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      Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

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          Abstract

          Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer.

          Abstract

          Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

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          Mechanisms of change in gene copy number.

          Deletions and duplications of chromosomal segments (copy number variants, CNVs) are a major source of variation between individual humans and are an underlying factor in human evolution and in many diseases, including mental illness, developmental disorders and cancer. CNVs form at a faster rate than other types of mutation, and seem to do so by similar mechanisms in bacteria, yeast and humans. Here we review current models of the mechanisms that cause copy number variation. Non-homologous end-joining mechanisms are well known, but recent models focus on perturbation of DNA replication and replication of non-contiguous DNA segments. For example, cellular stress might induce repair of broken replication forks to switch from high-fidelity homologous recombination to non-homologous repair, thus promoting copy number change.
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            The evolutionary history of 2,658 cancers

            Cancer develops through a process of somatic evolution 1,2 . Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes 3 . Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) 4 , we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.
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              Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes.

              Neuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this often lethal tumour. Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%). Here we present a whole-genome sequence analysis of 87 neuroblastoma of all stages. Few recurrent amino-acid-changing mutations were found. In contrast, analysis of structural defects identified a local shredding of chromosomes, known as chromothripsis, in 18% of high-stage neuroblastoma. These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization. In addition, ATRX, TIAM1 and a series of regulators of the Rac/Rho pathway were mutated, further implicating defects in neuritogenesis in neuroblastoma. Most tumours with defects in these genes were aggressive high-stage neuroblastomas, but did not carry MYCN amplifications. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromothripsis and neuritogenesis gene alterations, which frequently occur in high-risk tumours.
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                Author and article information

                Contributors
                peter_park@hms.harvard.edu
                Journal
                Nat Genet
                Nat. Genet
                Nature Genetics
                Nature Publishing Group US (New York )
                1061-4036
                1546-1718
                5 February 2020
                5 February 2020
                2020
                : 52
                : 3
                : 331-341
                Affiliations
                [1 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Biomedical Informatics, , Harvard Medical School, ; Boston, MA USA
                [2 ]Ludwig Center at Harvard, Boston, MA USA
                [3 ]ISNI 0000000121885934, GRID grid.5335.0, Centre for Molecular Science Informatics, Department of Chemistry, , University of Cambridge, ; Cambridge, UK
                [4 ]ISNI 0000 0001 2256 9319, GRID grid.11135.37, School of Mathematical Sciences and Center for Statistical Science, , Peking University, ; Beijing, China
                [5 ]ISNI 0000 0004 1936 7822, GRID grid.170205.1, Ben May Department for Cancer Research, , University of Chicago, ; Chicago, IL USA
                [6 ]ISNI 0000 0004 1936 7822, GRID grid.170205.1, Department of Human Genetics, , The University of Chicago, ; Chicago, IL USA
                [7 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, , US National Institutes of Health, ; Durham, NC USA
                [8 ]ISNI 0000 0001 2110 5790, GRID grid.280664.e, Integrative Bioinformatics Group, National Institute of Environmental Health Sciences, US National Institutes of Health, ; Durham, NC USA
                [9 ]ISNI 0000 0001 2106 9910, GRID grid.65499.37, Department of Data Sciences, , Dana-Farber Cancer Institute, ; Boston, MA USA
                [10 ]ISNI 0000 0001 2106 9910, GRID grid.65499.37, Department of Pediatric Oncology, , Dana-Farber Cancer Institute, ; Boston, MA USA
                [11 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Cell Biology, , Harvard Medical School, Blavatnik Institute, ; Boston, MA USA
                [12 ]ISNI 0000 0001 2167 1581, GRID grid.413575.1, Howard Hughes Medical Institute, ; Boston, MA USA
                [15 ]ISNI 0000 0000 9709 7726, GRID grid.225360.0, Present Address: European Molecular Biology Laboratory, European Bioinformatics Institute, ; Hinxton, UK
                [16 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, University of Texas MD Anderson Cancer Center, ; Houston, TX USA
                [17 ]ISNI 0000000109410645, GRID grid.11794.3a, Department of Zoology, Genetics and Physical Anthropology, , Universidade de Santiago de Compostela, ; Santiago de Compostela, Spain
                [18 ]ISNI 0000000109410645, GRID grid.11794.3a, Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS), , Universidade de Santiago de Compostela, ; Santiago de Compostela, Spain
                [19 ]ISNI 0000 0001 2097 6738, GRID grid.6312.6, The Biomedical Research Centre (CINBIO), , Universidade de Vigo, ; Vigo, Spain
                [20 ]ISNI 0000000121885934, GRID grid.5335.0, Transmissible Cancer Group, Department of Veterinary Medicine, , University of Cambridge, ; Cambridge, UK
                [21 ]GRID grid.66859.34, Broad Institute of MIT and Harvard, ; Cambridge, MA USA
                [22 ]ISNI 0000 0001 2106 9910, GRID grid.65499.37, Department of Medical Oncology, , Dana-Farber Cancer Institute, ; Boston, MA USA
                [23 ]ISNI 000000041936754X, GRID grid.38142.3c, Harvard Medical School, ; Boston, MA USA
                [24 ]ISNI 0000 0004 0626 690X, GRID grid.419890.d, Computational Biology Program, Ontario Institute for Cancer Research, ; Toronto, Ontario Canada
                [25 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Medical Biophysics, , University of Toronto, ; Toronto, Ontario Canada
                [26 ]ISNI 0000 0001 2157 2938, GRID grid.17063.33, Department of Pharmacology, , University of Toronto, ; Toronto, Ontario Canada
                [27 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, University of California Los Angeles, ; Los Angeles, CA USA
                [28 ]ISNI 0000000403978434, GRID grid.1055.1, Peter MacCallum Cancer Centre, ; Melbourne, Victoria Australia
                [29 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Sir Peter MacCallum Department of Oncology, , University of Melbourne, ; Melbourne, Victoria Australia
                [30 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [31 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [32 ]ISNI 0000 0001 0328 4908, GRID grid.5253.1, National Center for Tumor Diseases (NCT) Heidelberg, ; Heidelberg, Germany
                [33 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Johns Hopkins School of Medicine, ; Baltimore, MD USA
                [34 ]ISNI 0000000121885934, GRID grid.5335.0, Department of Haematology, , University of Cambridge, ; Cambridge, UK
                [35 ]ISNI 0000 0004 0606 5382, GRID grid.10306.34, Wellcome Sanger Institute, ; Hinxton, UK
                [36 ]ISNI 0000 0001 2182 2255, GRID grid.28046.38, Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, ; Ottawa, Ontario Canada
                [37 ]ISNI 0000 0004 0387 1602, GRID grid.10097.3f, Barcelona Supercomputing Center (BSC), ; Barcelona, Spain
                [38 ]ISNI 0000000121885934, GRID grid.5335.0, Cancer Research UK Cambridge Institute, , University of Cambridge, ; Cambridge, UK
                [39 ]ISNI 0000000121885934, GRID grid.5335.0, University of Cambridge, ; Cambridge, UK
                [40 ]Sidra Medicine, Doha, Qatar
                [41 ]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
                [42 ]ISNI 0000 0004 1937 0503, GRID grid.22098.31, The Azrieli Faculty of Medicine, Bar-Ilan University, ; Safed, Israel
                [43 ]ISNI 0000 0001 2097 5006, GRID grid.16750.35, Department of Computer Science, , Princeton University, ; Princeton, NJ USA
                [44 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Computer Science, , Yale University, ; New Haven, CT USA
                [45 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Molecular Biophysics and Biochemistry, , Yale University, ; New Haven, CT USA
                [46 ]ISNI 0000000419368710, GRID grid.47100.32, Program in Computational Biology and Bioinformatics, , Yale University, ; New Haven, CT USA
                [47 ]ISNI 0000 0001 0740 6917, GRID grid.205975.c, Biomolecular Engineering Department, , University of California, Santa Cruz, ; Santa Cruz, CA USA
                [48 ]ISNI 0000 0004 1936 9473, GRID grid.253264.4, Brandeis University, ; Waltham, MA USA
                [49 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Massachusetts General Hospital Center for Cancer Research, ; Charlestown, MA USA
                [50 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, German Cancer Consortium (DKTK), ; Heidelberg, Germany
                [51 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Heidelberg Center for Personalized Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [52 ]GRID grid.429884.b, New York Genome Center, ; New York, NY USA
                [53 ]ISNI 000000041936877X, GRID grid.5386.8, Weill Cornell Medicine, ; New York, NY USA
                [54 ]Hopp Children’s Cancer Center (KiTZ), Heidelberg, Germany
                [55 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [56 ]ISNI 0000 0001 2292 0500, GRID grid.37172.30, Korea Advanced Institute of Science and Technology, ; Daejeon, South Korea
                [57 ]ISNI 0000 0004 0555 3608, GRID grid.454320.4, Skolkovo Institute of Science and Technology, ; Moscow, Russia
                [58 ]ISNI 0000 0004 0619 6198, GRID grid.435025.5, A. A. Kharkevich Institute of Information Transmission Problems, ; Moscow, Russia
                [59 ]GRID grid.465331.6, Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, ; Moscow, Russia
                [60 ]ISNI 0000 0001 0302 820X, GRID grid.412484.f, Center For Medical Innovation, Seoul National University Hospital, ; Seoul, South Korea
                [61 ]ISNI 0000 0001 0302 820X, GRID grid.412484.f, Department of Internal Medicine, , Seoul National University Hospital, ; Seoul, South Korea
                [62 ]ISNI 0000 0000 9709 7726, GRID grid.225360.0, European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), ; Hinxton, UK
                [63 ]ISNI 0000 0004 0495 846X, GRID grid.4709.a, Genome Biology Unit, European Molecular Biology Laboratory (EMBL), ; Heidelberg, Germany
                [64 ]ISNI 0000 0004 0378 8438, GRID grid.2515.3, Division of Genetics and Genomics, , Boston Children’s Hospital and Harvard Medical School, ; Boston, MA USA
                [65 ]ISNI 0000 0001 0721 1626, GRID grid.11914.3c, School of Medicine/School of Mathematics and Statistics, , University of St Andrews, ; St Andrews, UK
                [66 ]ISNI 000000041936877X, GRID grid.5386.8, Department of Physiology and Biophysics, , Weill Cornell Medicine, ; New York, NY USA
                [67 ]ISNI 000000041936877X, GRID grid.5386.8, Englander Institute for Precision Medicine, Weill Cornell Medicine, ; New York, NY USA
                [68 ]ISNI 000000041936877X, GRID grid.5386.8, Institute for Computational Biomedicine, Weill Cornell Medicine, ; New York, NY USA
                [69 ]ISNI 0000 0001 2106 9910, GRID grid.65499.37, Dana-Farber Cancer Institute, ; Boston, MA USA
                [70 ]ISNI 0000 0001 2151 536X, GRID grid.26999.3d, The Institute of Medical Science, , The University of Tokyo, ; Tokyo, Japan
                [71 ]RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
                [72 ]GRID grid.11478.3b, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, ; Barcelona, Spain
                [73 ]ISNI 0000 0001 2190 1447, GRID grid.10392.39, Institute of Medical Genetics and Applied Genomics, , University of Tübingen, ; Tübingen, Germany
                [74 ]ISNI 0000 0001 2172 2676, GRID grid.5612.0, Universitat Pompeu Fabra (UPF), ; Barcelona, Spain
                [75 ]ISNI 0000 0001 2294 1395, GRID grid.1049.c, Department of Genetics and Computational Biology, , QIMR Berghofer Medical Research Institute, ; Brisbane, Queensland Australia
                [76 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, Institute for Molecular Bioscience, , University of Queensland, ; Brisbane, Queensland Australia
                [77 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [78 ]ISNI 0000 0001 2157 6568, GRID grid.30064.31, School of Molecular Biosciences and Center for Reproductive Biology, , Washington State University, ; Pullman, WA USA
                [79 ]ISNI 0000 0001 2106 9910, GRID grid.65499.37, Department of Cancer Biology, , Dana-Farber Cancer Institute, ; Boston, MA USA
                [80 ]GRID grid.475435.4, Finsen Laboratory, Righospitalet, ; Copenhagen, Denmark
                [81 ]ISNI 0000 0000 9011 8547, GRID grid.239395.7, Cancer Research Institute, Beth Israel Deaconess Medical Center, ; Boston, MA USA
                [82 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Sir Peter MacCallum Department of Oncology, , University of Melbourne, ; Melbourne, Victoria Australia
                [83 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, , University of Copenhagen, ; Copenhagen, Denmark
                [84 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, Faculty of Biosciences, , Heidelberg University, ; Heidelberg, Germany
                [85 ]ISNI 0000 0000 9601 989X, GRID grid.425902.8, Institució Catalana de Recerca i Estudis Avançats (ICREA), ; Barcelona, Spain
                [86 ]ISNI 0000 0001 2218 4662, GRID grid.6363.0, Department of Urology, , Charité Universitätsmedizin Berlin, ; Berlin, Germany
                [87 ]ISNI 000000041936877X, GRID grid.5386.8, Tri-Institutional PhD Program of Computational Biology and Medicine, Weill Cornell Medicine, ; New York, NY USA
                Author information
                http://orcid.org/0000-0002-2036-494X
                http://orcid.org/0000-0003-1348-4094
                http://orcid.org/0000-0001-7545-7361
                http://orcid.org/0000-0002-8399-1836
                http://orcid.org/0000-0003-3048-2576
                http://orcid.org/0000-0001-8825-7158
                http://orcid.org/0000-0001-9378-960X
                Article
                576
                10.1038/s41588-019-0576-7
                7058534
                32025003
                16138984-12c1-4852-9a7a-9b031513ea1c
                © 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
                : 28 May 2018
                : 20 December 2019
                Funding
                Funded by: Ludwig Center at Harvard
                Funded by: FundRef https://doi.org/10.13039/100010686, EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology);
                Award ID: 703543
                Award Recipient :
                Funded by: National Cancer Institute: K22CA193848
                Funded by: US National Institutes of Health Intramural Research Program Project Z1AES103266
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                © The Author(s), under exclusive licence to Springer Nature America, Inc. 2020

                Genetics
                cancer,computational biology and bioinformatics,genomics
                Genetics
                cancer, computational biology and bioinformatics, genomics

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