Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Genetic instability: tipping the balance

Oncogene volume 32, pages 4459–4470 (2013)Cite this article

Subjects

Abstract

Tumor cells typically contain a genome that is highly divergent from the genome of normal, non-transformed cells. This genetic divergence is caused by a number of distinct changes that the tumor cell acquires during its transformation from a normal cell into a tumorigenic counterpart. Changes to the genome include mutations, deletions, insertions, and also gross chromosomal aberrations, such as chromosome translocations and whole chromosome gains or losses. This genetic disorder of the tumor cell has complicated the identification of crucial driver mutations that cause cancer. Moreover, the large genetic divergence between different tumors causes them to behave very differently, and makes it difficult to predict response to therapy. In addition, tumor cells are genetically unstable and frequently acquire new mutations and/or gross chromosomal aberrations as they divide. This is beneficial for the overall capacity of a tumor to adapt to changes in its environment, but newly acquired genetic alterations can also compromise the genetic dominance of the tumor cell and thus affect tumor cell viability. Here, we review the mechanisms that can cause gross chromosomal aberrations, and discuss how these affect tumor cell viability.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Mitelman F, Johansson B, Mandahl N, Mertens F . Clinical significance of cytogenetic findings in solid tumors. Cancer Genet Cytogenet 1997; 95: 1–8.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. Nowell PC . The minute chromosome (Phl) in chronic granulocytic leukemia. Blut 1962; 8: 65–66.

    CAS  PubMed  Google Scholar 

  4. Look AT . Oncogenic transcription factors in the human acute leukemias. Science 1997; 278: 1059–1064.

    CAS  PubMed  Google Scholar 

  5. Nambiar M, Kari V, Raghavan SC . Chromosomal translocations in cancer. Biochim Biophys Acta 2008; 1786: 139–13 52.

    CAS  PubMed  Google Scholar 

  6. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J et al. The landscape of somatic copy-number alteration across human cancers. Nature 2010; 463: 899–905.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Castro MA, Onsten TG, Moreira JC, de Almeida RM . Chromosome aberrations in solid tumors have a stochastic nature. Mutat Res 2006; 600: 150–164.

    CAS  PubMed  Google Scholar 

  8. Mitelman F, Johansson B, Mertens F . Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancerhttp://cgap.nci.nih.gov/Chromosomes/Mitelman2012.

  9. Roschke AV, Tonon G, Gehlhaus KS, McTyre N, Bussey KJ, Lababidi S et al. Karyotypic complexity of the NCI-60 drug-screening panel. Cancer Res 2003; 63: 8634–8647.

    CAS  PubMed  Google Scholar 

  10. Abdel-Rahman WM, Katsura K, Rens W, Gorman PA, Sheer D, Bicknell D et al. Spectral karyotyping suggests additional subsets of colorectal cancers characterized by pattern of chromosome rearrangement. Proc Natl Acad Sci USA 2001; 98: 2538–2543.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Davidson JM, Gorringe KL, Chin SF, Orsetti B, Besret C, Courtay-Cahen C et al. Molecular cytogenetic analysis of breast cancer cell lines. Br J Cancer 2000; 83: 1309–1317.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Thompson SL, Compton DA . Chromosome missegregation in human cells arises through specific types of kinetochore-microtubule attachment errors. Proc Natl Acad Sci USA 2011; 108: 17974–17978.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Nishizaki T, Chew K, Chu L, Isola J, Kallioniemi A, Weidner N et al. Genetic alterations in lobular breast cancer by comparative genomic hybridization. Int J Cancer 1997; 74: 513–517.

    CAS  PubMed  Google Scholar 

  14. Nishizaki T, DeVries S, Chew K, Goodson WH, Ljung BM, Thor A et al. Genetic alterations in primary breast cancers and their metastases: direct comparison using modified comparative genomic hybridization. Genes Chromosomes Cancer 1997; 19: 267–272.

    CAS  PubMed  Google Scholar 

  15. Natarajan AT, Palitti F . DNA repair and chromosomal alterations. Mutat Res 2008; 657: 3–7.

    CAS  PubMed  Google Scholar 

  16. Obe G, Durante M . DNA double strand breaks and chromosomal aberrations. Cytogenet Genome Res 2010; 128: 8–16.

    CAS  PubMed  Google Scholar 

  17. Obe G, Pfeiffer P, Savage JR, Johannes C, Goedecke W, Jeppesen P et al. Chromosomal aberrations: formation, identification and distribution. Mutat Res 2002; 504: 17–36.

    CAS  PubMed  Google Scholar 

  18. Duker NJ . Chromosome breakage syndromes and cancer. Am J Med Genet [Review] 2002; 115: 125–129.

    PubMed  Google Scholar 

  19. Bender MA, Griggs HG, Bedford JS . Mechanisms of chromosomal aberration production. 3. Chemicals and ionizing radiation. Mutat Res [Review] 1974; 23: 197–212.

    CAS  PubMed  Google Scholar 

  20. McClintock B . The production of homozygous deficient tissues with mutant characteristics by means of the aberrant mitotic behavior of ring-shaped chromosomes. Genetics 1938; 23: 315–376.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. McClintock B . The stability of broken ends of chromosomes in Zea mays. Genetics 1941; 26: 234–282.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Hastie ND, Allshire RC . Human telomeres: fusion and interstitial sites. Trends Genet [Review] 1989; 5: 326–331.

    CAS  PubMed  Google Scholar 

  23. Gisselsson D, Jonson T, Petersen A, Strombeck B, Dal Cin P, Hoglund M et al. Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors. Proc Natl Acad Sci USA 2001; 98: 12683–12688.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Gisselsson D, Bjork J, Hoglund M, Mertens F, Dal Cin P, Akerman M et al. Abnormal nuclear shape in solid tumors reflects mitotic instability. Am J Pathol 2001; 158: 199–206.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Gisselsson D, Pettersson L, Hoglund M, Heidenblad M, Gorunova L, Wiegant J et al. Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity. Proc Natl Acad Sci USA 2000; 97: 5357–5362.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Heim S, Mitelman F . Numerical chromosome aberrations in human neoplasia. Cancer Genet Cytogenet 1986; 22: 99–108.

    CAS  PubMed  Google Scholar 

  27. Baudis M . Genomic imbalances in 5918 malignant epithelial tumors: an explorative meta-analysis of chromosomal CGH data. BMC cancer 2007; 7: 226.

    PubMed  PubMed Central  Google Scholar 

  28. Rehen SK, Yung YC, McCreight MP, Kaushal D, Yang AH, Almeida BS et al. Constitutional aneuploidy in the normal human brain. J Neurosci 2005; 25: 2176–2180.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Duncan AW, Taylor MH, Hickey RD, Hanlon Newell AE, Lenzi ML, Olson SB et al. The ploidy conveyor of mature hepatocytes as a source of genetic variation. Nature 2010; 467: 707–710.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Lengauer C, Kinzler KW, Vogelstein B . Genetic instability in colorectal cancers. Nature 1997; 386: 623–627.

    CAS  PubMed  Google Scholar 

  31. Lengauer C, Kinzler KW, Vogelstein B . Genetic instabilities in human cancers. Nature 1998; 396: 643–649.

    CAS  PubMed  Google Scholar 

  32. Choi CM, Seo KW, Jang SJ, Oh YM, Shim TS, Kim WS et al. Chromosomal instability is a risk factor for poor prognosis of adenocarcinoma of the lung: Fluorescence in situ hybridization analysis of paraffin-embedded tissue from Korean patients. Lung Cancer 2009; 64: 66–70.

    PubMed  Google Scholar 

  33. Carter SL, Eklund AC, Kohane IS, Harris LN, Szallasi Z . A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet 2006; 38: 1043–1048.

    CAS  PubMed  Google Scholar 

  34. Walther A, Houlston R, Tomlinson I . Association between chromosomal instability and prognosis in colorectal cancer: a meta-analysis. Gut 2008; 57: 941–950.

    CAS  PubMed  Google Scholar 

  35. Bakhoum SF, Danilova OV, Kaur P, Levy NB, Compton DA . Chromosomal instability substantiates poor prognosis in patients with diffuse large B-cell lymphoma. Clin Cancer Res 2011; 17: 7704–7711.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kuukasjarvi T, Karhu R, Tanner M, Kahkonen M, Schaffer A, Nupponen N et al. Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer. Cancer Res 1997; 57: 1597–1604.

    CAS  PubMed  Google Scholar 

  37. Gao C, Furge K, Koeman J, Dykema K, Su Y, Cutler ML et al. Chromosome instability, chromosome transcriptome, and clonal evolution of tumor cell populations. Proc Natl Acad Sci USA 2007; 104: 8995–9000.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Sheffer M, Bacolod MD, Zuk O, Giardina SF, Pincas H, Barany F et al. Association of survival and disease progression with chromosomal instability: a genomic exploration of colorectal cancer. Proc Natl Acad Sci USA 2009; 106: 7131–7136.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. McClelland SE, Burrell RA, Swanton C . Chromosomal instability: a composite phenotype that influences sensitivity to chemotherapy. Cell Cycle 2009; 8: 3262–3266.

    CAS  PubMed  Google Scholar 

  40. Lee AJ, Endesfelder D, Rowan AJ, Walther A, Birkbak NJ, Futreal PA et al. Chromosomal instability confers intrinsic multidrug resistance. Cancer Res 2011; 71: 1858–1870.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Swanton C, Nicke B, Schuett M, Eklund AC, Ng C, Li Q et al. Chromosomal instability determines taxane response. Proc Natl Acad Sci USA 2009; 106: 8671–8676.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Kolodner RD, Cleveland DW, Putnam CD . Cancer. aneuploidy drives a mutator phenotype in cancer. Science 2011; 333: 942–943.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Weaver BA, Cleveland DW . Does aneuploidy cause cancer? Curr Opin Cell Biol 2006; 18: 658–667.

    CAS  PubMed  Google Scholar 

  44. Duesberg P, Stindl R, Hehlmann R . Explaining the high mutation rates of cancer cells to drug and multidrug resistance by chromosome reassortments that are catalyzed by aneuploidy. Proc Natl Acad Sci USA 2000; 97: 14295–14300.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Duesberg P, Li R, Sachs R, Fabarius A, Upender MB, Hehlmann R . Cancer drug resistance: the central role of the karyotype. Drug Resist Updat 2007; 10: 51–58.

    CAS  PubMed  Google Scholar 

  46. Pfau SJ, Amon A . Chromosomal instability and aneuploidy in cancer: from yeast to man. EMBO Rep 2012; 13: 515–527.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Nowak MA, Komarova NL, Sengupta A, Jallepalli PV, Shih IeM, Vogelstein B et al. The role of chromosomal instability in tumor initiation. Proc Natl Acad Sci USA 2002; 99: 16226–16231.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Rajagopalan H, Nowak MA, Vogelstein B, Lengauer C . The significance of unstable chromosomes in colorectal cancer. Nat Rev Cancer 2003; 3: 695–701.

    CAS  PubMed  Google Scholar 

  49. Musacchio A, Salmon ED . The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol 2007; 8: 379–393.

    CAS  PubMed  Google Scholar 

  50. Kops GJ, Weaver BA, Cleveland DW . On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer 2005; 5: 773–785.

    CAS  PubMed  Google Scholar 

  51. Michel LS, Liberal V, Chatterjee A, Kirchwegger R, Pasche B, Gerald W et al. MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature 2001; 409: 355–359.

    CAS  PubMed  Google Scholar 

  52. Kops GJ, Foltz DR, Cleveland DW . Lethality to human cancer cells through massive chromosome loss by inhibition of the mitotic checkpoint. Proc Natl Acad Sci USA 2004; 101: 8699–8704.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Kalitsis P, Earle E, Fowler KJ, Choo KH . Bub3 gene disruption in mice reveals essential mitotic spindle checkpoint function during early embryogenesis. Genes Dev 2000; 14: 2277–2282.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Michel L, Diaz-Rodriguez E, Narayan G, Hernando E, Murty VV, Benezra R . Complete loss of the tumor suppressor MAD2 causes premature cyclin B degradation and mitotic failure in human somatic cells. Proc Natl Acad Sci USA. 2004; 101: 4459–4464.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Babu JR, Jeganathan KB, Baker DJ, Wu X, Kang-Decker N, van Deursen JM . Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation. J Cell Biol 2003; 160: 341–353.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Dai W, Wang Q, Liu T, Swamy M, Fang Y, Xie S et al. Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency. Cancer Res 2004; 64: 440–445.

    CAS  PubMed  Google Scholar 

  57. Baker DJ, Jeganathan KB, Cameron JD, Thompson M, Juneja S, Kopecka A et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat Genet 2004; 36: 744–749.

    CAS  PubMed  Google Scholar 

  58. Iwanaga Y, Chi YH, Miyazato A, Sheleg S, Haller K, Peloponese JM et al. Heterozygous deletion of mitotic arrest-deficient protein 1 (MAD1) increases the incidence of tumors in mice. Cancer Res 2007; 67: 160–166.

    CAS  PubMed  Google Scholar 

  59. Janssen A, Kops GJ, Medema RH . Elevating the frequency of chromosome mis-segregation as a strategy to kill tumor cells. Proc Natl Acad Sci USA. 2009; 106: 19108–19113.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kalitsis P, Fowler KJ, Griffiths B, Earle E, Chow CW, Jamsen K et al. Increased chromosome instability but not cancer predisposition in haploinsufficient Bub3 mice. Genes Chromosomes Cancer 2005; 44: 29–36.

    CAS  PubMed  Google Scholar 

  61. Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD et al. Mutations of mitotic checkpoint genes in human cancers. Nature 1998; 392: 300–303.

    CAS  PubMed  Google Scholar 

  62. Tighe A, Johnson VL, Albertella M, Taylor SS . Aneuploid colon cancer cells have a robust spindle checkpoint. EMBO Rep 2001; 2: 609–614.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Hanks S, Coleman K, Reid S, Plaja A, Firth H, Fitzpatrick D et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat Genet 2004; 36: 1159–1161.

    CAS  PubMed  Google Scholar 

  64. Matsuura S, Matsumoto Y, Morishima K, Izumi H, Matsumoto H, Ito E et al. Monoallelic BUB1B mutations and defective mitotic-spindle checkpoint in seven families with premature chromatid separation (PCS) syndrome. Am J Med Genet A 2006; 140: 358–367.

    PubMed  Google Scholar 

  65. Wang X, Jin DY, Ng RW, Feng H, Wong YC, Cheung AL et al. Significance of MAD2 expression to mitotic checkpoint control in ovarian cancer cells. Cancer Res 2002; 62: 1662–1668.

    CAS  PubMed  Google Scholar 

  66. Wang X, Jin DY, Wong YC, Cheung AL, Chun AC, Lo AK et al. Correlation of defective mitotic checkpoint with aberrantly reduced expression of MAD2 protein in nasopharyngeal carcinoma cells. Carcinogenesis 2000; 21: 2293–2297.

    CAS  PubMed  Google Scholar 

  67. Kasai T, Iwanaga Y, Iha H, Jeang KT . Prevalent loss of mitotic spindle checkpoint in adult T-cell leukemia confers resistance to microtubule inhibitors. J Biol Chem 2002; 277: 5187–5193.

    CAS  PubMed  Google Scholar 

  68. Yoon DS, Wersto RP, Zhou W, Chrest FJ, Garrett ES, Kwon TK et al. Variable levels of chromosomal instability and mitotic spindle checkpoint defects in breast cancer. Am J Pathol 2002; 161: 391–397.

    PubMed  PubMed Central  Google Scholar 

  69. Li Y, Benezra R . Identification of a human mitotic checkpoint gene: hsMAD2. Science 1996; 274: 246–248.

    CAS  PubMed  Google Scholar 

  70. Minhas KM, Singh B, Jiang WW, Sidransky D, Califano JA . Spindle assembly checkpoint defects and chromosomal instability in head and neck squamous cell carcinoma. Int J Cancer 2003; 107: 46–52.

    CAS  PubMed  Google Scholar 

  71. Saeki A, Tamura S, Ito N, Kiso S, Matsuda Y, Yabuuchi I et al. Frequent impairment of the spindle assembly checkpoint in hepatocellular carcinoma. Cancer 2002; 94: 2047–2054.

    CAS  PubMed  Google Scholar 

  72. Sze KM, Ching YP, Jin DY, Ng IO . Association of MAD2 expression with mitotic checkpoint competence in hepatoma cells. J Biomed Sci 2004; 11: 920–927.

    CAS  PubMed  Google Scholar 

  73. Takahashi T, Haruki N, Nomoto S, Masuda A, Saji S, Osada H et al. Identification of frequent impairment of the mitotic checkpoint and molecular analysis of the mitotic checkpoint genes, hsMAD2 and p55CDC, in human lung cancers. Oncogene 1999; 18: 4295–4300.

    CAS  PubMed  Google Scholar 

  74. Weitzel DH, Vandre DD . Differential spindle assembly checkpoint response in human lung adenocarcinoma cells. Cell Tissue Res 2000; 300: 57–65.

    CAS  PubMed  Google Scholar 

  75. Hempen PM, Kurpad H, Calhoun ES, Abraham S, Kern SE . A double missense variation of the BUB1 gene and a defective mitotic spindle checkpoint in the pancreatic cancer cell line Hs766T. Hum Mutat 2003; 21: 445.

    PubMed  Google Scholar 

  76. Ouyang B, Knauf JA, Ain K, Nacev B, Fagin JA . Mechanisms of aneuploidy in thyroid cancer cell lines and tissues: evidence for mitotic checkpoint dysfunction without mutations in BUB1 and BUBR1. Clin Endocrinol 2002; 56: 341–350.

    CAS  Google Scholar 

  77. Suijkerbuijk SJ, van Osch MH, Bos FL, Hanks S, Rahman N, Kops GJ . Molecular causes for BUBR1 dysfunction in the human cancer predisposition syndrome mosaic variegated aneuploidy. Cancer Res 2010; 70: 4891–4900.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Matsuura S, Ito E, Tauchi H, Komatsu K, Ikeuchi T, Kajii T . Chromosomal instability syndrome of total premature chromatid separation with mosaic variegated aneuploidy is defective in mitotic-spindle checkpoint. Am J Hum Genet 2000; 67: 483–486.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Wang Q, Liu T, Fang Y, Xie S, Huang X, Mahmood R et al. BUBR1 deficiency results in abnormal megakaryopoiesis. Blood 2004; 103: 1278–1285.

    CAS  PubMed  Google Scholar 

  80. Cahill DP, da Costa LT, Carson-Walter EB, Kinzler KW, Vogelstein B, Lengauer C . Characterization of MAD2B and other mitotic spindle checkpoint genes. Genomics 1999; 58: 181–187.

    CAS  PubMed  Google Scholar 

  81. Myrie KA, Percy MJ, Azim JN, Neeley CK, Petty EM . Mutation and expression analysis of human BUB1 and BUB1B in aneuploid breast cancer cell lines. Cancer Lett 2000; 152: 193–199.

    CAS  PubMed  Google Scholar 

  82. Haruki N, Saito H, Harano T, Nomoto S, Takahashi T, Osada H et al. Molecular analysis of the mitotic checkpoint genes BUB1, BUBR1 and BUB3 in human lung cancers. Cancer Lett 2001; 162: 201–205.

    CAS  PubMed  Google Scholar 

  83. Yuan B, Xu Y, Woo JH, Wang Y, Bae YK, Yoon DS et al. Increased expression of mitotic checkpoint genes in breast cancer cells with chromosomal instability. Clin Cancer Res 2006; 12: 405–410.

    CAS  PubMed  Google Scholar 

  84. Grabsch H, Takeno S, Parsons WJ, Pomjanski N, Boecking A, Gabbert HE et al. Overexpression of the mitotic checkpoint genes BUB1, BUBR1, and BUB3 in gastric cancer—association with tumour cell proliferation. J Pathol 2003; 200: 16–22.

    CAS  PubMed  Google Scholar 

  85. Daniel J, Coulter J, Woo JH, Wilsbach K, Gabrielson E . High levels of the Mps1 checkpoint protein are protective of aneuploidy in breast cancer cells. Proc Natl Acad Sci USA 2011; 108: 5384–5389.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Tanaka K, Nishioka J, Kato K, Nakamura A, Mouri T, Miki C et al. Mitotic checkpoint protein hsMAD2 as a marker predicting liver metastasis of human gastric cancers. Jpn J Cancer Res 2001; 92: 952–958.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403: 503–511.

    CAS  PubMed  Google Scholar 

  88. Garber ME, Troyanskaya OG, Schluens K, Petersen S, Thaesler Z, Pacyna-Gengelbach M et al. Diversity of gene expression in adenocarcinoma of the lung. Proc Natl Acad Sci USA 2001; 98: 13784–13789.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Ryan SD, Britigan EM, Zasadil LM, Witte K, Audhya A, Roopra A et al. Up-regulation of the mitotic checkpoint component Mad1 causes chromosomal instability and resistance to microtubule poisons. Proc Natl Acad Sci USA. 2012; 109: E2205–E2214.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Hernando E, Nahle Z, Juan G, Diaz-Rodriguez E, Alaminos M, Hemann M et al. Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Nature 2004; 430: 797–802.

    CAS  PubMed  Google Scholar 

  91. Manning AL, Dyson NJ . pRB a tumor suppressor with a stabilizing presence. Trends Cell Biol 2011; 21: 433–441.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Manning AL, Longworth MS, Dyson NJ . Loss of pRB causes centromere dysfunction and chromosomal instability. Genes Dev 2010; 24: 1364–1376.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Sotillo R, Hernando E, Diaz-Rodriguez E, Teruya-Feldstein J, Cordon-Cardo C, Lowe SW et al. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 2007; 11: 9–23.

    CAS  PubMed  Google Scholar 

  94. Schvartzman JM, Duijf PH, Sotillo R, Coker C, Benezra R . Mad2 is a critical mediator of the chromosome instability observed upon Rb and p53 pathway inhibition. Cancer Cell 2011; 19: 701–714.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Iwaizumi M, Shinmura K, Mori H, Yamada H, Suzuki M, Kitayama Y et al. Human Sgo1 downregulation leads to chromosomal instability in colorectal cancer. Gut 2009; 58: 249–260.

    CAS  PubMed  Google Scholar 

  96. Barber TD, McManus K, Yuen KW, Reis M, Parmigiani G, Shen D et al. Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers. Proc Natl Acad Sci USA. 2008; 105: 3443–3448.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Jallepalli PV, Waizenegger IC, Bunz F, Langer S, Speicher MR, Peters JM et al. Securin is required for chromosomal stability in human cells. Cell 2001; 105: 445–457.

    CAS  PubMed  Google Scholar 

  98. Wang Z, Cummins JM, Shen D, Cahill DP, Jallepalli PV, Wang TL et al. Three classes of genes mutated in colorectal cancers with chromosomal instability. Cancer Res 2004; 64: 2998–3001.

    CAS  PubMed  Google Scholar 

  99. Solomon DA, Kim T, Diaz-Martinez LA, Fair J, Elkahloun AG, Harris BT et al. Mutational inactivation of STAG2 causes aneuploidy in human cancer. Science 2011; 333: 1039–1043.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Zhang N, Ge G, Meyer R, Sethi S, Basu D, Pradhan S et al. Overexpression of Separase induces aneuploidy and mammary tumorigenesis. Proc Natl Acad Sci USA 2008; 105: 13033–13038.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Nasmyth K, Haering CH . Cohesin: its roles and mechanisms. Annu Rev Genet [Review] 2009; 43: 525–558.

    CAS  PubMed  Google Scholar 

  102. Remeseiro S, Cuadrado A, Carretero M, Martinez P, Drosopoulos WC, Canamero M et al. Cohesin-SA1 deficiency drives aneuploidy and tumourigenesis in mice due to impaired replication of telomeres. EMBO J 2012; 31: 2076–2089.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Thompson SL, Compton DA . Examining the link between chromosomal instability and aneuploidy in human cells. J Cell Biol 2008; 180: 665–672.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Gascoigne KE, Taylor SS . Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell 2008; 14: 111–122.

    CAS  PubMed  Google Scholar 

  105. Cimini D, Fioravanti D, Salmon ED, Degrassi F . Merotelic kinetochore orientation versus chromosome mono-orientation in the origin of lagging chromosomes in human primary cells. J Cell Sci 2002; 115 (Pt 3): 507–515.

    CAS  PubMed  Google Scholar 

  106. Cimini D, Howell B, Maddox P, Khodjakov A, Degrassi F, Salmon ED . Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells. J Cell Biol 2001; 153: 517–527.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Cimini D, Moree B, Canman JC, Salmon ED . Merotelic kinetochore orientation occurs frequently during early mitosis in mammalian tissue cells and error correction is achieved by two different mechanisms. J Cell Sci 2003; 116 (Pt 20): 4213–4225.

    CAS  PubMed  Google Scholar 

  108. Cimini D, Cameron LA, Salmon ED . Anaphase spindle mechanics prevent mis-segregation of merotelically oriented chromosomes. Curr Biol 2004; 14: 2149–2155.

    CAS  PubMed  Google Scholar 

  109. van der Waal MS, Hengeveld RC, van der Horst A, Lens SM . Cell division control by the chromosomal passenger complex. Exp Cell Res 2012; 318: 1407–1420.

    CAS  PubMed  Google Scholar 

  110. Heneen WK . Kinetochores and microtubules in multipolar mitosis and chromosome orientation. Exp Cell Res 1975; 91: 57–62.

    CAS  PubMed  Google Scholar 

  111. Sluder G, Thompson EA, Miller FJ, Hayes J, Rieder CL . The checkpoint control for anaphase onset does not monitor excess numbers of spindle poles or bipolar spindle symmetry. J Cell Sci 1997; 110 (Pt 4): 421–429.

    CAS  PubMed  Google Scholar 

  112. Lingle WL, Barrett SL, Negron VC, D'Assoro AB, Boeneman K, Liu W et al. Centrosome amplification drives chromosomal instability in breast tumor development. Proc Natl Acad Sci USA. 2002; 99: 1978–1983.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Sato N, Mizumoto K, Nakamura M, Maehara N, Minamishima YA, Nishio S et al. Correlation between centrosome abnormalities and chromosomal instability in human pancreatic cancer cells. Cancer Genet Cytogenet 2001; 126: 13–19.

    CAS  PubMed  Google Scholar 

  114. Pihan GA, Purohit A, Wallace J, Malhotra R, Liotta L, Doxsey SJ . Centrosome defects can account for cellular and genetic changes that characterize prostate cancer progression. Cancer Res 2001; 61: 2212–2219.

    CAS  PubMed  Google Scholar 

  115. Ghadimi BM, Sackett DL, Difilippantonio MJ, Schrock E, Neumann T, Jauho A et al. Centrosome amplification and instability occurs exclusively in aneuploid, but not in diploid colorectal cancer cell lines, and correlates with numerical chromosomal aberrations. Genes Chromosomes Cancer 2000; 27: 183–190.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Nigg EA . Centrosome aberrations: cause or consequence of cancer progression? Nat Rev Cancer 2002; 2: 815–825.

    CAS  PubMed  Google Scholar 

  117. Shi Q, King RW . Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines. Nature 2005; 437: 1038–1042.

    CAS  PubMed  Google Scholar 

  118. Silkworth WT, Nardi IK, Scholl LM, Cimini D . Multipolar spindle pole coalescence is a major source of kinetochore mis-attachment and chromosome mis-segregation in cancer cells. PLoS One 2009; 4: e6564.

    PubMed  PubMed Central  Google Scholar 

  119. Ganem NJ, Godinho SA, Pellman D . A mechanism linking extra centrosomes to chromosomal instability. Nature 2009; 460: 278–282.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Fujiwara T, Bandi M, Nitta M, Ivanova EV, Bronson RT, Pellman D . Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 2005; 437: 1043–1047.

    CAS  PubMed  Google Scholar 

  121. Davoli T, de Lange T . Telomere-driven tetraploidization occurs in human cells undergoing crisis and promotes transformation of mouse cells. Cancer Cell 2012; 21: 765–776.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Overholtzer M, Mailleux AA, Mouneimne G, Normand G, Schnitt SJ, King RW et al. A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion. Cell 2007; 131: 966–979.

    CAS  PubMed  Google Scholar 

  123. Overholtzer M, Brugge JS . The cell biology of cell-in-cell structures. Nat Rev Mol Cell Biol 2008; 9: 796–809.

    CAS  PubMed  Google Scholar 

  124. Kracjovic M, Johnson NB, Sun Q, Normand G, Hoover N, Yao E et al. A non-genetic route to aneuploidy in human cancers. Nature Cell Biol 2010.

  125. Janssen A, Medema RH . Entosis: aneuploidy by invasion. Nat Cell Biol 2011; 13: 199–201.

    CAS  PubMed  Google Scholar 

  126. Stolz A, Ertych N, Kienitz A, Vogel C, Schneider V, Fritz B et al. The CHK2-BRCA1 tumour suppressor pathway ensures chromosomal stability in human somatic cells. Nat Cell Biol 2010; 12: 492–499.

    CAS  PubMed  Google Scholar 

  127. Bartek J, J Lukas . Chk1and Chk2 kinases in checkpoint control and cancer. Cancer Cell 2003; 3: 421–429.

    CAS  PubMed  Google Scholar 

  128. Bakhoum SF, Genovese G, Compton DA . Deviant kinetochore microtubule dynamics underlie chromosomal instability. Curr Biol 2009; 19: 1937–1942.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Bakhoum SF, Thompson SL, Manning AL, Compton DA . Genome stability is ensured by temporal control of kinetochore-microtubule dynamics. Nat Cell Biol 2009; 11: 27–35.

    CAS  PubMed  Google Scholar 

  130. Kabeche L, Compton DA . Checkpoint-independent stabilization of kinetochore-microtubule attachments by Mad2 in human cells. Curr Biol 2012; 22: 638–644.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Salimian KJ, Ballister ER, Smoak EM, Wood S, Panchenko T, Lampson MA et al. Feedback control in sensing chromosome biorientation by the Aurora B kinase. Curr Biol 2011; 21: 1158–1165.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB et al. Identification of FAP locus genes from chromosome 5q21. Science 1991; 253: 661–665.

    CAS  PubMed  Google Scholar 

  133. Clevers H . Wnt/beta-catenin signaling in development and disease. Cell [Review] 2006; 127: 469–480.

    CAS  PubMed  Google Scholar 

  134. Rusan NM, Peifer M . Original CIN: reviewing roles for APC in chromosome instability. J Cell Biol 2008; 181: 719–726.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Kaplan KB, Burds AA, Swedlow JR, Bekir SS, Sorger PK, Nathke IS . A role for the Adenomatous Polyposis Coli protein in chromosome segregation. Nat Cell Biol 2001; 3: 429–432.

    CAS  PubMed  Google Scholar 

  136. Fodde R, Kuipers J, Rosenberg C, Smits R, Kielman M, Gaspar C et al. Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol 2001; 3: 433–438.

    CAS  PubMed  Google Scholar 

  137. Dikovskaya D, Schiffmann D, Newton IP, Oakley A, Kroboth K, Sansom O et al. Loss of APC induces polyploidy as a result of a combination of defects in mitosis and apoptosis. J Cell Biol 2007; 176: 183–195.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Draviam VM, Shapiro I, Aldridge B, Sorger PK . Misorientation and reduced stretching of aligned sister kinetochores promote chromosome missegregation in EB1- or APC-depleted cells. EMBO J 2006; 25: 2814–2827.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Zhang J, Ahmad S, Mao Y . BubR1 and APC/EB1 cooperate to maintain metaphase chromosome alignment. J Cell Biol 2007; 178: 773–784.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Aoki K, Aoki M, Sugai M, Harada N, Miyoshi H, Tsukamoto T et al. Chromosomal instability by beta-catenin/TCF transcription in APC or beta-catenin mutant cells. Oncogene 2007; 26: 3511–3520.

    CAS  PubMed  Google Scholar 

  141. Aoki K, Taketo MM . Adenomatous polyposis coli (APC): a multi-functional tumor suppressor gene. J Cell Sci 2007; 120 (Pt 19): 3327–3335.

    CAS  PubMed  Google Scholar 

  142. Heun P, Erhardt S, Blower MD, Weiss S, Skora AD, Karpen GH . Mislocalization of the Drosophila centromere-specific histone CID promotes formation of functional ectopic kinetochores. Dev Cell 2006; 10: 303–315.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Olszak AM, van Essen D, Pereira AJ, Diehl S, Manke T, Maiato H et al. Heterochromatin boundaries are hotspots for de novo kinetochore formation. Nat Cell Biol 2011; 13: 799–808.

    CAS  PubMed  Google Scholar 

  144. Pampalona J, Soler D, Genesca A, Tusell L . Whole chromosome loss is promoted by telomere dysfunction in primary cells. Genes Chromosomes Cancer 2010; 49: 368–378.

    CAS  PubMed  Google Scholar 

  145. Ichijima Y, Yoshioka K, Yoshioka Y, Shinohe K, Fujimori H, Unno J et al. DNA lesions induced by replication stress trigger mitotic aberration and tetraploidy development. PLoS One 2010; 5: e8821.

    PubMed  PubMed Central  Google Scholar 

  146. Chan KL, Palmai-Pallag T, Ying S, Hickson ID . Replication stress induces sister-chromatid bridging at fragile site loci in mitosis. Nat Cell Biol 2009; 11: 753–760.

    CAS  PubMed  Google Scholar 

  147. Stewenius Y, Jin Y, Ora I, de Kraker J, Bras J, Frigyesi A et al. Defective chromosome segregation and telomere dysfunction in aggressive Wilms' tumors. Clin Cancer Res 2007; 13 (22 Pt 1): 6593–6602.

    CAS  PubMed  Google Scholar 

  148. Chan KL, North PS, Hickson ID . BLM is required for faithful chromosome segregation and its localization defines a class of ultrafine anaphase bridges. EMBO J 2007; 26: 3397–3409.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Allshire RC, Karpen GH . Epigenetic regulation of centromeric chromatin: old dogs, new tricks? Nat Rev Genet 2008; 9: 923–937.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Hu Z, Huang G, Sadanandam A, Gu S, Lenburg ME, Pai M et al. The expression level of HJURP has an independent prognostic impact and predicts the sensitivity to radiotherapy in breast cancer. Breast Cancer Res 2010; 12: R18.

    PubMed  PubMed Central  Google Scholar 

  151. Tomonaga T, Matsushita K, Yamaguchi S, Oohashi T, Shimada H, Ochiai T et al. Overexpression and mistargeting of centromere protein-A in human primary colorectal cancer. Cancer Res 2003; 63: 3511–3516.

    CAS  PubMed  Google Scholar 

  152. Van Hooser AA, Ouspenski II, Gregson HC, Starr DA, Yen TJ, Goldberg ML et al. Specification of kinetochore-forming chromatin by the histone H3 variant CENP-A. J Cell Sci 2001; 114 (Pt 19): 3529–3542.

    CAS  PubMed  Google Scholar 

  153. Barnhart MC, Kuich PH, Stellfox ME, Ward JA, Bassett EA, Black BE et al. HJURP is a CENP-A chromatin assembly factor sufficient to form a functional de novo kinetochore. J Cell Biol 2011; 194: 229–243.

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV, Pan Y et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature 2012; 482: 53–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Janssen A, van der Burg M, Szuhai K, Kops GJ, Medema RH . Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science 2011; 333: 1895–1898.

    CAS  PubMed  Google Scholar 

  156. Sheltzer JM, Blank HM, Pfau SJ, Tange Y, George BM, Humpton TJ et al. Aneuploidy drives genomic instability in yeast. Science 2011; 333: 1026–1030.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Fabarius A, Hehlmann R, Duesberg PH . Instability of chromosome structure in cancer cells increases exponentially with degrees of aneuploidy. Cancer Genet Cytogenet 2003; 143: 59–72.

    CAS  PubMed  Google Scholar 

  158. Duesberg P, Rausch C, Rasnick D, Hehlmann R . Genetic instability of cancer cells is proportional to their degree of aneuploidy. Proc Natl Acad Sci USA 1998; 95: 13692–13697.

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Burds AA, Lutum AS, Sorger PK . Generating chromosome instability through the simultaneous deletion of Mad2 and p53. Proc Natl Acad Sci USA 2005; 102: 11296–11301.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Torres EM, Sokolsky T, Tucker CM, Chan LY, Boselli M, Dunham MJ et al. Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 2007; 317: 916–924.

    CAS  PubMed  Google Scholar 

  161. Williams BR, Prabhu VR, Hunter KE, Glazier CM, Whittaker CA, Housman DE et al. Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science 2008; 322: 703–709.

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Harrigan JA, Belotserkovskaya R, Coates J, Dimitrova DS, Polo SE, Bradshaw CR et al. Replication stress induces 53BP1-containing OPT domains in G1 cells. J Cell Biol 2011; 193: 97–108.

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Lukas C, Savic V, Bekker-Jensen S, Doil C, Neumann B, Pedersen RS et al. 53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress. Nat Cell Biol 2011; 13: 243–253.

    CAS  PubMed  Google Scholar 

  164. Guerrero AA, Gamero MC, Trachana V, Futterer A, Pacios-Bras C, Diaz-Concha NP et al. Centromere-localized breaks indicate the generation of DNA damage by the mitotic spindle. Proc Natl Acad Sci USA. 2009; 107: 4159–4164.

    Google Scholar 

  165. Boveri T . Zur Frage der Entstehung maligner Tumoren vol. 1. Jena, Gustav Fischer, 1914.

  166. Hansemann DPv . Ueber patologische Mitosen. Archiv für pathologische Anatomie and Physiologie und für klinische Medicin 1891; 119: 299–326.

    Google Scholar 

  167. Ricke RM, van Ree JH, van Deursen JM . Whole chromosome instability and cancer: a complex relationship. Trends Genet 2008; 24: 457–466.

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Rajagopalan H, Lengauer C . Aneuploidy and cancer. Nature 2004; 432: 338–341.

    CAS  PubMed  Google Scholar 

  169. Pei L, Melmed S . Isolation and characterization of a pituitary tumor-transforming gene (PTTG). Mol Endocrinol 1997; 11: 433–441.

    CAS  PubMed  Google Scholar 

  170. Zhang D, Hirota T, Marumoto T, Shimizu M, Kunitoku N, Sasayama T et al. Cre-loxP-controlled periodic Aurora-A overexpression induces mitotic abnormalities and hyperplasia in mammary glands of mouse models. Oncogene 2004; 23: 8720–8730.

    CAS  PubMed  Google Scholar 

  171. Weaver BA, Silk AD, Montagna C, Verdier-Pinard P, Cleveland DW . Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell 2007; 11: 25–36.

    CAS  PubMed  Google Scholar 

  172. Pavelka N, Rancati G, Zhu J, Bradford WD, Saraf A, Florens L et al. Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast. Nature 2010; 468: 321–325.

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Rancati G, Pavelka N, Fleharty B, Noll A, Trimble R, Walton K et al. Aneuploidy underlies rapid adaptive evolution of yeast cells deprived of a conserved cytokinesis motor. Cell 2008; 135: 879–893.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. McGranahan N, Burrell RA, Endesfelder D, Novelli MR, Swanton C . Cancer chromosomal instability: therapeutic and diagnostic challenges. EMBO Rep 2012; 13: 528–538.

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Holland AJ, Cleveland DW . Losing balance: the origin and impact of aneuploidy in cancer. EMBO Rep 2012; 13: 501–514.

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Dobles M, Liberal V, Scott ML, Benezra R, Sorger PK . Chromosome missegregation and apoptosis in mice lacking the mitotic checkpoint protein Mad2. Cell 2000; 101: 635–645.

    CAS  PubMed  Google Scholar 

  177. Baker DJ, Jeganathan KB, Malureanu L, Perez-Terzic C, Terzic A, van Deursen JM . Early aging-associated phenotypes in Bub3/Rae1 haploinsufficient mice. J Cell Biol 2006; 172: 529–540.

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Jeganathan K, Malureanu L, Baker DJ, Abraham SC, van Deursen JM . Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis. J Cell Biol 2007; 179: 255–267.

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Weaver BA, Bonday ZQ, Putkey FR, Kops GJ, Silk AD, Cleveland DW . Centromere-associated protein-E is essential for the mammalian mitotic checkpoint to prevent aneuploidy due to single chromosome loss. J Cell Biol 2003; 162: 551–563.

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Ricke RM, Jeganathan KB, van Deursen JM . Bub1 overexpression induces aneuploidy and tumor formation through Aurora B kinase hyperactivation. J Cell Biol 2011; 193: 1049–1064.

    CAS  PubMed  PubMed Central  Google Scholar 

  181. van Ree JH, Jeganathan KB, Malureanu L, van Deursen JM . Overexpression of the E2 ubiquitin-conjugating enzyme UbcH10 causes chromosome missegregation and tumor formation. J Cell Biol 2010; 188: 83–100.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Baker DJ, Jin F, Jeganathan KB, van Deursen JM . Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterozygosity. Cancer Cell 2009; 16: 475–486.

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Rao CV, Yang YM, Swamy MV, Liu T, Fang Y, Mahmood R et al. Colonic tumorigenesis in BubR1+/-ApcMin/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability. Proc Natl Acad Sci USA. 2005; 102: 4365–4370.

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Baker DJ, Perez-Terzic C, Jin F, Pitel K, Niederlander NJ, Jeganathan K et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat Cell Biol 2008; 10: 825–836.

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Thompson SL, Compton DA . Proliferation of aneuploid human cells is limited by a p53-dependent mechanism. J Cell Biol 2010; 188: 369–381.

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Torres EM, Dephoure N, Panneerselvam A, Tucker CM, Whittaker CA, Gygi SP et al. Identification of aneuploidy-tolerating mutations. Cell 2010; 143: 71–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Duesberg P, Fabarius A, Hehlmann R . Aneuploidy the primary cause of the multilateral genomic instability of neoplastic and preneoplastic cells. IUBMB Life 2004; 56: 65–81.

    CAS  PubMed  Google Scholar 

  188. Li M, Fang X, Baker DJ, Guo L, Gao X, Wei Z et al. The ATM-p53 pathway suppresses aneuploidy-induced tumorigenesis. Proc Natl Acad Sci USA. 2010; 107: 14188–14193.

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Luongo C, Moser AR, Gledhill S, Dove WF . Loss of Apc+ in intestinal adenomas from Min mice. Cancer Res 1994; 54: 5947–5952.

    CAS  PubMed  Google Scholar 

  190. Birkbak NJ, Eklund AC, Li Q, McClelland SE, Endesfelder D, Tan P et al. Paradoxical relationship between chromosomal instability and survival outcome in cancer. Cancer Res 2011; 71: 3447–3452.

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Roylance R, Endesfelder D, Gorman P, Burrell RA, Sander J, Tomlinson I et al. Relationship of extreme chromosomal instability with long-term survival in a retrospective analysis of primary breast cancer. Cancer Epidemiol Biomarkers Prev 2011; 20: 2183–2194.

    PubMed  PubMed Central  Google Scholar 

  192. Janssen A, Medema RH . Mitosis as an anti-cancer target. Oncogene [Review] 2011; 30: 2799–2809.

    CAS  PubMed  Google Scholar 

  193. Chi YH, Ward JM, Cheng LI, Yasunaga J, Jeang KT . Spindle assembly checkpoint and p53 deficiencies cooperate for tumorigenesis in mice. Int J Cancer 2009; 124: 1483–1489.

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Schliekelman M, Cowley DO, O’Quinn R, Oliver TG, Lu L, Salmon ED et al. Impaired Bub1 function in vivo compromises tension-dependent checkpoint function leading to aneuploidy and tumorigenesis. Cancer Res 2009; 69: 45–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Sotillo R, Schvartzman JM, Socci ND, Benezra R . Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. Nature 2010; 464: 436–440.

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Garcia-Higuera I, Manchado E, Dubus P, Canamero M, Mendez J, Moreno S et al. Genomic stability and tumour suppression by the APC/C cofactor Cdh1. Nat Cell Biol 2008; 10: 802–811.

    PubMed  Google Scholar 

  197. Diaz-Rodriguez E, Sotillo R, Schvartzman JM, Benezra R . Hec1 overexpression hyperactivates the mitotic checkpoint and induces tumor formation in vivo. Proc Natl Acad Sci USA 2008; 105: 16719–16724.

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Malureanu L, Jeganathan KB, Jin F, Baker DJ, van Ree JH, Gullon O et al. Cdc20 hypomorphic mice fail to counteract de novo synthesis of cyclin B1 in mitosis. J Cell Biol 2010; 191: 313–329.

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Li M, Fang X, Wei Z, York JP, Zhang P . Loss of spindle assembly checkpoint-mediated inhibition of Cdc20 promotes tumorigenesis in mice. J Cell Biol 2009; 185: 983–994.

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Chesnokova V, Kovacs K, Castro AV, Zonis S, Melmed S . Pituitary hypoplasia in Pttg-/- mice is protective for Rb+/- pituitary tumorigenesis. Mol Endocrinol 2005; 19: 2371–2379.

    CAS  PubMed  Google Scholar 

  201. Wang Z, Yu R, Melmed S . Mice lacking pituitary tumor transforming gene show testicular and splenic hypoplasia, thymic hyperplasia, thrombocytopenia, aberrant cell cycle progression, and premature centromere division. Mol Endocrinol. 2001; 15: 1870–1879.

    CAS  PubMed  Google Scholar 

  202. Uren AG, Wong L, Pakusch M, Fowler KJ, Burrows FJ, Vaux DL et al. Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype. Curr Biol. [Research Support, Non-U.S. Gov't] 2000; 10: 1319–1328.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    A Janssen & R H Medema

  2. Department of Medical Oncology and Cancer Genomics Center, University Medical Center Utrecht, Utrecht, The Netherlands

    A Janssen

Authors
  1. A Janssen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R H Medema
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R H Medema.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Janssen, A., Medema, R. Genetic instability: tipping the balance. Oncogene 32, 4459–4470 (2013). https://doi.org/10.1038/onc.2012.576

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2012.576

Keywords

This article is cited by

Search

Advanced search

Quick links