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Cited by 201Microtubule and mitosis dynamicsCancer-related Molecular PathwaysCancer Genomics and Diagnostics

Single-chromosome Gains Commonly Function as Tumor Suppressors

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Sheltzer, Jason M., Ko, Julie H., Replogle, John M., Habibe Burgos, Nicole C., Chung, Erica S., Meehl, Colleen M., Sayles, Nicole M., Passerini, Verena +2 more·2017·Cancer Cell
DOI 10.1016/j.ccell.2016.12.004PMC PMC5713901

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Abstract

Aneuploidy is a hallmark of cancer, although its effects on tumorigenesis are unclear. Here, we investigated the relationship between aneuploidy and cancer development using cells engineered to harbor single extra chromosomes. We found that nearly all trisomic cell lines grew poorly in vitro and as xenografts, relative to genetically matched euploid cells. Moreover, the activation of several oncogenic pathways failed to alleviate the fitness defect induced by aneuploidy. However, following prolonged growth, trisomic cells acquired additional chromosomal alterations that were largely absent from their euploid counterparts and that correlated with improved fitness. Thus, while single-chromosome gains can suppress transformation, the genome-destabilizing effects of aneuploidy confer an evolutionary flexibility that may contribute to the aggressive growth of advanced malignancies with complex karyotypes.

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  • The emergence, and subsequent tolerance, of CIN represents an important bottleneck during tumor evolution.

    “The emergence, and subsequent tolerance, of CIN represents an important bottleneck during tumor evolution38–40.”

    From Chromosomal instability drives metastasis through a cytosolic DNA response (2018) · cites this paper as [38]

    The Results (no page supplied) show that chromosome gains and transiently induced karyotypic abnormalities impair proliferation and transformation, consistent with a barrier to tumor development. But the authors explicitly avoided continuous CIN in those experiments; the paper does not establish that the emergence and subsequent tolerance of CIN itself is a bottleneck during tumor evolution. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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References 67 · Cited by 201

Research works printed but not linked: 55

  1. Ahuja D Sáenz-Robles MT Pipas JM 2005 SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation Oncogene 24 7729 7745 16299533
  2. Balaban GB Herlyn M Clark WH Jr Nowell PC 1986 Karyotypic evolution in human malignant melanoma Cancer Genet. Cytogenet 19 113 122 3940171
  3. Blank HM Sheltzer JM Meehl CM Amon A 2015 Mitotic entry in the presence of DNA damage is a widespread property of aneuploidy in yeast Mol. Biol. Cell 26 1440 1451 25694455 PMC4395125
  4. Boveri T 2008 Concerning the origin of malignant tumours by Theodor Boveri Harris Henry and annotated J. Cell Sci 121 1 84 18089652
  5. Di Capua Sacoto C Budia Alba A Alapont Alacreu JM Ruiz Cerda JL Jimenez Cruz JF 2011 In vivo aneuploidization during the expansion of renal adenocarcinoma Urol. Int 86 466 469 21546757
  6. Crasta K Ganem NJ Dagher R Lantermann AB Ivanova EV Pan Y Nezi L Protopopov A Chowdhury D Pellman D 2012 DNA breaks and chromosome pulverization from errors in mitosis Nature 482 53 58 22258507 PMC3271137
  7. Davoli T Xu AW Mengwasser KE Sack LM Yoon JC Park PJ Elledge SJ 2013 Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns to shape the cancer genome Cell 155 948 962 24183448 PMC3891052
  8. Dephoure N Hwang S O’Sullivan C Dodgson SE Gygi SP Amon A Torres EM 2014 Quantitative proteomic analysis reveals posttranslational responses to aneuploidy in yeast Elife 3 e03023 25073701 PMC4129440
  9. Donnelly N Passerini V Dürrbaum M Stingele S Storchová Z 2014 HSF1 deficiency and impaired HSP90-dependent protein folding are hallmarks of aneuploid human cells EMBO J 33 2374 2387 25205676 PMC4253526
  10. Duesberg P Rasnick D Li R Winters L Rausch C Hehlmann R 1999 How aneuploidy may cause cancer and genetic instability Anticancer Res 19 4887 4906 10697602
  11. Dürrbaum M Kuznetsova AY Passerini V Stingele S Stoehr G Storchová Z 2014 Unique features of the transcriptional response to model aneuploidy in human cells BMC Genomics 15 139 24548329 PMC3932016
  12. El-Rifai W Sarlomo-Rikala M Andersson LC Knuutila S Miettinen M 2000 DNA sequence copy number changes in gastrointestinal stromal tumors: tumor progression and prognostic significance Cancer Res 60 3899 3903 10919666
  13. Foijer F Xie SZ Simon JE Bakker PL Conte N Davis SH Kregel E Jonkers J Bradley A Sorger PK 2014 Chromosome instability induced by Mps1 and p53 mutation generates aggressive lymphomas exhibiting aneuploidy-induced stress Proc. Natl. Acad. Sci. USA 111 13427 13432 25197064 PMC4169945
  14. Gallimore PH Turnell AS 2001 Adenovirus E1A: remodelling the host cell, a life or death experience Oncogene 20 7824 7835 11753665
  15. Gordon DJ Resio B Pellman D 2012 Causes and consequences of aneuploidy in cancer Nat. Rev. Genet 13 189 203 22269907
  16. Hewitt L Tighe A Santaguida S White AM Jones CD Musacchio A Green S Taylor SS 2010 Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1–C-Mad2 core complex J. Cell Biol 190 25 34 20624899 PMC2911659
  17. Holland AJ Cleveland DW 2009 Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis Nat. Rev. Mol. Cell Biol 10 478 487 19546858 PMC3154738
  18. 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 1895 1898 21960636
  19. Lai LA Paulson TG Li X Sanchez CA Maley C Odze RD Reid BJ Rabinovitch PS 2007 Increasing genomic instability during premalignant neoplastic progression revealed through high resolution array-CGH Genes. Chromosomes Cancer 46 532 542 17330261
  20. Land H Parada LF Weinberg RA 1983 Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes Nature 304 596 602 6308472
  21. Lentini L Barra V Schillaci T Di Leonardo A 2012 MAD2 depletion triggers premature cellular senescence in human primary fibroblasts by activating a p53 pathway preventing aneuploid cells propagation J. Cell Physiol 227 3324 3332 22170163
  22. 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 185 983 994 19528295 PMC2711613
  23. Loncarevic IF Roitzheim B Ritterbach J Viehmann S Borkhardt A Lampert F Harbott J 1999 Trisomy 21 is a recurrent secondary aberration in childhood acute lymphoblastic leukemia with TEL/AML1 gene fusion Genes. Chromosomes Cancer 24 272 277 10451708
  24. Magnani I Guerneri S Pollo B Cirenei N Colombo BM Broggi G Galli C Bugiani O DiDonato S Finocchiaro G 1994 Increasing complexity of the karyotype in 50 human gliomas: progressive evolution and de novo occurrence of cytogenetic alterations Cancer Genet. Cytogenet 75 77 89 8055485
  25. McShane E Sin C Zauber H Wells JN Donnelly N Wang X Hou J Chen W Storchova Z Marsh JA 2016 Kinetic analysis of protein stability reveals age-dependent degradation Cell 167 803 815 e21 27720452
  26. Michel LS Liberal V Chatterjee A Kirchwegger R Pasche B Gerald W Dobles M Sorger PK Murty VVVS Benezra R 2001 MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells Nature 409 355 359 11201745
  27. Nižetić D Groet J 2012 Tumorigenesis in Down’s syndrome: big lessons from a small chromosome Nat. Rev. Cancer 12 721 732 22996602
  28. Oromendia AB Dodgson SE Amon A 2012 Aneuploidy causes proteotoxic stress in yeast Genes Dev 26 2696 2708 23222101 PMC3533075
  29. Ozery-Flato M Linhart C Trakhtenbrot L Izraeli S Shamir R 2011 Large-scale analysis of chromosomal aberrations in cancer karyotypes reveals two distinct paths to aneuploidy Genome Biol 12 R61 21714908 PMC3218849
  30. Park I Lee H Choi E Lee Y-K Kwon M-S Min J Park P-G Lee S Kong Y-Y Gong G 2013 Loss of BubR1 acetylation causes defects in spindle assembly checkpoint signaling and promotes tumor formation J. Cell Biol 202 295 309 23878276 PMC3718975
  31. Passerini V Ozeri-Galai E de Pagter MS Donnelly N Schmalbrock S Kloosterman WP Kerem B Storchová Z 2016 The presence of extra chromosomes leads to genomic instability Nat. Commun 7 10754 26876972 PMC4756715
  32. Pavelka N Rancati G Zhu J Bradford WD Saraf A Florens L Sanderson BW Hattem GL Li R 2010 Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast Nature 468 321 325 20962780 PMC2978756
  33. Rasnick D Duesberg PH 1999 How aneuploidy affects metabolic control and causes cancer Biochem. J 340 621 630 10359645 PMC1220292
  34. Rutledge SD Douglas TA Nicholson JM Vila-Casadesús M Kantzler CL Wangsa D Barroso-Vilares M Kale SD Logarinho E Cimini D 2016 Selective advantage of trisomic human cells cultured in non-standard conditions Sci. Rep 6 22828 26956415 PMC4783771
  35. Santaguida S Tighe A D’Alise AM Taylor SS Musacchio A 2010 Dissecting the role of MPS1 in chromosome biorientation and the spindle checkpoint through the small molecule inhibitor reversine J. Cell Biol 190 73 87 20624901 PMC2911657
  36. Santaguida S Vasile E White E Amon A 2015 Aneuploidy-induced cellular stresses limit autophagic degradation Genes Dev 29 2010 2021 26404941 PMC4604343
  37. Seewald L Taub JW Maloney KW McCabe ERB 2012 Acute leukemias in children with Down syndrome Mol. Genet. Metab 107 25 30 22867885
  38. Shaulian E Zauberman A Ginsberg D Oren M 1992 Identification of a minimal transforming domain of p53: negative dominance through abrogation of sequence-specific DNA binding Mol. Cell. Biol 12 5581 5592 1448088 PMC360497
  39. Sheltzer JM 2013 A transcriptional and metabolic signature of primary aneuploidy is present in chromosomally unstable cancer cells and informs clinical prognosis Cancer Res 73 6401 6412 24041940 PMC3901577
  40. Sheltzer JM Amon A 2011 The aneuploidy paradox: costs and benefits of an incorrect karyotype Trends Genet 27 446 453 21872963 PMC3197822
  41. Sheltzer JM Blank HM Pfau SJ Tange Y George BM Humpton TJ Brito IL Hiraoka Y Niwa O Amon A 2011 Aneuploidy drives genomic instability in yeast Science 333 1026 1030 21852501 PMC3278960
  42. Sheltzer JM Torres EM Dunham MJ Amon A 2012 Transcriptional consequences of aneuploidy Proc. Natl. Acad. Sci. USA 109 12644 12649 22802626 PMC3411958
  43. Shin SI Freedman VH Risser R Pollack R 1975 Tumorigenicity of virus-transformed cells in nude mice is correlated specifically with anchorage independent growth in vitro Proc. Natl. Acad. Sci. USA 72 4435 4439 172908 PMC388736
  44. Silk AD Zasadil LM Holland AJ Vitre B Cleveland DW Weaver BA 2013 Chromosome missegregation rate predicts whether aneuploidy will promote or suppress tumors Proc. Natl. Acad. Sci. USA 110 E4134 E4141 24133140 PMC3816416
  45. Sotillo R Hernando E Díaz-Rodríguez E Teruya-Feldstein J Cordón-Cardo C Lowe SW Benezra R 2007 Mad2 overexpression promotes aneuploidy and tumorigenesis in mice Cancer Cell 11 9 23 17189715 PMC1850996
  46. Sotillo R Schvartzman J-M Socci ND Benezra R 2010 Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal Nature 464 436 440 20173739 PMC2841716
  47. Stingele S Stoehr G Peplowska K Cox J Mann M Storchova Z 2012 Global analysis of genome, transcriptome and proteome reveals the response to aneuploidy in human cells Mol. Syst. Biol 8 608 22968442 PMC3472693
  48. Tang Y-C Williams BR Siegel JJ Amon A 2011 Identification of aneuploidy-selective antiproliferation compounds Cell 144 499 512 21315436 PMC3532042
  49. Thompson SL Compton DA 2010 Proliferation of aneuploid human cells is limited by a p53-dependent mechanism J. Cell Biol 188 369 381 20123995 PMC2819684
  50. Torres EM Sokolsky T Tucker CM Chan LY Boselli M Dunham MJ Amon A 2007 Effects of aneuploidy on cellular physiology and cell division in haploid yeast Science 317 916 924 17702937
  51. Torres EM Dephoure N Panneerselvam A Tucker CM Whittaker CA Gygi SP Dunham MJ Amon A 2010 Identification of aneuploidy-tolerating mutations Cell 143 71 78 20850176 PMC2993244
  52. Weaver BA Cleveland DW 2006 Does aneuploidy cause cancer? Curr. Opin. Cell Biol 18 658 667 17046232
  53. Weaver BAA Silk AD Montagna C Verdier-Pinard P Cleveland DW 2007 Aneuploidy acts both oncogenically and as a tumor suppressor Cancer Cell 11 25 36 17189716
  54. Williams BR Prabhu VR Hunter KE Glazier CM Whittaker CA Housman DE Amon A 2008 Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells Science 322 703 709 18974345 PMC2701511
  55. Zack TI Schumacher SE Carter SL Cherniack AD Saksena G Tabak B Lawrence MS Zhang C-Z Wala J Mermel CH 2013 Pan-cancer patterns of somatic copy number alteration Nat. Genet 45 1134 1140 24071852 PMC3966983

Authors
Sheltzer, J. M., Ko, J. H., Replogle, J. M., Habibe Burgos, N. C., Chung, E. S., Meehl, C. M., Sayles, N. M., Passerini, V., Storchova, Z., & Amon, A.
Affiliations
  • Howard Hughes Medical Institute (US)
  • Albert Einstein College of Medicine (US)
  • Cold Spring Harbor Laboratory (US)
  • Max Planck Institute of Biochemistry (DE)
Corresponding author
  • Sheltzer, Jason M.
  • Amon, Angelika
ORCID
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2017-02
Volume
31
Issue
2
Pages
240-255
ISSN
1535-6108 (ISSN-L)
DOI
10.1016/j.ccell.2016.12.004
PMC
PMC5713901
OpenAlex
W2573221347
Cited by
201
References
67
Citations by year
2026: 9 · 2025: 11 · 2024: 22 · 2023: 22 · 2022: 17 · 2021: 31 · 2020: 21 · 2019: 24 · 2018: 28 · 2017: 14 · 2016: 2
FWCI
12.70
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Cell (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
Funders
  • NIH (P30-CA14051, GM056800)
  • Kathy and the Curt Marble Cancer Research Fund
  • Whitaker Health Sciences Fund Fellowship
  • MIT School of Science Fellowship
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
aneuploidy, trisomy, tumor suppressor function, oncogenic pathway activation, genomic instability, chromosomal abnormalities, xenograft tumor growth, karyotype complexity, carcinogenesis
MeSH terms
Aneuploidy, Animals, Cell Transformation, Neoplastic, Chromosome Aberrations, Humans, Neoplasms, Oncogenes, Genes, ras, Genomic Instability, HCT116 Cells, Cell Proliferation

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