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Causes and consequences of aneuploidy in cancer

Key Points

  • Genomic instability, including whole-chromosome aneuploidy, is a hallmark of cancer.

  • The disruption of multiple pathways, including defects in kinetochore–microtubule attachments and dynamics, centrosome number, spindle assembly checkpoint (SAC) and chromosome cohesion, can lead to aneuploidy.

  • Aneuploidy is generally detrimental in non-transformed cells and can result in imbalances at the level of the transcriptome and proteome.

  • A key question and area of research is how cells can adapt to tolerate aneuploidy.

  • Aneuploidy can be an effective mechanism to generate phenotypic variation and adaptation under a selective pressure.

  • Aneuploidy can both promote and inhibit tumorigenesis.

  • Aneuploidy is a highly attractive target in cancer therapy.

  • Therapeutics that target aneuploidy could either target aneuploidy generally or target specific recurrent aneuploidies that are associated with certain cancers.

Abstract

Genetic instability, which includes both numerical and structural chromosomal abnormalities, is a hallmark of cancer. Whereas the structural chromosome rearrangements have received substantial attention, the role of whole-chromosome aneuploidy in cancer is much less well-understood. Here we review recent progress in understanding the roles of whole-chromosome aneuploidy in cancer, including the mechanistic causes of aneuploidy, the cellular responses to chromosome gains or losses and how cells might adapt to tolerate these usually detrimental alterations. We also explore the role of aneuploidy in cellular transformation and discuss the possibility of developing aneuploidy-specific therapies.

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Figure 1: Chromosomal instability.
Figure 2: Pathways to aneuploidy.
Figure 3: Proteotoxic stress.
Figure 4: Aneuploidy-specifc therapeutic strategies.

References

  1. 1

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

    CAS  Google Scholar 

  2. 2

    Ricke, R. M., van Ree, J. H. & van Deursen, J. M. Whole chromosome instability and cancer: a complex relationship. Trends Genet. 24, 457–466 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Teixeira, M. R. & Heim, S. Multiple numerical chromosome aberrations in cancer: what are their causes and what are their consequences? Semin. Cancer Biol. 15, 3–12 (2005).

    CAS  PubMed  Google Scholar 

  4. 4

    Schvartzman, J. M., Sotillo, R. & Benezra, R. Mitotic chromosomal instability and cancer: mouse modelling of the human disease. Nature Rev. Cancer 10, 102–115 (2010).

    CAS  Google Scholar 

  5. 5

    Hanks, S. et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nature Genet. 36, 1159–1161 (2004).

    CAS  PubMed  Google Scholar 

  6. 6

    Thompson, S. L. & Compton, D. A. Chromosomes and cancer cells. Chromosome Res. 19, 433–444 (2011).

    PubMed  PubMed Central  Google Scholar 

  7. 7

    Thompson, S. L., Bakhoum, S. F. & Compton, D. A. Mechanisms of chromosomal instability. Curr. Biol. 20, R285–R295 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Chandhok, N. S. & Pellman, D. A little CIN may cost a lot: revisiting aneuploidy and cancer. Curr. Opin. Genet. Dev. 19, 74–81 (2009).

    CAS  PubMed  Google Scholar 

  9. 9

    Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010). This study shows that one-quarter of the genome of a typical cancer cell is affected by either whole-arm or whole-chromosome somatic copy number alterations.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Mitelman, F., Johannson, B. & Mertens, F. Mitelman Database of Chromosome Aberrations in Cancer [online], (2012).

  11. 11

    Ozery-Flato, M., Linhart, C., Trakhtenbrot, L., Izraeli, S. & Shamir, R. Large-scale analysis of chromosomal aberrations in cancer karyotypes reveals two distinct paths to aneuploidy. Genome Biol. 12, R61 (2011).

    PubMed  PubMed Central  Google Scholar 

  12. 12

    Barnard, D. R. et al. Morphologic, immunologic, and cytogenetic classification of acute myeloid leukemia and myelodysplastic syndrome in childhood: a report from the Childrens Cancer Group. Leukemia 10, 5–12 (1996).

    CAS  PubMed  Google Scholar 

  13. 13

    Maurici, D. et al. Frequency and implications of chromosome 8 and 12 gains in Ewing sarcoma. Cancer Genet. Cytogenet. 100, 106–110 (1998).

    CAS  PubMed  Google Scholar 

  14. 14

    Qi, H. et al. Trisomies 8 and 20 in desmoid tumors. Cancer Genet. Cytogenet. 92, 147–149 (1996).

    CAS  PubMed  Google Scholar 

  15. 15

    Barnard, D. R. et al. Acute myeloid leukemia and myelodysplastic syndrome in children treated for cancer: comparison with primary presentation. Blood 100, 427–434 (2002).

    CAS  PubMed  Google Scholar 

  16. 16

    Paulsson, K. & Johansson, B. Trisomy 8 as the sole chromosomal aberration in acute myeloid leukemia and myelodysplastic syndromes. Pathol. Biol. 55, 37–48 (2007).

    CAS  PubMed  Google Scholar 

  17. 17

    Thompson, S. L. & Compton, D. A. Examining the link between chromosomal instability and aneuploidy in human cells. J. Cell Biol. 180, 665–672 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Cimini, D., Tanzarella, C. & Degrassi, F. Differences in malsegregation rates obtained by scoring ana-telophases or binucleate cells. Mutagenesis 14, 563–568 (1999).

    CAS  PubMed  Google Scholar 

  19. 19

    Compton, D. A. Mechanisms of aneuploidy. Curr. Opin. Cell Biol. 23, 109–113 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Cimini, D. Merotelic kinetochore orientation, aneuploidy, and cancer. Biochim. Biophys. Acta 1786, 32–40 (2008).

    CAS  PubMed  Google Scholar 

  21. 21

    Cimini, D. et al. Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells. J. Cell Biol. 153, 517–527 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Gregan, J., Polakova, S., Zhang, L., Tolic´-Nørrelykke, I. M. & Cimini, D. Merotelic kinetochore attachment: causes and effects. Trends Cell Biol. 21, 374–381 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Ganem, N. J., Godinho, S. A. & Pellman, D. A mechanism linking extra centrosomes to chromosomal instability. Nature 460, 278–282 (2009). This study provides a mechanistic link between extra centrosomes and CIN by demonstrating that supernumerary centrosomes increase the frequency of merotelic attachments and chromosome segregation errors.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Silkworth, W. T., Nardi, I. K., Scholl, L. M. & Cimini, D. Multipolar spindle pole coalescence is a major source of kinetochore mis-attachment and chromosome mis-segregation in cancer cells. PLoS ONE 4, e6564 (2009).

    PubMed  PubMed Central  Google Scholar 

  25. 25

    Bakhoum, S. F., Genovese, G. & Compton, D. A. Deviant kinetochore microtubule dynamics underlie chromosomal instability. Curr. Biol. 19, 1937–1942 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Tada, K., Susumu, H., Sakuno, T. & Watanabe, Y. Condensin association with histone H2A shapes mitotic chromosomes. Nature 474, 477–483 (2011).

    CAS  PubMed  Google Scholar 

  27. 27

    Corbett, K. D. et al. The monopolin complex crosslinks kinetochore components to regulate chromosome-microtubule attachments. Cell 142, 556–567 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Bakhoum, S. F., Thompson, S. L., Manning, A. L. & Compton, D. A. Genome stability is ensured by temporal control of kinetochore-microtubule dynamics. Nature Cell Biol. 11, 27–35 (2009).

    CAS  Google Scholar 

  29. 29

    Nigg, E. A. Origins and consequences of centrosome aberrations in human cancers. Int. J. Cancer 119, 2717–2723 (2006).

    CAS  PubMed  Google Scholar 

  30. 30

    Pihan, G. A. et al. Centrosome defects and genetic instability in malignant tumors. Cancer Res. 58, 3974–3985 (1998).

    CAS  PubMed  Google Scholar 

  31. 31

    Pihan, G. A., Wallace, J., Zhou, Y. & Doxsey, S. J. Centrosome abnormalities and chromosome instability occur together in pre-invasive carcinomas. Cancer Res. 63, 1398–1404 (2003).

    CAS  PubMed  Google Scholar 

  32. 32

    Nigg, E. A. Centrosome aberrations: cause or consequence of cancer progression? Nature Rev. Cancer 2, 815–825 (2002).

    CAS  Google Scholar 

  33. 33

    Boveri, T. The Origin of Malignant Tumors (Waverly Press, Baltimore, Maryland, 1929).

    Google Scholar 

  34. 34

    Holland, A. J. & Cleveland, D. W. Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nature Rev. Mol. Cell Biol. 10, 478–487 (2009).

    CAS  Google Scholar 

  35. 35

    Brinkley, B. R. Managing the centrosome numbers game: from chaos to stability in cancer cell division. Trends Cell Biol. 11, 18–21 (2001).

    CAS  PubMed  Google Scholar 

  36. 36

    Ring, D., Hubble, R. & Kirschner, M. Mitosis in a cell with multiple centrioles. J. Cell Biol. 94, 549–556 (1982).

    CAS  PubMed  Google Scholar 

  37. 37

    Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instability in colorectal cancers. Nature 386, 623–627 (1997).

    CAS  PubMed  Google Scholar 

  38. 38

    Rajagopalan, H., Nowak, M. A., Vogelstein, B. & Lengauer, C. The significance of unstable chromosomes in colorectal cancer. Nature Rev. Cancer 3, 695–701 (2003).

    CAS  Google Scholar 

  39. 39

    Cahill, D. P. et al. Characterization of MAD2B and other mitotic spindle checkpoint genes. Genomics 58, 181–187 (1999).

    CAS  PubMed  Google Scholar 

  40. 40

    Haruki, N. et al. Molecular analysis of the mitotic checkpoint genes BUB1, BUBR1 and BUB3 in human lung cancers. Cancer Lett. 162, 201–205 (2001).

    CAS  PubMed  Google Scholar 

  41. 41

    Myrie, K. A., Percy, M. J., Azim, J. N., Neeley, C. K. & Petty, E. M. Mutation and expression analysis of human BUB1 and BUB1B in aneuploid breast cancer cell lines. Cancer Lett. 152, 193–199 (2000).

    CAS  PubMed  Google Scholar 

  42. 42

    Kops, G. J., Weaver, B. A. & Cleveland, D. W. On the road to cancer: aneuploidy and the mitotic checkpoint. Nature Rev. Cancer 5, 773–785 (2005).

    CAS  Google Scholar 

  43. 43

    Wang, Z. et al. Three classes of genes mutated in colorectal cancers with chromosomal instability. Cancer Res. 64, 2998–3001 (2004).

    CAS  PubMed  Google Scholar 

  44. 44

    Gascoigne, K. E. & Taylor, S. S. Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell 14, 111–122 (2008).

    CAS  Google Scholar 

  45. 45

    Tighe, A., Johnson, V. L., Albertella, M. & Taylor, S. S. Aneuploid colon cancer cells have a robust spindle checkpoint. EMBO Rep. 2, 609–614 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Haruta, M. et al. Combined BubR1 protein down-regulation and RASSF1A hypermethylation in Wilms tumors with diverse cytogenetic changes. Mol. Carcinog. 47, 660–666 (2008).

    CAS  PubMed  Google Scholar 

  47. 47

    Park, H. Y. et al. Differential promoter methylation may be a key molecular mechanism in regulating BubR1 expression in cancer cells. Exp. Mol. Med. 39, 195–204 (2007).

    CAS  PubMed  Google Scholar 

  48. 48

    Morgan, D. O. The Cell Cycle: Principles of Control (Sinauer Associates, Sunderland, Maryland, 2007).

    Google Scholar 

  49. 49

    Musacchio, A. & Salmon, E. D. The spindle-assembly checkpoint in space and time. Nature Rev. Mol. Cell Biol. 8, 379–393 (2007).

    CAS  Google Scholar 

  50. 50

    Barber, T. D. et al. Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers. Proc. Natl Acad. Sci. USA 105, 3443–3448 (2008).

    CAS  PubMed  Google Scholar 

  51. 51

    Solomon, D. A. et al. Mutational inactivation of STAG2 causes aneuploidy in human cancer. Science 333, 1039–1043 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Dorsett, D. Cohesin: genomic insights into controlling gene transcription and development. Curr. Opin. Genet. Dev. 21, 199–206 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Torres, E. M., Williams, B. R. & Amon, A. Aneuploidy: cells losing their balance. Genetics 179, 737–746 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Torres, E. M. et al. Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 317, 916–924 (2007). This study uses a chromosome transfer strategy and selectable markers to generate isogenic aneuploid yeast strains with a single extra chromosome.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Sheltzer, J. M. et al. Aneuploidy drives genomic instability in yeast. Science 333, 1026–1030 (2011). This study shows that aneuploidy in yeast can generate genomic instability, including increased chromosome loss, mutation rate and defective DNA damage repair.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Niwa, O., Tange, Y. & Kurabayashi, A. Growth arrest and chromosome instability in aneuploid yeast. Yeast 23, 937–950 (2006).

    CAS  PubMed  Google Scholar 

  57. 57

    Williams, B. R. et al. Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science 322, 703–709 (2008). This study establishes and characterizes isogenic MEF cell lines that are trisomic for chromosomes 1, 13, 16 or 19 using balanced Robertsonian translocations.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Rasmussen, S. A., Wong, L. Y., Yang, Q., May, K. M. & Friedman, J. M. Population-based analyses of mortality in trisomy 13 and trisomy 18. Pediatrics 111, 777–784 (2003).

    PubMed  Google Scholar 

  59. 59

    Segal, D. J. & McCoy, E. E. Studies on Down's syndrome in tissue culture. I. Growth rates and protein contents of fibroblast cultures. J. Cell Physiol. 83, 85–90 (1974).

    CAS  PubMed  Google Scholar 

  60. 60

    Taylor, A. I. Cell selection in vivo in normal-G trisomic mosaics. Nature 219, 1028–1030 (1968).

    CAS  PubMed  Google Scholar 

  61. 61

    Yurov, Y. B. et al. Aneuploidy and confined chromosomal mosaicism in the developing human brain. PLoS ONE 2, e558 (2007).

    PubMed  PubMed Central  Google Scholar 

  62. 62

    Yurov, Y. B. et al. The variation of aneuploidy frequency in the developing and adult human brain revealed by an interphase FISH study. J. Histochem. Cytochem. 53, 385–390 (2005).

    CAS  PubMed  Google Scholar 

  63. 63

    Gasch, A. P. et al. Genomic expression programs in the response of yeast cells to environmental changes. Mol. Biol. Cell 11, 4241–4257 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Pavelka, N. et al. Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast. Nature 468, 321–325 (2010). This study describes the induction of meiosis in yeast strains with an odd ploidy (3N or 5N) to produce isogenic aneuploid strains.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    ElBaradi, T. T., van der Sande, C. A., Mager, W. H., Raue, H. A. & Planta, R. J. The cellular level of yeast ribosomal protein L25 is controlled principally by rapid degradation of excess protein. Curr. Genet. 10, 733–739 (1986).

    CAS  PubMed  Google Scholar 

  66. 66

    Maicas, E., Pluthero, F. G. & Friesen, J. D. The accumulation of three yeast ribosomal proteins under conditions of excess mRNA is determined primarily by fast protein decay. Mol. Cell. Biol. 8, 169–175 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Torres, E. M. et al. Identification of aneuploidy-tolerating mutations. Cell 143, 71–83 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Collier, T. S. et al. Comparison of stable-isotope labeling with amino acids in cell culture and spectral counting for relative quantification of protein expression. Rapid Commun. Mass Spectrom. 25, 2524–2532 (2011).

    CAS  PubMed  Google Scholar 

  69. 69

    Collier, T. S. et al. Direct comparison of stable isotope labeling by amino acids in cell culture and spectral counting for quantitative proteomics. Anal. Chem. 82, 8696–8702 (2010).

    CAS  PubMed  Google Scholar 

  70. 70

    St. Charles, J., Hamilton, M. L. & Petes, T. D. Meiotic chromosome segregation in triploid strains of Saccharomyces cerevisiae. Genetics 186, 537–550 (2010).

    CAS  PubMed  Google Scholar 

  71. 71

    Storchova, Z. et al. Genome-wide genetic analysis of polyploidy in yeast. Nature 443, 541–547 (2006).

    CAS  PubMed  Google Scholar 

  72. 72

    Ganem, N. J., Storchova, Z. & Pellman, D. Tetraploidy, aneuploidy and cancer. Curr. Opin. Genet. Dev. 17, 157–162 (2007).

    CAS  PubMed  Google Scholar 

  73. 73

    Thompson, S. L. & Compton, D. A. Proliferation of aneuploid human cells is limited by a p53-dependent mechanism. J. Cell Biol. 188, 369–381 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Tomasini, R., Mak, T. W. & Melino, G. The impact of p53 and p73 on aneuploidy and cancer. Trends Cell Biol. 18, 244–252 (2008).

    CAS  PubMed  Google Scholar 

  75. 75

    Bunz, F. et al. Targeted inactivation of p53 in human cells does not result in aneuploidy. Cancer Res. 62, 1129–1133 (2002).

    CAS  PubMed  Google Scholar 

  76. 76

    Kingsbury, M. A. et al. Aneuploid neurons are functionally active and integrated into brain circuitry. Proc. Natl Acad. Sci. USA 102, 6143–6147 (2005).

    CAS  PubMed  Google Scholar 

  77. 77

    Rehen, S. K. et al. Chromosomal variation in neurons of the developing and adult mammalian nervous system. Proc. Natl Acad. Sci. USA 98, 13361–13366 (2001).

    CAS  PubMed  Google Scholar 

  78. 78

    Li, M. et al. The ATM–p53 pathway suppresses aneuploidy-induced tumorigenesis. Proc. Natl Acad. Sci. USA 107, 14188–14193 (2010).

    CAS  PubMed  Google Scholar 

  79. 79

    Guo, Z., Kozlov, S., Lavin, M. F., Person, M. D. & Paull, T. T. ATM activation by oxidative stress. Science 330, 517–521 (2010).

    CAS  Google Scholar 

  80. 80

    Weaver, B. A., Silk, A. D., Montagna, C., Verdier-Pinard, P. & Cleveland, D. W. Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell 11, 25–36 (2007).

    CAS  PubMed  Google Scholar 

  81. 81

    Weaver, B. A. & Cleveland, D. W. The role of aneuploidy in promoting and suppressing tumors. J. Cell Biol. 185, 935–937 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Weaver, B. A. & Cleveland, D. W. The aneuploidy paradox in cell growth and tumorigenesis. Cancer Cell 14, 431–433 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Manning, A. L., Longworth, M. S. & Dyson, N. J. Loss of pRB causes centromere dysfunction and chromosomal instability. Genes Dev. 24, 1364–1376 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Zheng, L. & Lee, W. H. Retinoblastoma tumor suppressor and genome stability. Adv. Cancer Res. 85, 13–50 (2002).

    CAS  PubMed  Google Scholar 

  85. 85

    Knudsen, E. S., Sexton, C. R. & Mayhew, C. N. Role of the retinoblastoma tumor suppressor in the maintenance of genome integrity. Curr. Mol. Med. 6, 749–757 (2006).

    CAS  PubMed  Google Scholar 

  86. 86

    Manning, A. L. & Dyson, N. J. pRB, a tumor suppressor with a stabilizing presence. Trends Cell Biol. 21, 433–441 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Coschi, C. H. et al. Mitotic chromosome condensation mediated by the retinoblastoma protein is tumor-suppressive. Genes Dev. 24, 1351–1363 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    van Harn, T. et al. Loss of Rb proteins causes genomic instability in the absence of mitogenic signaling. Genes Dev. 24, 1377–1388 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Schvartzman, J. M., Duijf, P. H., Sotillo, R., Coker, C. & Benezra, R. Mad2 is a critical mediator of the chromosome instability observed upon Rb and p53 pathway inhibition. Cancer Cell 19, 701–714 (2011). This study shows that the overexpression of the mitotic checkpoint protein MAD2 is required for the CIN that results from the inhibition of the RB and p53 pathways, two pathways that are frequently inactivated in human cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Sotillo, R. et al. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 11, 9–23 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Pavelka, N., Rancati, G. & Li, R. Dr Jekyll and Mr Hyde: role of aneuploidy in cellular adaptation and cancer. Curr. Opin. Cell Biol. 22, 809–815 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Rancati, G. et al. Aneuploidy underlies rapid adaptive evolution of yeast cells deprived of a conserved cytokinesis motor. Cell 135, 879–893 (2008). This work demonstrates the beneficial and synergistic effects of small changes in gene expression owing to aneuploidy in yeast with defects in cytokinesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Bianchi, A. B., Aldaz, C. M. & Conti, C. J. Nonrandom duplication of the chromosome bearing a mutated Ha-ras-1 allele in mouse skin tumors. Proc. Natl Acad. Sci. USA 87, 6902–6906 (1990).

    CAS  PubMed  Google Scholar 

  94. 94

    Zhuang, Z. et al. Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nature Genet. 20, 66–69 (1998).

    CAS  PubMed  Google Scholar 

  95. 95

    Fischer, J. et al. Duplication and overexpression of the mutant allele of the MET proto-oncogene in multiple hereditary papillary renal cell tumours. Oncogene 17, 733–739 (1998).

    CAS  PubMed  Google Scholar 

  96. 96

    Beghini, A. et al. Trisomy 4 leading to duplication of a mutated KIT allele in acute myeloid leukemia with mast cell involvement. Cancer Genet. Cytogenet. 119, 26–31 (2000).

    CAS  PubMed  Google Scholar 

  97. 97

    Langabeer, S. E., Beghini, A. & Larizza, L. AML with t(8;21) and trisomy 4: possible involvement of c-kit? Leukemia 17, 1915; author reply 1915–1916 (2003).

    CAS  PubMed  Google Scholar 

  98. 98

    Sotillo, R., Schvartzman, J. M., Socci, N. D. & Benezra, R. Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. Nature 464, 436–440 (2010). This study shows that KRAS-driven tumours that develop CIN and aneuploidy owing to transient MAD2 overexpression recur at a markedly elevated rate after the withdrawal of the KRAS oncogene.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Malinge, S., Izraeli, S. & Crispino, J. D. Insights into the manifestations, outcomes and mechanisms of leukemogenesis in Down syndrome. Blood 113, 2619–2628 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Baek, K. H. et al. Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature 459, 1126–1130 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Ng, A. P. et al. Trisomy of Erg is required for myeloproliferation in a mouse model of Down syndrome. Blood 115, 3966–3969 (2010).

    CAS  PubMed  Google Scholar 

  102. 102

    Baetz, K., Measday, V. & Andrews, B. Revealing hidden relationships among yeast genes involved in chromosome segregation using systematic synthetic lethal and synthetic dosage lethal screens. Cell Cycle 5, 592–595 (2006).

    CAS  PubMed  Google Scholar 

  103. 103

    Measday, V. et al. Systematic yeast synthetic lethal and synthetic dosage lethal screens identify genes required for chromosome segregation. Proc. Natl Acad. Sci. USA 102, 13956–13961 (2005).

    CAS  PubMed  Google Scholar 

  104. 104

    Lin, H. et al. Polyploids require Bik1 for kinetochore–microtubule attachment. J. Cell Biol. 155, 1173–1184 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Kramer, A., Maier, B. & Bartek, J. Centrosome clustering and chromosomal (in) stability: A matter of life and death. Mol. Oncol. 5, 324–335 (2011).

    PubMed  PubMed Central  Google Scholar 

  106. 106

    Kwon, M. et al. Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. Genes Dev. 22, 2189–2203 (2008). In this study, a genome-wide siRNA screen was used to identify new mechanisms by which cells suppress multipolar divisions.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Tang, Y. C., Williams, B. R., Siegel, J. J. & Amon, A. Identification of aneuploidy-selective antiproliferation compounds. Cell 144, 499–512 (2011). This study identifies drugs with aneuploidy-specific lethality.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Chng, W. J. et al. Molecular dissection of hyperdiploid multiple myeloma by gene expression profiling. Cancer Res. 67, 2982–2989 (2007).

    CAS  PubMed  Google Scholar 

  109. 109

    Mateos, M. V. et al. Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenace. Blood 118, 4547–4553 (2011).

    CAS  Google Scholar 

  110. 110

    Usmani, S. Z., Bona, R. & Li, Z. 17 AAG for HSP90 inhibition in cancer—from bench to bedside. Curr. Mol. Med. 9, 654–664 (2009).

    CAS  PubMed  Google Scholar 

  111. 111

    Taub, J. W. & Ge, Y. Down syndrome, drug metabolism and chromosome 21. Pediatr. Blood Cancer 44, 33–39 (2005).

    PubMed  Google Scholar 

  112. 112

    Zhang, L. et al. Reduced folate carrier gene expression in childhood acute lymphoblastic leukemia: relationship to immunophenotype and ploidy. Clin. Cancer Res. 4, 2169–2177 (1998).

    CAS  PubMed  Google Scholar 

  113. 113

    Belkov, V. M. et al. Reduced folate carrier expression in acute lymphoblastic leukemia: a mechanism for ploidy but not lineage differences in methotrexate accumulation. Blood 93, 1643–1650 (1999).

    CAS  PubMed  Google Scholar 

  114. 114

    Meaburn, K. J., Parris, C. N. & Bridger, J. M. The manipulation of chromosomes by mankind: the uses of microcell-mediated chromosome transfer. Chromosoma 114, 263–274 (2005).

    PubMed  Google Scholar 

  115. 115

    Doherty, A. M. & Fisher, E. M. Microcell-mediated chromosome transfer (MMCT): small cells with huge potential. Mamm. Genome 14, 583–592 (2003).

    PubMed  Google Scholar 

  116. 116

    Upender, M. B. et al. Chromosome transfer induced aneuploidy results in complex dysregulation of the cellular transcriptome in immortalized and cancer cells. Cancer Res. 64, 6941–6949 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Hughes, T. R. et al. Widespread aneuploidy revealed by DNA microarray expression profiling. Nature Genet. 25, 333–337 (2000).

    CAS  Google Scholar 

  118. 118

    Selmecki, A., Forche, A. & Berman, J. Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science 313, 367–370 (2006). This study demonstrates that that the in vivo acquisition of extra copies of an isochromosome by Candida albicans confers resistance to fluconazole through the action of two specific genes in a copy-number-dependent manner.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Selmecki, A., Gerami-Nejad, M., Paulson, C., Forche, A. & Berman, J. An isochromosome confers drug resistance in vivo by amplification of two genes, ERG11 and TAC1. Mol. Microbiol. 68, 624–641 (2008).

    CAS  PubMed  Google Scholar 

  120. 120

    Duesberg, P. et al. How aneuploidy may cause cancer and genetic instability. Anticancer Res. 19, 4887–4906 (1999).

    CAS  PubMed  Google Scholar 

  121. 121

    Duesberg, P., Li, R., Fabarius, A. & Hehlmann, R. Aneuploidy and cancer: from correlation to causation. Contrib. Microbiol. 13, 16–44 (2006).

    PubMed  Google Scholar 

  122. 122

    Su, X. et al. Mechanism underlying the dual-mode regulation of microtubule dynamics by Kip/3kinesin-8. Mol. Cell 43, 751–763 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Fujiwara, T. et al. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437, 1043–1047 (2005).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We apologize to the authors whose work was not discussed or cited owing to space limitations. The authors are grateful to members of the Pellman laboratory, in particular Hubo Li, for helpful discussions. The authors thank Z. Storchova, A. Amon and R. Li for sharing results before publication. The authors thank E. Ivanova for providing the SKY karyotype for Fig. 1.

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Glossary

Aneuploidy

The presence of an abnormal number of chromosomes, either more or less than the diploid number. Aneuploidy is associated with cell and organismal inviability, cancer and birth defects.

Chromosomal instability

(CIN). A persistently high rate of gain and loss of chromosomes.

Kinetochore

A large protein complex that assembles at centromeres. It is composed of inner and outer regions that contain >80 proteins, which are required for spindle attachment, chromosome movement and regulation of the mitotic checkpoint.

Centrosome

An organelle that serves as the main microtubule-organizing centre of the cell, as well as a regulator of cell cycle progression.

Spindle assembly checkpoint

(SAC). A highly conserved surveillance mechanism in mitosis and meiosis that minimizes chromosome loss by preventing chromosomes from initiating anaphase until all kinetochores have successfully captured spindle microtubules.

Merotelic attachments

Abnormal kinetochore–microtubule attachments that occur when a single kinetochore attaches to microtubules that arise from both poles of the spindle.

Mosaic variegated aneuploidy

A rare, recessive condition that is characterized by growth restriction, microcephaly, childhood cancer and constitutional mosaicism for chromosomal gains and losses.

Co-culture

A cell culture containing a mixture of two different cell types.

Proteasome inhibitors

A class of drugs, including MG132 and bortezomib, that block the action of proteasomes, which are cellular complexes involved in protein degradation.

Dosage compensation

The counterbalancing of gene and protein imbalances that arise from unequal numbers of chromosomes, such as sex chromosomes in normal cells or potentially any chromosome in aneuploid cells.

Environmental stress response

(ESR). A gene set signature defined in yeast that has been grown under stressful conditions and at slow growth rates.

Proteotoxic stress

Results from the accumulation of unfolded, misfolded and aggregated proteins in a cell.

Robertsonian translocation

A chromosomal abnormality in which two acrocentric chromosomes become joined by a common centromere.

Reactive oxygen species

(ROS). Ions or small molecules — including oxygen ions, free radicals, inorganic peroxides and organic peroxides — that are highly reactive owing to the presence of unpaired valence shell electrons. They are a by-product of the normal metabolism of oxygen and have important roles in cell signalling. Increased levels owing to environmental stress can result in damage to cells.

Mutator phenotype

The loss-of-function of one gene, such as one for the repair of damaged DNA, that greatly increases the mutation rates at other loci.

Chromosome congression

The process of aligning chromosomes on the spindle during mitosis.

Oncogene addiction

The dependence of a cancer cell on one overactive gene or pathway for survival, growth and proliferation.

Synthetic lethality

Two genes are synthetic lethal if mutation of either alone is compatible with viability, but mutation of both leads to cell death.

AICAR

Short for 5-aminoimidazole-4-carboxamide ribonucleotide, this is an activator of AMP-activated protein kinase (AMPK), which is a metabolic master regulator that is activated in times of reduced energy availability.

HSP90 inhibitor

A class of drugs, including 17-allylaminogeldanamycin (17-AAG), that inhibit the function of the molecular chaperone heat shock protein 90 (HSP90), which is involved in protein folding.

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Gordon, D., Resio, B. & Pellman, D. Causes and consequences of aneuploidy in cancer. Nat Rev Genet 13, 189–203 (2012). https://doi.org/10.1038/nrg3123

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