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The Diverse Effects of Complex Chromosome Rearrangements and Chromothripsis in Cancer Development

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Chromosomal Instability in Cancer Cells

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 200))

Abstract

In recent years, enormous progress has been made with respect to the identification of somatic mutations that contribute to cancer development. Mutation types range from small substitutions to large structural genomic rearrangements, including complex reshuffling of the genome. Sets of mutations in individual cancer genomes may show specific signatures, which can be provoked by both exogenous and endogenous forces. One of the most remarkable mutation patterns observed in human cancers involve massive rearrangement of just a few chromosomal regions. This phenomenon has been termed chromothripsis and appears widespread in a multitude of cancer types. Chromothripsis provides a way for cancer to rapidly evolve through a one-off massive change in genome structure as opposed to a gradual process of mutation and selection. This chapter focuses on the origin, prevalence and impact of chromothripsis and related complex genomic rearrangements during cancer development.

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References

  • Adhvaryu SG et al (1988) Complex translocation involving chromosomes #1, #9, and #22 in a patient with chronic myelogenous leukemia. Cancer Genet Cytogenet 32(2):277–280

    Article  CAS  PubMed  Google Scholar 

  • Alexandrov LB et al (2013) Signatures of mutational processes in human cancer. Nature 500(7463):415–421

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Alves IT et al (2013) Gene fusions by chromothripsis of chromosome 5q in the VCaP prostate cancer cell line. Hum Genet 132(6):709–713

    Article  Google Scholar 

  • Baca SC et al (2013) Punctuated evolution of prostate cancer genomes. Cell 153(3):666–677

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bass AJ et al (2011) Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nat Genet 43(10):964–968

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bassaganyas L et al (2013) Sporadic and reversible chromothripsis in chronic lymphocytic leukemia revealed by longitudinal genomic analysis. Leukemia 27(12):2376–2379

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bayani J et al (2003) Spectral karyotyping identifies recurrent complex rearrangements of chromosomes 8, 17, and 20 in osteosarcomas. Genes Chromosomes Cancer 36(1):7–16

    Article  CAS  PubMed  Google Scholar 

  • Berger MF et al (2011) The genomic complexity of primary human prostate cancer. Nature 470(7333):214–220

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Beroukhim R et al (2007) Assessing the significance of chromosomal aberrations in cancer: methodology and application to glioma. Proc Natl Acad Sci USA 104(50):20007–20012

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Beroukhim R et al (2010) The landscape of somatic copy-number alteration across human cancers. Nature 463(7283):899–905

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bignell GR et al (2007) Architectures of somatic genomic rearrangement in human cancer amplicons at sequence-level resolution. Genome Res 17(9):1296–1303

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cai H et al (2014) Chromothripsis-like patterns are recurring but heterogeneously distributed features in a survey of 22,347 cancer genome screens. BMC Genom 15:82

    Article  Google Scholar 

  • Campbell PJ et al (2008) Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat Genet 40(6):722–729

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Campbell PJ et al (2010) The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467(7319):1109–1113

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Carter SL et al (2006) A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet 38(9):1043–1048

    Article  CAS  PubMed  Google Scholar 

  • Carter SL et al (2012) Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol 30(5):413–421

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Carvalho CM et al (2009) Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching. Hum Mol Genet 18(12):2188–2203

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chiang C et al (2012) Complex reorganization and predominant non-homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration. Nat Genet 44(4):390–397, S1

    Google Scholar 

  • Conlin LK et al (2010) Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis. Hum Mol Genet 19(7):1263–1275

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cowell JK (1982) Double minutes and homogeneously staining regions: gene amplification in mammalian cells. Annu Rev Genet 16:21–59

    Article  CAS  PubMed  Google Scholar 

  • Cowell JK, Miller OJ (1983) Occurrence and evolution of homogeneously staining regions may be due to breakage-fusion-bridge cycles following telomere loss. Chromosoma 88(3):216–221

    Article  CAS  PubMed  Google Scholar 

  • Crasta K et al (2012) DNA breaks and chromosome pulverization from errors in mitosis. Nature 482(7383):53–58

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ding L et al (2010) Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464(7291):999–1005

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Donley N, Thayer MJ (2013) DNA replication timing, genome stability and cancer: late and/or delayed DNA replication timing is associated with increased genomic instability. Semin Cancer Biol 23(2):80–89

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fitzgerald PH, Morris CM (1991) Complex chromosomal translocations in the Philadelphia chromosome leukemias. Serial translocations or a concerted genomic rearrangement? Cancer Genet Cytogenet 57(2):143–151

    Article  CAS  PubMed  Google Scholar 

  • Forment JV, Kaidi A, Jackson SP (2012) Chromothripsis and cancer: causes and consequences of chromosome shattering. Nat Rev Cancer 12(10):663–670

    Article  CAS  PubMed  Google Scholar 

  • Govind SK et al (2014) ShatterProof: operational detection and quantification of chromothripsis. BMC Bioinformatics 15:78

    Article  PubMed Central  PubMed  Google Scholar 

  • Hastings PJ, Ira G, Lupski JR (2009) A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet 5(1):e1000327

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hatch EM et al (2013) Catastrophic nuclear envelope collapse in cancer cell micronuclei. Cell 154(1):47–60

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hillmer AM et al (2011) Comprehensive long-span paired-end-tag mapping reveals characteristic patterns of structural variations in epithelial cancer genomes. Genome Res 21(5):665–675

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Holland AJ, Cleveland DW (2012) Chromoanagenesis and cancer: mechanisms and consequences of localized, complex chromosomal rearrangements. Nat Med 18(11):1630–1638

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hoogstraat M et al (2014) Genomic and transcriptomic plasticity in treatment-naive ovarian cancer. Genome Res 24(2):200–211

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Johnson RT, Rao PN (1970) Mammalian cell fusion: induction of premature chromosome condensation in interphase nuclei. Nature 226(5247):717–722

    Article  CAS  PubMed  Google Scholar 

  • Kadam PR, Nanjangud GJ, Advani SH (1990) The occurrence of variant Ph translocations in chronic myeloid leukemia (CML): a report of six cases. Hematol Oncol 8(6):303–312

    Article  CAS  PubMed  Google Scholar 

  • Kim TM et al (2013) Functional genomic analysis of chromosomal aberrations in a compendium of 8000 cancer genomes. Genome Res 23(2):217–227

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kloosterman WP, Cuppen E (2013) Chromothripsis in congenital disorders and cancer: similarities and differences. Curr Opin Cell Biol 25(3):341–348

    Article  CAS  PubMed  Google Scholar 

  • Kloosterman WP et al (2011a) Chromothripsis is a common mechanism driving genomic rearrangements in primary and metastatic colorectal cancer. Genome Biol 12(10):R103

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kloosterman WP et al (2011b) Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline. Hum Mol Genet 20(10):1916–1924

    Article  CAS  PubMed  Google Scholar 

  • Kloosterman WP et al (2012) Constitutional chromothripsis rearrangements involve clustered double-stranded DNA breaks and nonhomologous repair mechanisms. Cell Rep 1(6):648–655

    Article  CAS  PubMed  Google Scholar 

  • Kloosterman WP, Koster J, Molenaar JJ (2014) Prevalence and clinical implications of chromothripsis in cancer genomes. Curr Opin Oncol 26(1):64–72

    Article  CAS  PubMed  Google Scholar 

  • Korbel JO, Campbell PJ (2013) Criteria for inference of chromothripsis in cancer genomes. Cell 152(6):1226–1236

    Article  CAS  PubMed  Google Scholar 

  • Korbel JO et al (2007) Paired-end mapping reveals extensive structural variation in the human genome. Science 318(5849):420–426

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Leary RJ et al (2010) Development of personalized tumor biomarkers using massively parallel sequencing. Sci Transl Med 2(20):20ra14

    Google Scholar 

  • Leary RJ et al (2012) Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing. Sci Transl Med 4(162):162ra154

    Google Scholar 

  • Li Y et al (2014) Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia. Nature 508(7494):98–102

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Liu P et al (2011) Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell 146(6):889–903

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Magrangeas F et al (2011) Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients. Blood 118(3):675–678

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Maher CA, Wilson RK (2012) Chromothripsis and human disease: piecing together the shattering process. Cell 148(1–2):29–32

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Malhotra A et al (2013) Breakpoint profiling of 64 cancer genomes reveals numerous complex rearrangements spawned by homology-independent mechanisms. Genome Res 23(5):762–776

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mardis ER (2009) New strategies and emerging technologies for massively parallel sequencing: applications in medical research. Genome Med 1(4):40

    Article  PubMed Central  PubMed  Google Scholar 

  • McBride DJ et al (2010) Use of cancer-specific genomic rearrangements to quantify disease burden in plasma from patients with solid tumors. Genes Chromosomes Cancer 49(11):1062–1069

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • McBride DJ et al (2012) Tandem duplication of chromosomal segments is common in ovarian and breast cancer genomes. J Pathol 227(4):446–455

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • McEvoy J et al (2014) RB1 gene inactivation by chromothripsis in human retinoblastoma. Oncotarget 5(2):438–450

    Article  PubMed Central  PubMed  Google Scholar 

  • Mehine M et al (2013) Characterization of uterine leiomyomas by whole-genome sequencing. N Engl J Med 369(1):43–53

    Article  CAS  PubMed  Google Scholar 

  • Mitelman F, Johansson B, Mertens F (2007) The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer 7(4):233–245

    Article  CAS  PubMed  Google Scholar 

  • Molenaar JJ et al (2012) Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature 483(7391):589–593

    Article  CAS  PubMed  Google Scholar 

  • Moore JK, Haber JE (1996) Cell cycle and genetic requirements of two pathways of nonhomologous end-joining repair of double-strand breaks in Saccharomyces cerevisiae. Mol Cell Biol 16(5):2164–2173

    PubMed Central  CAS  PubMed  Google Scholar 

  • Moorman AV et al (2007) Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21). Blood 109(6):2327–2330

    Article  CAS  PubMed  Google Scholar 

  • Morin RD et al (2013) Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing. Blood 122(7):1256–1265

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Morrison CD et al (2014) Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer. Proc Natl Acad Sci USA 111(6):E672–E681

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nik-Zainal S et al (2012) Mutational processes molding the genomes of 21 breast cancers. Cell 149(5):979–993

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nilbert M et al (1989) Complex karyotypic anomalies in a bizarre leiomyoma of the uterus. Genes Chromosomes Cancer 1(2):131–134

    Article  CAS  PubMed  Google Scholar 

  • Nishi Y, Akiyama K, Korf BR (1992) Characterization of N-myc amplification in a human neuroblastoma cell line by clones isolated following the phenol emulsion reassociation technique and by hexagonal field gel electrophoresis. Mamm Genome 2(1):11–20

    Article  CAS  PubMed  Google Scholar 

  • Northcott PA et al (2012) Subgroup-specific structural variation across 1000 medulloblastoma genomes. Nature 488(7409):49–56

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Parker M et al (2014) C11orf95-RELA fusions drive oncogenic NF-kappaB signalling in ependymoma. Nature 506(7489):451–455

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rausch T et al (2012) Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 148(1–2):59–71

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rosson D, Reddy EP (1988) Activation of the abl oncogene and its involvement in chromosomal translocations in human leukemia. Mutat Res 195(3):231–243

    Article  CAS  PubMed  Google Scholar 

  • Rowley JD (1973) Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243(5405):290–293

    Article  CAS  PubMed  Google Scholar 

  • Shimizu N (2009) Extrachromosomal double minutes and chromosomal homogeneously staining regions as probes for chromosome research. Cytogenet Genome Res 124(3–4):312–326

    Article  CAS  PubMed  Google Scholar 

  • Shimizu N et al (2005) When, where and how the bridge breaks: anaphase bridge breakage plays a crucial role in gene amplification and HSR generation. Exp Cell Res 302(2):233–243

    Article  CAS  PubMed  Google Scholar 

  • Shtivelman E et al (1985) Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature 315(6020):550–554

    Article  CAS  PubMed  Google Scholar 

  • Solinas-Toldo S et al (1997) Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances. Genes Chromosomes Cancer 20(4):399–407

    Article  CAS  PubMed  Google Scholar 

  • Sorzano CO et al (2013) Chromothripsis: breakage-fusion-bridge over and over again. Cell Cycle 12(13):2016–2023

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sperling K, Rao PN (1974) Mammalian cell fusion. V. Replication behaviour of heterochromatin as observed by premature chromosome condensation. Chromosoma 45(2):121–131

    Article  CAS  PubMed  Google Scholar 

  • Stephens PJ et al (2009) Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462(7276):1005–1010

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Stephens PJ et al (2011) Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144(1):27–40

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Taylor BJ et al (2013) DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis. Elife 2:e00534

    Article  PubMed Central  PubMed  Google Scholar 

  • Terradas M et al (2009) DNA lesions sequestered in micronuclei induce a local defective-damage response. DNA Repair (Amst) 8(10):1225–1234

    Article  CAS  Google Scholar 

  • Vogelstein B et al (2013) Cancer genome landscapes. Science 339(6127):1546–1558

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yang L et al (2013) Diverse mechanisms of somatic structural variations in human cancer genomes. Cell 153(4):919–929

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zack TI et al (2013) Pan-cancer patterns of somatic copy number alteration. Nat Genet 45(10):1134–1140

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang F et al (2009) The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans. Nat Genet 41(7):849–853

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang W et al (2011) DNA damage response is suppressed by the high cyclin-dependent kinase 1 activity in mitotic mammalian cells. J Biol Chem 286(41):35899–35905

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang CZ, Leibowitz ML, Pellman D (2013) Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements. Genes Dev 27(23):2513–2530

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang CZ et al (2015) Chromothripsis from DNA damage in micronuclei. Nature 522(7555):179–184

    Google Scholar 

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Authors and Affiliations

  1. Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands

    Mirjam S. de Pagter & Wigard P. Kloosterman

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  1. Mirjam S. de Pagter
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  2. Wigard P. Kloosterman
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Correspondence to Wigard P. Kloosterman .

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Editors and Affiliations

  1. Visceral and Pediatric Surgery, Department of General, Göttingen, Germany

    B. Michael Ghadimi

  2. Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA

    Thomas Ried

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de Pagter, M.S., Kloosterman, W.P. (2015). The Diverse Effects of Complex Chromosome Rearrangements and Chromothripsis in Cancer Development. In: Ghadimi, B., Ried, T. (eds) Chromosomal Instability in Cancer Cells. Recent Results in Cancer Research, vol 200. Springer, Cham. https://doi.org/10.1007/978-3-319-20291-4_8

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  • DOI: https://doi.org/10.1007/978-3-319-20291-4_8

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