Download 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])
was already well recognized 100 years ago. The prevalence 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 heterozygosity (LOH) of tumor suppressor genes seemed to offer
a simple, direct molecular mechanism for Boveri’s
hypothesis. This has not, however, resulted in consensus. 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 contributes to tumor progression but not tumor initiation
[6].
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 with
tumorigenicity
Aneuploidy, an aberrant chromosome number that deviates 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 frequently 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 cytokinesis), are also observed in solid tumors, although not as
commonly as near-diploid karyotypes (Table 1).
Although methodological advances have permitted significantly more refined analysis of the chromosomal
abnormalities in cancer cells in recent years, the abundance of aneuploid chromosome contents in tumor cells
Current Opinion in Cell Biology 2006, 18:658–667
Genetic instability due to mutations in mismatch repair
(MMR) enzymes has become well established as a causative 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 mutations 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 endometrial 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 aneuploidy 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 frequency. However, a definitive empirical test of this
hypothesis has not yet been reported, and alternative
interpretations cannot be excluded. Here we summarize
www.sciencedirect.com
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 Number of aneuploid tumors Number of aneuploid tumors with a
or lost chromosomes *
with a near-diploid number of near- tetraploid number of
chromosomes (68)
chromosomes (69)
Solid tumors
Astrocytoma, grade III–IV
Basal cell carcinoma
Breast cancer
Cervical cancer
Colon adenocarcinoma
Embryonal rhabdomyosarcoma
Hepatoblastoma
Leiomyosarcoma
Lung cancer
Malignant melanoma
Neuroblastoma
Osteosarcoma
Ovarian cancer
Prostate cancer
Retinoblastoma
Squamous cell carcinoma
Teratoma
Percent of solid tumors (n = 2780)
Haematopoietic cancers
Acute myeloid leukemia
Adult T-cell lymphoma/leukemia
B-prolymphocytic leukemia
Burkitt lymphoma/leukemia
Chronic myeloid leukemia
Follicular lymphoma
Hodgkins disease
Multiple myeloma
T-prolymphocytic leukemia
Percent of haematopoietic cancers
(n = 1973)
Percent of solid and haematopoietic
cancers (n = 4753)
10
23
31
4
1
9
17
7
36
30
28
6
5
16
10
12
3
8.9%
228
75
140
51
124
53
80
68
119
138
109
86
158
141
111
149
166
71.8%
62
4
29
29
19
12
3
34
45
31
58
59
37
43
1
39
31
19.3%
88
21
20
86
90
55
26
64
25
24.1%
207
224
72
75
110
228
129
217
111
69.6%
3
8
1
2
0
17
77
17
0
6.3%
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 cycle
checkpoint guarding against aneuploidy
Beginning 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 checkpoint. The mitotic checkpoint prevents chromosome
missegregation and aneuploidy by inhibiting the irreversible transition to anaphase until all of the replicated
chromosomes have made productive attachments to spindle 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).
www.sciencedirect.com
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 separase. 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 anaphase onset [12,13].
Treatment of cells with drugs producing depolymerization 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
Current Opinion in Cell Biology 2006, 18:658–667
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 colorectal 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 completely 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
Current Opinion in Cell Biology 2006, 18:658–667
and Aurora B) and mutation in any one could lead to
weakening of the checkpoint. Additionally, mutations
leading to complete inactivation of the mitotic checkpoint 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. Consistent with this, mice that are heterozygous for the checkpoint proteins MAD2, BUBR1 and BUB3 exhibit an
impaired mitotic checkpoint response and develop aneuploidy in vitro and in vivo [17–19]. The mechanism by
which overexpression of individual checkpoint proteins
www.sciencedirect.com
Does aneuploidy cause cancer? Weaver and Cleveland 661
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
Breast
Breast
Breast
Colorectal
Head and neck
Hepatocellular carcinoma
6
7
1
7
3
6
5
100%
78%
100%
70%
100%
100%
62%
Reduced expression of MAD1 in all, MAD2 in two
No mutations in BUB1, BUBR1 or CDC20
[66]
[67]
[68]
[67]
[16]
[69]
[70]
Hepatoma
Lung
Lung adenocarcinoma
6 of 11
4 of 9
1 of 2
55%
44%
50%
Reduced expression of Mad2 in all
No mutations in MAD2 or CDC20
Levels of MAD2 and BUB1 similar in both lines
[71]
[72]
[73]
Nasopharyngeal carcinoma
2 of 5
40%
[74]
Ovarian
3 of 7
43%
No mutations in MAD2, MAD1 or CDC20. Reduced
expression of MAD1 and MAD2 in both
Reduced expression of MAD2 and MAD1 in all three
Pancreatic
Rhabdomyosarcoma
Thyroid
3 of 3
1 of 1
4 of 8
100%
100%
50%
MAD2 expression at wild-type levels
Reduced BUBR1 expression in 3 of 4
of
of
of
of
of
of
of
6
9
1
10
3
6
8
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 components 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 aneuploidy
Multiple 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 reduction 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). Conversely, complete inactivation of the mitotic checkpoint
resulting from elimination of a key component such as
MAD2 or BUBR1 leads to rampant aneuploidy and massive 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 missegregation events that occur when the kinetochore of a
single replicated chromosome becomes attached to microtubules from both spindle poles, a situation known as
www.sciencedirect.com
Reduced expression of Mad2
CIN correlated with lack of a mitotic checkpoint
[75]
[76]
[68]
[77]
merotelic attachment. Since the chromosome is attached
and under tension, no mitotic checkpoint signal is generated [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 mitotic 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 chromosomes make productive attachments to two of the available
poles. When three or more daughter cells are created by
multiple cytokinetic furrows, aneuploid progeny are produced (Figure 1e).
By contrast, cells containing monopolar spindles (resulting 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 understood (and frequently poorly defined) process that occurs
when cells exit mitosis after long-term mitotic arrest without 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 nondisjunction produces tetraploid cells instead of the expected
Current Opinion in Cell Biology 2006, 18:658–667
662 Cell division, growth and death
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]
Colorectal, 1/31, [78]
Colorectal, 1/1, [76]
Leukemia (ATLL), 4/10, [79]
Leukemia (T lymphoblastic), 2/2,
[80]
Lung, 1/60, [81]
Lung, 1/88, [82]
Thyroid, 1/27, [77]
Barrett’s oesophagus
(precancercous), 12/33, [48]
Breast, 20/21, [83]
Gastric, 36/43, [84]
Gastric, 8/20, [84,85]
Melanoma, 21/30, [86]
Leukemia, (t-AML), not specified,
[87]
Oesophageal, 1/4, [48]
Barrett’s oesophagus
(precancerous), 9/33, [48]
Colorectal, 10/110, [78]
Gastric, 4/20, [85]
Oesophageal, 1/4, [48]
BUBR1
Mitotic checkpoint
Colorectal, 2/19, [16]
Lymphoma, 1/8, [79]
MVAa, 5/8, [56]
MVA, 6/6, [57]
Breast 20/21, [83]
Gastric, 29/43, [84]
Lung, 8/8, [88]
Colorectal, 10/116, [78]
Thyroid, 3/8, [77]
BUB3
Mitotic checkpoint
Breast, 2/21, [83]
Lung, 7/18, [89]
MAD1
Mitotic checkpoint
Breast, 18/21, [83]
Gastric, 34/43, [84]
Lung, 5/18, [89]
Breast, 16/17, [83]
Lung, 13/14, [90]
MAD2
Mitotic checkpoint
Breast, 1/22, [91]
Breast, 1/1, [68]
Gastric, 23/54, [92]
Barrett’s oesophagus
(precancerous), 8/33, [48]
Bladder, not specified, [93]
Breast, 3/13, [83]
Breast, 15/21, [83]
Colorectal, not specified, [94,95]
Neuroblastoma, not specified, [93]
Oesophageal, 1/4, [48]
Barrett’s oesophagus
(precancerous), 8/33, [48]
Breast, 5/21, [68,83]
Hepatocellular carcinoma, 5/10,
[96]
Hepatoma, 6/11, [71]
Leukemia (ATL), 2/6 [66]
Nasopharyngeal, 3/5, [74]
Oesophageal, 2/4, [48]
Ovarian, 3/7, [75]
AdAPC b
Tumor suppressor
Colorectal, 76/115, [97]
Duodenum, 16/19, [98]
BRCA1 c
Tumor suppressor
BRCA2 d
Tumor suppressor
Msh2 e
DNA mismatch repair
Breast, 3/32, [103]
Familial breast, 41/264, [104]
Ovarian 1/12, [103]
Ovarian, 15/103, [105]
Ovarian, 39/649, [106]
Breast, 2/70, [111]
Familial breast, 60/264, [104]
Ovarian, 0/55, [111]
Ovarian, 21/649, [106]
Colorectal, 1/509, [112]
Colorectal with replication errors,
1/63, [112]
Nasopharyngeal, 3/5, [74]
Leukemia (ATL), 6/6, [66]
Breast, 11/27, [99]
Colorectal, 110/137, [100]
Oesophageal, 4/35, [101]
Oral, 15/50, [102]
Breast, 39/48, [107]
Breast, 51/162, [108]
Colon, 5/5, [109]
Ovarian, 54/76, [110]
Pancreatic, 25/50, [107]
Gallbladder, 35/46, [113]
Urothelial, 17/17, [114]
Leukemia (ATL), 11/11, [115]
Melanoma, 45/106, [116]
Skin (SCC), 2/125, [117]
a
Mosaic 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 missegregation of individual chromosomes into their two nuclei
than do cells still in anaphase. This led to the conclusion
Current Opinion in Cell Biology 2006, 18:658–667
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
www.sciencedirect.com
Does aneuploidy cause cancer? Weaver and Cleveland 663
primary cells that displayed elevated levels of nondisjunction (due to specific disruption of the gene encoding the
mitotic motor CENP-E) showed no increase in binucleation [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 to
aneuploidy?
Exit from mitosis without attempting cytokinesis (or with a
failed cytokinesis) produces tetraploid cells containing two
centrosomes. After replication, these centrosomes are capable 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 preventing genomic instability caused by multipolar mitoses.
However, recent work has raised concerns about the evidence 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 concentration 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 / fibroblasts [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 DNA
mismatch repair genes generate aneuploidy
Germline mutations in the tumor suppressor gene adenomatous polyposis coli (AdAPC) cause familial adenomatous 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,
www.sciencedirect.com
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 interactions during mitosis, which cooperate to produce lagging
chromosomes in anaphase [36–38,39,40]. Thus, mutations 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 tumorigenesis through both the DNA damage and aneuploidy pathways.
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 on
whether aneuploidy is a direct cause of cancer
Aneuploidy is a remarkably common characteristic of
tumor cells (Figure 1), which is a major reason why it
has been proposed to initiate tumorigenesis. This proposal 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
Current Opinion in Cell Biology 2006, 18:658–667
664 Cell division, growth and death
of a single chromosome can indeed result in the misregulation of 100–200 genes. Strikingly, only 5–20% of misregulated 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 wellknown 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 predisposition 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 checkpoint [62], aging and fertility [18]. BUB3 acts as a transcriptional 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 chromosome segregation. Ultimately, a true test of the aneuploidy hypothesis will require a method to generate
aneuploidy in the absence of other defects, a feat not
yet reported.
References and recommended reading
Papers of particular interest, published within the annual period of
review, have been highlighted as:
of special interest
of outstanding interest
1.
Mitelman F, Johansson B, Mertens FE: Mitelman Database of
Chromosome Aberrations in Cancer (2006). URL:
http://cgap.nci.nih.gov/Chromosomes/Mitelman 2006.
Current Opinion in Cell Biology 2006, 18:658–667
2.
Boveri T: Ueber mehrpolige Mitosen als Mittel zur Analyse des
Zellkerns. URL for English translation: http://8e.devbio.com/
article.php?ch=4&id=24.
3.
Boveri T: Zur Frage der Entstehung maligner Tumoren.
(The origin of malignant tumors.). Gustav Fischer, Jena 1914.
4.
Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL,
Brooks MW, Weinberg RA: Creation of human tumour cells with
defined genetic elements. Nature 1999, 400:464-468.
5.
Marx J: Debate surges over the origins of genomic defects in
cancer. Science 2002, 297:544-546.
6.
Zimonjic D, Brooks MW, Popescu N, Weinberg RA, Hahn WC:
Derivation of human tumor cells in vitro without widespread
genomic instability. Cancer Res 2001, 61:8838-8844.
7.
Strate LL, Syngal S: Hereditary colorectal cancer syndromes.
Cancer Causes Control 2005, 16:201-213.
8.
Rajagopalan H, Lengauer C: CIN-ful cancers. Cancer Chemother
Pharmacol 2004, 54(Suppl 1):S65-S68.
9.
von Hansemann D: Ueber asymmetrische Zelltheilung in
Epithelkrebsen und deren biologische Bedeutung. Virchow’s
Arch Path Anat. 1890, 119:299-326.
10. Kops GJ, Weaver BA, Cleveland DW: On the road to cancer:
aneuploidy and the mitotic checkpoint. Nat Rev Cancer 2005,
5:773-785.
11. Taylor SS, Scott MI, Holland AJ: The spindle checkpoint: a
quality control mechanism which ensures accurate
chromosome segregation. Chromosome Res 2004, 12:599-616.
12. Rieder CL, Cole RW, Khodjakov A, Sluder G: The checkpoint
delaying anaphase in response to chromosome
monoorientation is mediated by an inhibitory signal
produced by unattached kinetochores. J Cell Biol 1995,
130:941-948.
13. Rieder CL, Schultz A, Cole R, Sluder G: Anaphase onset in
vertebrate somatic cells is controlled by a checkpoint that
monitors sister kinetochore attachment to the spindle.
J Cell Biol 1994, 127:1301-1310.
14. Kops GJ, Foltz DR, Cleveland DW: Lethality to human cancer
cells through massive chromosome loss by inhibition
of the mitotic checkpoint. Proc Natl Acad Sci USA 2004,
101:8699-8704.
See annotation to [15].
15. Michel L, Diaz-Rodriguez E, Narayan G, Hernando E, Murty VV,
Benezra R: Complete loss of the tumor suppressor MAD2
causes premature cyclin B degradation and mitotic
failure in human somatic cells. Proc Natl Acad Sci USA 2004,
101:4459-4464.
This paper and [14] demonstrate that complete loss of the mitotic
checkpoint due to severe depletion of MAD2 or BUBR1 causes rapid
cell death.
16. Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD,
Kinzler KW, Vogelstein B: Mutations of mitotic checkpoint
genes in human cancers. Nature 1998, 392:300-303.
17. 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.
18. Baker DJ, Jeganathan KB, Cameron JD, Thompson M,
Juneja S, Kopecka A, Kumar R, Jenkins RB, de Groen PC,
Roche P et al.: BubR1 insufficiency causes early onset of
aging-associated phenotypes and infertility in mice.
Nat Genet 2004, 36:744-749.
19. Michel LS, Liberal V, Chatterjee A, Kirchwegger R, Pasche B,
Gerald W, Dobles M, Sorger PK, Murty VV, Benezra R: MAD2
haplo-insufficiency causes premature anaphase and
chromosome instability in mammalian cells. Nature 2001,
409:355-359.
20. Fang G, Yu H, Kirschner MW: The checkpoint protein MAD2 and
the mitotic regulator CDC20 form a ternary complex with the
anaphase-promoting complex to control anaphase initiation.
Genes Dev 1998, 12:1871-1883.
www.sciencedirect.com
Does aneuploidy cause cancer? Weaver and Cleveland 665
21. Cimini D, Howell B, Maddox P, Khodjakov A, Degrassi F,
Salmon ED: Merotelic kinetochore orientation is a major
mechanism of aneuploidy in mitotic mammalian tissue cells.
J Cell Biol 2001, 153:517-527.
22. Cimini D, Cameron LA, Salmon ED: Anaphase spindle
mechanics prevent mis-segregation of merotelically oriented
chromosomes. Curr Biol 2004, 14:2149-2155.
23. Shi Q, King RW: Chromosome nondisjunction yields tetraploid
rather than aneuploid cells in human cell lines. Nature 2005,
437:1038-1042.
This paper makes the surprising claim that nondisjunction results in
cytokinesis failure and tetraploidization instead of near-diploid aneuploidy, on the basis of a correlation between nondisjunction and binucleation.
24. Weaver BAA, Silk AD, Cleveland DW: Nondisjunction,
aneuploidy and tetraploidy. Nature 2006, 442:E9-E10.
25. Limwongse C, Schwartz S, Bocian M, Robin NH: Child with
mosaic variegated aneuploidy and embryonal
rhabdomyosarcoma. Am J Med Genet 1999, 82:20-24.
26. 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.
dynamics and chromosome alignment. Mol Biol Cell 2005,
16:4609-4622.
See annotation to [40].
40. Tighe A, Johnson VL, Taylor SS: Truncating APC mutations have
dominant effects on proliferation, spindle checkpoint control,
survival and chromosome stability. J Cell Sci 2004,
117:6339-6353.
This paper and [39] show that mutations in single copy of AdAPC can act
dominantly to weaken the mitotic checkpoint, weaken the interactions
between kinetochores and microtubules, and drive aneuploidy.
41. Wang RH, Yu H, Deng CX: A requirement for breast-cancer
associated gene 1 (BRCA1) in the spindle checkpoint. Proc Natl
Acad Sci USA 2004, 101:17108-17113.
This study shows mitotic defects in cells expressing a mutant form of
BRCA1. The mitotic defects may be caused by deficiency in MAD2, as
BRCA1 upregulates transcription of MAD2.
42. Daniels MJ, Wang Y, Lee M, Venkitaraman AR: Abnormal
cytokinesis in cells deficient in the breast cancer susceptibility
protein BRCA2. Science 2004, 306:876-879.
This work shows that BRCA2 mutant cells fail cytokinesis, offering a
possible explanation for the aneuploidy and supernumery centrosomes
observed in BRCA2 mutant cells.
27. Uetake Y, Sluder G: Cell cycle progression after cleavage
failure: mammalian somatic cells do not possess a
‘‘tetraploidy checkpoint’’. J Cell Biol 2004, 165:609-615.
43. Tutt A, Gabriel A, Bertwistle D, Connor F, Paterson H, Peacock J,
Ross G, Ashworth A: Absence of Brca2 causes genome
instability by chromosome breakage and loss associated with
centrosome amplification. Curr Biol 1999, 9:1107-1110.
28. Wong C, Stearns T: Mammalian cells lack checkpoints for
tetraploidy, aberrant centrosome number, and cytokinesis
failure. BMC Cell Biol 2005, 6:6.
44. Duensing S, Munger K: Mechanisms of genomic instability in
human cancer: insights from studies with human
papillomavirus oncoproteins. Int J Cancer 2004, 109:157-162.
29. Kumada K, Yao R, Kawaguchi T, Karasawa M, Hoshikawa Y,
Ichikawa K, Sugitani Y, Imoto I, Inazawa J, Sugawara M et al.: The
selective continued linkage of centromeres from mitosis to
interphase in the absence of mammalian separase.
J Cell Biol 2006, 172:835-846.
45. Ried T, Heselmeyer-Haddad K, Blegen H, Schrock E, Auer G:
Genomic changes defining the genesis, progression, and
malignancy potential in solid human tumors: a phenotype/
genotype correlation. Genes Chromosomes Cancer 1999,
25:195-204.
30. Wirth KG, Wutz G, Kudo NR, Desdouets C, Zetterberg A,
Taghybeeglu S, Seznec J, Ducos GM, Ricci R, Firnberg N et al.:
Separase: a universal trigger for sister chromatid disjunction
but not chromosome cycle progression. J Cell Biol 2006,
172:847-860.
46. Ai H, Barrera JE, Meyers AD, Shroyer KR, Varella-Garcia M:
Chromosomal aneuploidy precedes morphological changes
and supports multifocality in head and neck lesions.
Laryngoscope 2001, 111:1853-1858.
31. Campbell MR, Wang Y, Andrew SE, Liu Y: Msh2 deficiency leads
to chromosomal abnormalities, centrosome amplification,
and telomere capping defect. Oncogene 2006, 25:2531-2536.
This paper presents the first evidence that defects in a mismatch repair
protein (Msh2) that lead to MIN also lead to aneuploidy.
32. Kalitsis P, Fowler KJ, Griffiths B, Earle E, Chow CW, Jamsen K,
Choo KH: Increased chromosome instability but not cancer
predisposition in haploinsufficient Bub3 mice. Genes
Chromosomes Cancer 2005.
33. Saavedra HI, Maiti B, Timmers C, Altura R, Tokuyama Y,
Fukasawa K, Leone G: Inactivation of E2F3 results in
centrosome amplification. Cancer Cell 2003, 3:333-346.
34. Guidotti JE, Bregerie O, Robert A, Debey P, Brechot C,
Desdouets C: Liver cell polyploidization: a pivotal role for
binuclear hepatocytes. J Biol Chem 2003, 278:19095-19101.
35. Hanson CA, Miller JR: Non-traditional roles for the
Adenomatous Polyposis Coli (APC) tumor suppressor protein.
Gene 2005, 361:1-12.
36. Fodde R, Kuipers J, Rosenberg C, Smits R, Kielman M, Gaspar C,
van Es JH, Breukel C, Wiegant J, Giles RH et al.: Mutations in the
APC tumour suppressor gene cause chromosomal instability.
Nat Cell Biol 2001, 3:433-438.
37. Kaplan KB, Burds AA, Swedlow JR, Bekir SS, Sorger PK,
Nathke IS: A role for the Adenomatous Polyposis Coli protein in
chromosome segregation. Nat Cell Biol 2001, 3:429-432.
38. Green RA, Kaplan KB: Chromosome instability in colorectal
tumor cells is associated with defects in microtubule plus-end
attachments caused by a dominant mutation in APC. J Cell Biol
2003, 163:949-961.
39. Green RA, Wollman R, Kaplan KB: APC and EB1
function together in mitosis to regulate spindle
www.sciencedirect.com
47. Cardoso J, Molenaar L, de Menezes RX, van Leerdam M,
Rosenberg C, Moslein G, Sampson J, Morreau H, Boer JM,
Fodde R: Chromosomal instability in MYH- and APC-mutant
adenomatous polyps. Cancer Res 2006, 66:2514-2519.
48. Doak SH, Jenkins GJ, Parry EM, Griffiths AP, Baxter JN, Parry JM:
Differential expression of the MAD2, BUB1 and HSP27 genes
in Barrett’s oesophagus-their association with aneuploidy and
neoplastic progression. Mutat Res 2004, 547:133-144.
49. Amiel A, Gronich N, Yukla M, Suliman S, Josef G, Gaber E, Drori G,
Fejgin MD, Lishner M: Random aneuploidy in neoplastic and
pre-neoplastic diseases, multiple myeloma, and monoclonal
gammopathy. Cancer Genet Cytogenet 2005, 162:78-81.
50. Medina D: Biological and molecular characteristics of the
premalignant mouse mammary gland. Biochim Biophys Acta
2002, 1603:1-9.
51. Dooley TP, Mattern VL, Moore CM, Porter PA, Robinson ES,
VandeBerg JL: Cell lines derived from ultraviolet radiationinduced benign melanocytic nevi in Monodelphis domestica
exhibit cytogenetic aneuploidy. Cancer Genet Cytogenet 1993,
71:55-66.
52. Upender MB, Habermann JK, McShane LM, Korn EL, Barrett JC,
Difilippantonio MJ, Ried T: Chromosome transfer induced
aneuploidy results in complex dysregulation of the cellular
transcriptome in immortalized and cancer cells. Cancer Res
2004, 64:6941-6949.
This paper offers a proof-of-concept experiment showing that aneuploidy
does indeed cause misregulation of global transcription, as had been
previously proposed.
53. 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.
54. Dai W, Wang Q, Liu T, Swamy M, Fang Y, Xie S, Mahmood R,
Yang YM, Xu M, Rao CV: Slippage of mitotic arrest and
Current Opinion in Cell Biology 2006, 18:658–667
666 Cell division, growth and death
enhanced tumor development in mice with BubR1
haploinsufficiency. Cancer Res 2004, 64:440-445.
55. Rao CV, Yang YM, Swamy MV, Liu T, Fang Y, Mahmood R,
Jhanwar-Uniyal M, Dai W: Colonic tumorigenesis in BubR1+/
SApcMin/+ compound mutant mice is linked to premature
separation of sister chromatids and enhanced genomic
instability. Proc Natl Acad Sci USA 2005, 102:4365-4370.
56. Hanks S, Coleman K, Reid S, Plaja A, Firth H, Fitzpatrick D, Kidd A,
Mehes K, Nash R, Robin N et al.: Constitutional aneuploidy and
cancer predisposition caused by biallelic mutations in BUB1B.
Nat Genet 2004, 36:1159-1161.
This paper provides the first evidence linking germline mutations in an
essential mitotic checkpoint gene (BUBR1, also known as BUB1B) to an
inherited cancer susceptibility syndrome.
57. Matsuura S, Matsumoto Y, Morishima K, Izumi H, Matsumoto H,
Ito E, Tsutsui K, Kobayashi J, Tauchi H, Kajiwara Y et al.: Monoallelic
BUB1B mutations and defective mitotic-spindle checkpoint in
seven families with premature chromatid separation (PCS)
syndrome. Am J Med Genet A 2006, 140:358-367.
58. Baek KH, Shin HJ, Jeong SJ, Park JW, McKeon F, Lee CW,
Kim CM: Caspases-dependent cleavage of mitotic checkpoint
proteins in response to microtubule inhibitor. Oncol Res 2005,
15:161-168.
59. Kim M, Murphy K, Liu F, Parker SE, Dowling ML, Baff W, Kao GD:
Caspase-mediated specific cleavage of BubR1 is a determinant
of mitotic progression. Mol Cell Biol 2005, 25:9232-9248.
60. Shin HJ, Baek KH, Jeon AH, Park MT, Lee SJ, Kang CM, Lee HS,
Yoo SH, Chung DH, Sung YC et al.: Dual roles of human BubR1, a
mitotic checkpoint kinase, in the monitoring of chromosomal
instability. Cancer Cell 2003, 4:483-497.
61. Wang Q, Liu T, Fang Y, Xie S, Huang X, Mahmood R,
Ramaswamy G, Sakamoto KM, Darzynkiewicz Z, Xu M et al.:
BUBR1 deficiency results in abnormal megakaryopoiesis.
Blood 2004, 103:1278-1285.
62. Fang Y, Liu T, Wang X, Yang YM, Deng H, Kunicki J, Traganos F,
Darzynkiewicz Z, Lu L, Dai W: BubR1 is involved in regulation of
DNA damage responses. Oncogene 2006.
63. Yoon YM, Baek KH, Jeong SJ, Shin HJ, Ha GH, Jeon AH,
Hwang SG, Chun JS, Lee CW: WD repeat-containing mitotic
checkpoint proteins act as transcriptional repressors during
interphase. FEBS Lett 2004, 575:23-29.
64. Sugimoto I, Murakami H, Tonami Y, Moriyama A, Nakanishi M:
DNA replication checkpoint control mediated by the spindle
checkpoint protein Mad2p in fission yeast. J Biol Chem 2004,
279:47372-47378.
65. Myung K, Smith S, Kolodner RD: Mitotic checkpoint function in
the formation of gross chromosomal rearrangements in
Saccharomyces cerevisiae. Proc Natl Acad Sci USA 2004,
101:15980-15985.
72. Takahashi T, Haruki N, Nomoto S, Masuda A, Saji S, Osada H,
Takahashi T: Identification of frequent impairment of the
mitotic checkpoint and molecular analysis of the mitotic
checkpoint genes, hsMAD2 and p55CDC, in human lung
cancers. Oncogene 1999, 18:4295-4300.
73. Weitzel DH, Vandre DD: Differential spindle assembly
checkpoint response in human lung adenocarcinoma cells.
Cell Tissue Res 2000, 300:57-65.
74. Wang X, Jin DY, Wong YC, Cheung AL, Chun AC, Lo AK, Liu Y,
Tsao SW: Correlation of defective mitotic checkpoint with
aberrantly reduced expression of MAD2 protein in
nasopharyngeal carcinoma cells. Carcinogenesis 2000,
21:2293-2297.
75. Wang X, Jin DY, Ng RW, Feng H, Wong YC, Cheung AL, Tsao SW:
Significance of MAD2 expression to mitotic checkpoint
control in ovarian cancer cells. Cancer Res 2002, 62:1662-1668.
76. Hempen PM, Kurpad H, Calhoun ES, Abraham S, Kern SE:
Erratum: A double missense variation of the BUB1 gene and a
defective mitotic spindle checkpoint in the pancreatic cancer
cell line Hs766T. Hum Mutat 2003, 21:445.
77. Ouyang B, Knauf JA, Ain K, Nacev B, Fagin JA: Mechanisms of
aneuploidy in thyroid cancer cell lines and tissues: evidence
for mitotic checkpoint dysfunction without mutations in BUB1
and BUBR1. Clin Endocrinol (Oxf) 2002, 56:341-350.
78. Shichiri M, Yoshinaga K, Hisatomi H, Sugihara K, Hirata Y: Genetic
and epigenetic inactivation of mitotic checkpoint genes
hBUB1 and hBUBR1 and their relationship to survival.
Cancer Res 2002, 62:13-17.
79. Ohshima K, Haraoka S, Yoshioka S, Hamasaki M, Fujiki T,
Suzumiya J, Kawasaki C, Kanda M, Kikuchi M: Mutation analysis
of mitotic checkpoint genes (hBUB1 and hBUBR1) and
microsatellite instability in adult T-cell leukemia/lymphoma.
Cancer Lett 2000, 158:141-150.
80. Ru HY, Chen RL, Lu WC, Chen JH: hBUB1 defects in leukemia
and lymphoma cells. Oncogene 2002, 21:4673-4679.
81. Gemma A, Seike M, Seike Y, Uematsu K, Hibino S, Kurimoto F,
Yoshimura A, Shibuya M, Harris CC, Kudoh S: Somatic mutation
of the hBUB1 mitotic checkpoint gene in primary lung cancer.
Genes Chromosomes Cancer 2000, 29:213-218.
82. Sato M, Sekido Y, Horio Y, Takahashi M, Saito H, Minna JD,
Shimokata K, Hasegawa Y: Infrequent mutation of the hBUB1
and hBUBR1 genes in human lung cancer. Jpn J Cancer Res
2000, 91:504-509.
83. Yuan B, Xu Y, Woo JH, Wang Y, Bae YK, Yoon DS, Wersto RP,
Tully E, Wilsbach K, Gabrielson E: Increased expression of
mitotic checkpoint genes in breast cancer cells with
chromosomal instability. Clin Cancer Res 2006, 12:405-410.
66. Kasai T, Iwanaga Y, Iha H, Jeang KT: Prevalent loss of mitotic
spindle checkpoint in adult T-cell leukemia confers resistance
to microtubule inhibitors. J Biol Chem 2002, 277:5187-5193.
84. Grabsch H, Takeno S, Parsons WJ, Pomjanski N, Boecking A,
Gabbert HE, Mueller W: Overexpression of the mitotic
checkpoint genes BUB1, BUBR1, and BUB3 in gastric
cancer–association with tumour cell proliferation.
J Pathol 2003, 200:16-22.
67. Yoon DS, Wersto RP, Zhou W, Chrest FJ, Garrett ES, Kwon TK,
Gabrielson E: Variable levels of chromosomal instability and
mitotic spindle checkpoint defects in breast cancer.
Am J Pathol 2002, 161:391-397.
85. Shigeishi H, Oue N, Kuniyasu H, Wakikawa A, Yokozaki H,
Ishikawa T, Yasui W: Expression of Bub1 gene correlates with
tumor proliferating activity in human gastric carcinomas.
Pathobiology 2001, 69:24-29.
68. Li Y, Benezra R: Identification of a human mitotic checkpoint
gene: hsMAD2. Science 1996, 274:246-248.
86. Lewis TB, Robison JE, Bastien R, Milash B, Boucher K,
Samlowski WE, Leachman SA, Dirk Noyes R, Wittwer CT,
Perreard L et al.: Molecular classification of melanoma using
real-time quantitative reverse transcriptase-polymerase chain
reaction. Cancer 2005, 104:1678-1686.
69. Minhas KM, Singh B, Jiang WW, Sidransky D, Califano JA: Spindle
assembly checkpoint defects and chromosomal instability in
head and neck squamous cell carcinoma. Int J Cancer 2003,
107:46-52.
70. Saeki A, Tamura S, Ito N, Kiso S, Matsuda Y, Yabuuchi I, Kawata S,
Matsuzawa Y: Frequent impairment of the spindle assembly
checkpoint in hepatocellular carcinoma. Cancer 2002,
94:2047-2054.
71. Sze KM, Ching YP, Jin DY, Ng IO: Association of MAD2
expression with mitotic checkpoint competence in hepatoma
cells. J Biomed Sci 2004, 11:920-927.
Current Opinion in Cell Biology 2006, 18:658–667
87. Qian Z, Fernald AA, Godley LA, Larson RA, Le Beau MM:
Expression profiling of CD34+ hematopoietic stem/progenitor
cells reveals distinct subtypes of therapy-related acute
myeloid leukaemia. Proc Natl Acad Sci USA 2002,
99:14925-14930.
88. Seike M, Gemma A, Hosoya Y, Hosomi Y, Okano T, Kurimoto F,
Uematsu K, Takenaka K, Yoshimura A, Shibuya M et al.: The
promoter region of the human BUBR1 gene and its expression
analysis in lung cancer. Lung Cancer 2002, 38:229-234.
www.sciencedirect.com
Does aneuploidy cause cancer? Weaver and Cleveland 667
89. Miura K, Bowman ED, Simon R, Peng AC, Robles AI, Jones RT,
Katagiri T, He P, Mizukami H, Charboneau L et al.: Laser
capture microdissection and microarray expression analysis
of lung adenocarcinoma reveals tobacco smoking- and
prognosis-related molecular profiles. Cancer Res 2002,
62:3244-3250.
90. Coe BP, Lee EH, Chi B, Girard L, Minna JD, Gazdar AF, Lam S,
MacAulay C, Lam WL: Gain of a region on 7p22.3, containing
MAD1L1, is the most frequent event in small-cell lung cancer
cell lines. Genes Chromosomes Cancer 2006, 45:11-19.
91. Percy MJ, Myrie KA, Neeley CK, Azim JN, Ethier SP, Petty EM:
Expression and mutational analyses of the human MAD2L1
gene in breast cancer cells. Genes Chromosomes Cancer 2000,
29:356-362.
92. Kim HS, Park KH, Kim SA, Wen J, Park SW, Park B, Gham CW,
Hyung WJ, Noh SH, Kim HK et al.: Frequent mutations of human
Mad2, but not Bub1, in gastric cancers cause defective mitotic
spindle checkpoint. Mutat Res 2005, 578:187-201.
93. Hernando E, Nahle Z, Juan G, Diaz-Rodriguez E, Alaminos M,
Hemann M, Michel L, Mittal V, Gerald W, Benezra R et al.: Rb
inactivation promotes genomic instability by uncoupling
cell cycle progression from mitotic control. Nature 2004,
430:797-802.
94. Li GQ, Zhang HF: Mad2 and p27 expression profiles in
colorectal cancer and its clinical significance. World J
Gastroenterol 2004, 10:3218-3220.
95. Li GQ, Li H, Zhang HF: Mad2 and p53 expression profiles in
colorectal cancer and its clinical significance. World J
Gastroenterol 2003, 9:1972-1975.
96. Jeong SJ, Shin HJ, Kim SJ, Ha GH, Cho BI, Baek KH, Kim CM,
Lee CW: Transcriptional abnormality of the hsMAD2 mitotic
checkpoint gene is a potential link to hepatocellular
carcinogenesis. Cancer Res 2004, 64:8666-8673.
97. Huang J, Papadopoulos N, McKinley AJ, Farrington SM, Curtis LJ,
Wyllie AH, Zheng S, Willson JK, Markowitz SD, Morin P et al.: APC
mutations in colorectal tumors with mismatch repair
deficiency. Proc Natl Acad Sci USA 1996, 93:9049-9054.
98. Esaki M, Matsumoto T, Yao S, Nakamura S, Hirahashi M, Yao T,
Iida M: Immunohistochemical characteristics of duodenal
adenomas in familial adenomatous polyposis with special
reference to cell kinetics. Hum Pathol 2005, 36:66-73.
99. Ho KY, Kalle WH, Lo TH, Lam WY, Tang CM: Reduced
expression of APC and DCC gene protein in breast cancer.
Histopathology 1999, 35:249-256.
100. Arnold CN, Goel A, Niedzwiecki D, Dowell JM, Wasserman L,
Compton C, Mayer RJ, Bertagnolli MM, Boland CR: APC
promoter hypermethylation contributes to the loss of APC
expression in colorectal cancers with allelic loss on 5q. Cancer
Biol Ther 2004, 3:960-964.
101. Bektas N, Donner A, Wirtz C, Heep H, Gabbert HE, Sarbia M:
Allelic loss involving the tumor suppressor genes APC and
MCC and expression of the APC protein in the development
of dysplasia and carcinoma in Barrett esophagus.
Am J Clin Pathol 2000, 114:890-895.
102. Uesugi H, Uzawa K, Kawasaki K, Shimada K, Moriya T, Tada A,
Shiiba M, Tanzawa H: Status of reduced expression and
hypermethylation of the APC tumor suppressor gene in human
oral squamous cell carcinoma. Int J Mol Med 2005, 15:597-602.
103. Futreal PA, Liu Q, Shattuck-Eidens D, Cochran C, Harshman K,
Tavtigian S, Bennett LM, Haugen-Strano A, Swensen J, Miki Y
et al.: BRCA1 mutations in primary breast and ovarian
carcinomas. Science 1994, 266:120-122.
104. Infante M, Duran M, Esteban-Cardenosa E, Miner C, Velasco E:
High proportion of novel mutations of BRCA1 and BRCA2 in
breast/ovarian cancer patients from Castilla-Leon (central
Spain). J Hum Genet 2006.
www.sciencedirect.com
105. Berchuck A, Heron KA, Carney ME, Lancaster JM, Fraser EG,
Vinson VL, Deffenbaugh AM, Miron A, Marks JR, Futreal PA et al.:
Frequency of germline and somatic BRCA1 mutations in
ovarian cancer. Clin Cancer Res 1998, 4:2433-2437.
106. Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Kwan E,
Jack E, Vesprini DJ, Kuperstein G, Abrahamson JL et al.:
Prevalence and penetrance of germline BRCA1 and BRCA2
mutations in a population series of 649 women with ovarian
cancer. Am J Hum Genet 2001, 68:700-710.
107. Al-Mulla F, Abdulrahman M, Varadharaj G, Akhter N, Anim JT:
BRCA1 gene expression in breast cancer: a correlative study
between real-time RT-PCR and immunohistochemistry.
J Histochem Cytochem 2005, 53:621-629.
108. Yoshikawa K, Honda K, Inamoto T, Shinohara H, Yamauchi A,
Suga K, Okuyama T, Shimada T, Kodama H, Noguchi S et al.:
Reduction of BRCA1 protein expression in Japanese sporadic
breast carcinomas and its frequent loss in BRCA1-associated
cases. Clin Cancer Res 1999, 5:1249-1261.
109. Romagnolo DF, Chirnomas RB, Ku J, Jeffy BD, Payne CM,
Holubec H, Ramsey L, Bernstein H, Bernstein C, Kunke K et al.:
Deoxycholate, an endogenous tumor promoter and DNA
damaging agent, modulates BRCA-1 expression in apoptosissensitive epithelial cells: loss of BRCA-1 expression in colonic
adenocarcinomas. Nutr Cancer 2003, 46:82-92.
110. Wang C, Horiuchi A, Imai T, Ohira S, Itoh K, Nikaido T,
Katsuyama Y, Konishi I: Expression of BRCA1 protein in benign,
borderline, and malignant epithelial ovarian neoplasms and its
relationship to methylation and allelic loss of the BRCA1 gene.
J Pathol 2004, 202:215-223.
111. Lancaster JM, Wooster R, Mangion J, Phelan CM, Cochran C,
Gumbs C, Seal S, Barfoot R, Collins N, Bignell G et al.: BRCA2
mutations in primary breast and ovarian cancers. Nat Genet
1996, 13:238-240.
112. Aaltonen LA, Salovaara R, Kristo P, Canzian F, Hemminki A,
Peltomaki P, Chadwick RB, Kaariainen H, Eskelinen M, Jarvinen H
et al.: Incidence of hereditary nonpolyposis colorectal cancer
and the feasibility of molecular screening for the disease. N
Engl J Med 1998, 338:1481-1487.
113. Xuan YH, Choi YL, Shin YK, Kook MC, Chae SW, Park SM,
Chae HB, Kim SH: An immunohistochemical study of the
expression of cell-cycle-regulated proteins p53, cyclin D1, RB,
p27, Ki67 and MSH2 in gallbladder carcinoma and its
precursor lesions. Histol Histopathol 2005, 20:59-66.
114. Leach FS, Hsieh JT, Molberg K, Saboorian MH, McConnell JD,
Sagalowsky AI: Expression of the human mismatch repair gene
hMSH2: a potential marker for urothelial malignancy.
Cancer 2000, 88:2333-2341.
115. Morimoto H, Tsukada J, Kominato Y, Tanaka Y: Reduced
expression of human mismatch repair genes in adult T-cell
leukemia. Am J Hematol 2005, 78:100-107.
116. Korabiowska M, Brinck U, Dengler H, Stachura J, Schauer A,
Droese M: Analysis of the DNA mismatch repair proteins
expression in malignant melanomas. Anticancer Res 2000,
20:4499-4505.
117. Liang SB, Furihata M, Takeuchi T, Sonobe H, Ohtsuki Y: Reduced
human mismatch repair protein expression in the
development of precancerous skin lesions to squamous cell
carcinoma. Virchows Arch 2001, 439:622-627.
118. Turnbull C, Hodgson S: Genetic predisposition to cancer.
Clin Med 2005, 5:491-498.
119. Deng CX: BRCA1: cell cycle checkpoint, genetic instability,
DNA damage response and cancer evolution. Nucleic Acids
Res 2006, 34:1416-1426.
120. Lux MP, Fasching PA, Beckmann MW: Hereditary breast and
ovarian cancer: review and future perspectives. J Mol Med
2006, 84:16-28.
Current Opinion in Cell Biology 2006, 18:658–667