Reader TTS

ABSTRACT One form of chromosome instability (CIN), the recurrent missegregation of whole chromosomes during cell division (W-CIN), leads to aneuploidy. Although W-CIN is a hallmark of most

cancers, mutations in genes involved in chromosome segregation are exceedingly rare. We discuss an oncogene-induced mitotic stress model that provides a mechanistic framework to explain this

paradox. We also review the tumor-promoting and tumor-suppressing consequences of W-CIN. Importantly, we do this in the context of cancer as a complex systemic disease, rather than as a

simple linearly progressing disorder that arises from a single abnormal cell population. Accordingly, we highlight the often neglected effects of W-CIN on key non-cell-autonomous entities,

such as the immune system and the tumor microenvironment. Distinct tissue-specific susceptibilities to W-CIN-induced tumorigenesis and the clinical implications of W-CIN are also discussed.

Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this

journal Receive 50 print issues and online access $259.00 per year only $5.18 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now

Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer

support SIMILAR CONTENT BEING VIEWED BY OTHERS CHROMOSOMAL INSTABILITY AS A DRIVER OF CANCER PROGRESSION Article 29 July 2024 THE TWO SIDES OF CHROMOSOMAL INSTABILITY: DRIVERS AND BRAKES IN

CANCER Article Open access 29 March 2024 A PAN-CANCER COMPENDIUM OF CHROMOSOMAL INSTABILITY Article 15 June 2022 REFERENCES * Holland AJ, Cleveland DW . Boveri revisited: chromosomal

instability, aneuploidy and tumorigenesis. _Nat Rev Mol Cell Biol_ 2009; 10: 478–487. CAS  PubMed  PubMed Central  Google Scholar  * Schvartzman JM, Sotillo R, Benezra R . Mitotic

chromosomal instability and cancer: mouse modelling of the human disease. _Nat Rev Cancer_ 2010; 10: 102–115. CAS  PubMed  PubMed Central  Google Scholar  * Thompson SL, Bakhoum SF, Compton

DA . Mechanisms of chromosomal instability. _Curr Biol_ 2010; 20: R285–R295. CAS  PubMed  PubMed Central  Google Scholar  * Ricke RM, Van Ree JH, Van Deursen JM . Whole chromosome

instability and cancer: a complex relationship. _Trends Genet_ 2008; 24: 457–466. CAS  PubMed  PubMed Central  Google Scholar  * Gordon DJ, Resio B, Pellman D . Causes and consequences of

aneuploidy in cancer. _Nat Rev Genet_ 2012; 13: 189–203. CAS  PubMed  Google Scholar  * Duensing A, Duensing S . Centrosomes, polyploidy and cancer. _Adv Exp Med Biol_ 2010; 676: 93–103. CAS

  PubMed  Google Scholar  * Oliveira RA, Nasmyth K . Getting through anaphase: splitting the sisters and beyond. _Biochem Soc Trans_ 2010; 38: 1639–1644. CAS  PubMed  Google Scholar  *

Solomon DA, Kim T, Diaz-Martinez LA, Fair J, Elkahloun AG, Harris BT _et al_. Mutational inactivation of STAG2 causes aneuploidy in human cancer. _Science_ 2011; 333: 1039–1043. CAS  PubMed

  PubMed Central  Google Scholar  * Malumbres M . Oncogene-induced mitotic stress: p53 and pRb get mad too. _Cancer Cell_ 2011; 19: 691–692. CAS  PubMed  Google Scholar  * Sherr CJ,

McCormick F . The RB and p53 pathways in cancer. _Cancer Cell_ 2002; 2: 103–112. CAS  PubMed  Google Scholar  * Saavedra HI, Fukasawa K, Conn CW, Stambrook PJ . MAPK mediates RAS-induced

chromosome instability. _J Biol Chem_ 1999; 274: 38083–38090. CAS  PubMed  Google Scholar  * Nelsen CJ, Kuriyama R, Hirsch B, Negron VC, Lingle WL, Goggin MM _et al_. Short term cyclin D1

overexpression induces centrosome amplification, mitotic spindle abnormalities, and aneuploidy. _J Biol Chem_ 2005; 280: 768–776. CAS  PubMed  Google Scholar  * Kamata T, Hussain J, Giblett

S, Hayward R, Marais R, Pritchard C . BRAF inactivation drives aneuploidy by deregulating CRAF. _Cancer Res_ 2010; 70: 8475–8486. CAS  PubMed  PubMed Central  Google Scholar  * Cui Y,

Borysova MK, Johnson JO, Guadagno TM . Oncogenic B-Raf(V600E) induces spindle abnormalities, supernumerary centrosomes, and aneuploidy in human melanocytic cells. _Cancer Res_ 2010; 70:

675–684. CAS  PubMed  Google Scholar  * Coschi CH, Martens AL, Ritchie K, Francis SM, Chakrabarti S, Berube NG _et al_. Mitotic chromosome condensation mediated by the retinoblastoma protein

is tumor-suppressive. _Genes Dev_ 2010; 24: 1351–1363. CAS  PubMed  PubMed Central  Google Scholar  * Van Harn T, Foijer F, Van Vugt M, Banerjee R, Yang F, Oostra A _et al_. Loss of Rb

proteins causes genomic instability in the absence of mitogenic signaling. _Genes Dev_ 2010; 24: 1377–1388. CAS  PubMed  PubMed Central  Google Scholar  * Manning AL, Longworth MS, Dyson NJ

. Loss of pRB causes centromere dysfunction and chromosomal instability. _Genes Dev_ 2010; 24: 1364–1376. CAS  PubMed  PubMed Central  Google Scholar  * Fukasawa K, Choi T, Kuriyama R,

Rulong S, Vande Woude GF . Abnormal centrosome amplification in the absence of p53. _Science_ 1996; 271: 1744–1747. CAS  PubMed  Google Scholar  * Hernando E, Nahle Z, Juan G, Diaz-Rodriguez

E, Alaminos M, Hemann M _et al_. Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. _Nature_ 2004; 430: 797–802. CAS  PubMed  Google

Scholar  * Sotillo R, Hernando E, Diaz-Rodriguez E, Teruya-Feldstein J, Cordon-Cardo C, Lowe SW _et al_. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. _Cancer Cell_

2007; 11: 9–23. CAS  PubMed  Google Scholar  * Schvartzman JM, Duijf PH, Sotillo R, Coker C, Benezra R . Mad2 is a critical mediator of the chromosome instability observed upon Rb and p53

pathway inhibition. _Cancer Cell_ 2011; 19: 701–714. CAS  PubMed  PubMed Central  Google Scholar  * Kabeche L, Compton DA . Checkpoint-Independent Stabilization of Kinetochore-Microtubule

Attachments by Mad2 in Human Cells. _Curr Biol_ 2012; 22: 638–644. CAS  PubMed  PubMed Central  Google Scholar  * Liu G, Parant JM, Lang G, Chau P, Chavez-Reyes A, El-Naggar AK _et al_.

Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. _Nat Genet_ 2004; 36: 63–68. CAS  PubMed  Google Scholar  * Barboza JA,

Liu G, Ju Z, El-Naggar AK, Lozano G . p21 delays tumor onset by preservation of chromosomal stability. _Proc Natl Acad Sci USA_ 2006; 103: 19842–19847. CAS  PubMed  PubMed Central  Google

Scholar  * Mukherjee M, Ge G, Zhang N, Huang E, Nakamura LV, Minor M _et al_. Separase loss of function cooperates with the loss of p53 in the initiation and progression of T- and B-cell

lymphoma, leukemia and aneuploidy in mice. _PLoS One_ 2011; 6: e22167. CAS  PubMed  PubMed Central  Google Scholar  * Celton-Morizur S, Desdouets C . Polyploidization of liver cells. _Adv

Exp Med Biol_ 2010; 676: 123–135. CAS  PubMed  Google Scholar  * Duncan AW, Taylor MH, Hickey RD, Hanlon Newell AE, Lenzi ML, Olson SB _et al_. The ploidy conveyor of mature hepatocytes as a

source of genetic variation. _Nature_ 2010; 467: 707–710. CAS  PubMed  PubMed Central  Google Scholar  * Weaver BA, Silk AD, Montagna C, Verdier-Pinard P, Cleveland DW . Aneuploidy acts

both oncogenically and as a tumor suppressor. _Cancer Cell_ 2007; 11: 25–36. CAS  PubMed  Google Scholar  * Duijf PH, Schultz N, Benezra R . Cancer cells preferentially lose small

chromosomes. _Int J Cancer_ (e-pub ahead of print 5 November 2012; doi:10.1002/ijc.27924). PubMed  PubMed Central  Google Scholar  * Hanahan D, Weinberg RA . Hallmarks of cancer: the next

generation. _Cell_ 2011; 144: 646–674. Article  CAS  PubMed  Google Scholar  * Lengauer C, Kinzler KW, Vogelstein B . Genetic instabilities in human cancers. _Nature_ 1998; 396: 643–649. CAS

  PubMed  Google Scholar  * Pavelka N, Rancati G, Zhu J, Bradford WD, Saraf A, Florens L _et al_. Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast.

_Nature_ 2010; 468: 321–325. CAS  PubMed  PubMed Central  Google Scholar  * Rodriguez-Paredes M, Esteller M . Cancer epigenetics reaches mainstream oncology. _Nat Med_ 2011; 17: 330–339. CAS

  PubMed  Google Scholar  * Jones PA, Baylin SB . The epigenomics of cancer. _Cell_ 2007; 128: 683–692. CAS  PubMed  PubMed Central  Google Scholar  * Visconti R, Grieco D . New insights on

oxidative stress in cancer. _Curr Opin Drug Discov Devel_ 2009; 12: 240–245. CAS  PubMed  Google Scholar  * Li M, Fang X, Baker DJ, Guo L, Gao X, Wei Z _et al_. The ATM-p53 pathway

suppresses aneuploidy-induced tumorigenesis. _Proc Natl Acad Sci USA_ 2010; 107: 14188–14193. CAS  PubMed  PubMed Central  Google Scholar  * Wang Z, Yu R, Melmed S . Mice lacking pituitary

tumor transforming gene show testicular and splenic hypoplasia, thymic hyperplasia, thrombocytopenia, aberrant cell cycle progression, and premature centromere division. _Mol Endocrinol_

2001; 15: 1870–1879. CAS  PubMed  Google Scholar  * Garcia-Higuera I, Manchado E, Dubus P, Canamero M, Mendez J, Moreno S _et al_. Genomic stability and tumour suppression by the APC/C

cofactor Cdh1. _Nat Cell Biol_ 2008; 10: 802–811. PubMed  Google Scholar  * Nguyen HG, Makitalo M, Yang D, Chinnappan D, Hilaire C, Ravid K . Deregulated Aurora-B induced tetraploidy

promotes tumorigenesis. _FASEB J_ 2009; 23: 2741–2748. CAS  PubMed  PubMed Central  Google Scholar  * Loeb LA . A mutator phenotype in cancer. _Cancer Res_ 2001; 61: 3230–3239. CAS  PubMed 

Google Scholar  * Sheltzer JM, Blank HM, Pfau SJ, Tange Y, George BM, Humpton TJ _et al_. Aneuploidy drives genomic instability in yeast. _Science_ 2011; 333: 1026–1030. CAS  PubMed  PubMed

Central  Google Scholar  * Torres EM, Sokolsky T, Tucker CM, Chan LY, Boselli M, Dunham MJ _et al_. Effects of aneuploidy on cellular physiology and cell division in haploid yeast. _Science_

2007; 317: 916–924. CAS  PubMed  Google Scholar  * Williams BR, Prabhu VR, Hunter KE, Glazier CM, Whittaker CA, Housman DE _et al_. Aneuploidy affects proliferation and spontaneous

immortalization in mammalian cells. _Science_ 2008; 322: 703–709. CAS  PubMed  PubMed Central  Google Scholar  * Gogvadze V, Orrenius S, Zhivotovsky B . Mitochondria in cancer cells: what is

so special about them? _Trends Cell Biol_ 2008; 18: 165–173. CAS  PubMed  Google Scholar  * Hayashi MT, Cesare AJ, Fitzpatrick JA, Lazzerini-Denchi E, Karlseder J . A telomere-dependent DNA

damage checkpoint induced by prolonged mitotic arrest. _Nat Struct Mol Biol_ 2012; 19: 387–394. CAS  PubMed  PubMed Central  Google Scholar  * Janssen A, Van der Burg M, Szuhai K, Kops GJ,

Medema RH . Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. _Science_ 2011; 333: 1895–1898. CAS  PubMed  Google Scholar  * Guerrero AA, Gamero

MC, Trachana V, Futterer A, Pacios-Bras C, Diaz-Concha NP _et al_. Centromere-localized breaks indicate the generation of DNA damage by the mitotic spindle. _Proc Natl Acad Sci USA_ 2010;

107: 4159–4164. CAS  PubMed  PubMed Central  Google Scholar  * Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV, Pan Y _et al_. DNA breaks and chromosome pulverization from errors in

mitosis. _Nature_ 2012; 482: 53–58. CAS  PubMed  PubMed Central  Google Scholar  * Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ _et al_. Massive genomic rearrangement

acquired in a single catastrophic event during cancer development. _Cell_ 2011; 144: 27–40. CAS  PubMed  PubMed Central  Google Scholar  * Liu P, Erez A, Nagamani SC, Dhar SU, Kolodziejska

KE, Dharmadhikari AV _et al_. Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. _Cell_ 2011; 146: 889–903. CAS  PubMed  PubMed Central  Google

Scholar  * Molenaar JJ, Koster J, Zwijnenburg DA, Van Sluis P, Valentijn LJ, Van der Ploeg I _et al_. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis

genes. _Nature_ 2012; 483: 589–593. CAS  PubMed  Google Scholar  * Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J _et al_. The landscape of somatic copy-number alteration

across human cancers. _Nature_ 2010; 463: 899–905. CAS  PubMed  PubMed Central  Google Scholar  * TCGARN, Integrated genomic analyses of ovarian carcinoma. _Nature_ 2011; 474: 609–615.

Google Scholar  * Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ _et al_. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups.

_Nature_ 2012; 486: 346–352. CAS  PubMed  PubMed Central  Google Scholar  * Puente XS, Pinyol M, Quesada V, Conde L, Ordonez GR, Villamor N _et al_. Whole-genome sequencing identifies

recurrent mutations in chronic lymphocytic leukaemia. _Nature_ 2011; 475: 101–105. CAS  PubMed  PubMed Central  Google Scholar  * Baker DJ, Jeganathan KB, Malureanu L, Perez-Terzic C, Terzic

A, Van Deursen JM . Early aging-associated phenotypes in Bub3/Rae1 haploinsufficient mice. _J Cell Biol_ 2006; 172: 529–540. CAS  PubMed  PubMed Central  Google Scholar  * Schliekelman M,

Cowley DO, O’Quinn R, Oliver TG, Lu L, Salmon ED _et al_. Impaired Bub1 function _in vivo_ compromises tension-dependent checkpoint function leading to aneuploidy and tumorigenesis. _Cancer

Res_ 2009; 69: 45–54. Article  CAS  PubMed  PubMed Central  Google Scholar  * Hasle H, Clemmensen IH, Mikkelsen M . Risks of leukaemia and solid tumours in individuals with Down's

syndrome. _Lancet_ 2000; 355: 165–169. CAS  PubMed  Google Scholar  * Satge D, Sasco AJ, Carlsen NL, Stiller CA, Rubie H, Hero B _et al_. A lack of neuroblastoma in Down syndrome: a study

from 11 European countries. _Cancer Res_ 1998; 58: 448–452. CAS  PubMed  Google Scholar  * Yang Q, Rasmussen SA, Friedman JM . Mortality associated with Down's syndrome in the USA from

1983 to 1997: a population-based study. _Lancet_ 2002; 359: 1019–1025. PubMed  Google Scholar  * Swerdlow AJ, Schoemaker MJ, Higgins CD, Wright AF, Jacobs PA . Cancer incidence and mortality

in men with Klinefelter syndrome: a cohort study. _J Natl Cancer Inst_ 2005; 97: 1204–1210. PubMed  Google Scholar  * Hasle H, Mellemgaard A, Nielsen J, Hansen J . Cancer incidence in men

with Klinefelter syndrome. _Br J Cancer_ 1995; 71: 416–420. CAS  PubMed  PubMed Central  Google Scholar  * Torres EM, Dephoure N, Panneerselvam A, Tucker CM, Whittaker CA, Gygi SP _et al_.

Identification of aneuploidy-tolerating mutations. _Cell_ 2010; 143: 71–83. CAS  PubMed  PubMed Central  Google Scholar  * Lakovschek IC, Streubel B, Ulm B . Natural outcome of trisomy 13,

trisomy 18, and triploidy after prenatal diagnosis. _Am J Med Genet A_ 2011; 155A: 2626–2633. PubMed  Google Scholar  * Grivennikov SI, Greten FR, Karin M . Immunity, inflammation, and

cancer. _Cell_ 2010; 140: 883–899. CAS  PubMed  PubMed Central  Google Scholar  * Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD . Cancer immunoediting: from immunosurveillance to tumor

escape. _Nat Immunol_ 2002; 3: 991–998. CAS  PubMed  Google Scholar  * Chang CC, Ogino T, Mullins DW, Oliver JL, Yamshchikov GV, Bandoh N _et al_. Defective human leukocyte antigen class

I-associated antigen presentation caused by a novel beta2-microglobulin loss-of-function in melanoma cells. _J Biol Chem_ 2006; 281: 18763–18773. CAS  PubMed  Google Scholar  * Sanda MG,

Restifo NP, Walsh JC, Kawakami Y, Nelson WG, Pardoll DM _et al_. Molecular characterization of defective antigen processing in human prostate cancer. _J Natl Cancer Inst_ 1995; 87: 280–285.

CAS  PubMed  Google Scholar  * Khong HT, Restifo NP . Natural selection of tumor variants in the generation of ‘tumor escape’ phenotypes. _Nat Immunol_ 2002; 3: 999–1005. CAS  PubMed  PubMed

Central  Google Scholar  * Schreiber RD, Old LJ, Smyth MJ . Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. _Science_ 2011; 331: 1565–1570. CAS

  PubMed  Google Scholar  * DuPage M, Mazumdar C, Schmidt LM, Cheung AF, Jacks T . Expression of tumour-specific antigens underlies cancer immunoediting. _Nature_ 2012; 482: 405–409. CAS 

PubMed  PubMed Central  Google Scholar  * Yamada HY, Yao Y, Wang X, Zhang Y, Huang Y, Dai W _et al_. Haploinsufficiency of SGO1 results in deregulated centrosome dynamics, enhanced

chromosomal instability and colon tumorigenesis. _Cell Cycle_ 2012; 11: 479–488. CAS  PubMed  PubMed Central  Google Scholar  * Oshima M, Dinchuk JE, Kargman SL, Oshima H, Hancock B, Kwong E

_et al_. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). _Cell_ 1996; 87: 803–809. CAS  PubMed  Google Scholar  * Chulada PC,

Thompson MB, Mahler JF, Doyle CM, Gaul BW, Lee C _et al_. Genetic disruption of Ptgs-1, as well as Ptgs-2, reduces intestinal tumorigenesis in Min mice. _Cancer Res_ 2000; 60: 4705–4708. CAS

  PubMed  Google Scholar  * Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, Raza SR _et al_. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine

secretion. _Nat Cell Biol_ 2009; 11: 973–979. CAS  PubMed  PubMed Central  Google Scholar  * Zheng L, Dai H, Zhou M, Li M, Singh P, Qiu J _et al_. Fen1 mutations result in autoimmunity,

chronic inflammation and cancers. _Nat Med_ 2007; 13: 812–819. CAS  PubMed  Google Scholar  * Joyce JA, Pollard JW . Microenvironmental regulation of metastasis. _Nat Rev Cancer_ 2009; 9:

239–252. CAS  PubMed  Google Scholar  * Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A . Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability.

_Carcinogenesis_ 2009; 30: 1073–1081. CAS  PubMed  Google Scholar  * Lonkar P, Dedon PC . Reactive species and DNA damage in chronic inflammation: reconciling chemical mechanisms and

biological fates. _Int J Cancer_ 2011; 128: 1999–2009. CAS  PubMed  PubMed Central  Google Scholar  * Aivaliotis IL, Pateras IS, Papaioannou M, Glytsou C, Kontzoglou K, Johnson EO _et al_.

How do cytokines trigger genomic instability? _J Biomed Biotechnol_ 2012; 2012: 536761. PubMed  PubMed Central  Google Scholar  * Sotillo R, Schvartzman JM, Socci ND, Benezra R .

Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. _Nature_ 2010; 464: 436–440. CAS  PubMed  PubMed Central  Google Scholar  * Galluzzi L, Vanden

Berghe T, Vanlangenakker N, Buettner S, Eisenberg T, Vandenabeele P _et al_. Programmed necrosis from molecules to health and disease. _Int Rev Cell Mol Biol_ 2011; 289: 1–35. CAS  PubMed 

Google Scholar  * Kimmelman AC . The dynamic nature of autophagy in cancer. _Genes Dev_ 2011; 25: 1999–2010. CAS  PubMed  PubMed Central  Google Scholar  * White E . Deconvoluting the

context-dependent role for autophagy in cancer. _Nat Rev Cancer_ 2012; 12: 401–410. CAS  PubMed  PubMed Central  Google Scholar  * Baker DJ, Jeganathan KB, Cameron JD, Thompson M, Juneja S,

Kopecka A _et al_. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. _Nat Genet_ 2004; 36: 744–749. CAS  PubMed  Google Scholar  * Babu JR,

Jeganathan KB, Baker DJ, Wu X, Kang-Decker N, Van Deursen JM . Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation. _J Cell Biol_

2003; 160: 341–353. CAS  PubMed  PubMed Central  Google Scholar  * Chesnokova V, Kovacs K, Castro AV, Zonis S, Melmed S . Pituitary hypoplasia in Pttg−/− mice is protective for Rb+/−

pituitary tumorigenesis. _Mol Endocrinol_ 2005; 19: 2371–2379. CAS  PubMed  Google Scholar  * Li M, Fang X, Wei Z, York JP, Zhang P . Loss of spindle assembly checkpoint-mediated inhibition

of Cdc20 promotes tumorigenesis in mice. _J Cell Biol_ 2009; 185: 983–994. CAS  PubMed  PubMed Central  Google Scholar  * Andreassen PR, Lohez OD, Lacroix FB, Margolis RL . Tetraploid state

induces p53-dependent arrest of nontransformed mammalian cells in G1. _Mol Biol Cell_ 2001; 12: 1315–1328. CAS  PubMed  PubMed Central  Google Scholar  * Rieder CL, Maiato H . Stuck in

division or passing through: what happens when cells cannot satisfy the spindle assembly checkpoint. _Dev Cell_ 2004; 7: 637–651. CAS  PubMed  Google Scholar  * Zhang D, Shimizu T, Araki N,

Hirota T, Yoshie M, Ogawa K _et al_. Aurora A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice. _Oncogene_ 2008; 27: 4305–4314.

CAS  PubMed  Google Scholar  * Bitomsky N, Hofmann TG . Apoptosis and autophagy: Regulation of apoptosis by DNA damage signalling - roles of p53, p73 and HIPK2. _FEBS J_ 2009; 276:

6074–6083. CAS  PubMed  Google Scholar  * Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, Zieger K _et al_. DNA damage response as a candidate anti-cancer barrier in early human

tumorigenesis. _Nature_ 2005; 434: 864–870. CAS  PubMed  Google Scholar  * Vakifahmetoglu H, Olsson M, Zhivotovsky B . Death through a tragedy: mitotic catastrophe. _Cell Death Differ_ 2008;

15: 1153–1162. CAS  PubMed  Google Scholar  * Manchado E, Guillamot M, Malumbres M . Killing cells by targeting mitosis. _Cell Death Differ_ 2012; 19: 369–377. CAS  PubMed  PubMed Central 

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

CAS  PubMed  Google Scholar  * Terrano DT, Upreti M, Chambers TC . Cyclin-dependent kinase 1-mediated Bcl-xL/Bcl-2 phosphorylation acts as a functional link coupling mitotic arrest and

apoptosis. _Mol Cell Biol_ 2010; 30: 640–656. CAS  PubMed  Google Scholar  * Thompson SL, Compton DA . Proliferation of aneuploid human cells is limited by a p53-dependent mechanism. _J Cell

Biol_ 2010; 188: 369–381. CAS  PubMed  PubMed Central  Google Scholar  * Mikule K, Delaval B, Kaldis P, Jurcyzk A, Hergert P, Doxsey S . Loss of centrosome integrity induces

p38-p53-p21-dependent G1-S arrest. _Nat Cell Biol_ 2007; 9: 160–170. CAS  PubMed  Google Scholar  * Lanni JS, Jacks T . Characterization of the p53-dependent postmitotic checkpoint following

spindle disruption. _Mol Cell Biol_ 1998; 18: 1055–1064. CAS  PubMed  PubMed Central  Google Scholar  * Minn AJ, Boise LH, Thompson CB . Expression of Bcl-xL and loss of p53 can cooperate

to overcome a cell cycle checkpoint induced by mitotic spindle damage. _Genes Dev_ 1996; 10: 2621–2631. CAS  PubMed  Google Scholar  * Reinhardt HC, Schumacher B . The p53 network: cellular

and systemic DNA damage responses in aging and cancer. _Trends Genet_ 2012; 28: 128–136. CAS  PubMed  PubMed Central  Google Scholar  * Deng Y, Chan SS, Chang S . Telomere dysfunction and

tumour suppression: the senescence connection. _Nat Rev Cancer_ 2008; 8: 450–458. CAS  PubMed  PubMed Central  Google Scholar  * Burds AA, Lutum AS, Sorger PK . Generating chromosome

instability through the simultaneous deletion of Mad2 and p53. _Proc Natl Acad Sci USA_ 2005; 102: 11296–11301. CAS  PubMed  PubMed Central  Google Scholar  * Greaves M, Maley CC . Clonal

evolution in cancer. _Nature_ 2012; 481: 306–313. CAS  PubMed  PubMed Central  Google Scholar  * Hanahan D, Coussens LM . Accessories to the crime: functions of cells recruited to the tumor

microenvironment. _Cancer Cell_ 2012; 21: 309–322. CAS  PubMed  Google Scholar  * Ostrand-Rosenberg S . Immune surveillance: a balance between protumor and antitumor immunity. _Curr Opin

Genet Dev_ 2008; 18: 11–18. CAS  PubMed  PubMed Central  Google Scholar  * Mason SD, Joyce JA . Proteolytic networks in cancer. _Trends Cell Biol_ 2011; 21: 228–237. CAS  PubMed  Google

Scholar  * Lewis CE, De Palma M, Naldini L . Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. _Cancer Res_ 2007; 67: 8429–8432. CAS  PubMed  Google

Scholar  * Seremet T, Brasseur F, Coulie PG . Tumor-specific antigens and immunologic adjuvants in cancer immunotherapy. _Cancer J_ 2011; 17: 325–330. CAS  PubMed  Google Scholar  * Granot

Z, Henke E, Comen EA, King TA, Norton L, Benezra R . Tumor entrained neutrophils inhibit seeding in the premetastatic lung. _Cancer Cell_ 2011; 20: 300–314. CAS  PubMed  PubMed Central 

Google Scholar  * Png KJ, Halberg N, Yoshida M, Tavazoie SF . A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells. _Nature_ 2012; 481: 190–194. CAS 

Google Scholar  * Carter SL, Eklund AC, Kohane IS, Harris LN, Szallasi Z . A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple

human cancers. _Nat Genet_ 2006; 38: 1043–1048. CAS  PubMed  Google Scholar  * Gutenberg A, Gerdes JS, Jung K, Sander B, Gunawan B, Bock HC _et al_. High chromosomal instability in brain

metastases of colorectal carcinoma. _Cancer Genet Cytogenet_ 2010; 198: 47–51. CAS  PubMed  Google Scholar  * Bhattacharya A, Roy R, Snijders AM, Hamilton G, Paquette J, Tokuyasu T _et al_.

Two distinct routes to oral cancer differing in genome instability and risk for cervical node metastasis. _Clin Cancer Res_ 2011; 17: 7024–7034. CAS  PubMed  PubMed Central  Google Scholar 

* Kreike B, Halfwerk H, Armstrong N, Bult P, Foekens JA, Veltkamp SC _et al_. Local recurrence after breast-conserving therapy in relation to gene expression patterns in a large series of

patients. _Clin Cancer Res_ 2009; 15: 4181–4190. CAS  PubMed  Google Scholar  * Smid M, Hoes M, Sieuwerts AM, Sleijfer S, Zhang Y, Wang Y _et al_. Patterns and incidence of chromosomal

instability and their prognostic relevance in breast cancer subtypes. _Breast Cancer Res Treat_ 2011; 128: 23–30. CAS  PubMed  Google Scholar  * Skirnisdottir I, Sorbe B, Karlsson M, Seidal

T . Prognostic importance of DNA ploidy and p53 in early stages of epithelial ovarian carcinoma. _Int J Oncol_ 2001; 19: 1295–1302. CAS  PubMed  Google Scholar  * Warth A, Herpel E, Krysa S,

Hoffmann H, Schnabel PA, Schirmacher P _et al_. Chromosomal instability is more frequent in metastasized than in non-metastasized pulmonary carcinoids but is not a reliable predictor of

metastatic potential. _Exp Mol Med_ 2009; 41: 349–353. CAS  PubMed  PubMed Central  Google Scholar  * Schardt JA, Meyer M, Hartmann CH, Schubert F, Schmidt-Kittler O, Fuhrmann C _et al_.

Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer. _Cancer Cell_ 2005; 8: 227–239. CAS  PubMed  Google Scholar  *

Schmidt-Kittler O, Ragg T, Daskalakis A, Granzow M, Ahr A, Blankenstein TJ _et al_. From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer

progression. _Proc Natl Acad Sci USA_ 2003; 100: 7737–7742. CAS  PubMed  PubMed Central  Google Scholar  * Stoecklein NH, Hosch SB, Bezler M, Stern F, Hartmann CH, Vay C _et al_. Direct

genetic analysis of single disseminated cancer cells for prediction of outcome and therapy selection in esophageal cancer. _Cancer Cell_ 2008; 13: 441–453. CAS  PubMed  Google Scholar  *

Weckermann D, Polzer B, Ragg T, Blana A, Schlimok G, Arnholdt H _et al_. Perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer. _J Clin Oncol_

2009; 27: 1549–1556. PubMed  Google Scholar  * McClelland SE, Burrell RA, Swanton C . Chromosomal instability: a composite phenotype that influences sensitivity to chemotherapy. _Cell Cycle_

2009; 8: 3262–3266. CAS  PubMed  Google Scholar  * Duesberg P, Stindl R, Hehlmann R . Explaining the high mutation rates of cancer cells to drug and multidrug resistance by chromosome

reassortments that are catalyzed by aneuploidy. _Proc Natl Acad Sci USA_ 2000; 97: 14295–14300. CAS  PubMed  PubMed Central  Google Scholar  * Swanton C, Nicke B, Schuett M, Eklund AC, Ng C,

Li Q _et al_. Chromosomal instability determines taxane response. _Proc Natl Acad Sci USA_ 2009; 106: 8671–8676. CAS  PubMed  PubMed Central  Google Scholar  * Bedard PL, Di Leo A,

Piccart-Gebhart MJ . Taxanes: optimizing adjuvant chemotherapy for early-stage breast cancer. _Nat Rev Clin Oncol_ 2010; 7: 22–36. CAS  PubMed  Google Scholar  * Janssen A, Kops GJ, Medema

RH . Elevating the frequency of chromosome mis-segregation as a strategy to kill tumor cells. _Proc Natl Acad Sci USA_ 2009; 106: 19108–19113. CAS  PubMed  PubMed Central  Google Scholar  *

Rebacz B, Larsen TO, Clausen MH, Ronnest MH, Loffler H, Ho AD _et al_. Identification of griseofulvin as an inhibitor of centrosomal clustering in a phenotype-based screen. _Cancer Res_

2007; 67: 6342–6350. CAS  PubMed  Google Scholar  * Karna P, Rida PC, Pannu V, Gupta KK, Dalton WB, Joshi H _et al_. A novel microtubule-modulating noscapinoid triggers apoptosis by inducing

spindle multipolarity via centrosome amplification and declustering. _Cell Death Differ_ 2011; 18: 632–644. CAS  PubMed  Google Scholar  * Kwon M, Godinho SA, Chandhok NS, Ganem NJ, Azioune

A, Thery M _et al_. Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. _Genes Dev_ 2008; 22: 2189–2203. CAS  PubMed  PubMed Central  Google Scholar  * Wu G,

Qiu XL, Zhou L, Zhu J, Chamberlin R, Lau J _et al_. Small molecule targeting the Hec1/Nek2 mitotic pathway suppresses tumor cell growth in culture and in animal. _Cancer Res_ 2008; 68:

8393–8399. CAS  PubMed  PubMed Central  Google Scholar  * Tang YC, Williams BR, Siegel JJ, Amon A . Identification of aneuploidy-selective antiproliferation compounds. _Cell_ 2011; 144:

499–512. CAS  PubMed  PubMed Central  Google Scholar  * Ishida S, Huang E, Zuzan H, Spang R, Leone G, West M _et al_. Role for E2F in control of both DNA replication and mitotic functions as

revealed from DNA microarray analysis. _Mol Cell Biol_ 2001; 21: 4684–4699. CAS  PubMed  PubMed Central  Google Scholar  * Polager S, Kalma Y, Berkovich E, Ginsberg D . E2Fs up-regulate

expression of genes involved in DNA replication, DNA repair and mitosis. _Oncogene_ 2002; 21: 437–446. CAS  PubMed  Google Scholar  * Ren B, Cam H, Takahashi Y, Volkert T, Terragni J, Young

RA _et al_. E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. _Genes Dev_ 2002; 16: 245–256. CAS  PubMed  PubMed Central  Google Scholar  * Zhou Y,

Mehta KR, Choi AP, Scolavino S, Zhang X . DNA damage-induced inhibition of securin expression is mediated by p53. _J Biol Chem_ 2003; 278: 462–470. CAS  PubMed  Google Scholar  * Oikawa T,

Okuda M, Ma Z, Goorha R, Tsujimoto H, Inokuma H _et al_. Transcriptional control of BubR1 by p53 and suppression of centrosome amplification by BubR1. _Mol Cell Biol_ 2005; 25: 4046–4061.

CAS  PubMed  PubMed Central  Google Scholar  * Lu LY, Wood JL, Ye L, Minter-Dykhouse K, Saunders TL, Yu X _et al_. Aurora A is essential for early embryonic development and tumor

suppression. _J Biol Chem_ 2008; 283: 31785–31790. CAS  PubMed  PubMed Central  Google Scholar  * Iwanaga Y, Chi YH, Miyazato A, Sheleg S, Haller K, Peloponese JM _et al_. Heterozygous

deletion of mitotic arrest-deficient protein 1 (MAD1) increases the incidence of tumors in mice. _Cancer Res_ 2007; 67: 160–166. CAS  PubMed  Google Scholar  * Michel LS, Liberal V,

Chatterjee A, Kirchwegger R, Pasche B, Gerald W _et al_. MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. _Nature_ 2001; 409: 355–359. CAS 

PubMed  Google Scholar  * Lu LY, Wood JL, Minter-Dykhouse K, Ye L, Saunders TL, Yu X _et al_. Polo-like kinase 1 is essential for early embryonic development and tumor suppression. _Mol Cell

Biol_ 2008; 28: 6870–6876. CAS  PubMed  PubMed Central  Google Scholar  * Ko MA, Rosario CO, Hudson JW, Kulkarni S, Pollett A, Dennis JW _et al_. Plk4 haploinsufficiency causes mitotic

infidelity and carcinogenesis. _Nat Genet_ 2005; 37: 883–888. CAS  PubMed  Google Scholar  * Jeganathan K, Malureanu L, Baker DJ, Abraham SC, Van Deursen JM . Bub1 mediates cell death in

response to chromosome missegregation and acts to suppress spontaneous tumorigenesis. _J Cell Biol_ 2007; 179: 255–267. CAS  PubMed  PubMed Central  Google Scholar  * Ricke RM, Jeganathan

KB, Van Deursen JM . Bub1 overexpression induces aneuploidy and tumor formation through Aurora B kinase hyperactivation. _J Cell Biol_ 2011; 193: 1049–1064. CAS  PubMed  PubMed Central 

Google Scholar  * Diaz-Rodriguez E, Sotillo R, Schvartzman JM, Benezra R . Hec1 overexpression hyperactivates the mitotic checkpoint and induces tumor formation _in vivo_. _Proc Natl Acad

Sci USA_ 2008; 105: 16719–16724. CAS  PubMed  PubMed Central  Google Scholar  * Van Ree JH, Jeganathan KB, Malureanu L, Van Deursen JM . Overexpression of the E2 ubiquitin-conjugating enzyme

UbcH10 causes chromosome missegregation and tumor formation. _J Cell Biol_ 2010; 188: 83–100. CAS  PubMed  PubMed Central  Google Scholar  * Janisson-Dargaud D, Durlach A, Lorenzato M,

Grange F, Bernard P, Birembaut P . Aneuploidy, but not Ki-67 or EGFR expression, is associated with recurrences in basal cell carcinoma. _J Cutan Pathol_ 2008; 35: 916–921. PubMed  Google

Scholar  * Susini T, Olivieri S, Molino C, Amunni G, Rapi S, Taddei G _et al_. DNA ploidy is stronger than lymph node metastasis as prognostic factor in cervical carcinoma: 10-year results

of a prospective study. _Int J Gynecol Cancer_ 2011; 21: 678–684. PubMed  Google Scholar  * Walther A, Houlston R, Tomlinson I . Association between chromosomal instability and prognosis in

colorectal cancer: a meta-analysis. _Gut_ 2008; 57: 941–950. CAS  PubMed  Google Scholar  * Lagarde P, Perot G, Kauffmann A, Brulard C, Dapremont V, Hostein I _et al_. Mitotic checkpoints

and chromosome instability are strong predictors of clinical outcome in gastrointestinal stromal tumors. _Clin Cancer Res_ 2012; 18: 826–838. CAS  PubMed  Google Scholar  * Choi CM, Seo KW,

Jang SJ, Oh YM, Shim TS, Kim WS _et al_. Chromosomal instability is a risk factor for poor prognosis of adenocarcinoma of the lung: Fluorescence in situ hybridization analysis of

paraffin-embedded tissue from Korean patients. _Lung Cancer_ 2009; 64: 66–70. PubMed  Google Scholar  * Ehlers JP, Worley L, Onken MD, Harbour JW . Integrative genomic analysis of aneuploidy

in uveal melanoma. _Clin Cancer Res_ 2008; 14: 115–122. CAS  PubMed  Google Scholar  * Sato H, Uzawa N, Takahashi K, Myo K, Ohyama Y, Amagasa T . Prognostic utility of chromosomal

instability detected by fluorescence in situ hybridization in fine-needle aspirates from oral squamous cell carcinomas. _BMC Cancer_ 2010; 10: 182. PubMed  PubMed Central  Google Scholar  *

Pinto AE, Silva GL, Pereira T, Cabrera RA, Santos JR, Leite V . S-phase fraction and ploidy as predictive markers in primary disease and recurrence of papillary thyroid carcinoma. _Clin

Endocrinol (Oxf)_ 2012; 77: 302–309. Google Scholar  Download references ACKNOWLEDGEMENTS We thank Peter J Cook, Zvi Granot, Rozario I Thomas, Daniel Marks and Rocío Sotillo for critical

reading of the manuscript. PHGD is supported by a _Young Investigator Award_ from Alex’s Lemonade Stand Foundation and RB by the Breast Cancer Research Foundation. AUTHOR INFORMATION AUTHORS

AND AFFILIATIONS * Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA P H G Duijf & R Benezra * The University of Queensland Diamantina

Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia P H G Duijf Authors * P H G Duijf View author publications You can also search for this author inPubMed Google

Scholar * R Benezra View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHORS Correspondence to P H G Duijf or R Benezra. ETHICS DECLARATIONS

COMPETING INTERESTS The authors declare no conflict of interest. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Duijf, P., Benezra, R. The cancer

biology of whole-chromosome instability. _Oncogene_ 32, 4727–4736 (2013). https://doi.org/10.1038/onc.2012.616 Download citation * Received: 28 September 2012 * Revised: 12 November 2012 *

Accepted: 15 November 2012 * Published: 14 January 2013 * Issue Date: October 2013 * DOI: https://doi.org/10.1038/onc.2012.616 SHARE THIS ARTICLE Anyone you share the following link with

will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt

content-sharing initiative KEYWORDS * whole-chromosome instability * aneuploidy * cancer biology * oncogene-induced mitotic stress * non-cell autonomous * tumor microenvironment