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Context is everything: aneuploidy in cancer

Nature Reviews Genetics volume 21, pages 44–62 (2020)Cite this article

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Abstract

Cancer is driven by multiple types of genetic alterations, which range in size from point mutations to whole-chromosome gains and losses, known as aneuploidy. Chromosome instability, the process that gives rise to aneuploidy, can promote tumorigenesis by increasing genetic heterogeneity and promoting tumour evolution. However, much less is known about how aneuploidy itself contributes to tumour formation and progression. Unlike some pan-cancer oncogenes and tumour suppressor genes that drive transformation in virtually all cell types and cellular contexts, aneuploidy is not a universal promoter of tumorigenesis. Instead, recent studies suggest that aneuploidy is a context-dependent, cancer-type-specific oncogenic event that may have clinical relevance as a prognostic marker and as a potential therapeutic target.

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Fig. 1: Definitions of aneuploidy.
Fig. 2: The relationship between karyotype and fitness.
Fig. 3: The context-dependent role of aneuploidy during tumour development.
Fig. 4: The importance of cell type and genomic context in shaping the aneuploidy landscape during tumorigenesis.
Fig. 5: The cellular microenvironment shapes the cancer karyotype.
Fig. 6: Strategies to identify drivers of recurrent aneuploidies.
Fig. 7: Strategies to target recurrent aneuploidies in cancer.

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References

  1. Boveri, T. Concerning the origin of malignant tumours by Theodor Boveri. Translated and annotated by Henry Harris. J. Cell Sci. 121, 1–84 (2008).

    Article  PubMed  Google Scholar 

  2. Gordon, D. J., Resio, B. & Pellman, D. Causes and consequences of aneuploidy in cancer. Nat. Rev. Genet. 13, 189–203 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. van Jaarsveld, R. H. & Kops, G. Difference makers: chromosomal instability versus aneuploidy in cancer. Trends Cancer 2, 561–571 (2016).

    Article  PubMed  Google Scholar 

  4. Sheltzer, J. M. & Amon, A. The aneuploidy paradox: costs and benefits of an incorrect karyotype. Trends Genet. 27, 446–453 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sheltzer, J. M. et al. Single-chromosome gains commonly function as tumor suppressors. Cancer Cell 31, 240–255 (2017). This study shows that the experimental introduction of extra chromosomes into mammalian cells is tumour-suppressive.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Santaguida, S. & Amon, A. Short- and long-term effects of chromosome mis-segregation and aneuploidy. Nat. Rev. Mol. Cell Biol. 16, 473–485 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Torres, E. M. et al. Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 317, 916–924 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Williams, B. R. et al. Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science 322, 703–709 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Taylor, A. M. et al. Genomic and functional approaches to understanding cancer aneuploidy. Cancer Cell 33, 676–689.e3 (2018). This report presents a comprehensive pan-cancer analysis of aneuploidy across more than 10,000 human tumours.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zack, T. I. et al. Pan-cancer patterns of somatic copy number alteration. Nat. Genet. 45, 1134–1140 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Carter, S. L. et al. Absolute quantification of somatic DNA alterations in human cancer. Nat. Biotechnol. 30, 413–421 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Knouse, K. A., Davoli, T., Elledge, S. J. & Amon, A. Aneuploidy in cancer: seq-ing answers to old questions. Annu. Rev. Cancer Biol. 1, 335–354 (2017).

    Article  Google Scholar 

  14. Ben-David, U. et al. Patient-derived xenografts undergo mouse-specific tumor evolution. Nat. Genet. 49, 1567–1575 (2017). This research shows that aneuploidies that are highly recurrent in human tumours can be selected against when human tumours are transplanted into recipient mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Stingele, S. et al. Global analysis of genome, transcriptome and proteome reveals the response to aneuploidy in human cells. Mol. Syst. Biol. 8, 608 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Thomas, R., Marks, D. H., Chin, Y. & Benezra, R. Whole chromosome loss and associated breakage-fusion-bridge cycles transform mouse tetraploid cells. EMBO J. 37, 201–218 (2018). This study shows that aneuploidy can cause transformation in polyploid cells.

    Article  CAS  PubMed  Google Scholar 

  18. Essletzbichler, P. et al. Megabase-scale deletion using CRISPR/Cas9 to generate a fully haploid human cell line. Genome Res. 24, 2059–2065 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Adikusuma, F., Williams, N., Grutzner, F., Hughes, J. & Thomas, P. Targeted deletion of an entire chromosome using CRISPR/Cas9. Mol. Ther. 25, 1736–1738 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sheltzer, J. M. A transcriptional and metabolic signature of primary aneuploidy is present in chromosomally unstable cancer cells and informs clinical prognosis. Cancer Res. 73, 6401–6412 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sansregret, L. & Swanton, C. The role of aneuploidy in cancer evolution. Cold Spring Harb. Perspect. Med. 7, a028373 (2017). This recent review summarizes the clinical implications of CIN.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Sansregret, L., Vanhaesebroeck, B. & Swanton, C. Determinants and clinical implications of chromosomal instability in cancer. Nat. Rev. Clin. Oncol. 15, 139–150 (2018).

    Article  CAS  PubMed  Google Scholar 

  23. Simonetti, G., Bruno, S., Padella, A., Tenti, E. & Martinelli, G. Aneuploidy: cancer strength or vulnerability? Int. J. Cancer 144, 8–25 (2019).

    Article  CAS  PubMed  Google Scholar 

  24. Targa, A. & Rancati, G. Cancer: a CINful evolution. Curr. Opin. Cell Biol. 52, 136–144 (2018).

    Article  CAS  PubMed  Google Scholar 

  25. Lens, S. M. A. & Medema, R. H. Cytokinesis defects and cancer. Nat. Rev. Cancer 19, 32–45 (2019).

    Article  CAS  PubMed  Google Scholar 

  26. Luijten, M. N. H., Lee, J. X. T. & Crasta, K. C. Mutational game changer: chromothripsis and its emerging relevance to cancer. Mutat. Res. 777, 29–51 (2018).

    Article  CAS  Google Scholar 

  27. Bakhoum, S. F. & Landau, D. A. Chromosomal instability as a driver of tumor heterogeneity and evolution. Cold Spring Harb. Perspect. Med. 7, a029611 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Ben-David, U. et al. Aneuploidy induces profound changes in gene expression, proliferation and tumorigenicity of human pluripotent stem cells. Nat. Commun. 5, 4825 (2014).

    Article  CAS  PubMed  Google Scholar 

  29. Danielsen, H. E., Pradhan, M. & Novelli, M. Revisiting tumour aneuploidy — the place of ploidy assessment in the molecular era. Nat. Rev. Clin. Oncol. 13, 291–304 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Carter, S. L., Eklund, A. C., Kohane, I. S., Harris, L. N. & Szallasi, Z. A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat. Genet. 38, 1043–1048 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Buccitelli, C. et al. Pan-cancer analysis distinguishes transcriptional changes of aneuploidy from proliferation. Genome Res. 27, 501–511 (2017). This study demonstrates that high degrees of aneuploidy and CIN are not directly associated with gene expression programs of proliferation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Andor, N. et al. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity. Nat. Med. 22, 105–113 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. Birkbak, N. J. et al. Paradoxical relationship between chromosomal instability and survival outcome in cancer. Cancer Res. 71, 3447–3452 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Duijf, P. H., Schultz, N. & Benezra, R. Cancer cells preferentially lose small chromosomes. Int. J. Cancer 132, 2316–2326 (2013).

    Article  CAS  PubMed  Google Scholar 

  35. Davoli, T., Uno, H., Wooten, E. C. & Elledge, S. J. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science 355, eaaf8399 (2017). This research shows that immune evasion is correlated with aneuploidy in human cancers.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Liu, X. et al. Trisomy eight in ES cells is a common potential problem in gene targeting and interferes with germ line transmission. Dev. Dyn. 209, 85–91 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Ben-David, U. & Benvenisty, N. High prevalence of evolutionarily conserved and species-specific genomic aberrations in mouse pluripotent stem cells. Stem Cells 30, 612–622 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Zhang, M. et al. Aneuploid embryonic stem cells exhibit impaired differentiation and increased neoplastic potential. EMBO J. 35, 2285–2300 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Rutledge, S. D. et al. Selective advantage of trisomic human cells cultured in non-standard conditions. Sci. Rep. 6, 22828 (2016). This study demonstrates that aneuploidies that inhibit proliferation under normal culture conditions can promote proliferation under conditions of stress.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pavelka, N. et al. Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast. Nature 468, 321–325 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yona, A. H. et al. Chromosomal duplication is a transient evolutionary solution to stress. Proc. Natl Acad. Sci. USA 109, 21010–21015 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rowald, K. et al. Negative selection and chromosome instability induced by Mad2 overexpression delay breast cancer but facilitate oncogene-independent outgrowth. Cell Rep. 15, 2679–2691 (2016). This study shows that complex karyotypes that suppress tumorigenesis can also promote resistance to oncogene withdrawal.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. de Carcer, G. et al. Plk1 overexpression induces chromosomal instability and suppresses tumor development. Nat. Commun. 9, 3012 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Baker, D. J., Jin, F., Jeganathan, K. B. & van Deursen, J. M. Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterozygosity. Cancer Cell 16, 475–486 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ricke, R. M., Jeganathan, K. B. & van Deursen, J. M. Bub1 overexpression induces aneuploidy and tumor formation through Aurora B kinase hyperactivation. J. Cell Biol. 193, 1049–1064 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wijshake, T. et al. Reduced life- and healthspan in mice carrying a mono-allelic BubR1 MVA mutation. PLOS Genet. 8, e1003138 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Levine, M. S. et al. Centrosome amplification is sufficient to promote spontaneous tumorigenesis in mammals. Dev. Cell 40, 313–322.e5 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hoevenaar, W. H. M. et al. Degree and site of chromosomal instability define its oncogenic potential. Preprint at bioRxiv http://www.biorxiv.org/content/10.1101/638460 (2019).

  50. 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).

    Article  CAS  PubMed  Google Scholar 

  51. Foijer, F. et al. Chromosome instability induced by Mps1 and p53 mutation generates aggressive lymphomas exhibiting aneuploidy-induced stress. Proc. Natl Acad. Sci. USA 111, 13427–13432 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Foijer, F. et al. Deletion of the MAD2L1 spindle assembly checkpoint gene is tolerated in mouse models of acute T-cell lymphoma and hepatocellular carcinoma. eLife 6, e20873 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Laucius, C. D., Orr, B. & Compton, D. A. Chromosomal instability suppresses the growth of K-Ras-induced lung adenomas. Cell Cycle 18, 1702–1713 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Burrell, R. A. et al. Replication stress links structural and numerical cancer chromosomal instability. Nature 494, 492–496 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lamm, N. et al. Genomic instability in human pluripotent stem cells arises from replicative stress and chromosome condensation defects. Cell Stem Cell 18, 253–261 (2016).

    Article  CAS  PubMed  Google Scholar 

  56. Ly, P. et al. Chromosome segregation errors generate a diverse spectrum of simple and complex genomic rearrangements. Nat. Genet. 51, 705–715 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mayshar, Y. et al. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell 7, 521–531 (2010).

    Article  CAS  PubMed  Google Scholar 

  58. International Stem Cell Initiative. et al. Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage. Nat. Biotechnol. 29, 1132–1144 (2011).

    Article  CAS  Google Scholar 

  59. Anders, K. R. et al. A strategy for constructing aneuploid yeast strains by transient nondisjunction of a target chromosome. BMC Genet. 10, 36 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Ravichandran, M. C., Fink, S., Clarke, M. N., Hofer, F. C. & Campbell, C. S. Genetic interactions between specific chromosome copy number alterations dictate complex aneuploidy patterns. Genes Dev. 32, 1485–1498 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Westcott, P. M. et al. The mutational landscapes of genetic and chemical models of Kras-driven lung cancer. Nature 517, 489–492 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Nassar, D., Latil, M., Boeckx, B., Lambrechts, D. & Blanpain, C. Genomic landscape of carcinogen-induced and genetically induced mouse skin squamous cell carcinoma. Nat. Med. 21, 946–954 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. Ben-David, U. et al. The landscape of chromosomal aberrations in breast cancer mouse models reveals driver-specific routes to tumorigenesis. Nat. Commun. 7, 12160 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Laubert, T. et al. Stage-specific frequency and prognostic significance of aneuploidy in patients with sporadic colorectal cancer-a meta-analysis and current overview. Int. J. Colorectal Dis. 30, 1015–1028 (2015).

    Article  PubMed  Google Scholar 

  65. Ross-Innes, C. S. et al. Whole-genome sequencing provides new insights into the clonal architecture of Barrett’s esophagus and esophageal adenocarcinoma. Nat. Genet. 47, 1038–1046 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Heselmeyer, K. et al. Gain of chromosome 3q defines the transition from severe dysplasia to invasive carcinoma of the uterine cervix. Proc. Natl Acad. Sci. USA 93, 479–484 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Gao, R. et al. Punctuated copy number evolution and clonal stasis in triple-negative breast cancer. Nat. Genet. 48, 1119–1130 (2016). This study shows that aneuploidy develops in punctuated bursts during breast cancer tumorigenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Eriksson, E. T., Schimmelpenning, H., Aspenblad, U., Zetterberg, A. & Auer, G. U. Immunohistochemical expression of the mutant p53 protein and nuclear DNA content during the transition from benign to malignant breast disease. Hum. Pathol. 25, 1228–1233 (1994).

    Article  CAS  PubMed  Google Scholar 

  69. Teixeira, V. H. et al. Deciphering the genomic, epigenomic, and transcriptomic landscapes of pre-invasive lung cancer lesions. Nat. Med. 25, 517–525 (2019).

    Article  CAS  PubMed  Google Scholar 

  70. Auslander, N. et al. Cancer-type specific aneuploidies hard-wire chromosome-wide gene expression patterns of their tissue of origin. Preprint at bioRxiv http://www.biorxiv.org/content/10.1101/563858 (2019).

  71. Gerstung, M. et al. The evolutionary history of 2,658 cancers. Preprint at bioRxiv http://www.biorxiv.org/content/10.1101/161562 (2018).

  72. Mitchell, T. J. et al. Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal. Cell 173, 611–623.e17 (2018). This whole-genome analysis of renal tumours reveals that chromosome arm 3p loss is often the initiating driver of this tumour type.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Bakhoum, S. F. et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 553, 467–472 (2018). This study shows that chromosomally unstable tumour cells activate innate immune pathways to spread into distant organs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bakhoum, S. F. & Cantley, L. C. The multifaceted role of chromosomal instability in cancer and its microenvironment. Cell 174, 1347–1360 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Liu, W. et al. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat. Med. 15, 559–565 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Brastianos, P. K. et al. Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov. 5, 1164–1177 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Gibson, W. J. et al. The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis. Nat. Genet. 48, 848–855 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Reiter, J. G. et al. Minimal functional driver gene heterogeneity among untreated metastases. Science 361, 1033–1037 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Turajlic, S. et al. Tracking cancer evolution reveals constrained routes to metastases: TRACERx renal. Cell 173, 581–594.e12 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Vasudevan, A. et al. Single chromosome gains can function as metastasis suppressors and metastasis promoters. Preprint at bioRxiv http://www.biorxiv.org/content/10.1101/590547 (2019).

  81. Gao, C. et al. Chromosome instability drives phenotypic switching to metastasis. Proc. Natl Acad. Sci. USA 113, 14793–14798 (2016). This study suggests that epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions select for specific distinct karyotypes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Graham, N. A. et al. Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures. Mol. Syst. Biol. 13, 914 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Hoadley, K. A. et al. Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell 173, 291–304.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Davoli, T. et al. Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome. Cell 155, 948–962 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Sack, L. M. et al. Profound tissue specificity in proliferation control underlies cancer drivers and aneuploidy patterns. Cell 173, 499–514.e23 (2018). This TCGA analysis shows that tissue-specific gene expression underlies the tissue specificity of aneuploidy patterns.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ben-David, U., Mayshar, Y. & Benvenisty, N. Large-scale analysis reveals acquisition of lineage-specific chromosomal aberrations in human adult stem cells. Cell Stem Cell 9, 97–102 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. Levine, A. J., Jenkins, N. A. & Copeland, N. G. The roles of initiating truncal mutations in human cancers: the order of mutations and tumor cell type matters. Cancer Cell 35, 10–15 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Herbet, M., Salomon, A., Feige, J. J. & Thomas, M. Acquisition order of Ras and p53 gene alterations defines distinct adrenocortical tumor phenotypes. PLOS Genet. 8, e1002700 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ortmann, C. A. et al. Effect of mutation order on myeloproliferative neoplasms. N. Engl. J. Med. 372, 601–612 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Kent, D. G. & Green, A. R. Order matters: the order of somatic mutations influences cancer evolution. Cold Spring Harb. Perspect. Med. 7, a027060 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Gatza, M. L., Silva, G. O., Parker, J. S., Fan, C. & Perou, C. M. An integrated genomics approach identifies drivers of proliferation in luminal-subtype human breast cancer. Nat. Genet. 46, 1051–1059 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Bielski, C. M. et al. Genome doubling shapes the evolution and prognosis of advanced cancers. Nat. Genet. 50, 1189–1195 (2018). This TCGA analysis demonstrates that whole-genome doubling increases the aneuploidy tolerance of tumour cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ben-David, U., Beroukhim, R. & Golub, T. R. Genomic evolution of cancer models: perils and opportunities. Nat. Rev. Cancer 19, 97–109 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Li, X. et al. Organoid cultures recapitulate esophageal adenocarcinoma heterogeneity providing a model for clonality studies and precision therapeutics. Nat. Commun. 9, 2983 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Bolhaqueiro, A. C. F. et al. Ongoing chromosomal instability and karyotype evolution in human colorectal cancer organoids. Nat. Genet. 51, 824–834 (2019).

    Article  CAS  PubMed  Google Scholar 

  97. Ben-David, U. et al. Genetic and transcriptional evolution alters cancer cell line drug response. Nature 560, 325–330 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wangsa, D. et al. The evolution of single cell-derived colorectal cancer cell lines is dominated by the continued selection of tumor specific genomic imbalances, despite random chromosomal instability. Carcinogenesis 39, 993–1005 (2018).

  99. Harding, S. M. et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548, 466–470 (2017). This article identifies micronuclei as the source of cGAS-activating immunostimulatory DNA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Mackenzie, K. J. et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 548, 461–465 (2017). This study shows that micronuclei activate a cell-intrinsic immune surveillance pathway controlled by cGAS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Santaguida, S. et al. Chromosome mis-segregation generates cell-cycle-arrested cells with complex karyotypes that are eliminated by the immune system. Dev. Cell 41, 638–651.e5 (2017). This research shows that cells with highly aberrant karyotypes are recognized by natural killer cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Sheltzer, J. M., Torres, E. M., Dunham, M. J. & Amon, A. Transcriptional consequences of aneuploidy. Proc. Natl Acad. Sci. USA 109, 12644–12649 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Santaguida, S., Vasile, E., White, E. & Amon, A. Aneuploidy-induced cellular stresses limit autophagic degradation. Genes Dev. 29, 2010–2021 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Netea-Maier, R. T., Plantinga, T. S., van de Veerdonk, F. L., Smit, J. W. & Netea, M. G. Modulation of inflammation by autophagy: consequences for human disease. Autophagy 12, 245–260 (2016).

    Article  CAS  PubMed  Google Scholar 

  105. McGranahan, N. et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell 171, 1259–1271.e11 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Das, K. & Tan, P. Molecular cytogenetics: recent developments and applications in cancer. Clin. Genet. 84, 315–325 (2013).

    Article  CAS  PubMed  Google Scholar 

  107. van den Bos, H., Bakker, B., Spierings, D. C. J., Lansdorp, P. M. & Foijer, F. Single-cell sequencing to quantify genomic integrity in cancer. Int. J. Biochem. Cell Biol. 94, 146–150 (2018).

    Article  PubMed  CAS  Google Scholar 

  108. Auer, G. U., Caspersson, T. O. & Wallgren, A. S. DNA content and survival in mammary carcinoma. Anal. Quant. Cytol. 2, 161–165 (1980).

    CAS  PubMed  Google Scholar 

  109. Steinbeck, R. G., Heselmeyer, K. M. & Auer, G. U. DNA ploidy in human colorectal adenomas. Anal. Quant. Cytol. Histol. 16, 196–202 (1994).

    CAS  PubMed  Google Scholar 

  110. Hieronymus, H. et al. Tumor copy number alteration burden is a pan-cancer prognostic factor associated with recurrence and death. eLife 7, e37294 (2018). This study identifies a strong association between high CNA levels, largely driven by aneuploidy, and adverse prognosis across multiple tumour types.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  112. Araujo, J. P., Lourenco, P., Rocha-Goncalves, F., Ferreira, A. & Bettencourt, P. Nutritional markers and prognosis in cardiac cachexia. Int. J. Cardiol. 146, 359–363 (2011).

    Article  PubMed  Google Scholar 

  113. Sinicrope, F. A. et al. Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients. Gastroenterology 131, 729–737 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Mouradov, D. et al. Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations. Am. J. Gastroenterol. 108, 1785–1793 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Hveem, T. S. et al. Prognostic impact of genomic instability in colorectal cancer. Br. J. Cancer 110, 2159–2164 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Kristensen, G. B. et al. Large-scale genomic instability predicts long-term outcome for women with invasive stage I ovarian cancer. Ann. Oncol. 14, 1494–1500 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Macintyre, G. et al. Copy number signatures and mutational processes in ovarian carcinoma. Nat. Genet. 50, 1262–1270 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Gazic, B. et al. S-phase fraction determined on fine needle aspirates is an independent prognostic factor in breast cancer - a multivariate study of 770 patients. Cytopathology 19, 294–302 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. Karra, H. et al. Securin predicts aneuploidy and survival in breast cancer. Histopathology 60, 586–596 (2012).

    Article  PubMed  Google Scholar 

  120. Pinto, A. E. et al. DNA ploidy is an independent predictor of survival in breast invasive ductal carcinoma: a long-term multivariate analysis of 393 patients. Ann. Surg. Oncol. 20, 1530–1537 (2013).

    Article  PubMed  Google Scholar 

  121. Hemmer, J., Schon, E., Kreidler, J. & Haase, S. Prognostic implications of DNA ploidy in squamous cell carcinomas of the tongue assessed by flow cytometry. J. Cancer Res. Clin. Oncol. 116, 83–86 (1990).

    Article  CAS  PubMed  Google Scholar 

  122. Martinez, P. et al. Evolution of Barrett’s esophagus through space and time at single-crypt and whole-biopsy levels. Nat. Commun. 9, 794 (2018). This study tracks the evolution of Barrett oesophagus to oesophageal carcinoma and reveals that aneuploidy is associated with the likelihood of malignant progression.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Bird-Lieberman, E. L. et al. Population-based study reveals new risk-stratification biomarker panel for Barrett’s esophagus. Gastroenterology 143, 927–935.e3 (2012).

    Article  CAS  PubMed  Google Scholar 

  124. Lennartz, M. et al. The combination of DNA ploidy status and PTEN/6q15 deletions provides strong and independent prognostic information in prostate cancer. Clin. Cancer Res. 22, 2802–2811 (2016).

    Article  CAS  PubMed  Google Scholar 

  125. Deliveliotis, C. et al. The prognostic value of p53 and DNA ploidy following radical prostatectomy. World J. Urol. 21, 171–176 (2003).

    Article  CAS  PubMed  Google Scholar 

  126. Pretorius, M. E. et al. Large scale genomic instability as an additive prognostic marker in early prostate cancer. Cell Oncol. 31, 251–259 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Stopsack, K. H. et al. Aneuploidy drives lethal progression in prostate cancer. Proc. Natl Acad. Sci. USA 116, 11390–11395 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Garner, D. Clinical application of DNA ploidy to cervical cancer screening: a review. World J. Clin. Oncol. 5, 931–965 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Schramm, M. et al. Equivocal cytology in lung cancer diagnosis: improvement of diagnostic accuracy using adjuvant multicolor FISH, DNA-image cytometry, and quantitative promoter hypermethylation analysis. Cancer Cytopathol. 119, 177–192 (2011).

    Article  PubMed  Google Scholar 

  130. Choma, D., Daures, J. P., Quantin, X. & Pujol, J. L. Aneuploidy and prognosis of non-small-cell lung cancer: a meta-analysis of published data. Br. J. Cancer 85, 14–22 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Yang, J. & Zhou, Y. Detection of DNA aneuploidy in exfoliated airway epithelia cells of sputum specimens by the automated image cytometry and its clinical value in the identification of lung cancer. J. Huazhong Univ. Sci. Technol. Med. Sci. 24, 407–410 (2004).

    Article  CAS  Google Scholar 

  132. Xing, S. et al. Predictive value of image cytometry for diagnosis of lung cancer in heavy smokers. Eur. Respir. J. 25, 956–963 (2005).

    Article  CAS  PubMed  Google Scholar 

  133. Fonseca, R. et al. Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res. 64, 1546–1558 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Manier, S. et al. Genomic complexity of multiple myeloma and its clinical implications. Nat. Rev. Clin. Oncol. 14, 100–113 (2017).

    Article  CAS  PubMed  Google Scholar 

  135. Secker-Walker, L. M., Lawler, S. D. & Hardisty, R. M. Prognostic implications of chromosomal findings in acute lymphoblastic leukaemia at diagnosis. Br. Med. J. 2, 1529–1530 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Pui, C. H. et al. Hypodiploidy is associated with a poor prognosis in childhood acute lymphoblastic leukemia. Blood 70, 247–253 (1987).

    Article  CAS  PubMed  Google Scholar 

  137. Shago, M. Recurrent cytogenetic abnormalities in acute lymphoblastic leukemia. Methods Mol. Biol. 1541, 257–278 (2017).

    Article  CAS  PubMed  Google Scholar 

  138. Lee, A. J. et al. Chromosomal instability confers intrinsic multidrug resistance. Cancer Res. 71, 1858–1870 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Kuznetsova, A. Y. et al. Chromosomal instability, tolerance of mitotic errors and multidrug resistance are promoted by tetraploidization in human cells. Cell Cycle 14, 2810–2820 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Silk, A. D. et al. Chromosome missegregation rate predicts whether aneuploidy will promote or suppress tumors. Proc. Natl Acad. Sci. USA 110, E4134–E4141 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Roylance, R. et al. Relationship of extreme chromosomal instability with long-term survival in a retrospective analysis of primary breast cancer. Cancer Epidemiol. Biomarkers Prev. 20, 2183–2194 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Jamal-Hanjani, M. et al. Extreme chromosomal instability forecasts improved outcome in ER-negative breast cancer: a prospective validation cohort study from the TACT trial. Ann. Oncol. 26, 1340–1346 (2015).

    Article  CAS  PubMed  Google Scholar 

  143. Laughney, A. M., Elizalde, S., Genovese, G. & Bakhoum, S. F. Dynamics of tumor heterogeneity derived from clonal karyotypic evolution. Cell Rep. 12, 809–820 (2015).

    Article  CAS  PubMed  Google Scholar 

  144. Greenberg, P. et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89, 2079–2088 (1997).

    Article  CAS  PubMed  Google Scholar 

  145. Schanz, J. et al. Coalesced multicentric analysis of 2,351 patients with myelodysplastic syndromes indicates an underestimation of poor-risk cytogenetics of myelodysplastic syndromes in the international prognostic scoring system. J. Clin. Oncol. 29, 1963–1970 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Kawankar, N. & Vundinti, B. R. Cytogenetic abnormalities in myelodysplastic syndrome: an overview. Hematology 16, 131–138 (2011).

    Article  PubMed  Google Scholar 

  147. Deeg, H. J. et al. Five-group cytogenetic risk classification, monosomal karyotype, and outcome after hematopoietic cell transplantation for MDS or acute leukemia evolving from MDS. Blood 120, 1398–1408 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Giagounidis, A. A. Lenalidomide for del(5q) and non-del(5q) myelodysplastic syndromes. Semin. Hematol. 49, 312–322 (2012).

    Article  CAS  PubMed  Google Scholar 

  149. List, A., Ebert, B. L. & Fenaux, P. A decade of progress in myelodysplastic syndrome with chromosome 5q deletion. Leukemia 32, 1493–1499 (2018). This review summarizes strategies to target MDS with 5q loss, the first clinical targeting of a recurrent cancer aneuploidy.

    Article  PubMed  Google Scholar 

  150. Idbaih, A. et al. BAC array CGH distinguishes mutually exclusive alterations that define clinicogenetic subtypes of gliomas. Int. J. Cancer 122, 1778–1786 (2008).

    Article  CAS  PubMed  Google Scholar 

  151. Cancer Genome Atlas Research Network. et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N. Engl. J. Med. 372, 2481–2498 (2015).

    Article  CAS  Google Scholar 

  152. Wiestler, B. et al. Integrated DNA methylation and copy-number profiling identify three clinically and biologically relevant groups of anaplastic glioma. Acta Neuropathol. 128, 561–571 (2014).

    Article  CAS  PubMed  Google Scholar 

  153. Wahl, M. et al. Chemotherapy for adult low-grade gliomas: clinical outcomes by molecular subtype in a phase II study of adjuvant temozolomide. Neuro Oncol. 19, 242–251 (2017).

    CAS  PubMed  Google Scholar 

  154. Weller, M. et al. Personalized care in neuro-oncology coming of age: why we need MGMT and 1p/19q testing for malignant glioma patients in clinical practice. Neuro Oncol. 14 (Suppl. 4), iv100–iv108 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Wick, W. et al. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J. Clin. Oncol. 27, 5874–5880 (2009).

    Article  CAS  PubMed  Google Scholar 

  156. Cairncross, G. et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J. Clin. Oncol. 31, 337–343 (2013).

    Article  CAS  PubMed  Google Scholar 

  157. van den Bent, M. J. et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J. Clin. Oncol. 31, 344–350 (2013).

    Article  PubMed  CAS  Google Scholar 

  158. Bardi, G., Fenger, C., Johansson, B., Mitelman, F. & Heim, S. Tumor karyotype predicts clinical outcome in colorectal cancer patients. J. Clin. Oncol. 22, 2623–2634 (2004).

    Article  PubMed  Google Scholar 

  159. Fonseca, R. et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 101, 4569–4575 (2003).

    Article  CAS  PubMed  Google Scholar 

  160. Buccheri, V. et al. Prognostic and therapeutic stratification in CLL: focus on 17p deletion and p53 mutation. Ann. Hematol. 97, 2269–2278 (2018).

    Article  CAS  PubMed  Google Scholar 

  161. Zhang, C. Z. et al. Chromothripsis from DNA damage in micronuclei. Nature 522, 179–184 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Soto, M., Garcia-Santisteban, I., Krenning, L., Medema, R. H. & Raaijmakers, J. A. Chromosomes trapped in micronuclei are liable to segregation errors. J. Cell Sci. 131, jcs214742 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. He, B. et al. Chromosomes missegregated into micronuclei contribute to chromosomal instability by missegregating at the next division. Oncotarget 10, 2660–2674 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Olivier, M., Hollstein, M. & Hainaut, P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb. Perspect. Biol. 2, a001008 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Kastenhuber, E. R. & Lowe, S. W. Putting p53 in context. Cell 170, 1062–1078 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  167. Jamal-Hanjani, M., Quezada, S. A., Larkin, J. & Swanton, C. Translational implications of tumor heterogeneity. Clin. Cancer Res. 21, 1258–1266 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Dagogo-Jack, I. & Shaw, A. T. Tumour heterogeneity and resistance to cancer therapies. Nat. Rev. Clin. Oncol. 15, 81–94 (2018).

    Article  CAS  PubMed  Google Scholar 

  169. Jamal-Hanjani, M. et al. Tracking the evolution of non-small-cell lung cancer. N. Engl. J. Med. 376, 2109–2121 (2017). This study shows that CNA heterogeneity, but not point mutation heterogeneity, is strongly associated with clinical outcome.

    Article  CAS  PubMed  Google Scholar 

  170. Pilie, P. G., Tang, C., Mills, G. B. & Yap, T. A. State-of-the-art strategies for targeting the DNA damage response in cancer. Nat. Rev. Clin. Oncol. 16, 81–104 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Pao, W. & Chmielecki, J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat. Rev. Cancer 10, 760–774 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Zhu, J., Tsai, H. J., Gordon, M. R. & Li, R. Cellular Stress Associated with Aneuploidy. Dev. Cell 44, 420–431 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Chunduri, N. K. & Storchova, Z. The diverse consequences of aneuploidy. Nat. Cell Biol. 21, 54–62 (2019). This review summarizes the current understanding of the cellular stresses induced by aneuploidy.

    Article  CAS  PubMed  Google Scholar 

  174. Tsai, H. J. et al. Hypo-osmotic-like stress underlies general cellular defects of aneuploidy. Nature 570, 117–121 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Durrbaum, M. et al. Unique features of the transcriptional response to model aneuploidy in human cells. BMC Genomics 15, 139 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Goncalves, E. et al. Widespread post-transcriptional attenuation of genomic copy-number variation in cancer. Cell Syst. 5, 386–398.e4 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Dodgson, S. E., Santaguida, S., Kim, S., Sheltzer, J. & Amon, A. The pleiotropic deubiquitinase Ubp3 confers aneuploidy tolerance. Genes Dev. 30, 2259–2271 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Tang, Y. C., Williams, B. R., Siegel, J. J. & Amon, A. Identification of aneuploidy-selective antiproliferation compounds. Cell 144, 499–512 (2011). This study provides a proof of concept that highly aneuploid cancer cells can be targeted by exploiting non-chromosome-specific vulnerabilities of the aneuploid cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Donnelly, N., Passerini, V., Durrbaum, M., Stingele, S. & Storchova, Z. HSF1 deficiency and impaired HSP90-dependent protein folding are hallmarks of aneuploid human cells. EMBO J. 33, 2374–2387 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Hwang, S. et al. Serine-dependent sphingolipid synthesis is a metabolic liability of aneuploid cells. Cell Rep. 21, 3807–3818 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Tang, Y. C. et al. Aneuploid cell survival relies upon sphingolipid homeostasis. Cancer Res. 77, 5272–5286 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Simoes-Sousa, S. et al. The p38alpha stress kinase suppresses aneuploidy tolerance by inhibiting hif-1alpha. Cell Rep. 25, 749–760.e6 (2018). This article demonstrates that the p38 pathway regulates the cellular response to aneuploidy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Canovas, B. et al. Targeting p38alpha increases DNA damage, chromosome instability, and the anti-tumoral response to taxanes in breast cancer cells. Cancer Cell 33, 1094–1110.e8 (2018). This study demonstrates the therapeutic value of targeting mechanisms of aneuploidy tolerance.

    Article  CAS  PubMed  Google Scholar 

  185. Zhang, J. et al. Anti-apoptotic mutations desensitize human pluripotent stem cells to mitotic stress and enable aneuploid cell survival. Stem Cell Rep. 12, 557–571 (2019).

    Article  CAS  Google Scholar 

  186. Knudsen, E. S. & Knudsen, K. E. Tailoring to RB: tumour suppressor status and therapeutic response. Nat. Rev. Cancer 8, 714–724 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Sieber, O. M., Tomlinson, S. R. & Tomlinson, I. P. Tissue, cell and stage specificity of (epi)mutations in cancers. Nat. Rev. Cancer 5, 649–655 (2005).

    Article  CAS  PubMed  Google Scholar 

  188. Schaefer, M. H. & Serrano, L. Cell type-specific properties and environment shape tissue specificity of cancer genes. Sci. Rep. 6, 20707 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Bailey, M. H. et al. Comprehensive characterization of cancer driver genes and mutations. Cell 174, 1034–1035 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Martincorena, I. et al. Universal patterns of selection in cancer and somatic tissues. Cell 173, 1823 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Henrichsen, C. N. et al. Segmental copy number variation shapes tissue transcriptomes. Nat. Genet. 41, 424–429 (2009).

    Article  CAS  PubMed  Google Scholar 

  192. Pollack, J. R. et al. Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors. Proc. Natl Acad. Sci. USA 99, 12963–12968 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Schoch, C. et al. Genomic gains and losses influence expression levels of genes located within the affected regions: a study on acute myeloid leukemias with trisomy 8, 11, or 13, monosomy 7, or deletion 5q. Leukemia 19, 1224–1228 (2005).

    Article  CAS  PubMed  Google Scholar 

  194. Tsafrir, D. et al. Relationship of gene expression and chromosomal abnormalities in colorectal cancer. Cancer Res. 66, 2129–2137 (2006).

    Article  CAS  PubMed  Google Scholar 

  195. Ben-David, U., Mayshar, Y. & Benvenisty, N. Virtual karyotyping of pluripotent stem cells on the basis of their global gene expression profiles. Nat. Protoc. 8, 989–997 (2013).

    Article  PubMed  CAS  Google Scholar 

  196. Liu, Y. et al. Deletions linked to TP53 loss drive cancer through p53-independent mechanisms. Nature 531, 471–475 (2016). This study demonstrates that large CNAs are often driven by multiple genes, even when a strong tumour suppresses or oncogene resides on the affected chromosomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Xue, W. et al. A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions. Proc. Natl Acad. Sci. USA 109, 8212–8217 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Curtis, C. et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486, 346–352 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Bettegowda, C. et al. Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science 333, 1453–1455 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Suzuki, H. et al. Mutational landscape and clonal architecture in grade II and III gliomas. Nat. Genet. 47, 458–468 (2015).

    Article  CAS  PubMed  Google Scholar 

  201. Maser, R. S. et al. Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature 447, 966–971 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Herschkowitz, J. I. et al. Comparative oncogenomics identifies breast tumors enriched in functional tumor-initiating cells. Proc. Natl Acad. Sci. USA 109, 2778–2783 (2012).

    Article  CAS  PubMed  Google Scholar 

  203. Weaver, Z. A. et al. A recurring pattern of chromosomal aberrations in mammary gland tumors of MMTV-cmyc transgenic mice. Genes Chromosomes Cancer 25, 251–260 (1999).

    Article  CAS  PubMed  Google Scholar 

  204. Ebert, B. L. et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature 451, 335–339 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Kotini, A. G. et al. Functional analysis of a chromosomal deletion associated with myelodysplastic syndromes using isogenic human induced pluripotent stem cells. Nat. Biotechnol. 33, 646–655 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Cai, Y. et al. Loss of chromosome 8p governs tumor progression and drug response by altering lipid metabolism. Cancer Cell 29, 751–766 (2016). This article provides proof of concept that bystander genes can be exploited to target recurrent aneuploidies.

    Article  CAS  PubMed  Google Scholar 

  207. Nijhawan, D. et al. Cancer vulnerabilities unveiled by genomic loss. Cell 150, 842–854 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Paolella, B. R. et al. Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability. eLife 6, e23268 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Morrill, S. A. & Amon, A. Why haploinsufficiency persists. Proc. Natl Acad. Sci. USA 116, 11866–11871 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Inaki, K. et al. Systems consequences of amplicon formation in human breast cancer. Genome Res. 24, 1559–1571 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Mohanty, V., Akmamedova, O. & Komurov, K. Selective DNA methylation in cancers controls collateral damage induced by large structural variations. Oncotarget 8, 71385–71392 (2017).

    Article  PubMed  Google Scholar 

  212. Kryukov, G. V. et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 351, 1214–1218 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Mavrakis, K. J. et al. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science 351, 1208–1213 (2016).

    Article  CAS  PubMed  Google Scholar 

  214. Hosono, N. et al. Recurrent genetic defects on chromosome 5q in myeloid neoplasms. Oncotarget 8, 6483–6495 (2017).

    Article  PubMed  Google Scholar 

  215. Storchova, Z. & Kuffer, C. The consequences of tetraploidy and aneuploidy. J. Cell Sci. 121, 3859–3866 (2008).

    Article  CAS  PubMed  Google Scholar 

  216. Bostrom, J. et al. Mutation of the PTEN (MMAC1) tumor suppressor gene in a subset of glioblastomas but not in meningiomas with loss of chromosome arm 10q. Cancer Res. 58, 29–33 (1998).

    CAS  PubMed  Google Scholar 

  217. Dillon, L. M. & Miller, T. W. Therapeutic targeting of cancers with loss of PTEN function. Curr. Drug Targets 15, 65–79 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank Iris Fung for her assistance with figure design. The work by U.B.-D. described in this Review was supported by the European Molecular Biology Organization Long-Term Fellowship and by the Human Frontier Science Program Postdoctoral Fellowship. U.B.-D. is an Azrieli Faculty Fellow. The work by the Amon lab described in this Review was supported by NIH grants CA206157 and GM118066. A.A. is an investigator of the Howard Hughes Medical Institute and the Paul F. Glenn Centre for Biology of Ageing Research at MIT. The authors apologize to the authors of many important publications not cited due to space limitations.

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Authors and Affiliations

  1. Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Uri Ben-David

  2. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    Angelika Amon

  3. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA

    Angelika Amon

  4. Howard Hughes Medical Institute, Chevy Chase, MD, USA

    Angelika Amon

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  1. Uri Ben-David
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  2. Angelika Amon
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The authors contributed equally to all aspects of the article.

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Correspondence to Uri Ben-David or Angelika Amon.

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Glossary

Aneuploidy

A chromosome number that is not a multiple of the haploid complement. In cancer genomics, the term often includes copy number alterations of chromosome arms. Note that the mechanisms that lead to whole-chromosome mis-segregation are very different from those that cause arm-level copy number changes.

Complement

The set of all chromosomes. The haploid complement consists of one chromosome each, the diploid of two, and so forth.

Chromosome instability

(CIN). A high rate of chromosome mis-segregation that gives rise to aneuploidy.

Microcell-mediated chromosome transfer

A technique to transfer a chromosome from a donor cell line to a recipient cell line.

Cre–Lox recombination

A technique to introduce deletions, insertions, translocations or inversions at specific chromosomal locations.

CRISPR–Cas9 gene editing

A technique to introduce precise genetic alterations, ranging in size from point mutations to the deletion of entire chromosome arms.

Prognostic value

The degree to which a biomarker provides information about the patients’ overall survival, regardless of therapy.

Euploidy

A chromosome number that is an exact multiple of the haploid complement. Diploid, triploid, tetraploid and polyploid cells are all euploid.

Epithelial-to-mesenchymal transition

(EMT). A process by which epithelial cells lose their epithelial identity and adopt the properties of mesenchymal cells. They lose their ability to form cell–cell adhesion and gain migratory and invasive properties.

Polyploidy

A euploid genome comprising more than two sets of chromosomes.

Human leukocyte antigen complex

A gene complex that encodes the major histocompatibility complex proteins and is responsible for regulation of the immune system.

Single-nucleotide polymorphism arrays

A DNA microarray that is used to detect genetic variation (including copy number alterations) on a genome-wide scale.

Comparative genomic hybridization arrays

A molecular technique to detect copy number alterations on a genome-wide scale and with high resolution.

Predictive value

The degree to which a biomarker provides information about the effect of a therapeutic intervention.

The Cancer Genome Atlas

(TCGA). A cancer genomics repository that contains sequence information for over 20,000 primary cancers and matched normal samples across 33 cancer types.

CNA burden

The prevalence of copy number alterations (CNAs) within a tumour, commonly defined by the proportion of the genome that is affected by CNAs.

Overall survival

The length of time from diagnosis or start of treatment during which patients remain alive.

Disease-specific survival

The length of time from diagnosis or start of treatment during which patients have not died from that specific disease.

Recurrence-free survival

The length of time from treatment during which no sign of cancer is found.

Progression-free survival

The length of time from treatment during which patients live with a disease but it does not get worse.

Microsatellite instability

Predisposition of a cell to mutations (hypermutability) due to impaired DNA mismatch repair.

Prostate-specific antigen

(PSA). A protein produced by prostate cells. Its levels in the blood are elevated in prostate cancer. PSA is therefore used as a prostate cancer screening tool.

Gleason score

A commonly used system to stage prostate cancers, based on their pathological features.

Pap smears

The Papanicolaou test, a commonly used histological method to screen for cervical cancer.

Hyperdiploid MM

A subtype of multiple myeloma (MM) that is characterized by trisomy of eight specific chromosomes (3, 5, 7, 9, 11, 15, 19 and 21).

Non-hyperdiploid MM

A subtype of multiple myeloma (MM) that can be further subdivided into hypodiploid (≤44 chromosomes), pseudodiploid (45–46 chromosomes) and near-tetraploid (>75 chromosomes) subtypes.

Hyperdiploid ALL

A subtype of acute lymphoblastic lymphoma (ALL) that is characterized by a chromosome count of 51–65, often involving one additional copy of chromosomes X, 4, 6, 10, 14, 17 and 18, and two additional copies of chromosome 21.

Hypodiploid ALL

A subtype of acute lymphoblastic lymphoma (ALL) that can be further divided into near-haploid (24–31 chromosomes), low-hypodiploid (32–39 chromosomes) and high-hypodiploid (40–43 chromosomes) subtypes.

Chromothripsis

The shattering of an individual chromosome into many pieces and its religation in random order, with amplification of some segments (those that provide a growth advantage, including oncogenes) and loss of others (for example, tumour suppressors).

Intratumour heterogeneity

(ITH). Genomic and/or phenotypic cell-to-cell variability within a tumour.

Syntenic

Chromosomal regions that are conserved between two species.

Haploinsufficient

A state in which deletion of one copy of a gene in a diploid organism results in a phenotype.

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Ben-David, U., Amon, A. Context is everything: aneuploidy in cancer. Nat Rev Genet 21, 44–62 (2020). https://doi.org/10.1038/s41576-019-0171-x

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