Chromoanagenesis: Cataclysms Behind Complex Chromosomal Rearrangements Franck Pellestor1,2
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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. -
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. -
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. -
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. -
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. -
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. -
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. -
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. -
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. -
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. -
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. -
Chromothripsis-Like Patterns Are Recurring but Heterogeneously
Cai et al. BMC Genomics 2014, 15:82 http://www.biomedcentral.com/1471-2164/15/82 RESEARCH ARTICLE Open Access Chromothripsis-like patterns are recurring but heterogeneously distributed features in a survey of 22,347 cancer genome screens Haoyang Cai1,2, Nitin Kumar1,2, Homayoun C Bagheri3, Christian von Mering1,2, Mark D Robinson1,2* and Michael Baudis1,2* Abstract Background: Chromothripsis is a recently discovered phenomenon of genomic rearrangement, possibly arising during a single genome-shattering event. This could provide an alternative paradigm in cancer development, replacing the gradual accumulation of genomic changes with a “one-off” catastrophic event. However, the term has been used with varying operational definitions, with the minimal consensus being a large number of locally clustered copy number aberrations. The mechanisms underlying these chromothripsis-like patterns (CTLP) and their specific impact on tumorigenesis are still poorly understood. Results: Here, we identified CTLP in 918 cancer samples, from a dataset of more than 22,000 oncogenomic arrays covering 132 cancer types. Fragmentation hotspots were found to be located on chromosome 8, 11, 12 and 17. Among the various cancer types, soft-tissue tumors exhibited particularly high CTLP frequencies. Genomic context analysis revealed that CTLP rearrangements frequently occurred in genomes that additionally harbored multiple copy number aberrations (CNAs). An investigation into the affected chromosomal regions showed a large proportion of arm-level pulverization and telomere related events, which would be compatible to a number of underlying mechanisms. We also report evidence that these genomic events may be correlated with patient age, stage and survival rate. Conclusions: Through a large-scale analysis of oncogenomic array data sets, this study characterized features associated with genomic aberrations patterns, compatible to the spectrum of “chromothripsis”-definitions as previously used.