Skip to main content
SpringerLink
Log in

To Build or To Break: The Dual Impact of Interspersed Transposable Elements in Cancer

  • Chapter
  • First Online:
Human Genome Structure, Function and Clinical Considerations

  • 1371 Accesses

Abstract

Transposable elements (TEs) are sequences capable of “jumping” from one point to another in our DNA through different mechanisms. These genetic elements make up most of our genome and through the evolutionary time, they have been co-opted as a valuable resource to be part of the host regulatory network, given rise to transcription factor binding sites, enhancers, non-coding RNAs, and others. On the other hand, untamed and active elements that evade controlling cellular mechanisms can have a detrimental impact on cellular homeostasis. Studies have shown that TEs are implicated in the pathogenesis of various diseases, including cancer. In this case, their activity can result in somatically acquired insertions, which may cause driver mutations and genomic instability, resulting in a variety of alterations associated with the cancer hallmarks such as immortalization, immune evasion, inflammation, and metastasis, among others. In this chapter, we discuss the diversity and regulation of transposable elements, their impact in our genome, and delve into how their expression can promote tumor progression, impact cancer treatment response, and their possible uses in cancer precision medicine.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Bibliography

  1. McClintock B. The origin and behavior of mutable loci in maize. Proc Natl Acad Sci U S A. 1950;36:344–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. McClintock B. Intranuclear systems controlling gene action and mutation. Brookhaven Symp Biol. 1956:58–74.

    Google Scholar 

  3. Guio L, González J. New insights on the evolution of genome content: population dynamics of transposable elements in flies and humans. Methods Mol Biol. 2019;1910:505–30.

    Article  CAS  PubMed  Google Scholar 

  4. Platt RN, Vandewege MW, Ray DA. Mammalian transposable elements and their impacts on genome evolution. Chromosom Res. 2018;26:25–43.

    Article  CAS  Google Scholar 

  5. Platt RN, Blanco-Berdugo L, Ray DA. Accurate transposable element annotation is vital when analyzing new genome assemblies. Genome Biol Evol. 2016;8:403–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nishihara H. Transposable elements as genetic accelerators of evolution: contribution to genome size, gene regulatory network rewiring and morphological innovation. Genes Genet Syst. 2020;94:269–81.

    Article  PubMed  CAS  Google Scholar 

  7. Ricci M, Peona V, Guichard E, Taccioli C, Boattini A. Transposable elements activity is positively related to rate of speciation in mammals. J Mol Evol. 2018;86:303–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860–921.

    Article  CAS  PubMed  Google Scholar 

  9. de Koning APJ, Gu W, Castoe TA, Batzer MA, Pollock DD. Repetitive elements may comprise over two-thirds of the human genome. PLoS Genet. 2011;7:e1002384.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Finnegan DJ. Eukaryotic transposable elements and genome evolution. Trends Genet. 1989;5:103–7.

    Article  CAS  PubMed  Google Scholar 

  11. Sultana T, Zamborlini A, Cristofari G, Lesage P. Integration site selection by retroviruses and transposable elements in eukaryotes. Nat Rev Genet. 2017;18:292–308.

    Article  CAS  PubMed  Google Scholar 

  12. Wicker T, Sabot F, Hua-Van A, et al. A unified classification system for eukaryotic transposable elements. Nat Rev Genet. 2007;8:973–82.

    Article  CAS  PubMed  Google Scholar 

  13. Kapitonov VV, Jurka J. A universal classification of eukaryotic transposable elements implemented in Repbase. Nat Rev Genet. 2008;9:411–2. author reply 414

    Article  PubMed  Google Scholar 

  14. Arkhipova IR. Using bioinformatic and phylogenetic approaches to classify transposable elements and understand their complex evolutionary histories. Mob DNA. 2017;8:19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Kojima KK. Structural and sequence diversity of eukaryotic transposable elements. Genes Genet Syst. 2020;94:233–52.

    Article  PubMed  CAS  Google Scholar 

  16. Bao W, Kojima KK, Kohany O. Repbase update, a database of repetitive elements in eukaryotic genomes. Mob DNA. 2015;6:11.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kojima KK. Human transposable elements in Repbase: genomic footprints from fish to humans. Mob DNA. 2018;9:2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Ray DA, Feschotte C, Pagan HJT, Smith JD, Pritham EJ, Arensburger P, Atkinson PW, Craig NL. Multiple waves of recent DNA transposon activity in the bat, Myotis lucifugus. Genome Res. 2008;18:717–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mitra R, Li X, Kapusta A, Mayhew D, Mitra RD, Feschotte C, Craig NL. Functional characterization of piggyBat from the bat Myotis lucifugus unveils an active mammalian DNA transposon. Proc Natl Acad Sci U S A. 2013;110:234–9.

    Article  CAS  PubMed  Google Scholar 

  20. Huang S, Tao X, Yuan S, et al. Discovery of an active RAG transposon illuminates the origins of V(D)J recombination. Cell. 2016;166:102–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Carmona LM, Schatz DG. New insights into the evolutionary origins of the recombination-activating gene proteins and V(D)J recombination. FEBS J. 2017;284:1590–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kapitonov VV, Koonin EV. Evolution of the RAG1-RAG2 locus: both proteins came from the same transposon. Biol Direct. 2015;10:20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Pavelitz T, Gray LT, Padilla SL, Bailey AD, Weiner AM. PGBD5: a neural-specific intron-containing piggyBac transposase domesticated over 500 million years ago and conserved from cephalochordates to humans. Mob DNA. 2013;4:23.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Henssen AG, Henaff E, Jiang E, et al. Genomic DNA transposition induced by human PGBD5. elife. 2015;4:e10565. https://doi.org/10.7554/eLife.10565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Majumdar S, Singh A, Rio DC. The human THAP9 gene encodes an active P-element DNA transposase. Science. 2013;339:446–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cappello J, Handelsman K, Lodish HF. Sequence of Dictyostelium DIRS-1: an apparent retrotransposon with inverted terminal repeats and an internal circle junction sequence. Cell. 1985;43:105–15.

    Article  CAS  PubMed  Google Scholar 

  27. Malicki M, Spaller T, Winckler T, Hammann C. DIRS retrotransposons amplify via linear, single-stranded cDNA intermediates. Nucleic Acids Res. 2020;48:4230–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ishak CA, De Carvalho DD. Reactivation of endogenous retroelements in cancer development and therapy. Annu Rev Cancer Biol. 2020;4:159–76. https://doi.org/10.1146/annurev-cancerbio-030419-033525.

    Article  Google Scholar 

  29. Weiss RA. Human endogenous retroviruses: friend or foe? APMIS. 2016;124:4–10.

    Article  PubMed  Google Scholar 

  30. Wildschutte JH, Williams ZH, Montesion M, Subramanian RP, Kidd JM, Coffin JM. Discovery of unfixed endogenous retrovirus insertions in diverse human populations. Proc Natl Acad Sci U S A. 2016;113:E2326–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dupressoir A, Lavialle C, Heidmann T. From ancestral infectious retroviruses to bona fide cellular genes: role of the captured syncytins in placentation. Placenta. 2012;33:663–71.

    Article  CAS  PubMed  Google Scholar 

  32. Chuong EB, Elde NC, Feschotte C. Regulatory evolution of innate immunity through co-option of endogenous retroviruses. Science. 2016;351:1083–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kellner M, Makałowski W. Transposable elements significantly contributed to the core promoters in the human genome. Sci China Life Sci. 2019;62:489–97.

    Article  CAS  PubMed  Google Scholar 

  34. Guichard E, Peona V, Malagoli Tagliazucchi G, et al. Impact of non-LTR retrotransposons in the differentiation and evolution of anatomically modern humans. Mob DNA. 2018;9:28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Feusier J, Watkins WS, Thomas J, Farrell A, Witherspoon DJ, Baird L, Ha H, Xing J, Jorde LB. Pedigree-based estimation of human mobile element retrotransposition rates. Genome Res. 2019;29:1567–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Beck CR, Garcia-Perez JL, Badge RM, Moran JV. LINE-1 elements in structural variation and disease. Annu Rev Genomics Hum Genet. 2011;12:187–215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kazazian HH, Moran JV. Mobile DNA in health and disease. N Engl J Med. 2017;377:361–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Beck CR, Collier P, Macfarlane C, Malig M, Kidd JM, Eichler EE, Badge RM, Moran JV. LINE-1 retrotransposition activity in human genomes. Cell. 2010;141:1159–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Philippe C, Vargas-Landin DB, Doucet AJ, van Essen D, Vera-Otarola J, Kuciak M, Corbin A, Nigumann P, Cristofari G. Activation of individual L1 retrotransposon instances is restricted to cell-type dependent permissive loci. elife. 2016;5:e13926. https://doi.org/10.7554/eLife.13926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hancks DC, Kazazian HH. Roles for retrotransposon insertions in human disease. Mob DNA. 2016;7:9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Deininger P. Alu elements: know the SINEs. Genome Biol. 2011;12:236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kriegs JO, Churakov G, Jurka J, Brosius J, Schmitz J. Evolutionary history of 7SL RNA-derived SINEs in supraprimates. Trends Genet. 2007;23:158–61.

    Article  CAS  PubMed  Google Scholar 

  43. Kryatova MS, Steranka JP, Burns KH, Payer LM. Insertion and deletion polymorphisms of the ancient AluS family in the human genome. Mob DNA. 2017;8:6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Konkel MK, Walker JA, Hotard AB, Ranck MC, Fontenot CC, Storer J, Stewart C, Marth GT, 1000 Genomes Consortium, Batzer MA. Sequence analysis and characterization of active human alu subfamilies based on the 1000 genomes pilot project. Genome Biol Evol. 2015;7:2608–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Zeng L, Pederson SM, Cao D, Qu Z, Hu Z, Adelson DL, Wei C. Genome-wide analysis of the association of transposable elements with gene regulation suggests that Alu elements have the largest overall regulatory impact. J Comput Biol. 2018;25:551–62.

    Article  CAS  PubMed  Google Scholar 

  46. Ono M, Kawakami M, Takezawa T. A novel human nonviral retroposon derived from an endogenous retrovirus. Nucleic Acids Res. 1987;15:8725–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Raiz J, Damert A, Chira S, Held U, Klawitter S, Hamdorf M, Löwer J, Strätling WH, Löwer R, Schumann GG. The non-autonomous retrotransposon SVA is trans-mobilized by the human LINE-1 protein machinery. Nucleic Acids Res. 2012;40:1666–83.

    Article  CAS  PubMed  Google Scholar 

  48. Larsen PA. Transposable elements and the multidimensional genome. Chromosom Res. 2018;26:1–3.

    Article  CAS  Google Scholar 

  49. Gerdes P, Richardson SR, Mager DL, Faulkner GJ. Transposable elements in the mammalian embryo: pioneers surviving through stealth and service. Genome Biol. 2016;17:100.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Yang P, Wang Y, Macfarlan TS. The role of KRAB-ZFPs in transposable element repression and mammalian evolution. Trends Genet. 2017;33:871–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Imbeault M, Helleboid P-Y, Trono D. KRAB zinc-finger proteins contribute to the evolution of gene regulatory networks. Nature. 2017;543:550–4.

    Article  CAS  PubMed  Google Scholar 

  52. Ecco G, Cassano M, Kauzlaric A, Duc J, Coluccio A, Offner S, Imbeault M, Rowe HM, Turelli P, Trono D. transposable elements and their KRAB-ZFP controllers regulate gene expression in adult tissues. Dev Cell. 2016;36:611–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Jacobs FMJ, Greenberg D, Nguyen N, Haeussler M, Ewing AD, Katzman S, Paten B, Salama SR, Haussler D. An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons. Nature. 2014;516:242–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ohtani H, Liu M, Zhou W, Liang G, Jones PA. Switching roles for DNA and histone methylation depend on evolutionary ages of human endogenous retroviruses. Genome Res. 2018;28:1147–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Smallwood SA, Kelsey G. De novo DNA methylation: a germ cell perspective. Trends Genet. 2012;28:33–42.

    Article  CAS  PubMed  Google Scholar 

  56. Messerschmidt DM, Knowles BB, Solter D. DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos. Genes Dev. 2014;28:812–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zeng Y, Chen T. DNA methylation reprogramming during mammalian development. Genes (Basel). 2019;10(4):257. https://doi.org/10.3390/genes10040257.

    Article  CAS  Google Scholar 

  58. Coluccio A, Ecco G, Duc J, Offner S, Turelli P, Trono D. Individual retrotransposon integrants are differentially controlled by KZFP/KAP1-dependent histone methylation, DNA methylation and TET-mediated hydroxymethylation in naïve embryonic stem cells. Epigenetics Chromatin. 2018;11:7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Jansz N. DNA methylation dynamics at transposable elements in mammals. Essays Biochem. 2019;63:677–89.

    Article  CAS  PubMed  Google Scholar 

  60. Helleboid P-Y, Heusel M, Duc J, et al. The interactome of KRAB zinc finger proteins reveals the evolutionary history of their functional diversification. EMBO J. 2019;38:e101220.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Pontis J, Planet E, Offner S, Turelli P, Duc J, Coudray A, Theunissen TW, Jaenisch R, Trono D. Hominoid-Specific Transposable Elements and KZFPs Facilitate Human Embryonic Genome Activation and Control Transcription in Naive Human ESCs. Cell Stem Cell. 2019;24:724–735.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Knisbacher BA, Levanon EY. DNA editing of LTR retrotransposons reveals the impact of apobecs on vertebrate genomes. Mol Biol Evol. 2016;33:554–67.

    Article  CAS  PubMed  Google Scholar 

  63. Orecchini E, Frassinelli L, Galardi S, Ciafrè SA, Michienzi A. Post-transcriptional regulation of LINE-1 retrotransposition by AID/APOBEC and ADAR deaminases. Chromosom Res. 2018;26:45–59.

    Article  CAS  Google Scholar 

  64. Yang L, Emerman M, Malik HS, McLaughlin RN. Retrocopying expands the functional repertoire of APOBEC3 antiviral proteins in primates. elife. 2020;9:e58436. https://doi.org/10.7554/eLife.58436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Moreira DA, Lamarca AP, Soares RF, Coelho AMA, Furtado C, Scherer NM, Moreira MAM, Seuánez HN, Boroni M. Transcriptome of the Southern Muriqui Brachyteles arachnoides (Primates:Platyrrhini), a critically endangered new world monkey: evidence of adaptive evolution. Front Genet. 2020;11:831.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Navarro FCP, Galante PAF. A genome-wide landscape of retrocopies in primate genomes. Genome Biol Evol. 2015;7:2265–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Orecchini E, Doria M, Antonioni A, Galardi S, Ciafrè SA, Frassinelli L, Mancone C, Montaldo C, Tripodi M, Michienzi A. ADAR1 restricts LINE-1 retrotransposition. Nucleic Acids Res. 2017;45:155–68.

    Article  CAS  PubMed  Google Scholar 

  68. Russell SJ, LaMarre J. Transposons and the PIWI pathway: genome defense in gametes and embryos. Reproduction. 2018;156:R111–24.

    CAS  PubMed  Google Scholar 

  69. Molaro A, Falciatori I, Hodges E, Aravin AA, Marran K, Rafii S, McCombie WR, Smith AD, Hannon GJ. Two waves of de novo methylation during mouse germ cell development. Genes Dev. 2014;28:1544–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Pezic D, Manakov SA, Sachidanandam R, Aravin AA. piRNA pathway targets active LINE1 elements to establish the repressive H3K9me3 mark in germ cells. Genes Dev. 2014;28:1410–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Iwasaki YW, Murano K, Ishizu H, Shibuya A, Iyoda Y, Siomi MC, Siomi H, Saito K. Piwi modulates chromatin accessibility by regulating multiple factors including histone H1 to repress transposons. Mol Cell. 2016;63:408–19.

    Article  CAS  PubMed  Google Scholar 

  72. Tóth KF, Pezic D, Stuwe E, Webster A. The piRNA pathway guards the germline genome against transposable elements. Adv Exp Med Biol. 2016;886:51–77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Goodier JL. Restricting retrotransposons: a review. Mob DNA. 2016;7:16.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Baduel P, Quadrana L, Hunter B, Bomblies K, Colot V. Relaxed purifying selection in autopolyploids drives transposable element over-accumulation which provides variants for local adaptation. Nat Commun. 2019;10:5818.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Chuong EB, Elde NC, Feschotte C. Regulatory activities of transposable elements: from conflicts to benefits. Nat Rev Genet. 2017;18:71–86.

    Article  CAS  PubMed  Google Scholar 

  76. Zhou W, Liang G, Molloy PL, Jones PA. DNA methylation enables transposable element-driven genome expansion. Proc Natl Acad Sci U S A. 2020;117:19359–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Trizzino M, Park Y, Holsbach-Beltrame M, Aracena K, Mika K, Caliskan M, Perry GH, Lynch VJ, Brown CD. Transposable elements are the primary source of novelty in primate gene regulation. Genome Res. 2017;27:1623–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Jung J, Lee S, Cho H-S, Park K, Ryu J-W, Jung M, Kim J, Kim H, Kim D-S. Bioinformatic analysis of regulation of natural antisense transcripts by transposable elements in human mRNA. Genomics. 2019;111:159–66.

    Article  CAS  PubMed  Google Scholar 

  79. Kunarso G, Chia N-Y, Jeyakani J, Hwang C, Lu X, Chan Y-S, Ng H-H, Bourque G. Transposable elements have rewired the core regulatory network of human embryonic stem cells. Nat Genet. 2010;42:631–4.

    Article  CAS  PubMed  Google Scholar 

  80. Macfarlan TS, Gifford WD, Driscoll S, Lettieri K, Rowe HM, Bonanomi D, Firth A, Singer O, Trono D, Pfaff SL. Embryonic stem cell potency fluctuates with endogenous retrovirus activity. Nature. 2012;487:57–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Grow EJ, Flynn RA, Chavez SL, et al. Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells. Nature. 2015;522:221–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Durruthy-Durruthy J, Sebastiano V, Wossidlo M, et al. The primate-specific noncoding RNA HPAT5 regulates pluripotency during human preimplantation development and nuclear reprogramming. Nat Genet. 2016;48:44–52.

    Article  CAS  PubMed  Google Scholar 

  83. Erwin JA, Marchetto MC, Gage FH. Mobile DNA elements in the generation of diversity and complexity in the brain. Nat Rev Neurosci. 2014;15:497–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Baillie JK, Barnett MW, Upton KR, et al. Somatic retrotransposition alters the genetic landscape of the human brain. Nature. 2011;479:534–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chu C, Zhao B, Park PJ, Lee EA. Identification and genotyping of transposable element insertions from genome sequencing data. Curr Protoc Hum Genet. 2020;107:e102.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Testori A, Caizzi L, Cutrupi S, Friard O, De Bortoli M, Cora’ D, Caselle M. The role of transposable elements in shaping the combinatorial interaction of transcription factors. BMC Genomics. 2012;13:400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sundaram V, Wysocka J. Transposable elements as a potent source of diverse cis-regulatory sequences in mammalian genomes. Philos Trans R Soc Lond Ser B Biol Sci. 2020;375:20190347.

    Article  CAS  Google Scholar 

  88. Kelley D, Rinn J. Transposable elements reveal a stem cell-specific class of long noncoding RNAs. Genome Biol. 2012;13:R107.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Kapusta A, Kronenberg Z, Lynch VJ, Zhuo X, Ramsay L, Bourque G, Yandell M, Feschotte C. Transposable elements are major contributors to the origin, diversification, and regulation of vertebrate long noncoding RNAs. PLoS Genet. 2013;9:e1003470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Liang Z-Z, Guo C, Zou M-M, Meng P, Zhang T-T. circRNA-miRNA-mRNA regulatory network in human lung cancer: an update. Cancer Cell Int. 2020;20:173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zou F-W, Cao D, Tang Y-F, Shu L, Zuo Z, Zhang L-Y. Identification of CircRNA-miRNA-mRNA regulatory network in gastrointestinal stromal tumor. Front Genet. 2020;11:403.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Petri R, Brattås PL, Sharma Y, Jönsson ME, Pircs K, Bengzon J, Jakobsson J. LINE-2 transposable elements are a source of functional human microRNAs and target sites. PLoS Genet. 2019;15:e1008036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Diehl AG, Ouyang N, Boyle AP. Transposable elements contribute to cell and species-specific chromatin looping and gene regulation in mammalian genomes. Nat Commun. 2020;11:1796.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kubiak MR, Makałowska I. Protein-coding genes’ retrocopies and their functions. Viruses. 2017;9(4):80. https://doi.org/10.3390/v9040080.

    Article  CAS  PubMed Central  Google Scholar 

  95. Cerbin S, Jiang N. Duplication of host genes by transposable elements. Curr Opin Genet Dev. 2018;49:63–9.

    Article  CAS  PubMed  Google Scholar 

  96. Casola C, Betrán E. The genomic impact of gene retrocopies: what have we learned from comparative genomics, population genomics, and transcriptomic analyses? Genome Biol Evol. 2017;9:1351–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Burns KH. Transposable elements in cancer. Nat Rev Cancer. 2017;17:415–24.

    Article  CAS  PubMed  Google Scholar 

  98. Jönsson ME, Garza R, Johansson PA, Jakobsson J. Transposable elements: a common feature of neurodevelopmental and neurodegenerative disorders. Trends Genet. 2020;36:610–23.

    Article  PubMed  CAS  Google Scholar 

  99. Belancio VP, Deininger PL, Roy-Engel AM. LINE dancing in the human genome: transposable elements and disease. Genome Med. 2009;1:97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Chenais B. Transposable elements in cancer and other human diseases. Curr Cancer Drug Targets. 2015;15:227–42.

    Article  CAS  PubMed  Google Scholar 

  101. Lavi E, Carmel L. Alu exaptation enriches the human transcriptome by introducing new gene ends. RNA Biol. 2018;15:715–25.

    PubMed  PubMed Central  Google Scholar 

  102. Han JS, Szak ST, Boeke JD. Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes. Nature. 2004;429:268–74.

    Article  CAS  PubMed  Google Scholar 

  103. Saze H. Epigenetic regulation of intragenic transposable elements: a two-edged sword. J Biochem. 2018;164:323–8.

    Article  CAS  PubMed  Google Scholar 

  104. Underwood CJ, Choi K. Heterogeneous transposable elements as silencers, enhancers and targets of meiotic recombination. Chromosoma. 2019;128:279–96.

    Article  CAS  PubMed  Google Scholar 

  105. Roychowdhury T, Abyzov A. Chromatin organization modulates the origin of heritable structural variations in human genome. Nucleic Acids Res. 2019;47:2766–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Nazaryan-Petersen L, Bertelsen B, Bak M, Jønson L, Tommerup N, Hancks DC, Tümer Z. Germline chromothripsis driven by L1-mediated retrotransposition and Alu/Alu homologous recombination. Hum Mutat. 2016;37:385–95.

    Article  CAS  PubMed  Google Scholar 

  107. Cortés-Ciriano I, Lee JJ-K, Xi R, et al. Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing. Nat Genet. 2020;52:331–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Guffanti G, Gaudi S, Fallon JH, Sobell J, Potkin SG, Pato C, Macciardi F. Transposable elements and psychiatric disorders. Am J Med Genet B Neuropsychiatr Genet. 2014;165B:201–16.

    Article  PubMed  CAS  Google Scholar 

  109. Misiak B, Ricceri L, Sąsiadek MM. Transposable elements and their epigenetic regulation in mental disorders: current evidence in the field. Front Genet. 2019;10:580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Payer LM, Burns KH. Transposable elements in human genetic disease. Nat Rev Genet. 2019;20:760–72.

    Article  CAS  PubMed  Google Scholar 

  111. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  112. Wang Y, Bernhardy AJ, Nacson J, et al. BRCA1 intronic Alu elements drive gene rearrangements and PARP inhibitor resistance. Nat Commun. 2019;10:5661.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. The BRCA1 Exon 13 Duplication Screening Group. The exon 13 duplication in the BRCA1 gene is a founder mutation present in geographically diverse populations. The BRCA1 Exon 13 Duplication Screening Group. Am J Hum Genet. 2000;67:207–12.

    Article  Google Scholar 

  114. Kremeyer B, Soller M, Lagerstedt K, Maguire P, Mazoyer S, Nordling M, Wahlström J, Lindblom A. The BRCA1 exon 13 duplication in the Swedish population. Familial Cancer. 2005;4:191–4.

    Article  PubMed  Google Scholar 

  115. Judkins T, Rosenthal E, Arnell C, Burbidge LA, Geary W, Barrus T, Schoenberger J, Trost J, Wenstrup RJ, Roa BB. Clinical significance of large rearrangements in BRCA1 and BRCA2. Cancer. 2012;118:5210–6.

    Article  CAS  PubMed  Google Scholar 

  116. Concolino P, Rizza R, Hackmann K, Paris I, Minucci A, De Paolis E, Scambia G, Zuppi C, Schrock E, Capoluongo E. Characterization of a new BRCA1 rearrangement in an Italian woman with hereditary breast and ovarian cancer syndrome. Breast Cancer Res Treat. 2017;164:497–503.

    Article  CAS  PubMed  Google Scholar 

  117. Su L, Zhang J, Meng H, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, Xie Y. Prevalence of BRCA1/2 large genomic rearrangements in Chinese women with sporadic triple-negative or familial breast cancer. Clin Genet. 2018;94:165–9.

    Article  CAS  PubMed  Google Scholar 

  118. van der Merwe NC, Oosthuizen J, Theron M, Chong G, Foulkes WD. The contribution of large genomic rearrangements in BRCA1 and BRCA2 to South African familial breast cancer. BMC Cancer. 2020;20:391.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Jang HS, Shah NM, Du AY, et al. Transposable elements drive widespread expression of oncogenes in human cancers. Nat Genet. 2019;51:611–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Deniz Ö, Ahmed M, Todd CD, Rio-Machin A, Dawson MA, Branco MR. Endogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia. Nat Commun. 2020;11:3506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Roulois D, Loo Yau H, Singhania R, et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell. 2015;162:961–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Sheng W, LaFleur MW, Nguyen TH, et al. LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell. 2018;174:549–563.e19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Cañadas I, Thummalapalli R, Kim JW, et al. Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses. Nat Med. 2018;24:1143–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Scott EC, Gardner EJ, Masood A, Chuang NT, Vertino PM, Devine SE. A hot L1 retrotransposon evades somatic repression and initiates human colorectal cancer. Genome Res. 2016;26:745–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Helman E, Lawrence MS, Stewart C, Sougnez C, Getz G, Meyerson M. Somatic retrotransposition in human cancer revealed by whole-genome and exome sequencing. Genome Res. 2014;24:1053–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Rodríguez-Martín C, Cidre F, Fernández-Teijeiro A, Gómez-Mariano G, de la Vega L, Ramos P, Zaballos Á, Monzón S, Alonso J. Familial retinoblastoma due to intronic LINE-1 insertion causes aberrant and noncanonical mRNA splicing of the RB1 gene. J Hum Genet. 2016;61:463–6.

    Article  PubMed  CAS  Google Scholar 

  127. Ecsedi SI, Hernandez-Vargas H, Lima SC, Herceg Z, Adany R, Balazs M. Transposable hypomethylation is associated with metastatic capacity of primary melanomas. Int J Clin Exp Pathol. 2013;6:2943–8.

    PubMed  PubMed Central  Google Scholar 

  128. Mueller C, Aschacher T, Wolf B, Bergmann M. A role of LINE-1 in telomere regulation. Front Biosci (Landmark Ed). 2018;23:1310–9.

    Article  CAS  Google Scholar 

  129. Ponomaryova AA, Rykova EY, Gervas PA, Cherdyntseva NV, Mamedov IZ, Azhikina TL. Aberrant methylation of LINE-1 transposable elements: a search for cancer biomarkers. Cell. 2020;9(9):2017. https://doi.org/10.3390/cells9092017.

    Article  CAS  Google Scholar 

  130. Faulkner GJ, Garcia-Perez JL. L1 mosaicism in mammals: extent, effects, and evolution. Trends Genet. 2017;33:802–16.

    Article  CAS  PubMed  Google Scholar 

  131. Fernández LC, Torres M, Real FX. Somatic mosaicism: on the road to cancer. Nat Rev Cancer. 2016;16:43–55.

    Article  PubMed  CAS  Google Scholar 

  132. Lieberman PM. Retrotransposon-derived p53 binding sites enhance telomere maintenance and genome protection. BioEssays. 2016;38:943–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971;68:820–3.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Kaewkhaw R, Rojanaporn D. Retinoblastoma: etiology, modeling, and treatment. Cancers (Basel). 2020;12(8):2304. https://doi.org/10.3390/cancers12082304.

    Article  CAS  Google Scholar 

  135. Miki Y, Nishisho I, Horii A, Miyoshi Y, Utsunomiya J, Kinzler KW, Vogelstein B, Nakamura Y. Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. Cancer Res. 1992;52:643–5.

    CAS  PubMed  Google Scholar 

  136. Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998;62:676–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Montagna M, Santacatterina M, Torri A, Menin C, Zullato D, Chieco-Bianchi L, D’Andrea E. Identification of a 3 kb Alu-mediated BRCA1 gene rearrangement in two breast/ovarian cancer families. Oncogene. 1999;18:4160–5.

    Article  CAS  PubMed  Google Scholar 

  138. Kim S-H, Park E-R, Cho E, Jung W-H, Jeon J-Y, Joo H-Y, Lee K-H, Shin H-J. Mael is essential for cancer cell survival and tumorigenesis through protection of genetic integrity. Oncotarget. 2017;8:5026–37.

    Article  PubMed  Google Scholar 

  139. Kong Y, Rose CM, Cass AA, et al. Transposable element expression in tumors is associated with immune infiltration and increased antigenicity. Nat Commun. 2019;10:5228.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Zhu X, Fang H, Gladysz K, Barbour JA, Wong JWH. Overexpression of transposable elements underlies immune overdrive and poor clinical outcome in cancer patients. medRxiv. 2020; https://doi.org/10.1101/2020.07.14.20129031.

  141. Babaian A, Mager DL. Endogenous retroviral promoter exaptation in human cancer. Mob DNA. 2016;7:24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373:1136–52.

    Article  PubMed  CAS  Google Scholar 

  143. Li S, Mason CE, Melnick A. Genetic and epigenetic heterogeneity in acute myeloid leukemia. Curr Opin Genet Dev. 2016;36:100–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317:2402–16.

    Article  CAS  PubMed  Google Scholar 

  145. Xu K, Yang S, Zhao Y. Prognostic significance of BRCA mutations in ovarian cancer: an updated systematic review with meta-analysis. Oncotarget. 2017;8:285–302.

    Article  PubMed  Google Scholar 

  146. Faraoni I, Graziani G. Role of BRCA mutations in cancer treatment with poly(ADP-ribose) polymerase (PARP) inhibitors. Cancers (Basel). 2018;10(12):487. https://doi.org/10.3390/cancers10120487.

    Article  CAS  Google Scholar 

  147. Deblois G, Tonekaboni SAM, Grillo G, et al. Epigenetic switch-induced viral mimicry evasion in chemotherapy-resistant breast cancer. Cancer Discov. 2020;10:1312–29.

    Article  CAS  PubMed  Google Scholar 

  148. Wellenstein MD, de Visser KE. Cancer-cell-intrinsic mechanisms shaping the tumor immune landscape. Immunity. 2018;48:399–416.

    Article  CAS  PubMed  Google Scholar 

  149. Hargadon KM, Johnson CE, Williams CJ. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol. 2018;62:29–39.

    Article  CAS  PubMed  Google Scholar 

  150. Rohaan MW, Wilgenhof S, Haanen JBAG. Adoptive cellular therapies: the current landscape. Virchows Arch. 2019;474:449–61.

    Article  PubMed  Google Scholar 

  151. Kochenderfer JN, Somerville RPT, Lu T, et al. Long-duration complete remissions of diffuse large B cell lymphoma after anti-CD19 chimeric antigen receptor T cell therapy. Mol Ther. 2017;25:2245–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Chavez JC, Bachmeier C, Kharfan-Dabaja MA. CAR T-cell therapy for B-cell lymphomas: clinical trial results of available products. Ther Adv Hematol. 2019;10:2040620719841581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Hartmann J, Schüßler-Lenz M, Bondanza A, Buchholz CJ. Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med. 2017;9:1183–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Ivics Z, Hackett PB, Plasterk RH, Izsvák Z. Molecular reconstruction of Sleeping Beauty, a Tc1-like transposon from fish, and its transposition in human cells. Cell. 1997;91:501–10.

    Article  CAS  PubMed  Google Scholar 

  155. Wang Y, Pryputniewicz-Dobrinska D, Nagy EÉ, et al. Regulated complex assembly safeguards the fidelity of Sleeping Beauty transposition. Nucleic Acids Res. 2017;45:311–26.

    Article  CAS  PubMed  Google Scholar 

  156. Chicaybam L, Abdo L, Viegas M, Marques LVC, de Sousa P, Batista-Silva LR, Alves-Monteiro V, Bonecker S, Monte-Mór B, Bonamino MH. Transposon-mediated generation of CAR-T cells shows efficient anti B-cell leukemia response after ex vivo expansion. Gene Ther. 2020;27:85–95.

    Article  CAS  PubMed  Google Scholar 

  157. Kebriaei P, Singh H, Huls MH, et al. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J Clin Invest. 2016;126:3363–76.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Clark KJ, Geurts AM, Bell JB, Hackett PB. Transposon vectors for gene-trap insertional mutagenesis in vertebrates. Genesis. 2004;39:225–33.

    Article  CAS  PubMed  Google Scholar 

  159. Converse AD, Belur LR, Gori JL, Liu G, Amaya F, Aguilar-Cordova E, Hackett PB, McIvor RS. Counterselection and co-delivery of transposon and transposase functions for Sleeping Beauty-mediated transposition in cultured mammalian cells. Biosci Rep. 2004;24:577–94.

    Article  CAS  PubMed  Google Scholar 

  160. Ma K, Fu D, Yu D, Cui C, Wang L, Guo Z, Mao C. Targeted delivery of in situ PCR-amplified Sleeping Beauty transposon genes to cancer cells with lipid-based nanoparticle-like protocells. Biomaterials. 2017;121:55–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Ahmad I, Mui E, Galbraith L, et al. Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer. Proc Natl Acad Sci U S A. 2016;113:8290–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Grisard E, Coan M, Cesaratto L, et al. Sleeping beauty genetic screen identifies miR-23b::BTBD7 gene interaction as crucial for colorectal cancer metastasis. EBioMedicine. 2019;46:79–93.

    Article  PubMed  PubMed Central  Google Scholar 

  163. Takeda H, Rust AG, Ward JM, Yew CCK, Jenkins NA, Copeland NG. Sleeping Beauty transposon mutagenesis identifies genes that cooperate with mutant Smad4 in gastric cancer development. Proc Natl Acad Sci U S A. 2016;113:E2057–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Beckmann PJ, Larson JD, Larsson AT, et al. Sleeping beauty insertional mutagenesis reveals important genetic drivers of central nervous system embryonal tumors. Cancer Res. 2019;79:905–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Guimaraes-Young A, Feddersen CR, Dupuy AJ. Sleeping beauty mouse models of cancer: microenvironmental influences on cancer genetics. Front Oncol. 2019;9:611.

    Article  PubMed  PubMed Central  Google Scholar 

  166. Chang J-H, Mou KY, Mou C-Y. Sleeping beauty transposon-mediated asparaginase gene delivery by a nanoparticle platform. Sci Rep. 2019;9:11457.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Bioinformatics and Computational Biology Lab, Division of Experimental and Translational Research, Brazilian National Cancer Institute, Rio de Janeiro, RJ, Brazil

    Daniel Andrade Moreira, Cristóvão Antunes de Lanna, Jéssica Gonçalves Vieira da Cruz & Mariana Boroni

  2. Functional Genomics and Bioinformatics Lab, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, RJ, Brazil

    Daniel Andrade Moreira

Authors
  1. Daniel Andrade Moreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cristóvão Antunes de Lanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jéssica Gonçalves Vieira da Cruz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mariana Boroni
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mariana Boroni .

Editor information

Editors and Affiliations

  1. Department of Genetics and Evolutionary Biology, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil

    Luciana Amaral Haddad

Rights and permissions

Reprints and permissions

Copyright information

© 2021 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Moreira, D.A., de Lanna, C.A., da Cruz, J.G.V., Boroni, M. (2021). To Build or To Break: The Dual Impact of Interspersed Transposable Elements in Cancer. In: Haddad, L.A. (eds) Human Genome Structure, Function and Clinical Considerations. Springer, Cham. https://doi.org/10.1007/978-3-030-73151-9_8

Download citation

Publish with us

Policies and ethics

Search

Navigation