 2106 9910, GRID grid.65499.37, Dana-Farber Cancer Institute, ; Boston, MA USA
                [64 ]ISNI 0000 0001 2151 536X, GRID grid.26999.3d, The Institute of Medical Science, , The University of Tokyo, ; Tokyo, Japan
                [65 ]RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
                [66 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Molecular Biophysics and Biochemistry, , Yale University, ; New Haven, CT USA
                [67 ]ISNI 0000 0001 2172 2676, GRID grid.5612.0, Universitat Pompeu Fabra (UPF), ; Barcelona, Spain
                [68 ]GRID grid.473715.3, Centre for Genomic Regulation (CRG), , The Barcelona Institute of Science and Technology, ; Barcelona, Spain
                [69 ]ISNI 0000 0001 2190 1447, GRID grid.10392.39, Institute of Medical Genetics and Applied Genomics, , University of Tübingen, ; Tübingen, Germany
                [70 ]ISNI 0000 0001 2294 1395, GRID grid.1049.c, Department of Genetics and Computational Biology, , QIMR Berghofer Medical Research Institute, ; Brisbane, Queensland Australia
                [71 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, Institute for Molecular Bioscience, , University of Queensland, ; Brisbane, Queensland Australia
                [72 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [73 ]ISNI 0000 0001 2157 6568, GRID grid.30064.31, School of Molecular Biosciences and Center for Reproductive Biology, , Washington State University, ; Pullman, WA USA
                [74 ]ISNI 0000 0000 9011 8547, GRID grid.239395.7, Cancer Research Institute, , Beth Israel Deaconess Medical Center, ; Boston, MA USA
                [75 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, Faculty of Biosciences, , Heidelberg University, ; Heidelberg, Germany
                [76 ]ISNI 0000 0000 9601 989X, GRID grid.425902.8, Institució Catalana de Recerca i Estudis Avançats (ICREA), ; Barcelona, Spain
                [77 ]ISNI 0000 0004 1936 7822, GRID grid.170205.1, Ben May Department for Cancer Research, Department of Human Genetics, , The University of Chicago, ; Chicago, IL USA
                [78 ]ISNI 000000041936877X, GRID grid.5386.8, Tri-institutional PhD Program of Computational Biology and Medicine, , Weill Cornell Medicine, ; New York, NY USA
                Article
                1913
                10.1038/s41586-019-1913-9
                7025897
                32025012
                c3ad5ecc-a0c9-40b2-8e20-ab02b1bdcfe6
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 22 September 2017
                : 18 November 2019
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                © The Author(s), under exclusive licence to Springer Nature Limited 2020

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                cancer genomics,genomic instability
                Uncategorized
                cancer genomics, genomic instability

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