Does aneuploidy cause cancer?

Does aneuploidy cause cancer?Beth AA Weaver and Don W Cleveland

Aneuploidy has been recognized as a common characteristic of

cancer cells for>100 years. Aneuploidy frequently results from

errors of the mitotic checkpoint, the major cell cycle control

mechanism that acts to prevent chromosome missegregation.

The mitotic checkpoint is often compromised in human tumors,

although not as a result of germline mutations in genes

encoding checkpoint proteins. Less obviously, aneuploidy of

whole chromosomes rapidly results from mutations in genes

encoding several tumor suppressors and DNA mismatch repair

proteins, suggesting cooperation between mechanisms of

tumorigenesis that were previously thought to act

independently. Cumulatively, the current evidence suggests

that aneuploidy promotes tumorigenesis, at least at low

frequency, but a definitive test has not yet been reported.

Addresses

Ludwig Institute for Cancer Research, University of California at San

Diego, 9500 Gilman Drive, La Jolla, CA 92093-0670, USA

Corresponding author: Cleveland, Don W ([email protected])

Current Opinion in Cell Biology 2006, 18:658–667

This review comes from a themed issue on

Cell division, growth and death

Edited by Bill Earnshaw and Yuri Lazebnik

Available online 12th October 2006

0955-0674/$ – see front matter

# 2006 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.ceb.2006.10.002

Introduction: aneuploidy correlates withtumorigenicityAneuploidy, an aberrant chromosome number that devi-

ates from a multiple of the haploid, is a remarkably

common feature of human cancers (Table 1, compiled

from the Mitelman database of cancer chromosomes [1]).

Even haematological cancers, which typically maintain a

stable, near-diploid chromosome number, have fre-

quently gained or lost one or a few chromosomes

(Table 1). Near-tetraploid karyotypes, which result from

missegregation of single chromosomes before or after

doubling of the genome (usually from failure of cytokin-

esis), are also observed in solid tumors, although not as

commonly as near-diploid karyotypes (Table 1).

Although methodological advances have permitted sig-

nificantly more refined analysis of the chromosomal

abnormalities in cancer cells in recent years, the abun-

dance of aneuploid chromosome contents in tumor cells


was already well recognized 100 years ago. The pre-

valence of aneuploidy in cancer cells, and its relatively

low incidence in normal cells, led the German zoologist

and cytologist Theodor Boveri to propose aneuploidy as

a cause of tumorigenesis in 1902 [2] and 1914 [3]. Boveri

observed that sea urchin embryos manipulated to

undergo mitosis in the presence of multipolar spindles

produced aneuploid progeny and suggested that tumors

arise from normal cells that have become aneuploid as a

result of passage through an aberrant mitosis. With the

discovery of oncogenes and tumor suppressors in the

1970s and 1980s, aneuploidy-induced loss of heterozyg-

osity (LOH) of tumor suppressor genes seemed to offer

a simple, direct molecular mechanism for Boveri’s

hypothesis. This has not, however, resulted in consen-

sus. Some have argued aneuploidy to be irrelevant to

tumor initiation [4], while others have argued it to be a

completely benign side-effect of transformation [5], and

an additional hypothesis suggests that aneuploidy con-

tributes to tumor progression but not tumor initiation

[6].

Genetic instability due to mutations in mismatch repair

(MMR) enzymes has become well established as a cau-

sative mechanism for tumorigenesis. Biallelic mutations

in MMR genes lead to expansion and contraction of short,

repetitive sequences of DNA known as microsatellites,

causing microsatellite instability (MIN). Germline muta-

tions in one of five MMR genes, predominantly MSH2

and MLH1, are implicated in hereditary nonpolyposis

colon cancer (HNPCC), and predispose individuals to a

variety of cancers. HNPCC patients have an 80% lifetime

risk of colorectal cancer and a 30–50% chance of endo-

metrial cancer [7].

However, although MIN occurs in 90% of cancers in

HNPCC patients, it is found in only 15% of sporadic

cancers of the colon/rectum [7,8]. Aneuploidy represents

a second, more common form of genetic abnormality

found in human cancers. An important cause of aneu-

ploidy is chromosomal instability (CIN), a form of genetic

instability in which the gain or loss of entire chromosomes

is elevated, producing an evolving, unstable karyotype.

Although many aneuploid cells exhibit CIN, aneuploid

karyotypes may also be stably maintained, as observed in

some haematological cancers.

On the basis of the cumulative evidence, it is likely that

aneuploidy promotes tumorigenesis, at least at low fre-

quency. However, a definitive empirical test of this

hypothesis has not yet been reported, and alternative

interpretations cannot be excluded. Here we summarize

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Does aneuploidy cause cancer? Weaver and Cleveland 659

Table 1

The majority of human cancers are near-diploid.

Number of tumors that have not gained

or lost chromosomes*Number of aneuploid tumors

with a near-diploid number of

chromosomes (�68)

Number of aneuploid tumors with a

near- tetraploid number of

chromosomes (�69)

Solid tumors

Astrocytoma, grade III–IV 10 228 62

Basal cell carcinoma 23 75 4

Breast cancer 31 140 29

Cervical cancer 4 51 29

Colon adenocarcinoma 1 124 19

Embryonal rhabdomyosarcoma 9 53 12

Hepatoblastoma 17 80 3

Leiomyosarcoma 7 68 34

Lung cancer 36 119 45

Malignant melanoma 30 138 31

Neuroblastoma 28 109 58

Osteosarcoma 6 86 59

Ovarian cancer 5 158 37

Prostate cancer 16 141 43

Retinoblastoma 10 111 1

Squamous cell carcinoma 12 149 39

Teratoma 3 166 31

Percent of solid tumors (n = 2780) 8.9% 71.8% 19.3%

Haematopoietic cancers

Acute myeloid leukemia 88 207 3

Adult T-cell lymphoma/leukemia 21 224 8

B-prolymphocytic leukemia 20 72 1

Burkitt lymphoma/leukemia 86 75 2

Chronic myeloid leukemia 90 110 0

Follicular lymphoma 55 228 17

Hodgkins disease 26 129 77

Multiple myeloma 64 217 17

T-prolymphocytic leukemia 25 111 0

Percent of haematopoietic cancers

(n = 1973)

24.1% 69.6% 6.3%

Percent of solid and haematopoietic

cancers (n = 4753)

15.2% 70.9% 13.9%

* These cancer cells have 46 chromosomes containing translocations, inversions, deletions and/or additions but have not gained or lost entire

chromosomes.

the current evidence for and against a role for aneuploidy

and CIN in tumorigenesis.

The mitotic checkpoint: the major cell cyclecheckpoint guarding against aneuploidyBeginning with the drawings of aberrant mitosis in cancer

cells published by David van Hansemann in 1890 [9],

defects during mitosis have been implicated as a major

contributor to aneuploidy and CIN. The major cell cycle

control mechanism that acts during mitosis is the mitotic

checkpoint, also known as the spindle assembly check-

point. The mitotic checkpoint prevents chromosome

missegregation and aneuploidy by inhibiting the irrever-

sible transition to anaphase until all of the replicated

chromosomes have made productive attachments to spin-

dle microtubules (Figure 1a, panel 2). Mitotic checkpoint

proteins are recruited to the microtubule attachment sites

(kinetochores) of unattached chromosomes, where they

generate an at least partially diffusible signal that inhibits

the anaphase promoting complex/cyclosome (APC/C).


The APC/C is an E3 ubiquitin ligase that ubiquitinates

substrates whose degradation is required for anaphase

onset (securin) and mitotic exit (cyclin B). Destruction of

securin after its ubiquitination frees its binding partner

separase, while simultaneous loss of cyclin B-dependent

Cdk1 kinase activity leads to dephosphorylation of separ-

ase. Both events activate separase, which then cleaves the

cohesins that hold replicated chromosomes together and

initiates anaphase (reviewed in [10,11]). Even a single

unattached kinetochore can be sufficient to delay ana-

phase onset [12,13].

Treatment of cells with drugs producing depolymeriza-

tion of spindle microtubules causes mitotic arrest as a

result of activation of the mitotic checkpoint. >70% of

many types of asynchronously cycling cells with an intact

mitotic checkpoint accumulate in mitosis after 12–24 h

treatment with microtubule poisons. Complete absence

of the mitotic checkpoint leads to rapid cell-autonomous

lethality due to massive chromosome missegregation


660 Cell division, growth and death

Figure 1

Mechanisms generating aneuploidy. (a) Wild type division producing identical diploid progeny in a hypothetical cell containing four chromosomes.

(b–g) Mitotic errors that produce aneuploid progeny. For each part (a–g), from left to right, the first image depicts a diploid (a–f) or tetraploid (g)

cell in interphase. The second panel represents metaphase, the stage of mitosis when all chromosomes have aligned in the middle of the

mitotic spindle. Some errors (b,c,f) prevent full alignment of chromosomes in metaphase. The third image depicts chromosome segregation

in anaphase (a–e,g). The last image represents the daughter cells that were produced, now in G1. The ploidy of the initial cells and

their progeny is shown.

[14��,15��]. However, an impaired mitotic checkpoint

response, or more precisely an impaired ability to sustain

mitotic checkpoint signaling, has been observed in many

human tumor cell lines treated with microtubule poisons

(Table 2), as evidenced by a decreased percentage of cells

in mitosis and/or a decreased length of arrest.

In 1998, Vogelstein and colleagues reported mutations in

two mitotic checkpoint genes in a small subset of color-

ectal cancer cell lines [16]. This finding launched an

extensive search for additional mutations in mitotic

checkpoint genes. While mutations of several checkpoint

proteins have been found in multiple cancer types, these

mutations are not common (Table 3). This is not com-

pletely surprising, as a large number of gene products

contribute to the mitotic checkpoint response (including,

but not limited to, BUB1, BUBR1, BUB3, MAD1,

MAD2, MPS1, MAPK, ROD, ZW10, Zwint, CENP-E


and Aurora B) and mutation in any one could lead to

weakening of the checkpoint. Additionally, mutations

leading to complete inactivation of the mitotic check-

point would be eliminated by cell death.

In comparison to direct mutation, alterations in the level

of expression of mitotic checkpoint genes appear to occur

much more commonly (Table 3). Both decreases and,

more surprisingly, increases in expression have been

reported. Lower expression of checkpoint proteins would

be predicted to lead to CIN and aneuploidy, at least in

components whose accumulation was rate-limiting for

checkpoint signaling at individual kinetochores. Consis-

tent with this, mice that are heterozygous for the check-

point proteins MAD2, BUBR1 and BUB3 exhibit an

impaired mitotic checkpoint response and develop aneu-

ploidy in vitro and in vivo [17–19]. The mechanism by

which overexpression of individual checkpoint proteins



Table 2

Frequent impairment of the mitotic checkpoint in human cancers.

Tumor type Frequency with impaired

checkpoint

Percentage

frequency

Notes Reference

Adult T-cell leukemia 6 of 6 100% Reduced expression of MAD1 in all, MAD2 in two [66]

Breast 7 of 9 78% [67]

Breast 1 of 1 100% Reduced expression of Mad2 [68]

Breast 7 of 10 70% CIN correlated with lack of a mitotic checkpoint [67]

Colorectal 3 of 3 100% [16]

Head and neck 6 of 6 100% [69]

Hepatocellular carcinoma 5 of 8 62% No mutations in BUB1, BUBR1 or CDC20 [70]

Hepatoma 6 of 11 55% Reduced expression of Mad2 in all [71]

Lung 4 of 9 44% No mutations in MAD2 or CDC20 [72]

Lung adenocarcinoma 1 of 2 50% Levels of MAD2 and BUB1 similar in both lines [73]

Nasopharyngeal carcinoma 2 of 5 40% No mutations in MAD2, MAD1 or CDC20. Reduced

expression of MAD1 and MAD2 in both

[74]

Ovarian 3 of 7 43% Reduced expression of MAD2 and MAD1 in all three [75]

Pancreatic 3 of 3 100% [76]

Rhabdomyosarcoma 1 of 1 100% MAD2 expression at wild-type levels [68]

Thyroid 4 of 8 50% Reduced BUBR1 expression in 3 of 4 [77]

can provoke aneuploidy is not so clear. Two possibilities

are feasible. Overexpression of a single component, such as

MAD2, could disrupt signaling by trapping limiting com-

ponents in partial, non-productive signaling complexes.

Alternatively, and perhaps more simply, increased levels of

components that can directly bind to APC/C and/or its

activator Cdc20 may provoke sustained arrest, as has been

seen for Mad2 [20]. Escape from this type of arrest may

occur without cytokinesis, which would produce tetraploid

cells with two centrosomes that could produce aneuploid

progeny in a subsequent multipolar mitosis (see below).

Neither scenario has been demonstrated directly.

Mechanisms generating aneuploidyMultiple defects occurring during mitosis can lead to the

production of aneuploid cells. Mitotic checkpoint errors

can give rise to near-diploid aneuploidy or to cell death,

depending on the extent of the remaining checkpoint

signal. Weakening of the mitotic checkpoint due to reduc-

tion in levels of one or more checkpoint components leads

to near-diploid aneuploidy from nondisjunction errors, in

which both copies of one or a few replicated chromosomes

are deposited in the same daughter cell (Figure 1b). Con-

versely, complete inactivation of the mitotic checkpoint

resulting from elimination of a key component such as

MAD2 or BUBR1 leads to rampant aneuploidy and mas-

sive chromosome missegregation (Figure 1c). This

mechanism is not expected to make a major contribution

to tumorigenesis, as cells with an inactive checkpoint die

within six divisions as a result of rampant aneuploidy [14��].

Mitotic errors leading to aneuploidy can also occur despite

intact mitotic checkpoint signaling. These include misse-

gregation events that occur when the kinetochore of a

single replicated chromosome becomes attached to micro-

tubules from both spindle poles, a situation known as


merotelic attachment. Since the chromosome is attached

and under tension, no mitotic checkpoint signal is gener-

ated [21]. The inappropriate attachment is often resolved,

but in some cases it produces a lagging chromosome with a

stretched kinetochore [22] that either remains in the mito-

tic midzone, becoming excluded from both daughter cells

during cytokinesis (Figure 1d), or is segregated into one

daughter, where it may form a micronucleus. Segregation

errors resulting from multipolar spindles also cannot be

prevented by the mitotic checkpoint, because the chromo-

somes make productive attachments to two of the available

poles. When three or more daughter cells are created by

multiple cytokinetic furrows, aneuploid progeny are pro-

duced (Figure 1e).

By contrast, cells containing monopolar spindles (result-

ing from failure of centrosome duplication or inhibition of

the apparatus required for centrosome separation) have at

least a few unattached chromosomes and will undergo

sustained mitotic checkpoint-dependent arrest. Some of

these cells die during the prolonged mitotic arrest and

others undergo adaptation. Adaptation is a poorly under-

stood (and frequently poorly defined) process that occurs

when cells exit mitosis after long-term mitotic arrest with-

out undergoing cytokinesis to produce one tetraploid G1

cell, despite the fact that the cell still contains unattached

chromosomes and the mitotic checkpoint has not been

satisfied (Figure 1f). Weakening of mitotic checkpoint

signaling at individual kinetochores shortens the time a

cell remains arrested before adapting and may contribute to

the survival of cells treated with microtubule poisons. It is

not yet known what determines whether cells will die or

adapt after long-term mitotic arrest.

Recently, a surprising proposal was made that nondisjunc-

tion produces tetraploid cells instead of the expected



Table 3

Genes preventing aneuploidy that are mutated and/or misregulated in human cancers.

Gene Primary function Mutated in, frequency, reference Upregulated in, frequency,

reference

Downregulated in, frequency,

reference

BUB1 Mitotic checkpoint Colorectal, 2/19, [16] Barrett’s oesophagus

(precancercous), 12/33, [48]

Barrett’s oesophagus

(precancerous), 9/33, [48]Colorectal, 1/31, [78]

Colorectal, 1/1, [76] Breast, 20/21, [83] Colorectal, 10/110, [78]

Leukemia (ATLL), 4/10, [79] Gastric, 36/43, [84] Gastric, 4/20, [85]

Leukemia (T lymphoblastic), 2/2,

[80]

Gastric, 8/20, [84,85] Oesophageal, 1/4, [48]

Melanoma, 21/30, [86]

Lung, 1/60, [81] Leukemia, (t-AML), not specified,

[87]Lung, 1/88, [82]

Thyroid, 1/27, [77] Oesophageal, 1/4, [48]

BUBR1 Mitotic checkpoint Colorectal, 2/19, [16] Breast 20/21, [83] Colorectal, 10/116, [78]

Lymphoma, 1/8, [79] Gastric, 29/43, [84] Thyroid, 3/8, [77]

MVAa, 5/8, [56] Lung, 8/8, [88]

MVA, 6/6, [57]

BUB3 Mitotic checkpoint Breast, 18/21, [83] Breast, 2/21, [83]

Gastric, 34/43, [84] Lung, 7/18, [89]

Lung, 5/18, [89]

MAD1 Mitotic checkpoint Breast, 16/17, [83] Nasopharyngeal, 3/5, [74]

Lung, 13/14, [90] Leukemia (ATL), 6/6, [66]

MAD2 Mitotic checkpoint Breast, 1/22, [91] Barrett’s oesophagus

(precancerous), 8/33, [48]

Barrett’s oesophagus

(precancerous), 8/33, [48]Breast, 1/1, [68]

Gastric, 23/54, [92] Bladder, not specified, [93] Breast, 5/21, [68,83]

Breast, 3/13, [83] Hepatocellular carcinoma, 5/10,

[96]Breast, 15/21, [83]

Colorectal, not specified, [94,95] Hepatoma, 6/11, [71]

Neuroblastoma, not specified, [93] Leukemia (ATL), 2/6 [66]

Oesophageal, 1/4, [48] Nasopharyngeal, 3/5, [74]

Oesophageal, 2/4, [48]

Ovarian, 3/7, [75]

AdAPCb Tumor suppressor Colorectal, 76/115, [97] Breast, 11/27, [99]

Duodenum, 16/19, [98] Colorectal, 110/137, [100]

Oesophageal, 4/35, [101]

Oral, 15/50, [102]

BRCA1c Tumor suppressor Breast, 3/32, [103] Breast, 39/48, [107]

Familial breast, 41/264, [104] Breast, 51/162, [108]

Ovarian 1/12, [103] Colon, 5/5, [109]

Ovarian, 15/103, [105] Ovarian, 54/76, [110]

Ovarian, 39/649, [106] Pancreatic, 25/50, [107]

BRCA2d Tumor suppressor Breast, 2/70, [111]

Familial breast, 60/264, [104]

Ovarian, 0/55, [111]

Ovarian, 21/649, [106]

Msh2e DNA mismatch repair Colorectal, 1/509, [112] Gallbladder, 35/46, [113] Leukemia (ATL), 11/11, [115]

Colorectal with replication errors,

1/63, [112]

Urothelial, 17/17, [114] Melanoma, 45/106, [116]

Skin (SCC), 2/125, [117]

aMosaic variegated aneuplody (MVA) is a rare condition associated with childhood cancers and growth retardation. bPatients with germline mutations

in AdAPC have familial adenomatous polyposis (FAP) and develop colorectal cancer with almost 100% penetrance. FAP individuals also have an

increased risk of duodenum (50–90% risk), thyroid, hepatoblastoma and adrenal cancers [7,118]. cHeterozygous germline mutations in BRCA1 occur

in �20% of hereditary breast cancer patients. Individuals with germline mutations in BRCA1 have a 50–80% risk of developing breast cancer and a

40% risk of ovarian cancer [119,120]. dHeterozygous germline mutations in BRCA2 occur in �20% of hereditary breast cancer patients. Individuals

with germline mutations in BRCA2 have a 45% lifetime risk of breast cancer and an 11% risk of ovarian cancer [120]. ePatients with germline

mutations in Msh2 develop hereditary nonpolyposis colon cancer (HNPCC) syndrome and have increased risk of colorectal (80% lifetime risk),

endometrial (30–50% risk), gastric, ovarian, urothelial, pancreatic and biliary cancers [7,118].

2n + 1 and 2n � 1 aneuploid progeny [23�]. This idea was

based on fluorescence in situ hybridization (FISH) data

showing that cells that become binucleate after failing to

complete cytokinesis have a higher incidence of misse-

gregation of individual chromosomes into their two nuclei

than do cells still in anaphase. This led to the conclusion


that newly formed daughter cells are in some way able to

sense nondisjunction events and cause cytokinetic furrow

regression as a result. However, the correlation between

nondisjunction and binucleation does not prove causality

any more than does the correlation between aneuploidy

and cancer. A direct test of this hypothesis posed in



primary cells that displayed elevated levels of nondisjunc-

tion (due to specific disruption of the gene encoding the

mitotic motor CENP-E) showed no increase in binuclea-

tion [24]. Additionally, nondisjunction in mice and

humans produces high levels of near-diploid aneuploidy,

not tetraploidy [17,19,25]. Thus, nondisjunction produces

near-diploid aneuploidy in most instances and is unlikely

to serve as a major mechanism of tetraploidization.

How does tetraploidy contribute toaneuploidy?Exit from mitosis without attempting cytokinesis (or with a

failed cytokinesis) produces tetraploid cells containing two

centrosomes. After replication, these centrosomes are cap-

able of producing multipolar spindles with three or four

poles, which would result in the production of aneuploid

progeny during a subsequent mitosis, provided that the

tetraploid cells were able to undergo successful cytokinesis

(Figure 1g). However, a cell cycle checkpoint known as the

tetraploidy checkpoint has been proposed to sense the

presence of tetraploid cells and arrest them in G1 [26]. This

mechanism would have the obvious advantage of prevent-

ing genomic instability caused by multipolar mitoses.

However, recent work has raised concerns about the evi-

dence for such a checkpoint. Initially, nontransformed rat

embryonic fibroblasts were found to arrest in G1 after

treatment with an actin inhibitor (cytochalasin) caused

them to fail cytokinesis and become tetraploid. However,

re-examination of the same cells indicated that tetraploid

cells did proceed through the cell cycle if a lower concen-

tration of cytochalasin was used [27]. Additionally, similar

efforts with tetraploid primary human fibroblasts formed

by drug treatment or cell fusion did not support the

presence of a tetraploidy checkpoint [27,28]. Moreover,

primary murine fibroblasts cycle despite being tetraploid,

as recently observed with securin�/�separase�/� fibro-

blasts [29,30], and in numerous wild type examples

[31�,32,33]. Finally, tetraploid rat hepatocytes, HeLa cells

and telomerase-immortalized human keratinocytes (N/

TERT-1 cells) have recently been filmed undergoing

mitosis [23�,34]. Thus, the balance of the evidence weighs

heavily against the presence of a tetraploidy checkpoint as

a general mechanism for blocking the proliferation of

tetraploid cells.

Mutations in tumor suppressors and DNAmismatch repair genes generate aneuploidyGermline mutations in the tumor suppressor gene adeno-

matous polyposis coli (AdAPC) cause familial adenoma-

tous polyposis (FAP), a syndrome leading to the

development of hundreds to thousands of colorectal

polyps, resulting in colorectal cancer with almost complete

penetrance. A large percentage of spontaneous colorectal

tumors also contain mutations in AdAPC (Table 3). AdAPC

plays a well-characterized role in down-regulating Wnt

signaling by contributing to the degradation of b-catenin.

Mutations in AdAPC result in stabilization of b-catenin,


which leads to transcription of proliferation-associated

genes, including c-myc and cyclin D1 [35]. However, it

has recently been found that mutations in AdAPC also

produce whole chromosomal aneuploidy in mouse

embryonic stem cells [36,37]. Cells expressing truncated

or mutant versions of AdAPC have a weakened mitotic

checkpoint and unstable kinetochore-microtubule inter-

actions during mitosis, which cooperate to produce lagging

chromosomes in anaphase [36–38,39�,40�]. Thus, muta-

tions in AdAPC may contribute to tumorigenesis via two

distinct mechanisms, upregulation of Wnt signaling and

generation of aneuploidy and CIN.

Two other tumor suppressor genes, the breast cancer

associated genes BRCA1 and BRCA2, have also recently

been demonstrated to produce aneuploidy when mutated,

in addition to their previously identified roles in DNA

repair. Murine embryonic fibroblasts (MEFs) derived from

mice expressing mutated forms of BRCA1 or BRCA2

contain highly aneuploid numbers of chromosomes.

BRCA1 mutant cells exhibit lagging chromosomes and

an apparently weakened mitotic checkpoint, which may

be due to decreased expression of the essential mitotic

checkpoint protein MAD2 [41�]. BRCA2 mutant MEFs

exhibit cytokinesis defects [42�] and, consistent with this,

contain supernumery centrosomes [43]. Thus, mutations

in BRCA1 and BRCA2 appear to contribute to tumorigen-

esis through both the DNA damage and aneuploidy path-

ways.

Similarly, mutations in the MMR gene Msh2 appear to

cause both DNA damage and aneuploidy. As introduced

above, mutations in Msh2 lead to MIN. MIN is thought to

promote tumorigenesis when insertions or deletions of

microsatellites occur in growth-regulatory genes. However,

in addition to defects in MMR, Msh2�/� primary MEFs

develop rampant aneuploidy. Eighty percent of Msh2�/�

MEFs contained a non-diploid number of chromosomes at

passage 2, as compared to 30% of wild type cells [31�].Thus, mutations in Msh2 may contribute to tumorigenesis

through both the MIN and the CIN pathways.

Conclusions: the evidence is equivocal onwhether aneuploidy is a direct cause of cancerAneuploidy is a remarkably common characteristic of

tumor cells (Figure 1), which is a major reason why it

has been proposed to initiate tumorigenesis. This propo-

sal makes several predictions. First, aneuploidy should

precede transformation. Indeed, aneuploidy is found in

pre-cancerous lesions of the cervix [44,45], head and neck

[46], colon [45,47], oesophagus [48] and bone marrow

[49]. Aneuploidy has also been detected in premalignant

breast [50] and skin [51] lesions in experimental animals.

Second, aneuploidy should disrupt global transcription

leading to upregulation of growth-promoting genes and

downregulation of genes involved in growth control.

Recent work indicates that aneuploidy due to the gain



of a single chromosome can indeed result in the misregula-

tion of 100–200 genes. Strikingly, only 5–20% of misregu-

lated genes were contained on the trisomic chromosome

[52�]. Third, transformation and tumorigenesis due to

aneuploidy should require many generations to establish

the complicated karyotypes contained in human tumor

cells that permit patterns of gene misexpression supportive

of uninhibited cell growth. This is consistent with the well-

known increase in cancer incidence with age.

Although aneuploidy correlates with transformation,

empirical tests of the hypothesis that aneuploidy drives

tumorigenesis have been hampered by the difficulty of

generating aneuploidy without causing other cellular

defects, particularly DNA damage. Early attempts to test

the effects of aneuploidy relied on drugs, many of which

have subsequently been shown to be mutagenic. More

recent attempts have used mice expressing reduced levels

of mitotic checkpoint genes. Mice heterozygous for the

mitotic checkpoint gene MAD2 are more susceptible to

spontaneous, benign lung tumors after a long latency [19].

BUB3+/�mice are not predisposed to spontaneous tumors,

but they may be more susceptible to carcinogen-induced

tumors [17], as are mice expressing reduced levels of

BUBR1 [53,54]. Interestingly, BUBR1 heterozygosity

accelerates tumorigenesis in the large intestine and inhibits

tumorigenesis in the small intestine in mice expressing a

mutated allele of the AdAPC tumor suppressor gene [55].

Mutations in BUBR1 have also been found in families

exhibiting mosaic variegated aneuploidy (MVA) [56�,57], a

rare condition associated with growth retardation and pre-

disposition to various tumor types.

However, all of these checkpoint proteins are expressed

throughout the cell cycle and have been implicated in

diverse cellular processes. BUBR1 functions in apoptosis

[58–60], megakaryopoiesis [61], the DNA damage check-

point [62], aging and fertility [18]. BUB3 acts as a tran-

scriptional repressor [63] and MAD2 localizes to the

nucleus and nuclear pores and participates in the DNA

replication checkpoint [64]. All three contribute to gross

chromosomal rearrangements [65]. Thus, interpretation of

their tumor-prone phenotype is complicated by the fact

that they participate in cellular functions other than chro-

mosome segregation. Ultimately, a true test of the aneu-

ploidy hypothesis will require a method to generate

aneuploidy in the absence of other defects, a feat not

yet reported.

References and recommended readingPapers of particular interest, published within the annual period ofreview, have been highlighted as:

� of special interest�� of outstanding interest

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2. Boveri T: Ueber mehrpolige Mitosen als Mittel zur Analyse desZellkerns. URL for English translation: http://8e.devbio.com/article.php?ch=4&id=24.

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Does aneuploidy cause cancer?