DOCSLIB.ORG

The Ins and Outs of Telomere Crisis in Cancer Patrick Von Morgen and John Maciejowski*

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Ins and Outs of Telomere Crisis in Cancer Patrick Von Morgen and John Maciejowski* von Morgen and Maciejowski Genome Medicine (2018) 10:89 https://doi.org/10.1186/s13073-018-0596-4 COMMENT Open Access The ins and outs of telomere crisis in cancer Patrick von Morgen and John Maciejowski* – Editorial summary telomere telomere fusion and the creation of dicentric chromosomes (Fig. 1a). Although dicentric chromo- Telomere crisis is linked with many of the genomic somes are recognized as precipitants of instability, the alterations found in cancer genomes. A new precise mechanisms that give rise to genomic alteration understanding of how these alterations arise points during telomere crisis are not well understood. Intact di- towards an active role for innate immune sensors centric chromosomes persist throughout mitosis and de- during crisis and to new opportunities for the velop into DNA bridges [1]. DNA bridges trigger treatment and diagnosis of cancer. nuclear envelope rupturing in cells that have dicentric chromosomes, leading to their partial degradation by Three prime repair exonuclease 1 (TREX1), a cytosolic Telomere crisis shapes the cancer genome exonuclease that clears cytosolic DNA to prevent Telomeres protect genomic integrity by masking natural autoimmunity. chromosome ends from the DNA damage response and Nuclear envelope rupturing may be an important repair pathways. The erosion of telomeric sequence due to driver of genomic alteration during telomere crisis. Out- incomplete replication compromises this protection with side of telomere crisis, nuclear envelope rupturing broad consequences for aging. In the context of cancer, occurs in micronuclei, aberrant nuclear structures telomere shortening can exert a tumor-suppressive effect formed after errors in cell division, where it has been by enforcing a proliferation arrest. On the other hand, telo- linked with DNA damage and chromothripsis [4, 5]. Pri- mere deprotection can also enable cancer growth through mary nuclei can also undergo nuclear envelope ruptur- telomere crisis, a state of extensive genomic instability and ing in the context of p53 or Rb deficiency or during cell cell death. Telomere crisis causes numerous, cancer-rele- migration through tight constrictions [6]. Loss of nuclear vant genome alterations, including translocations, amplifi- compartmentalization in this context induces immediate cations, and deletions, and has now been linked with the DNA damage. The causes of nuclear envelope failure genesis of the mutational phenomena chromothripsis and during telomere crisis are not known but may derive kataegis [1]. Chromothripsis is characterized by clusters of from insufficient lamina coating, nuclear compression chromosome rearrangements that occur in a single event. or, as recently suggested, insufficient integration of spe- Although initially estimated to be present in only ~ 3% of cific nuclear envelope proteins [4]. cancers, revised estimates suggest that chromothripsis is The induction of APOBEC3 mutagenesis is another pervasive, with a frequency > 50% in several cancer types threat to genomic integrity during telomere crisis. The [2]. Kataegis is defined by the presence of clusters of cyto- APOBEC3s are a family of cytosine deaminases that spe- sine mutations, which are hypothesized to be caused by cifically target single-stranded DNA as part of their APOBEC3 (apolipoprotein B mRNA-editing enzyme, cata- normal function as anti-viral restriction factors. An lytic polypeptide-like 3)-catalyzed cytosine deamination [3]. APOBEC3-linked mutational signature is found in at least 22 cancer types, in which it can occur at high fre- quency. APOBEC3 mutations often cluster at rearrange- Sources of DNA damage in telomere crisis ment breakpoints, where they are termed kataegis During telomere crisis, the aberrant activation of DNA clusters, or they can be dispersed throughout the gen- repair pathways at natural chromosome ends results in ome. Observations to date suggest that APOBEC3 muta- * Correspondence: [email protected] genesis during telomere crisis is limited to kataegis Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan clusters. The cause of APOBEC3 dysfunction during Kettering Cancer Center, New York, NY 10065, USA © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. von Morgen and Maciejowski Genome Medicine (2018) 10:89 Page 2 of 4 (a) Dysfunctional telomeres (b) TERT locus Promoter 5’ UTR Telomere–telomere fusion –146C>T –124C>T TSS –43C>T ATG Dicentric chromosome –58 –34C>T 1 –29G>A Cell division errors ? Nuclear GABP MAX-MAD1 envelope transcriptional Transcriptional TREX1 failures activation repression DNA bridge cGAS (c) Dysfunctional telomeres Chromothripsis and kataegis * * Telomerase * * reactivation * * Pro-inflammatory IFN-β signaling? Telomere healing Fig. 1 a Dicentric chromosomes are formed by the fusion of dysfunctional telomeres during telomere crisis. Intact dicentrics persist through mitosis and form DNA bridges, which induce nuclear envelope failures resulting in the accumulation of Three prime repair exonuclease 1 (TREX1) and cyclic GMP-AMP synthase (cGAS) on the bridge DNA. Parts of the dicentric chromosome that are present in the DNA bridge undergo TREX1-mediated resection and extensive fragmentation. The fragmented chromosome undergoes haphazard repair, yielding a highly rearranged chromothripsis chromosome. Chromothripsis-associated breakpoints frequently display kataegis. Nuclear envelope failures at DNA bridges may result in a cGAS- dependent pro-inflammatory response. b Mutations in the telomerase reverse transcriptase (TERT) promoter drive telomerase reactivation through the creation of a GABP transcription factor binding site. Recently identified, recurrent mutations in the TERT 5′ untranslated region (UTR) associate with longer telomere length in clear cell renal cell carcinomas and are hypothesized to induce telomerase reactivation via inactivation of MAX- MAD1 transcriptional repression. c Telomerase reactivation heals dysfunctional telomeres to restore genomic stability and to provide a path out of telomere crisis crisis is not known but may be related to the observed and triggers a wide-ranging, anti-viral response that in- accumulation of single-stranded DNA at DNA bridges cludes the induction of type I interferons and other [1]. Likewise, the relationship between APOBEC3 muta- pro-inflammatory genes. The cGAS-STING pathway senses genesis and rearrangement breakpoints is not and responds to cytosolic DNA species that accumulate as well-defined but may reflect an active role for a result of genomic instability by activating an IRF3- and APOBEC3-dependent deamination in triggering DNA NFκB-dependent pro-inflammatory, transcriptional re- double-strand breaks and consequent chromosome sponse. This inflammatory response can induce senescence rearrangements. and even apoptosis and thus have pronounced effects on It is likely that TREX1 is not the only cytosolic factor to cancer cells. The full impact of this inflammatory response engage genomic DNA during telomere crisis. Loss of func- in a clinical setting is not known, but there is evidence that tion mutations in the Trex1 gene cause Aicardi-Goutières it can influence the efficacy of radio- and immunotherapies. syndrome, which is characterized by elevated type I inter- We speculate that the cGAS-STING pathway promotes feron levels and severe encephalitis. These symptoms have replicative senescence and limits escape from telomere cri- been linked with activation of the cyclic GMP-AMP syn- sis. In support of this view, cGAS, the DNA-sensing com- thase (cGAS)-stimulator of interferon genes (STING) cyto- ponent of this pathway, has been previously observed at solic DNA-sensing pathway, which detects cytosolic DNA DNA bridges [7]. von Morgen and Maciejowski Genome Medicine (2018) 10:89 Page 3 of 4 Telomerase activation: the path out of crisis result of its engagement of other components of the Genomic rearrangements that are induced during telo- cGAS-STING signaling pathway in addition to TREX1. mere crisis may contribute to carcinogenesis by driving cGAS and STING have pivotal roles in cancer immunity genetic change, but these alterations cannot accumulate and in the anti-tumor effects of immune checkpoint indefinitely because they would eventually inhibit cancer blockade. With this in mind, cGAS-STING activation by growth. Escape from telomere crisis requires re-activation DNA bridges may promote cancer immunogenicity. We of the telomerase reverse transcriptase (TERT), which is speculate that this pathway could boost the anti-tumor normally silenced during development. Telomerase can benefits of therapies targeting telomere maintenance. enable escape from telomere crisis by synthesizing telo- Future work will determine the extent of cGAS-STING meric repeats de novo at chromosome ends, thus healing activation during telomere crisis and how this activation shortened telomeres and restoring the capacity for DNA impacts cell viability, escape from crisis, immune en- proliferation. gagement,
Load more

Recommended publications
  • Intratumor Heterogeneity: Novel Approaches for Resolving Genomic Architecture and Clonal Evolution Ravi G
    Published OnlineFirst June 8, 2017; DOI: 10.1158/1541-7786.MCR-17-0070 Review Molecular Cancer Research Intratumor Heterogeneity: Novel Approaches for Resolving Genomic Architecture and Clonal Evolution Ravi G. Gupta and Robert A. Somer Abstract High-throughput genomic technologies have revealed a full mutational landscape of tumors could help reconstruct remarkably complex portrait of intratumor heterogeneity in their phylogenetic trees and trace the subclonal origins of cancer and have shown that tumors evolve through a reiterative therapeutic resistance, relapsed disease, and distant metastases, process of genetic diversification and clonal selection. This the major causes of cancer-related mortality. Real-time assess- discovery has challenged the classical paradigm of clonal ment of the tumor subclonal architecture, however, remains dominance and brought attention to subclonal tumor cell limited by the high rate of errors produced by most genome- populations that contribute to the cancer phenotype. Dynamic wide sequencing methods as well as the practical difficulties evolutionary models may explain how these populations grow associated with serial tumor genotyping in patients. This review within the ecosystem of tissues, including linear, branching, focuses on novel approaches to mitigate these challenges using neutral, and punctuated patterns. Recent evidence in breast bulk tumor, liquid biopsies, single-cell analysis, and deep cancer favors branching and punctuated evolution driven by sequencing techniques. The origins of intratumor heterogene- genome instability as well as nongenetic sources of heteroge- ity and the clinical, diagnostic, and therapeutic consequences neity, such as epigenetic variation, hierarchal tumor cell orga- in breast cancer are also explored. Mol Cancer Res; 15(9); 1127–37. nization, and subclonal cell–cell interactions.
    [Show full text]
  • Chromothripsis in Human Breast Cancer
    Author Manuscript Published OnlineFirst on September 24, 2020; DOI: 10.1158/0008-5472.CAN-20-1920 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Title: Chromothripsis in human breast cancer Michiel Bolkestein1*, John K.L. Wong2*, Verena Thewes2,3*, Verena Körber4, Mario Hlevnjak2,5, Shaymaa Elgaafary3,6, Markus Schulze2,5, Felix K.F. Kommoss7, Hans-Peter Sinn7, Tobias Anzeneder8, Steffen Hirsch9, Frauke Devens1, Petra Schröter2, Thomas Höfer4, Andreas Schneeweiss3, Peter Lichter2,6, Marc Zapatka2, Aurélie Ernst1# 1Group Genome Instability in Tumors, DKFZ, Heidelberg, Germany. 2Division of Molecular Genetics, DKFZ; DKFZ-Heidelberg Center for Personalized Oncology (HIPO) and German Cancer Consortium (DKTK), Heidelberg, Germany. 3National Center for Tumor Diseases (NCT), University Hospital and DKFZ, Heidelberg, Germany. 4Division of Theoretical Systems Biology, DKFZ, Heidelberg, Germany. 5Computational Oncology Group, Molecular Diagnostics Program at the National Center for Tumor Diseases (NCT) and DKFZ, Heidelberg, Germany. 6Molecular Diagnostics Program at the National Center for Tumor Diseases (NCT) and DKFZ, Heidelberg, Germany. 7Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany. 8Patients' Tumor Bank of Hope (PATH), Munich, Germany. 9Institute of Human Genetics, Heidelberg University, Heidelberg, Germany. *these authors contributed equally Running title: Chromothripsis in human breast cancer #corresponding author: Aurélie Ernst DKFZ, Im Neuenheimer Feld 580, 69115 Heidelberg, Germany 0049 6221 42 1512 [email protected] The authors have no conflict of interest to declare. 1 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 24, 2020; DOI: 10.1158/0008-5472.CAN-20-1920 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
    [Show full text]
  • Chromothripsis During Telomere Crisis Is Independent of NHEJ And
    Downloaded from genome.cshlp.org on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press 1 Chromothripsis during telomere crisis is independent of NHEJ and 2 consistent with a replicative origin 3 4 5 Kez Cleal1, Rhiannon E. Jones1, Julia W. Grimstead1, Eric A. Hendrickson2¶, Duncan M. 6 Baird1¶* 7 8 1 Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, 9 CF14 4XN, UK. 10 11 2Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota 12 Medical School, Minneapolis, MN 55455, USA 13 14 ¶joint senior authors 15 16 *Correspondence email: [email protected] 17 18 Keywords: Telomere, genome instability, chromothripsis, kataegis, cancer. 19 1 Downloaded from genome.cshlp.org on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press 20 Abstract 21 Telomere erosion, dysfunction and fusion can lead to a state of cellular crisis characterized 22 by large-scale genome instability. We investigated the impact of a telomere-driven crisis on 23 the structural integrity of the genome by undertaking whole genome sequence analyses of 24 clonal populations of cells that had escaped crisis. Quantification of large-scale structural 25 variants revealed patterns of rearrangement consistent with chromothripsis, but formed in 26 the absence of functional non-homologous end joining pathways. Rearrangements 27 frequently consisted of short fragments with complex mutational patterns, with a repair 28 topology that deviated from randomness showing preferential repair to local regions or 29 exchange between specific loci. We find evidence of telomere involvement with an 30 enrichment of fold-back inversions demarcating clusters of rearrangements.
    [Show full text]
  • Discrepant Outcomes in Two Brazilian
    Moreira et al. Journal of Medical Case Reports 2013, 7:284 JOURNAL OF MEDICAL http://www.jmedicalcasereports.com/content/7/1/284 CASE REPORTS CASE REPORT Open Access Discrepant outcomes in two Brazilian patients with Bloom syndrome and Wilms’ tumor: two case reports Marilia Borges Moreira1,2,3*, Caio Robledo DC Quaio1, Aline Cristina Zandoná-Teixeira1, Gil Monteiro Novo-Filho1, Evelin Aline Zanardo1, Leslie Domenici Kulikowski2 and Chong Ae Kim1 Abstract Introduction: Bloom syndrome is a rare, autosomal recessive, chromosomal instability disorder caused by mutations in the BLM gene that increase the risk of developing neoplasias, particularly lymphomas and leukemias, at an early age. Case presentation: Case 1 was a 10-year-old Brazilian girl, the third child of a non-consanguineous non-Jewish family, who was born at 36 weeks of gestation and presented with severe intrauterine growth restriction. She had Bloom syndrome and was diagnosed with a unilateral Wilms’ tumor at the age of 3.5 years. She responded well to oncological treatment and has remained disease-free for the last 17 years. Case 2 was a 2-year-old Brazilian girl born to non-Jewish first-degree cousins. Her gestation was marked by intrauterine growth restriction. She had Bloom syndrome; a unilateral stage II Wilms’ tumor was diagnosed at the age of 4 years after the evaluation of a sudden onset abdominal mass. Surgical removal, neoadjuvant chemotherapy and radiotherapy were not sufficient to control the neoplasia. The tumor recurred after 8 months and she died from clinical complications. Conclusion: Our study reports the importance of rapid diagnostics and clinical follow-up of these patients.
    [Show full text]
  • Chromothripsis-Like Chromosomal Rearrangements Induced by Ionizing Radiation Using Proton Microbeam Irradiation System
    www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 9 Chromothripsis-like chromosomal rearrangements induced by ionizing radiation using proton microbeam irradiation system Maki Morishita1,2,3, Tomoki Muramatsu1, Yumiko Suto4, Momoki Hirai4, Teruaki Konishi5, Shin Hayashi1, Daichi Shigemizu6,7, Tatsuhiko Tsunoda6,7, Keiji Moriyama2,8, Johji Inazawa1,8 1Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan 2 Department of Maxillofacial Orthognathics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan 3Research Fellow of the Japan Society for the Promotion of Science, Chiyoda-ku, Tokyo, Japan 4 Biodosimetry Research Team, Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, Inage-ku, Chiba-shi, Chiba, Japan 5Research Development and Support Center, National Institute of Radiological Sciences, Inage-ku, Chiba-shi, Chiba, Japan 6Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan 7Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Tsurumi, Yokohama, Japan 8Bioresource Research Center, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan Correspondence to: Johji Inazawa, e-mail: [email protected] Keywords: cancer, chromothripsis, microbeam, irradiation, DNA damage Received: December 08, 2015 Accepted: January 24, 2016 Published: February 04, 2016 ABSTRACT Chromothripsis is the massive but highly localized chromosomal rearrangement in response to a one-step catastrophic event, rather than an accumulation of a series of subsequent and random alterations. Chromothripsis occurs commonly in various human cancers and is thought to be associated with increased malignancy and carcinogenesis. However, the causes and consequences of chromothripsis remain unclear.
    [Show full text]
  • Breast Cancer's Somatic Mutation Landscape Points to DNA Damage
    Editorial Into the eye of the storm: breast cancer’s somatic mutation landscape points to DNA damage and repair Joanne Ngeow1,2, Emily Nizialek1,2,3, Charis Eng1,2,3,4,5 1Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA; 2Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA; 3Department of Genetics and Genome Sciences, and CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA; 4Stanley Shalom Zielony Institute of Nursing Excellence, Cleveland Clinic, Cleveland, Ohio 44195, USA; 5Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA Corresponding to: Charis Eng, MD, PhD. Genomic Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, Ohio 44195, USA. Email: [email protected]. Submitted Apr 05, 2013. Accepted for publication Apr 25, 2013. doi: 10.3978/j.issn.2218-676X.2013.04.15 Scan to your mobile device or view this article at: http://www.thetcr.org/article/view/1116/html Distinguishing the handful of somatic mutations expected hotspots and result in a catastrophic mutational event. to initiate and maintain cancer growth, so-called driver The authors call this “kataegis” (from the Greek for mutations, from mutations that play no role in cancer thunderstorm): although never described before, kataegis development, passenger mutations, remains a major hurdle was remarkably common occurring, to some extent, in the for understanding the mechanisms of cancer and the design of genomes of 13 of the 21 breast cancers. Within areas of more effective treatments. Recognizing this, National Cancer kataegis, one of the more commonly seen cancer somatic Institute’s “Provocative Questions” Project (1) specifically mutation signature is an overrepresentation of C-to-T highlights the urgent need to better discriminate between and C-to-G at the TpCpX dinucleotide.
    [Show full text]
  • Mutator Catalogues and That the Proportion of CG Muta- Types
    RESEARCH HIGHLIGHTS carcinoma. Moreover, the authors of APOBEC3B mRNA were generally GENOMICS found that 60–90% of mutations in higher, indicating that this is the these tumours affected CG base pairs, major mutator across the 13 cancer Mutator catalogues and that the proportion of CG muta- types. Using carcinogenic mutation tions correlated with the expression catalogues (such as the Cancer Gene of APOBEC3B across cancer types. Census and COSMIC) the authors Because APOBECs target cytosines found that APOBEC-signature within specific sequence contexts, mutations were prevalent in a subset the authors examined the cytosine of genes considered to be drivers of mutation signatures and found, for cancer, indicating that APOBEC- example, that those signatures in mediated mutation may initiate bladder and cervical cancers were and/or drive carcinogenesis. similar, and were biased towards the Taking a broader approach, optimum APOBEC3B motif (which Alexandrov and colleagues sought STOCKBYTE is TCA). The authors also found that to assess the mutational landscape bladder, cervical, head and neck, of >7,000 cancers, using exome and breast cancer, as well as lung and whole-genome sequence The sequencing of cancer genomes adenocarcinoma and lung squamous data. Their analyses revealed 21 has confirmed the complexity of cell carcinoma, all of which had distinct mutational signatures APOBEC3B is the somatic mutations that occur in the strongest APOBEC3B-specific that occurred, to different extents a mutator in tumours. However, there seem to cytosine mutation signatures, had the and in different combinations, be some patterns in the mutation highest levels of cytosine mutation across 30 cancer types. The most several types spectra, such as preference for muta- clustering.
    [Show full text]
  • How Chaotic Is Genome Chaos?
    cancers Review How Chaotic Is Genome Chaos? James A. Shapiro Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA; [email protected] Simple Summary: Cancer genomes can undergo major restructurings involving many chromosomal locations at key stages in tumor development. This restructuring process has been designated “genome chaos” by some authors. In order to examine how chaotic cancer genome restructuring may be, the cell and molecular processes for DNA restructuring are reviewed. Examination of the action of these processes in various cancers reveals a degree of specificity that indicates genome restructuring may be sufficiently reproducible to enable possible therapies that interrupt tumor progression to more lethal forms. Abstract: Cancer genomes evolve in a punctuated manner during tumor evolution. Abrupt genome restructuring at key steps in this evolution has been called “genome chaos.” To answer whether widespread genome change is truly chaotic, this review (i) summarizes the limited number of cell and molecular systems that execute genome restructuring, (ii) describes the characteristic signatures of DNA changes that result from activity of those systems, and (iii) examines two cases where genome restructuring is determined to a significant degree by cell type or viral infection. The conclusion is that many restructured cancer genomes display sufficiently unchaotic signatures to identify the cellular systems responsible for major oncogenic transitions, thereby identifying possible targets for therapies to inhibit tumor progression to greater aggressiveness. Keywords: DNA break repair; alternative end-joining (alt-EJ); chromothripsis; chromoplexy; chro- Citation: Shapiro, J.A. How Chaotic moanasynthesis; retrotransposition; target-primed reverse transcription (TPRT); immunoglobulin Is Genome Chaos? Cancers 2021, 13, VDJ joining; class switch recombination (CSR); human papillomavirus (HPV) 1358.
    [Show full text]
  • Copy Number Signatures Predict Chromothripsis and Associate with Poor Clinical Outcomes in Patients with Newly Diagnosed Multiple Myeloma
    bioRxiv preprint doi: https://doi.org/10.1101/2020.11.24.395939; this version posted November 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Copy number signatures predict chromothripsis and associate with poor clinical outcomes in patients with newly diagnosed multiple myeloma Kylee H Maclachlan1, Even H Rustad1, Andriy Derkach2, Binbin Zheng-Lin1, Venkata Yellapantula1, Benjamin Diamond1, Malin Hultcrantz1, Bachisio Ziccheddu3, Eileen Boyle4, Patrick Blaney4, Niccolò Bolli5,6, Yanming Zhang7, Ahmet Dogan8, Alexander Lesokhin1, Gareth Morgan4, Ola Landgren9* and Francesco Maura1,10* 1. Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 2. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 3. Department of Molecular Biotechnologies and Health Sciences, University of Turin, Turin, Italy. 4. NYU Perlmutter Cancer Center, New York, NY, USA. 5. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy. 6. Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 7 Cytogenetics Laboratory, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 8 Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 9. Sylvester Comprehensive Cancer Center, University of Miami. Miami, FL, USA. 10. Department of Medicine, Weill Cornell Medical College, New York, NY, USA. *Co-senior authors Keywords: Multiple myeloma, copy number signatures, APOBEC, prognosis, chromothripsis Corresponding author: Francesco Maura, MD, Myeloma Service, Department of Medicine Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 T: +1 646.608.3934 | F: +1 646.277.7116 [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2020.11.24.395939; this version posted November 24, 2020.
    [Show full text]
  • Chromoanagenesis: Cataclysms Behind Complex Chromosomal Rearrangements Franck Pellestor1,2
    Pellestor Molecular Cytogenetics (2019) 12:6 https://doi.org/10.1186/s13039-019-0415-7 REVIEW Open Access Chromoanagenesis: cataclysms behind complex chromosomal rearrangements Franck Pellestor1,2 Abstract Background: During the last decade, genome sequencing projects in cancer genomes as well as in patients with congenital diseases and healthy individuals have led to the identification of new types of massive chromosomal rearrangements arising during single chaotic cellular events. These unanticipated catastrophic phenomenon are termed chromothripsis, chromoanasynthesis and chromoplexis., and are grouped under the name of “chromoanagenesis”. Results: For each process, several specific features have been described, allowing each phenomenon to be distinguished from each other and to understand its mechanism of formation and to better understand its aetiology. Thus, chromothripsis derives from chromosome shattering followed by the random restitching of chromosomal fragments with low copy-number change whereas chromoanasynthesis results from erroneous DNA replication of a chromosome through serial fork stalling and template switching with variable copy-number gains, and chromoplexy refers to the occurrence of multiple inter-and intra-chromosomal translocations and deletions with little or no copy- number alterations in prostate cancer. Cumulating data and experimental models have shown that chromothripsis and chromoanasynthesis may essentially result from lagging chromosome encapsulated in micronuclei or telomere attrition andend-to-endtelomerefusion.
    [Show full text]
  • Somatic Mutation Distributions in Cancer Genomes Vary with Three-Dimensional Chromatin Structure
    ARTICLES https://doi.org/10.1038/s41588-020-0708-0 Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure Kadir C. Akdemir 1 ✉ , Victoria T. Le2, Justin M. Kim1,3, Sarah Killcoyne 4,5, Devin A. King6, Ya-Ping Lin7, Yanyan Tian8,9, Akira Inoue1, Samirkumar B. Amin 10, Frederick S. Robinson 11, Manjunath Nimmakayalu12, Rafael E. Herrera6, Erica J. Lynn8, Kin Chan13,14, Sahil Seth 11,15, Leszek J. Klimczak16, Moritz Gerstung 5, Dmitry A. Gordenin 13, John O’Brien 7, Lei Li8,17, Yonathan Lissanu Deribe1,18, Roel G. Verhaak 10, Peter J. Campbell19, Rebecca Fitzgerald 4, Ashby J. Morrison 6, Jesse R. Dixon 2 ✉ and P. Andrew Futreal 1 ✉ Somatic mutations in driver genes may ultimately lead to the development of cancer. Understanding how somatic mutations accumulate in cancer genomes and the underlying factors that generate somatic mutations is therefore crucial for develop- ing novel therapeutic strategies. To understand the interplay between spatial genome organization and specific mutational processes, we studied 3,000 tumor–normal-pair whole-genome datasets from 42 different human cancer types. Our analyses reveal that the change in somatic mutational load in cancer genomes is co-localized with topologically-associating-domain boundaries. Domain boundaries constitute a better proxy to track mutational load change than replication timing measure- ments. We show that different mutational processes lead to distinct somatic mutation distributions where certain processes generate mutations in active domains, and others generate mutations in inactive domains. Overall, the interplay between three-dimensional genome organization and active mutational processes has a substantial influence on the large-scale mutation-rate variations observed in human cancers.
    [Show full text]
  • APOBEC-Induced Mutations in Human Cancers Are Strongly Enriched on the Lagging DNA Strand During Replication
    Downloaded from genome.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Research APOBEC-induced mutations in human cancers are strongly enriched on the lagging DNA strand during replication Vladimir B. Seplyarskiy,1,2,3 Ruslan A. Soldatov,1,2 Konstantin Y. Popadin,4,5 Stylianos E. Antonarakis,4,5 Georgii A. Bazykin,1,2,3 and Sergey I. Nikolaev4,5,6 1Institute of Information Transmission Problems, Russian Academy of Sciences, Moscow, Russia, 127051; 2Lomonosov Moscow State University, Moscow, Russia, 119991; 3Pirogov Russian National Research Medical University, Moscow, Russia, 117997; 4Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland; 5Institute of Genetics and Genomics in Geneva, 1211 Geneva, Switzerland; 6Service of Genetic Medicine, University Hospitals of Geneva, 1211 Geneva, Switzerland APOBEC3A and APOBEC3B, cytidine deaminases of the APOBEC family, are among the main factors causing mutations in human cancers. APOBEC deaminates cytosines in single-stranded DNA (ssDNA). A fraction of the APOBEC-induced mu- tations occur as clusters (“kataegis”) in single-stranded DNA produced during repair of double-stranded breaks (DSBs). However, the properties of the remaining 87% of nonclustered APOBEC-induced mutations, the source and the genomic distribution of the ssDNA where they occur, are largely unknown. By analyzing genomic and exomic cancer databases, we show that >33% of dispersed APOBEC-induced mutations occur on the lagging strand during DNA replication, thus un- raveling the major source of ssDNA targeted by APOBEC in cancer. Although methylated cytosine is generally more mu- tation-prone than nonmethylated cytosine, we report that methylation reduces the rate of APOBEC-induced mutations by a factor of roughly two.
    [Show full text]