1932

Abstract

Aneuploidy, the state of having gained or lost chromosomes, is a hallmark of cancer. Approximately 90% of tumors have gained or lost at least one chromosome. In spite of aneuploidy occurring as frequently as, if not more often than, disruption of the p53 pathway, whether and how aneuploidy influences tumorigenesis is still poorly understood. Here, we take advantage of large-scale tumor sequencing efforts to assess karyotypic alterations across many cancer types and review recent sequencing studies that show how karyotypes change in space and time. We further summarize findings that describe the effects of aneuploidy on untransformed cells, the mechanisms by which aneuploidy could drive tumorigenesis, and the potential to target aneuploidy for cancer therapy.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-042616-072231
2017-03-06
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/cancerbio/1/1/annurev-cancerbio-042616-072231.html?itemId=/content/journals/10.1146/annurev-cancerbio-042616-072231&mimeType=html&fmt=ahah

Literature Cited

  1. Albertson DG, Collins C, McCormick F, Gray JW. 2003. Chromosome aberrations in solid tumors. Nat. Genet. 34:4369–76 [Google Scholar]
  2. Allison DC, Bose KK, Hruban RH, Piantadosi S, Dooley WC. et al. 1991. Pancreatic cancer cell DNA content correlates with long-term survival after pancreatoduodenectomy. Ann. Surg. 214:6648–56 [Google Scholar]
  3. Baek K-H, Zaslavsky A, Lynch RC, Britt C, Okada Y. et al. 2009. Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature 459:72501126–30 [Google Scholar]
  4. Baker DJ, Jeganathan KB, Cameron JD, Thompson M, Juneja S. et al. 2004. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat. Genet. 36:7744–49 [Google Scholar]
  5. Bakhoum SF, Genovese G, Compton DA. 2009. Deviant kinetochore microtubule dynamics underlie chromosomal instability. Curr. Biol. 19:221937–42 [Google Scholar]
  6. Barber TD, McManus K, Yuen KWY, Reis M, Parmigiani G. et al. 2008. Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers. PNAS 105:93443–48 [Google Scholar]
  7. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S. et al. 2010. The landscape of somatic copy-number alteration across human cancers. Nature 463:7283899–905 [Google Scholar]
  8. Boveri T. 1914. Zur Frage der Entstehung maligner Tumoren. Jena, Ger.: Gustav Fischer Verlag
  9. Brastianos PK, Carter SL, Santagata S, Cahill DP, Taylor-Weiner A. et al. 2015. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov 5:111164–77 [Google Scholar]
  10. Burrell RA, McClelland SE, Endesfelder D, Groth P, Weller M-C. et al. 2013. Replication stress links structural and numerical cancer chromosomal instability. Nature 494:7438492–96 [Google Scholar]
  11. Byrd JC, Mrózek K, Dodge RK, Carroll AJ, Edwards CG. et al. 2002. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 100:134325–36 [Google Scholar]
  12. Carter SL, Cibulskis K, Helman E, McKenna A, Shen H. et al. 2012. Absolute quantification of somatic DNA alterations in human cancer. Nat. Biotechnol. 30:5413–21 [Google Scholar]
  13. Chen G, Mulla WA, Kucharavy A, Tsai H-J, Rubinstein B. et al. 2015. Targeting the adaptability of heterogeneous aneuploids. Cell 160:4771–84 [Google Scholar]
  14. Chin K, de Solorzano CO, Knowles D, Jones A, Chou W. et al. 2004. In situ analyses of genome instability in breast cancer. Nat. Genet. 36:9984–88 [Google Scholar]
  15. Cimini D, Howell B, Maddox P, Khodjakov A, Degrassi F, Salmon ED. 2001. Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells. J. Cell Biol. 153:3517–27 [Google Scholar]
  16. Cimini D, Tanzarella C, Degrassi F. 1999. Differences in malsegregation rates obtained by scoring ana-telophases or binucleate cells. Mutagenesis 14:6563–68 [Google Scholar]
  17. Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV. et al. 2012. DNA breaks and chromosome pulverization from errors in mitosis. Nature 482:53–58 [Google Scholar]
  18. Dai C, Whitesell L, Rogers AB, Lindquist S. 2007. Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130:61005–18 [Google Scholar]
  19. Davoli T, de Lange T. 2011. The causes and consequences of polyploidy in normal development and cancer. Annu. Rev. Cell Dev. Biol. 27:1585–610 [Google Scholar]
  20. Davoli T, Denchi EL, de Lange T. 2010. Persistent telomere damage induces bypass of mitosis and tetraploidy. Cell 141:181–93 [Google Scholar]
  21. Davoli T, Xu AW, Mengwasser KE, Sack LM, Yoon JC. et al. 2013. Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome. Cell 155:4948–62 [Google Scholar]
  22. Dekanty A, Barrio L, Muzzopappa M, Auer H, Milán M. 2012. Aneuploidy-induced delaminating cells drive tumorigenesis in Drosophila epithelia. PNAS 109:5020549–54 [Google Scholar]
  23. Dodgson SE, Kim S, Costanzo M, Baryshnikova A, Morse DL. et al. 2016. Chromosome-specific and global effects of aneuploidy in Saccharomyces cerevisiae. Genetics 202:41395–409 [Google Scholar]
  24. Dunham MJ, Badrane H, Ferea T, Adams J, Brown PO. et al. 2002. Characteristic genome rearrangements in experimental evolution of Saccharomyces cerevisiae. PNAS 99:2516144–49 [Google Scholar]
  25. Emdin SO, Stenling R, Roos G. 1987. Prognostic value of DNA content in colorectal carcinoma: a flow cytometric study with some methodologic aspects. Cancer 60:61282–87 [Google Scholar]
  26. Ertych N, Stolz A, Stenzinger A, Weichert W, Kaulfuß S. et al. 2014. Increased microtubule assembly rates influence chromosomal instability in colorectal cancer cells. Nat. Cell Biol. 16:8779–91 [Google Scholar]
  27. Galipeau PC, Cowan DS, Sanchez CA, Barrett MT, Emond MJ. et al. 1996. 17p (p53) allelic losses, 4N (G2/tetraploid) populations, and progression to aneuploidy in Barrett's esophagus. PNAS 93:7081–84 [Google Scholar]
  28. Ganem NJ, Godinho SA, Pellman D. 2009. A mechanism linking extra centrosomes to chromosomal instability. Nature 460:7252278–82 [Google Scholar]
  29. Garraway LA, Lander ES. 2013. Lessons from the cancer genome. Cell 153:117–37 [Google Scholar]
  30. Gasch AP. 2007. Comparative genomics of the environmental stress response in ascomycete fungi. Yeast 24:11961–76 [Google Scholar]
  31. Gascoigne KE, Taylor SS. 2008. Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell 14:2111–22 [Google Scholar]
  32. Gibson WJ, Hoivik EA, Halle MK, Taylor-Weiner A, Cherniack AD. et al. 2016. The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis. Nat. Genet. 48:8848–55 [Google Scholar]
  33. Gogendeau D, Siudeja K, Gambarotto D, Pennetier C, Bardin AJ, Basto R. 2015. Aneuploidy causes premature differentiation of neural and intestinal stem cells. Nat. Commun. 6:8894 [Google Scholar]
  34. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C. et al. 1998. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. Blood 92:72322–33 [Google Scholar]
  35. Hande MP, Samper E, Lansdorp P, Blasco MA. 1999. Telomere length dynamics and chromosomal instability in cells derived from telomerase null mice. J. Cell Biol. 144:4589–601 [Google Scholar]
  36. Hanks S, Coleman K, Reid S, Plaja A, Firth H. et al. 2004. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat. Genet. 36:111159–61 [Google Scholar]
  37. Haruki N, Nomoto S, Masuda A, Saji S, Osada H, Takahashi T. 1999. Identification of frequent impairment of the mitotic checkpoint and molecular analysis of the mitotic checkpoint genes, hsMAD2 and p55CDC, in human lung cancers. Oncogene 18:304295–300 [Google Scholar]
  38. Haruki N, Saito H, Harano T, Nomoto S, Takahashi T. et al. 2001. Molecular analysis of the mitotic checkpoint genes BUB1,. BUBR1 and BUB3 in human lung cancers. Cancer Lett. 162:2201–5 [Google Scholar]
  39. Hasle H, Clemmensen IH, Mikkelsen M. 2000. Risks of leukaemia and solid tumours in individuals with Down's syndrome. Lancet 355:9199165–69 [Google Scholar]
  40. Hassold TJ, Jacobs PA. 1984. Trisomy in man. Annu. Rev. Genet. 18:69–97 [Google Scholar]
  41. Janssen A, van der Burg M, Szuhai K, Kops GJPL, Medema RH. 2011. Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science 333:60511895–98 [Google Scholar]
  42. Jeganathan K, Malureanu L, Baker DJ, Abraham SC, van Deursen JM. 2007. Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis. J. Cell Biol. 179:2255–67 [Google Scholar]
  43. Kajii T, Ikeuchi T, Yang ZQ, Nakamura Y, Tsuji Y. et al. 2001. Cancer-prone syndrome of mosaic variegated aneuploidy and total premature chromatid separation: report of five infants. Am. J. Med. Genet 104157–64 [Google Scholar]
  44. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B. et al. 2013. Mutational landscape and significance across 12 major cancer types. Nature 502:7471333–39 [Google Scholar]
  45. Klein CA. 2009. Parallel progression of primary tumours and metastases. Nat. Rev. Cancer 9:4302–12 [Google Scholar]
  46. Knouse KA, Wu J, Whittaker CA, Amon A. 2014. Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. PNAS 111:3713409–14 [Google Scholar]
  47. Kuukasjärvi T, Karhu R, Tanner M, Kähkönen M, Schäffer A. et al. 1997. Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer. Cancer Res 57:81597–604 [Google Scholar]
  48. Lane AA, Chapuy B, Lin CY, Tivey T, Li H. et al. 2014. Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation. Nat. Genet. 46:6618–23 [Google Scholar]
  49. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA. et al. 2014. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505:7484495–501 [Google Scholar]
  50. Li M, Fang X, Wei Z, York JP, Zhang P. 2009. Loss of spindle assembly checkpoint–mediated inhibition of Cdc20 promotes tumorigenesis in mice. J. Cell Biol. 185:6983–94 [Google Scholar]
  51. Li X, Galipeau PC, Paulson TG, Sanchez CA, Arnaudo J. et al. 2014. Temporal and spatial evolution of somatic chromosomal alterations: a case-cohort study of Barrett's esophagus. Cancer Prev. Res. 7:1114–27 [Google Scholar]
  52. Liu W, Laitinen S, Khan S, Vihinen M, Kowalski J. et al. 2009. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat. Med. 15:5559–65 [Google Scholar]
  53. Maley CC, Galipeau PC, Finley JC, Wongsurawat VJ, Li X. et al. 2006. Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nat. Genet. 38:4468–73 [Google Scholar]
  54. Meijer GA, Hermsen MAJA, Baak JPA, van Diest PJ, Meuwissen SGM. et al. 1998. Progression from colorectal adenoma to carcinoma is associated with non-random chromosomal gains as detected by comparative genomic hybridisation. J. Clin. Pathol. 51:901–9 [Google Scholar]
  55. Musacchio A, Salmon ED. 2007. The spindle-assembly checkpoint in space and time. Nat. Rev. Mol. Cell Biol. 8:5379–93 [Google Scholar]
  56. Navin N, Kendall J, Troge J, Andrews P, Rodgers L. et al. 2011. Tumour evolution inferred by single-cell sequencing. Nature 472:734190–94 [Google Scholar]
  57. Navin N, Krasnitz A, Rodgers L, Cook K, Meth J. et al. 2010. Inferring tumor progression from genomic heterogeneity. Genome Res 20:168–80 [Google Scholar]
  58. Nawata H, Kashino G, Tano K, Daino K, Shimada Y. et al. 2011. Dysregulation of gene expression in the artificial human trisomy cells of chromosome 8 associated with transformed cell phenotypes. PLOS ONE 6:9e25319 [Google Scholar]
  59. Niggli FK, Powell JE, Parkes SE, Ward K, Raafat F. et al. 1994. DNA ploidy and proliferative activity (S-phase) in childhood soft-tissue sarcomas: their value as prognostic indicators. Br. J. Cancer 69:61106–10 [Google Scholar]
  60. Ohyama S, Yonemura Y, Miyazaki I. 1990. Prognostic value of S-phase fraction and DNA ploidy studied with in vivo administration of bromodeoxyuridine on human gastric cancers. Cancer 65:1116–21 [Google Scholar]
  61. Oromendia AB, Dodgson SE, Amon A. 2012. Aneuploidy causes proteotoxic stress in yeast. Genes Dev 26:242696–708 [Google Scholar]
  62. Passerini V, Ozeri-Galai E, de Pagter MS, Donnelly N, Schmalbrock S. et al. 2016. The presence of extra chromosomes leads to genomic instability. Nat. Commun. 7:10754 [Google Scholar]
  63. Rancati G, Pavelka N, Fleharty B, Noll A, Trimble R. et al. 2008. Aneuploidy underlies rapid adaptive evolution of yeast cells deprived of a conserved cytokinesis motor. Cell 135:5879–93 [Google Scholar]
  64. Ried T, Heselmeyer-Haddad K, Blegen H, Schröck E, Auer G. 1999. Genomic changes defining the genesis, progression, and malignancy potential in solid human tumors: a phenotype/genotype correlation. Genes Chromosom. Cancer 25:3195–204 [Google Scholar]
  65. Ried T, Knutzen R, Steinbeck R, Blegen H, Schröck E. et al. 1996. Comparative genomic hybridization reveals a specific pattern of chromosomal gains and losses during the genesis of colorectal tumors. Genes Chromosom. Cancer 15:4234–45 [Google Scholar]
  66. Ross-Innes CS, Becq J, Warren A, Cheetham RK, Northen H. et al. 2015. Whole-genome sequencing provides new insights into the clonal architecture of Barrett's esophagus and esophageal adenocarcinoma. Nat. Genet. 47:91038–46 [Google Scholar]
  67. Rutledge SD, Douglas TA, Nicholson JM, Vila-Casadesús M, Kantzler CL. et al. 2016. Selective advantage of trisomic human cells cultured in non-standard conditions. Sci. Rep. 6:22828 [Google Scholar]
  68. Santagata S, Hu R, Lin NU, Mendillo ML, Collins LC. et al. 2011. High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer. PNAS 108:4518378–83 [Google Scholar]
  69. Selmecki AM, Forche A, Berman J. 2006. Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science 313:5785367–70 [Google Scholar]
  70. Sheltzer JM, Blank HM, Pfau SJ, Tange Y, George BM. et al. 2011. Aneuploidy drives genomic instability in yeast. Science 333:60451026–30 [Google Scholar]
  71. Sheltzer JM, Torres EM, Dunham MJ, Amon A. 2012. Transcriptional consequences of aneuploidy. PNAS 109:3112644–49 [Google Scholar]
  72. Silk AD, Zasadil LM, Holland AJ, Vitre B, Cleveland DW, Weaver BA. 2013. Chromosome missegregation rate predicts whether aneuploidy will promote or suppress tumors. PNAS 110:44E4134–41 [Google Scholar]
  73. Silkworth WT, Nardi IK, Scholl LM, Cimini D. 2009. Multipolar spindle pole coalescence is a major source of kinetochore mis-attachment and chromosome mis-segregation in cancer cells. PLOS ONE 4:8e6564 [Google Scholar]
  74. Solimini NL, Xu Q, Mermel CH, Liang AC, Schlabach MR. et al. 2012. Recurrent hemizygous deletions in cancers may optimize proliferative potential. Science 337:6090104–9 [Google Scholar]
  75. Sotillo R, Hernando E, Díaz-Rodríguez E, Teruya-Feldstein J, Cordon-Cardo C. et al. 2007. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 11:19–23 [Google Scholar]
  76. Stachler MD, Taylor-Weiner A, Peng S, McKenna A, Agoston AT. et al. 2015. Paired exome analysis of Barrett's esophagus and adenocarcinoma. Nat. Genet. 47:91047–55 [Google Scholar]
  77. Sussan TE, Yang A, Li F, Ostrowski MC, Reeves RH. 2008. Trisomy represses ApcMin-mediated tumours in mouse models of Down's syndrome. Nature 451:717473–75 [Google Scholar]
  78. Tang Y-C, Amon A. 2013. Gene copy-number alterations: a cost–benefit analysis. Cell 152:3394–405 [Google Scholar]
  79. Tang Y-C, Williams BR, Siegel JJ, Amon A. 2011. Identification of aneuploidy-selective antiproliferation compounds. Cell 144:4499–512 [Google Scholar]
  80. Taylor SR, Blatt J, Costantino JP, Roederer M, Murphy RF. 1988. Flow cytometric DNA analysis of neuroblastoma and ganglioneuroma: a 10-year retrospective study. Cancer 62:4749–54 [Google Scholar]
  81. Thompson SL, Compton DA. 2011. Chromosome missegregation in human cells arises through specific types of kinetochore-microtubule attachment errors. PNAS 108:4417974–78 [Google Scholar]
  82. Tighe A, Johnson VL, Albertella M, Taylor SS. 2001. Aneuploid colon cancer cells have a robust spindle checkpoint. EMBO Rep 2:7609–14 [Google Scholar]
  83. Tomita T, Yasue M, Engelhard HH, McLone DG, Gonzalez-Crussi F, Bauer KD. 1988. Flow cytometric DNA analysis of medulloblastoma: prognostic implication of aneuploidy. Cancer 61:4744–49 [Google Scholar]
  84. Torres EM, Sokolsky T, Tucker CM, Chan LY, Boselli M. et al. 2007a. Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 317:5840916–24 [Google Scholar]
  85. Torres L, Ribeiro FR, Pandis N, Andersen JA, Heim S, Teixeira MR. 2007b. Intratumor genomic heterogeneity in breast cancer with clonal divergence between primary carcinomas and lymph node metastases. Breast Cancer Res. Treat. 102:2143–55 [Google Scholar]
  86. Wang Y, Waters J, Leung ML, Unruh A, Roh W. et al. 2014. Clonal evolution in breast cancer revealed by single nucleus genome sequencing. Nature 512:7513155–60 [Google Scholar]
  87. Weaver BAA, Silk AD, Montagna C, Verdier-Pinard P, Cleveland DW. 2007. Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell 11:125–36 [Google Scholar]
  88. Wenger CR, Beardslee S, Owens MA, Pounds G, Oldaker T. et al. 1993. DNA ploidy, S-phase, and steroid receptors in more than 127,000 breast cancer patients. Breast Cancer Res. Treat. 28:19–20 [Google Scholar]
  89. Williams BR, Prabhu VR, Hunter KE, Glazier CM, Whittaker CA. et al. 2008. Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science 322:703–9 [Google Scholar]
  90. Wolman SR, Gundacker H, Appelbaum FR, Slovak ML. 2002. Impact of trisomy 8 (+8) on clinical presentation, treatment response, and survival in acute myeloid leukemia: a Southwest Oncology Group study. Blood 100:129–35 [Google Scholar]
  91. Yang Q, Rasmussen SA, Friedman JM. 2002. Mortality associated with Down's syndrome in the USA from 1983 to 1997: a population-based study. Lancet 359:93111019–25 [Google Scholar]
  92. Yates LR, Gerstung M, Knappskog S, Desmedt C, Gundem G. et al. 2015. Subclonal diversification of primary breast cancer revealed by multiregion sequencing. Nat. Med. 21:7751–59 [Google Scholar]
  93. Yona AH, Manor YS, Herbst RH, Romano GH, Mitchell A. et al. 2012. Chromosomal duplication is a transient evolutionary solution to stress. PNAS 109:5121010–15 [Google Scholar]
  94. Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G. et al. 2013. Pan-cancer patterns of somatic copy number alteration. Nat. Genet. 45:101134–40 [Google Scholar]
  95. Zhang C-Z, Spektor A, Cornils H, Francis JM, Jackson EK. et al. 2015. Chromothripsis from DNA damage in micronuclei. Nature 522:7555179–84 [Google Scholar]
  96. Zhu J, Pavelka N, Bradford WD, Rancati G, Li R. 2012. Karyotypic determinants of chromosome instability in aneuploid budding yeast. PLOS Genet 8:5e1002719 [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-042616-072231
Loading
/content/journals/10.1146/annurev-cancerbio-042616-072231
Loading

Data & Media loading...

Supplemental Material

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error