REVIEW

Aneuploidy in pluripotent stem cells and implications for cancerous transformation

  • Jie Na , 1 ,
  • Duncan Baker 2 ,
  • Jing Zhang 1 ,
  • Peter W. Andrews 3 ,
  • Ivana Barbaric , 3
Expand
  • 1. School of Medicine, Tsinghua University, Beijing 100084, China
  • 2. Sheffield Diagnostic Genetic Services, Sheffield Children’s Hospital, Sheffield S10 2TH, UK
  • 3. Centre for Stem Cell Biology, Department of Biomedical Science, The University of Sheffield, Sheffield S10 2TN, UK

Received date: 08 Apr 2014

Accepted date: 30 Apr 2014

Published date: 27 Aug 2014

Copyright

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg

Abstract

Owing to a unique set of attributes, human pluripotent stem cells (hPSCs) have emerged as a promising cell source for regenerative medicine, disease modeling and drug discovery. Assurance of genetic stability over long term maintenance of hPSCs is pivotal in this endeavor, but hPSCs can adapt to life in culture by acquiring non-random genetic changes that render them more robust and easier to grow. In separate studies between 12.5% and 34% of hPSC lines were found to acquire chromosome abnormalities over time, with the incidence increasing with passage number. The predominant genetic changes found in hPSC lines involve changes in chromosome number and structure (particularly of chromosomes 1, 12, 17 and 20), reminiscent of the changes observed in cancer cells. In this review, we summarize current knowledge on the causes and consequences of aneuploidy in hPSCs and highlight the potential links with genetic changes observed in human cancers and early embryos. We point to the need for comprehensive characterization of mechanisms underpinning both the acquisition of chromosomal abnormalities and selection pressures, which allow mutations to persist in hPSC cultures. Elucidation of these mechanisms will help to design culture conditions that minimize the appearance of aneuploid hPSCs. Moreover, aneuploidy in hPSCs may provide a unique platform to analyse the driving forces behind the genome evolution that may eventually lead to cancerous transformation.

Cite this article

Jie Na , Duncan Baker , Jing Zhang , Peter W. Andrews , Ivana Barbaric . Aneuploidy in pluripotent stem cells and implications for cancerous transformation[J]. Protein & Cell, 2014 , 5(8) : 569 -579 . DOI: 10.1007/s13238-014-0073-9

1
Adamah DJ, Gokhale PJ, Eastwood DJ, Rajpert De-Meyts E, Goepel J, Walsh JR, Moore HD, Andrews PW(2006) Dysfunction of the mitotic:meiotic switch as a potential cause of neoplastic conversion of primordial germ cells. Int J Androl29: 219−227

DOI

2
Alagaratnam S, Lind GE, Kraggerud SM, Lothe RA, Skotheim RI(2011) The testicular germ cell tumour transcriptome. Int J Androl34: e133−e150; discussion e150−131

3
Amps K, Andrews PW, Anyfantis G, Armstrong L, Avery S, Baharvand H, Baker J, Baker D, Munoz MB, Beil S (2011) Screening ethnically diverse human embryonic stem cells identifles a chromosome 20 minimal amplicon conferring growth advantage. Nat Biotechnol29: 1132−1144

DOI

4
Andrews PW, Bronson DL, Benham F, Strickland S, Knowles BB(1980) A comparative study of eight cell lines derived from human testicular teratocarcinoma. Int J Cancer26: 269−280

DOI

5
Andrews PW, Matin MM, Bahrami AR, Damjanov I, Gokhale P, Draper JS(2005) Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin. Biochem Soc Trans33: 1526−1530

DOI

6
Atkin NB, Baker MC(1982) Speciflc chromosome change, i(12p), in testicular tumours? Lancet2: 1349

DOI

7
Avery S, Hirst AJ, Baker D, Lim CY, Alagaratnam S, Skotheim RI, Lothe RA, Pera MF, Colman A, Robson P (2013) BCL-XL mediates the strong selective advantage of a 20q11.21 ampliflcation commonly found in human embryonic stem cell cultures. Stem Cell Rep1: 379−386

8
Baker DE, Harrison NJ, Maltby E, Smith K, Moore HD, Shaw PJ, Heath PR, Holden H, Andrews PW(2007) Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nat Biotechnol25: 207−215

DOI

9
Barbaric I, Biga V, Gokhale PJ, Jones M, Stavish D, Glen A, Coca D, Andrews PW(2014) Time-lapse analysis of human embryonic stem cells reveals multiple bottlenecks restricting colony formation and their relief upon culture adaptation. Stem Cell Rep (in press)

10
Becker KA, Ghule PN, Therrien JA, Lian JB, Stein JL, van Wijnen AJ, Stein GS(2006) Self-renewal of human embryonic stem cells is supported by a shortened G1 cell cycle phase. J Cell Physiol209: 883−893

DOI

11
Ben-David U, Mayshar Y, Benvenisty N(2011) Large-scale analysis reveals acquisition of lineage-speciflc chromosomal aberrations in human adult stem cells. Cell Stem Cell9: 97−102

DOI

12
Blum B, Benvenisty N(2009) The tumorigenicity of diploid and aneuploid human pluripotent stem cells. Cell Cycle8: 3822−3830

DOI

13
Blum B, Bar-Nur O, Golan-Lev T, Benvenisty N(2009) The antiapoptotic gene survivin contributes to teratoma formation by human embryonic stem cells. Nat Biotechnol27: 281−287

DOI

14
Boise LH, Gonzalez-Garcia M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nunez G, Thompson CB(1993) bcl-x, a bcl-2- related gene that functions as a dominant regulator of apoptotic cell death. Cell74: 597−608

DOI

15
Brimble SN, Zeng X, Weiler DA, Luo Y, Liu Y, Lyons IG, Freed WJ, Robins AJ, Rao MS, Schulz TC(2004) Karyotypic stability, genotyping, differentiation, feeder-free maintenance, and gene expression sampling in three human embryonic stem cell lines derived prior to August 9, 2001. Stem Cells Dev13: 585−597

DOI

16
Buzzard JJ, Gough NM, Crook JM, Colman A(2004) Karyotype of human ES cells during extended culture. Nat Biotechnol22: 381−382 author reply 382

17
Caisander G, Park H, Frej K, Lindqvist J, Bergh C, Lundin K, Hanson C(2006) Chromosomal integrity maintained in flve human embryonic stem cell lines after prolonged in vitro culture. Chromosome Res14: 131−137

DOI

18
Chatzimeletiou K, Morrison EE, Prapas N, Prapas Y, Handyside AH(2005) Spindle abnormalities in normally developing and arrested human preimplantation embryos in vitro identifled by confocal laser scanning microscopy. Hum Reprod20: 672−682

DOI

19
Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV, Pan Y, Nezi L, Protopopov A, Chowdhury D, Pellman D(2012) DNA breaks and chromosome pulverization from errors in mitosis. Nature482: 53−58

DOI

20
de Klein A, van Kessel AG, Grosveld G, Bartram CR, Hagemeijer A, Bootsma D, Spurr NK, Heisterkamp N, Groffen J, Stephenson JR(1982) A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature300: 765−767

DOI

21
Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, Dohner K, Bentz M, Lichter P(2000) Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med343: 1910−1916

DOI

22
Draper JS, Smith K, Gokhale P, Moore HD, Maltby E, Johnson J, Meisner L, Zwaka TP, Thomson JA, Andrews PW(2004) Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells. Nat Biotechnol22: 53−54

DOI

23
Duijf PH, Benezra R(2013) The cancer biology of whole-chromosome instability. Oncogene32: 4727−4736

DOI

24
Elliott AM, Elliott KA, Kammesheidt A(2010) High resolution array- CGH characterization of human stem cells using a stem cell focused microarray. Mol Biotechnol46: 234−242

DOI

25
Enver T, Soneji S, Joshi C, Brown J, Iborra F, Orntoft T, Thykjaer T, Maltby E, Smith K, Abu Dawud R (2005) Cellular differentiation hierarchies in normal and culture-adapted human embryonic stem cells. Hum Mol Genet14: 3129−3140

DOI

26
Fazeli A, Liew CG, Matin MM, Elliott S, Jeanmeure LF, Wright PC, Moore H, Andrews PW(2011) Altered patterns of differentiation in karyotypically abnormal human embryonic stem cells. Int J Dev Biol55: 175−180

DOI

27
Fragouli E, Wells D(2011) Aneuploidy in the human blastocyst. Cytogenet Genome Res133: 149−159

DOI

28
Fragouli E, Lenzi M, Ross R, Katz-Jaffe M, Schoolcraft WB, Wells D(2008) Comprehensive molecular cytogenetic analysis of the human blastocyst stage. Hum Reprod23: 2596−2608

DOI

29
Fragouli E, Alfarawati S, Spath K, Jaroudi S, Sarasa J, Enciso M, Wells D(2013) The origin and impact of embryonic aneuploidy. Hum Genet132: 1001−1013

DOI

30
Goldring CE, Duffy PA, Benvenisty N, Andrews PW, Ben-David U, Eakins R, French N, Hanley NA, Kelly L, Kitteringham NR (2011) Assessing the safety of stem cell therapeutics. Cell Stem Cell8: 618−628

DOI

31
Hanahan D, Weinberg RA(2011) Hallmarks of cancer: the next generation. Cell144: 646−674

DOI

32
Harrison NJ, Baker D, Andrews PW(2007) Culture adaptation of embryonic stem cells echoes germ cell malignancy. Int J Androl30: 275−281discussion 281

33
Harrison NJ, Barnes J, Jones M, Baker D, Gokhale PJ, Andrews PW(2009) CD30 expression reveals that culture adaptation of human embryonic stem cells can occur through differing routes. Stem cells27: 1057−1065

DOI

34
Hassold T, Hunt P(2001) To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet2: 280−291

DOI

35
Herszfeld D, Wolvetang E, Langton-Bunker E, Chung TL, Filipczyk AA, Houssami S, Jamshidi P, Koh K, Laslett AL, Michalska A (2006) CD30 is a survival factor and a biomarker for transformed human pluripotent stem cells. Nat Biotechnol24: 351−357

DOI

36
Holland AJ, Cleveland DW(2009) Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat Rev Mol Cell Biol10: 478−487

DOI

37
Hovatta O, Jaconi M, Tohonen V, Bena F, Gimelli S, Bosman A, Holm F, Wyder S, Zdobnov EM, Irion O (2010) A teratocarcinoma-like human embryonic stem cell (hESC) line and four hESC lines reveal potentially oncogenic genomic changes. PLoS One5: e10263

DOI

38
Inzunza J, Sahlen S, Holmberg K, Stromberg AM, Teerijoki H, Blennow E, Hovatta O, Malmgren H(2004) Comparative genomic hybridization and karyotyping of human embryonic stem cells reveals the occurrence of an isodicentric X chromosome after long-term cultivation. Mol Hum Reprod10: 461−466

DOI

39
Jones MJ, Jallepalli PV(2012) Chromothripsis: chromosomes in crisis. Dev Cell23: 908−917

DOI

40
Jones KT, Lane SI(2013) Molecular causes of aneuploidy in mammalian eggs. Development140: 3719−3730

DOI

41
Korkola JE, Houldsworth J, Chadalavada RS, Olshen AB, Dobrzynski D, Reuter VE, Bosl GJ, Chaganti RS(2006) Down-regulation of stem cell genes, including those in a 200-kb gene cluster at 12p13.31, is associated with in vivo differentiation of human male germ cell tumors. Cancer Res66: 820−827

DOI

42
Laurent LC, Ulitsky I, Slavin I, Tran H, Schork A, Morey R, Lynch C, Harness JV, Lee S, Barrero MJ (2011) Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell8: 106−118

DOI

43
Lefort N, Feyeux M, Bas C, Feraud O, Bennaceur-Griscelli A, Tachdjian G, Peschanski M, Perrier AL(2008) Human embryonic stem cells reveal recurrent genomic instability at 20q11.21. Nat Biotechnol26: 1364−1366

DOI

44
Maitra A, Arking DE, Shivapurkar N, Ikeda M, Stastny V, Kassauei K, Sui G, Cutler DJ, Liu Y, Brimble SN (2005) Genomic alterations in cultured human embryonic stem cells. Nat Genet37: 1099−1103

DOI

45
Mantel C, Guo Y, Lee MR, Kim MK, Han MK, Shibayama H, Fukuda S, Yoder MC, Pelus LM, Kim KS (2007) Checkpointapoptosis uncoupling in human and mouse embryonic stem cells: a source of karyotpic instability. Blood109: 4518−4527

DOI

46
Matthaei KI, Andrews PW, Bronson DL(1983) Retinoic acid fails to induce differentiation in human teratocarcinoma cell lines that express high levels of a cellular receptor protein. Exp Cell Res143: 471−474

DOI

47
Mayshar Y, Ben-David U, Lavon N, Biancotti JC, Yakir B, Clark AT, Plath K, Lowry WE, Benvenisty N(2010) Identiflcation and classiflcation of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell7: 521−531

DOI

48
McClintock B(1984) The signiflcance of responses of the genome to challenge. Science226: 792−801

DOI

49
Mitalipova MM, Rao RR, Hoyer DM, Johnson JA, Meisner LF, Jones KL, Dalton S, Stice SL(2005) Preserving the genetic integrity of human embryonic stem cells. Nat Biotechnol23: 19−20

DOI

50
Mitelman (2014). Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer. In: Mitelman F, Johansson B, Mertens F(eds). Accessed 2014-April-1

51
Murry CE, Keller G(2008) Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell132: 661−680

DOI

52
Musacchio A, Salmon ED(2007) The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol8: 379−393

DOI

53
Narva E, Autio R, Rahkonen N, Kong L, Harrison N, Kitsberg D, Borghese L, Itskovitz-Eldor J, Rasool O, Dvorak P (2010) High-resolution DNA analysis of human embryonic stem cell lines reveals culture-induced copy number changes and loss of heterozygosity. Nat Biotechnol28: 371−377

DOI

54
Nowell PC, Hungerford DA(1960) Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst25: 85−109

55
Olariu V, Harrison NJ, Coca D, Gokhale PJ, Baker D, Billings S, Kadirkamanathan V, Andrews PW(2010) Modeling the evolution of culture-adapted human embryonic stem cells. Stem Cell Res4: 50−56

DOI

56
Oosterhuis JW, Castedo SM, de Jong B (1990) Cytogenetics, ploidy and differentiation of human testicular, ovarian and extragonadal germ cell tumours. Cancer Surv9: 320−332

57
Pera MF, Andrade J, Houssami S, Reubinoff B, Trounson A, Stanley EG, Ward-van Oostwaard D, Mummery C(2004) Regulation of human embryonic stem cell differentiation by BMP-2 and its antagonist noggin. J Cell Sci117: 1269−1280

DOI

58
Ronen D, Benvenisty N(2012) Genomic stability in reprogramming. Curr Opin Genet Dev22: 444−449

DOI

59
Rowley JD(1973) A new consistent chromosomal abnormality in chronic myelogenous leukaemia identifled by quinacrine fluorescence and Giemsa staining. Nature243: 290−293

DOI

60
Schwartz SD, Hubschman JP, Heilwell G, Franco-Cardenas V, Pan CK, Ostrick RM, Mickunas E, Gay R, Klimanskaya I, Lanza R(2012) Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet379: 713−720

DOI

61
Sebestova J, Danylevska A, Novakova L, Kubelka M, Anger M(2012) Lack of response to unaligned chromosomes in mammalian female gametes. Cell Cycle11: 3011−3018

DOI

62
Selmecki A, Forche A, Berman J(2006) Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science313: 367−370

DOI

63
Selmecki A, Gerami-Nejad M, Paulson C, Forche A, Berman J(2008) An isochromosome confers drug resistance in vivo by ampliflcation of two genes, ERG11 and TAC1. Mol Microbiol68: 624−641

DOI

64
Skotheim RI, Monni O, Mousses S, Fossa SD, Kallioniemi OP, Lothe RA, Kallioniemi A(2002) New insights into testicular germ cell tumorigenesis from gene expression proflling. Cancer Res62: 2359−2364

65
Spits C, Mateizel I, Geens M, Mertzanidou A, Staessen C, Vandeskelde Y, Van der Elst J, Liebaers I, Sermon K(2008) Recurrent chromosomal abnormalities in human embryonic stem cells. Nat Biotechnol26: 1361−1363

DOI

66
Stratton MR(2011) Exploring the genomes of cancer cells: progress and promise. Science331: 1553−1558

DOI

67
Taapken SM, Nisler BS, Newton MA, Sampsell-Barron TL, Leonhard KA, McIntire EM, Montgomery KD(2011) Karotypic abnormalities in human induced pluripotent stem cells and embryonic stem cells. Nat Biotechnol29: 313−314

DOI

68
Takahashi K, Mitsui K, Yamanaka S(2003) Role of ERas in promoting tumour-like properties in mouse embryonic stem cells. Nature423: 541−545

DOI

69
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S(2007) Induction of pluripotent stem cells from adult human flbroblasts by deflned factors. Cell131: 861−872

DOI

70
Tang YC, Williams BR, Siegel JJ, Amon A(2011) Identiflcation of aneuploidy-selective antiproliferation compounds. Cell144: 499−512

DOI

71
Thompson SL, Compton DA(2010) Proliferation of aneuploid human cells is limited by a p53-dependent mechanism. J Cell Biol188: 369−381

DOI

72
Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM(1998) Embryonic stem cell lines derived from human blastocysts. Science282: 1145−1147

DOI

73
Torres EM, Sokolsky T, Tucker CM, Chan LY, Boselli M, Dunham MJ, Amon A(2007) Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science317: 916−924

DOI

74
Turkmen S, Riehn M, Klopocki E, Molkentin M, Reinhardt R, Burmeister T(2011) A BACH2-BCL2L1 fusion gene resulting from a t(6;20)(q15;q11.2) chromosomal translocation in the lymphoma cell line BLUE-1. Genes Chromosomes Cancer50: 389−396

DOI

75
Vanneste E, Voet T, Le Caignec C, Ampe M, Konings P, Melotte C, Debrock S, Amyere M, Vikkula M, Schuit F (2009) Chromosome instability is common in human cleavage-stage embryos. Nat Med15: 577−583

DOI

76
Wang N, Trend B, Bronson DL, Fraley EE(1980) Nonrandom abnormalities in chromosome 1 in human testicular cancers. Cancer Res40: 796−802

77
Werbowetski-Ogilvie TE, Bosse M, Stewart M, Schnerch A, Ramos-Mejia V, Rouleau A, Wynder T, Smith MJ, Dingwall S, Carter T (2009) Characterization of human embryonic stem cells with features of neoplastic progression. Nat Biotechnol27: 91−97

DOI

78
Xu RH, Chen X, Li DS, Li R, Addicks GC, Glennon C, Zwaka TP, Thomson JA(2002) BMP4 initiates human embryonic stem cell differentiation to trophoblast. Nat Biotechnol20: 1261−1264

DOI

79
Yan L, Yang M, Guo H, Yang L, Wu J, Li R, Liu P, Lian Y, Zheng X, Yan J (2013) Single-cell RNA-Seq proflling of human preimplantation embryos and embryonic stem cells. Nat Struct Mol Biol20: 1131−1139

DOI

80
Yang S, Lin G, Tan YQ, Zhou D, Deng LY, Cheng DH, Luo SW, Liu TC, Zhou XY, Sun Z (2008) Tumor progression of cultureadapted human embryonic stem cells during long-term culture. Genes Chromosomes Cancer47: 665−679

DOI

81
Zafarana G, Grygalewicz B, Gillis AJ, Vissers LE, van de Vliet W, van Gurp RJ, Stoop H, Debiec-Rychter M, Oosterhuis JW, van Kessel AG (2003) 12p-amplicon structure analysis in testicular germ cell tumors of adolescents and adults by array CGH. Oncogene22: 7695−7701

DOI

Outlines

/