Chromosome Res (2011) 19:433–444

DOI 10.1007/s10577-010-9179-y

Chromosomes and cancer cells

Sarah L. Thompson & Duane A. Compton

Published online: 29 December 2010

# Springer Science+Business Media B.V. 2010

Abstract Two prominent features of cancer cells are Abbreviations

abnormal numbers of chromosomes (aneuploidy) and CIN Chromosomal instability
large-scale structural rearrangements of chromosomes. CSI Chromosome structure instability
These chromosome aberrations are caused by genomic kMT Kinetochore–microtubule
instabilities inherent to most cancers. Aneuploidy arises
through chromosomal instability (CIN) by the persistent
loss and gain of whole chromosomes. Chromosomal
rearrangements occur through chromosome structure Introduction
instability (CSI) as a consequence of improper repair of
DNA damage. The mechanisms that cause CIN and CSI One of the most striking features of cancer cells is the
differ, but the phenotypic consequences of aneuploidy presence of chromosomal abnormalities. Aneuploidy,
and chromosomal rearrangements may overlap consid- an abnormal number of chromosomes, is found in
erably. Both CIN and CSI are associated with advanced most solid tumors and half of all leukemias and
stage tumors with increased invasiveness and resistance lymphomas (http://cgap.nci.nih.gov/Chromosomes/
to chemotherapy, indicating that targeted inhibition of Mitelman). Aneuploidy is caused by an underlying
these instabilities might slow tumor growth. Here, we erosion of mitotic fidelity called chromosomal instability
review recent efforts that define the mechanisms and (CIN) which is defined as a persistently high rate of loss
consequences of CIN and CSI. and gain of whole chromosomes (Lengauer et al. 1997).
Aneuploidy and CIN are associated with poor patient
Keywords chromosome . aneuploid . CIN . CSI . prognosis, metastasis, and resistance to chemotherapeu-
kinetochore . microtubule . merotely . translocation tics (Kuukasjärvi et al. 1997; Gao et al. 2007; Choi et
al. 2009; McClelland et al. 2009; Swanton et al. 2009;
Responsible Editor: James Wakefield and Herbert Macgregor Heilig et al. 2010). In addition to changes in chromo-
some numbers, structural defects in chromosomes are
S. L. Thompson : D. A. Compton (*)
present in a high percentage of both blood cancers and
Department of Biochemistry, Dartmouth Medical School,
405 Remsen Building, solid tumors. In leukemic and lymphomic cells, often
Hanover, NH 03755, USA only a single, balanced translocation is present which
e-mail: [email protected] drives tumorigenicity (Mitelman et al. 2007). Solid
S. L. Thompson : D. A. Compton
tumors often contain many structural rearrangements
Norris Cotton Cancer Center, involving multiple chromosomes, multiple breakpoints,
Lebanon, NH 03766, USA and frequently cells from the same tumor contain
434 S.L. Thompson, D.A. Compton

different rearranged chromosomes, indicative of ongo- cohesion (Jallepalli et al. 2001; Michel et al. 2001).
ing chromosome structure instability (CSI). The contri- However, direct analysis of chromosome segregation
bution of specific chromosomal translocations in blood in CIN cells shows that defects in checkpoint function
cancers to tumorigenesis is well established (Mitelman are unlikely to cause CIN in human cancers. Cancer
et al. 2007; Nambiar et al. 2008), and CSI is associated cells with CIN only enter anaphase after alignment of
with a large number of inherited syndromes with all chromosomes, and cells with CIN remain arrested
increased cancer risk (Duker 2002) and has been shown in mitosis when exposed to microtubule perturbing
to cause tumors in mice (Artandi et al. 2000; Luo et al. drugs (reviewed in Thompson et al. 2010). Instead,
2000). evidence from human cancer cell lines suggests a
CIN and CSI are evident in the karyotypes of specific kinetochore–microtubule (kMT) attachment
cancer cells. The chromosomal content of the U251 error called merotely is the major source of chromo-
glioblastoma cell line using spectral karyotyping some segregation errors causing CIN (Thompson and
(SKY) is depicted in Fig. 1. Panels a and b are Compton 2008). Merotelic attachments are defined by
karyotypes of two cells from this cell line providing single kinetochores attaching to microtubules emanat-
evidence for the ongoing chromosome mis- ing from more than one spindle pole (Fig. 2). Merotely
segregation associated with CIN by the numerical is not detected by the spindle checkpoint, and
changes in various chromosomes between the two chromosomes with merotelic attachments align at the
cells (e.g., chromosome 7 is present in five copies in metaphase plate (Khodjakov et al. 1997; Cimini et al.
panel a and only two copies in panel b). The ongoing 2002). Merotely occurs stochastically, and in early
structural changes of chromosomes associated with mitosis numerous chromosomes have merotelic kinet-
CSI are also shown by the structural rearrangements ochores. These errors are corrected in normal cells
of various chromosomes between the two cells [e.g., prior to anaphase onset to prevent chromosome mis-
rearranged chromosomes containing parts of chromo- segregation and preserve the diploid chromosome
somes 11, 10, and 15 are present in the karyotype of content (Cimini et al. 2002; Salmon et al. 2005). If a
the cell in panel a, but this is absent in the karyotype cell enters anaphase with a merotelic attachment, the
of the cell in panel b, while the karyotype of the cell chromatid attached to both poles can segregate to the
in panel b contains t(11;15) that is absent in the same daughter cell as its sister resulting in a mis-
karyotype of the cell in panel a]. The genome segregation that produces two aneuploid cells, one
instability depicted in this cell line is typical of many with an extra copy of the chromosome and the other
cancer cells and underscores the magnitude of missing a copy (Fig. 2).
ongoing genetic change that impacts cancer cells. In human cancer cells, the persistence of merotely
Here, we discuss how CIN generates aneuploidy, how at the time of anaphase onset is caused by two
CSI generates structural defects, and the consequen- different mechanisms, a decreased rate of error
ces of these chromosome aberrations on cancer cells. correction and an increased rate of merotelic forma-
tion. Merotelic errors are corrected by the detachment
of improperly oriented microtubules from kineto-
Mechanisms of chromosomal instability chores. This correction process relies upon the
reversible attachment of microtubules to kinetochores
Whole chromosome instability occurs through mis- and is reflected by the overall turnover (attachment/
segregation of chromosomes during mitosis. Cancer detachment dynamics) of kMTs. Human kinetochores
cells with CIN mis-segregate a chromosome about bind approximately 25 microtubules, and as cells
once every one to five divisions, compared to rates of progress through mitotic stages from prometaphase to
one chromosome per a hundred cell divisions in metaphase to anaphase the turnover of kMTs
stable, diploid cell lines (Cimini et al. 1999; decreases indicative of a gradual stabilization of
Thompson and Compton 2008). CIN can be mimicked kMT attachments (Zhai et al. 1995; Cimini et al.
in diploid cells grown in culture, elevating levels of 2006; Bakhoum et al. 2009a). In cancer cells with
aneuploidy through perturbations of proteins that play CIN, the turnover rate of kMTs is slower than in
key roles in mitosis including proteins that maintain chromosomally stable, diploid cells, demonstrating
the mitotic spindle checkpoint and sister chromatid that cancer cells with CIN have an inherently reduced
Chromosome aberrations in cancer cells 435

Fig. 1 Karyotype of human U251 glioblastoma cells. SKY chromosome painting of two different cells (a, b) from the same culture of
U251 cells illustrating the ongoing CIN (chromosomal instability) and CSI (chromosome structure instability)

capacity to correct erroneous kMT attachments CIN (Bakhoum et al. 2009a). Depletion and over-
(Bakhoum et al. 2009a, b). Increasing kMT turnover expression of numerous kinetochore proteins that
by overexpression of microtubule depolymerases regulate microtubule attachment or stability at the
Kif2b and MCAK restores kMT turnover rates to kinetochore leads to an increase in merotely, includ-
levels found in stable diploid cells and re-establishes ing MCAK, Kif2b, Aurora B, adenomatous polyposis
faithful chromosome segregation to cancer cells with coli (APC), CENP-E, CLASPs, the NDC80 complex,

Fig. 2 Merotelic attachments lead to segregation defects. merotelic kinetochore–microtubule attachments are not effi-
Merotely occurs stochastically in early mitosis in normal cells, ciently corrected during early mitosis, the chromosome attached
but is corrected efficiently to establish proper, bi-oriented to both spindle poles may mis-segregate during anaphase,
attachments needed for error-free segregation (top). When leading to aneuploidy in both daughter cells (bottom)
436 S.L. Thompson, D.A. Compton

Mps1, and Mad2 (Maney et al. 1998; Yao et al. 2000; the geometric assembly of spindles is disrupted by
Hauf et al. 2003; Kline-Smith et al. 2004; Cimini et extra centrosomes which have long been linked to
al. 2006; Knowlton et al. 2006; Pereira et al. 2006; CIN. Centrosomes dictate the number of spindle poles
Sotillo et al. 2007; Diaz-Rodriguez et al. 2008; formed in mitosis and there is a correlation between
Jelluma et al. 2008; Bakhoum et al. 2009a, b; Maffini extra centrosomes and multipolar spindles in cancer
et al. 2009). Whereas some of these proteins are cells (Ghadimi et al. 2000; Lingle et al. 2002).
mutated in some cancers (i.e., APC), acquired However, chromosome segregation during anaphase
mutation in the others is rare as shown by genomic in cells with multipolar spindles is lethal (Kwon et al.
sequencing of hundreds of tumors (Wood et al. 2007; 2008; Ganem et al. 2009). Thus, it is essential that cells
Jones et al. 2008; Parsons et al. 2008). evade a multipolar anaphase by clustering centrosomes
An intriguing hypothesis is that imbalances of to form two spindle poles (Quintyne et al. 2005).
mitotic proteins that are encoded by genes on However, the multipolar spindles that form transiently
aneusomic chromosomes actively promote CIN in cells with extra centrosomes undermine the geomet-
(Duesberg et al. 1998, 1999). For example, when ric constraints of normal kMT attachments and greatly
otherwise diploid, chromosomally stable cells are increase the rate of merotely and subsequent chromo-
forced to mis-segregate chromosomes for many some mis-segregation (Ganem et al. 2009; Silkworth et
generations, the aneuploid progeny develop high al. 2009). Experiments where extra centrosomes were
chromosome mis-segregation rates (Thompson and induced in chromosomally stable, diploid cells, which
Compton 2010). These findings indicate that aneu- have normal levels of microtubule turnover at the
ploidy can cause CIN and that CIN may be a self- kinetochore, led to increased rates of merotely and
propagating type of genome instability. Any imbal- chromosome mis-segregation, suggesting that the
ance in protein levels that results in suppressed kMT levels of merotely generated through transient multi-
dynamics can, in principle, cause CIN by under- polar spindles overwhelms the error correction ma-
mining the correction of kMT attachment errors. chinery (Ganem et al. 2009). Extra centrosomes arise
Given the multitude of proteins that contribute to through multiple pathways. Tetraploid or polyploid
appropriate kMT dynamics, there may be countless cells that arise from cytokinesis failure, fusion of two
chromosome combinations that would promote CIN. diploid cells, or endoreduplication often contain
Many of these will have direct effects on kMT supernumerary centrosomes (Ganem et al. 2007).
stability, but some may promote CIN indirectly. For Centrosome amplification also occurs when the strict
example, perturbation of regulatory proteins (e.g., cell cycle-dependent regulation of their duplication is
FoxM1, Rb, and REST) appears to promote CIN by lost through perturbation of cyclin E, SAS-4, SAS-6,
creating dosage imbalances in their downstream or Plk4 expression (reviewed in Bettencourt-Dias and
targets (Hernando et al. 2004; Laoukili et al. 2005; Glover 2007).
Guardavaccaro et al. 2008). Loss of Rb disrupts cell Another geometric constraint that discourages
cycle control at the G1/S transition, but also elevates merotelic attachment is the back-to-back positioning
the level of merotely and reduces chromosome of sister kinetochores on opposite sides of centromeric
segregation fidelity by the alteration in the appropriate chromatin. This geometric positioning exploits the
regulation of its downstream target gene expression centromeric chromatin to sterically impede kineto-
(Hernando et al. 2004; Ferretti et al. 2010; Manning et chores from attaching to microtubules other than from
al. 2010). the pole that they face, thereby promoting the proper
The CIN phenotype can also be caused by an attachment of each kinetochore’s microtubules ema-
increased rate of formation of merotelic kMT attach- nating from only one spindle pole (Indjeian and
ments. Any treatments that disrupt the normal geometric Murray 2007; Loncarek et al. 2007). Depletion of
assembly of the mitotic spindle increase merotelic kMT Rb protein suppresses expression of cohesin and
formation. This can be induced experimentally by the condensin subunits that decrease centromere cohe-
treatment of mitotic cells with compounds that revers- sion. As a consequence, interkinetochore distance
ibly disrupt spindle formation without disrupting the increases and horseshoe-shaped kinetochore pairs
endogenous correction machinery (Cimini et al. 2002, form. This suggests that the normally stiff centromeric
2003; Thompson and Compton 2008). In cancer cells, chromatin linking sister kinetochores has become
Chromosome aberrations in cancer cells 437

flexible and no longer effectively screens kinetochores either deregulating expression of specific target genes
from attaching to spindle microtubules from inappro- or by producing a hybrid, chimeric gene through
priate directions (Manning et al. 2010). Alterations to fusion of parts of two genes on separate chromosomes
the kinetochore itself may also increase the rate of (Mitelman et al. 2007). For example, Burkitt’s
formation of merotelic attachments. For example, Hec1 lymphoma is associated with a translocation that
overexpression increases the incidence of merotely and places the MYC gene adjacent to one of three
Hec1 levels increase in Rb-deficient cells (Diaz- immunoglobulin loci, most commonly the immuno-
Rodriguez et al. 2008; Ferretti et al. 2010). Presumably, globulin heavy chain locus in the translocation
excess Hec1 increases the microtubule binding capa- involving chromosomes 8 and 14 [t(8;14)(q23;q32)]
city of kinetochores, but it may also suppress the (Taub et al. 1982). The consequence of these trans-
efficiency with which attachment errors are corrected. locations is the hyperexpression of c-myc by the
potent enhancer that ordinarily regulates immuno-
globulin gene expression in B cells. Overexpression
Mechanisms of chromosome structure instability of translocated genes driven by immunoglobulin
enhancers occurs in a large percentage of B-cell
In addition to alterations in whole chromosome malignancies but not other types of cancer, suggesting
numbers, cancer cells often contain chromosomes that these translocations arise through aberrant rear-
with large structural rearrangements, including dele- rangement of immunoglobulin genes that are required
tions, duplications, inversions, isochromosomes, ring to produce antibody diversity (Küppers 2005). An
structures and marker chromosomes, and unbalanced example of a chimeric gene formed through chromo-
and balanced translocations. Balanced translocations somal translocation is BCR-Abl generated by the
are frequently associated with leukemias and lym- translocation of chromosomes 9 and 22 [t(9;22)(q34;
phomas, with specific translocations linked with q11)] found in 95% of patients with chronic myelog-
specific cancers (reviewed in Mitelman et al. 2007; enous leukemia (Nowell and Hungerford 1960;
Nambiar et al. 2008). These translocations usually Kurzrock et al. 2003). The chimeric protein created
represent the single oncogenic change responsible for by this translocation retains Abl kinase activity, but
these cancers as they create driver mutations that that activity is no longer appropriately regulated.
initiate and maintain the cancer cell phenotype. Recurrent translocations that generate chimeric
Chromosome structure rearrangements such as trans- fusions play a large role in driving tumorigenesis in
locations in solid tumors can be recurrent; however, blood cancers (Mitelman et al. 2007; Nambiar et al.
the vast majority of structural changes in these 2008). Recurrent gene fusions may also play a role in
contexts appear to be non-recurring and random tumorigenesis in solid tumors; however, they appear
(Castro et al. 2006). Additionally, unlike some blood to be quite rare with perhaps the exception of prostate
cancers which often have only one or two recurrent cancer (Tomlins et al. 2005; Mitelman et al. 2007).
translocations, solid tumors often contain numerous In the last decade, spectral karyotyping (SKY),
translocations, with different cells in the same tumor which labels each chromosome with a unique probe
containing different structural rearrangements and set, has allowed the in-depth characterization of the
more complex rearrangements suggestive of multiple translocations that occur in solid tumors. SKY
rounds of chromosome breakage and fusion. Some of karyotyping can identify the presence of a chromo-
these rearrangements have been found to amplify some if >1 Mb is present. Smaller scale chromosomal
oncogenes or delete copies to tumor suppressor genes, rearrangements can be detected using array compar-
which supports a causative role in tumorigenesis. ative genomic hybridization (CGH; Bayani and
However, it remains unknown if the majority of these Squire 2001). Evaluating cell lines derived from solid
structural rearrangements have a causative role in tumors represented in the NCI-60 panel with these
solid tumors, or if they are merely the result of tools revealed 15 clonal translocations per cell line, on
decreased DNA damage checkpoints, DNA repair average (Roschke et al. 2003). This number is
pathways, and/or mitotic segregation errors. comparable to other studies using cancer cell lines
Recurrent rearrangements such as those found in as well as numerous studies that have examined
leukemia and lymphoma influence tumorigenesis by karyotypes in a variety of tumor types including
438 S.L. Thompson, D.A. Compton

prostate, breast, lung, colon, and brain (Davidson et DNA double strand break repair mechanisms then
al. 2000; Abdel-Rahman et al. 2001; Castro et al. fuse the broken chromosomes generating chromo-
2006). Close examination of the chromosome rear- somal translocations that are, again, dicentric, and this
rangements found in these solid tumors reveals a high cycle continues for several cell cycles (Gisselsson et
level of complexity, often with portions of four or al. 2000, 2001). Cancer cells most often overcome
more chromosomes found on the same mosaic this cycle by activation of telomerase, but only after
chromosome providing evidence of repeated breakage several rounds of chromosome breakage leading to
and fusion resulting in regions of amplification or CSI as judged by the high numbers of chromosomal
deletion. Most of these rearrangements are not found translocations (Lo et al. 2002). It is thought that
in more than one cancer or all cells within a single mutations in proteins that permit cell cycle progres-
cancer, and are unbalanced (meaning the reciprocal sion in the presence of double stranded breaks (such
translocation is not present), which suggests these as mutations in p53, BRCA1, BRCA2, ATM, and
rearrangements form through a random mechanism ATR) may facilitate CSI (Lengauer et al. 1998).
and that these structural changes are ongoing during CSI is most often associated with cancer, although
tumor cell growth (Castro et al. 2006). We refer to this this type of instability also occurs in normal tissues of
ongoing genomic instability as chromosome structure individuals with rare autosomal recessive disorders
instability (CSI). Thus, the karyotypes of solid tumors including Bloom’s syndrome, ataxia telangiectasia,
are far more complex than the single chromosome and Fanconi anemia (Duker 2002). Bloom’s syn-
aberrations that drive many leukemias or lymphomas. drome is caused by mutations in the BLM gene
The impact of these highly rearranged chromosomes (which encodes a helicase; Ellis et al. 1995). Loss of
on cancer initiation or promotion remains unknown. function of the BLM protein greatly increases the
In principle, these rearrangements may alter the frequency of DNA double strand breaks leading to
expression of genes adjacent to the breakpoints or sister chromatid exchange as well as chromosome
create chimeric fusion proteins, although the number breakage, translocations, and other structural abnor-
of translocations and rearrangements and the point of malities (Wang et al. 2000). Ataxia telangiectasia is
breakage/fusion differ from cancer to cancer make it caused by mutations in ATM which encodes an
unlikely that these create driver mutations. Since the important protein in detecting and repairing double
majority of these translocations are unbalanced, it is strand breaks. Loss of ATM allows cells to progress
more likely that they generate partial or segmental through the cell cycle in the presence of double
aneuploidy. Interestingly, comparisons of aneuploid stranded breaks and greatly enhances the frequency of
and diploid colon cancer cell lines revealed that CSI (Savitsky et al. 1995; Lavin 2008). Fanconi
aneuploid cell lines have greater numbers of chromo- anemia is caused by mutations in one of 13 FANC
some structure rearrangements raising the intriguing genes. Loss of FANC proteins disrupts a pathway
possibility that there is a relationship between CIN involved in repair of DNA damage sustained during
and CSI (Abdel-Rahman et al. 2001). replication or from reactive oxygen species (Moldovan
Chromosomal translocations arise through inap- and D’Andrea 2009). The phenotypes associated
propriate repair of DNA double strand breaks. with these mechanisms for CSI are different—
Developing tumors often go through a period of Fanconi anemia patients have a short stature and are
elevated rates of chromosome structure change often born with birth defects including polydactyly
termed the breakage–fusion–bridge cycle (Gisselsson and microcephaly; ataxia telangiectasia patients suffer
et al. 2000). This occurs when the number of telomere from poor coordination, thin blood vessels, and
repeats (6-bp-repeat sequences which cap the ends of weakened immune systems; and Bloom’s syndrome
each chromosome—in humans, telomeres become is characterized by short stature, skin rashes that
shorter after each division) drop below a critical appear after exposure to sun, and areas of hypo- and/
threshold where they no longer prevent chromosomes or hyperpigmentation—yet they are all associated
from fusing to each other, leading to the formation of with elevated cancer susceptibility, with leukemias,
dicentric (possessing two centromeres) chromosomes. lymphomas, and solid tumors occurring with early
Dicentrics form bridges between daughter cells during onset (Duker 2002). Efforts to mimic CSI in mouse
late mitosis and frequently break during abscission. models has shown that mice with mutant Blm alleles
Chromosome aberrations in cancer cells 439

develop a wide variety of tumors (Luo et al. 2000). populations arrested in the cell cycle with elevated
Additionally, mice with combined telomerase defi- levels of p53 and the cyclin kinase inhibitor p21
ciency and knockout or heterozygosity of p53 (Thompson and Compton 2010). Elimination of p53
develop epithelial tumors at an increased rate function allowed for aneuploid cell proliferation,
(Artandi et al. 2000), most likely due to repeated suggesting that the p53 pathway prevents aneuploid
rearrangements in specific regions that result in cell growth and that aneuploidy itself is not detrimental
amplification of oncogenes/deletion of tumor sup- to cell viability. Aneuploid cell survival after disruption
pressors (O'Hagan et al. 2002; Maser et al. 2007). of the mitotic checkpoint also induced p53 dependent
response to aneuploidy; however, in checkpoint defec-
tive cells reactive oxygen species and activation of
Consequences of chromosome aberration ATM were responsible for activation of p53 (Li et al.
2010). Activation of p53 is commonly associated with
The adult human has approximately 100 trillion cells DNA damage, but in both studies no DNA damage
with about a hundred million cells dividing at any was detected as judged by staining for gamma-H2AX
given time (Alberts et al. 2002; Jorde et al. 2010). It foci, indicating that p53 is being activated in the
has been shown that diploid human cell lines grown absence of DNA double stranded breaks (Li et al.
in culture mis-segregate a chromosome about once 2010; Thompson and Compton 2010). Inhibition of the
every hundred cell divisions (Cimini et al. 1999; p38 stress kinase also allowed aneuploid cell growth
Thompson and Compton 2008). If the mis- leading to a model where chromosome mis-segregation
segregation rate were equivalent in somatic tissues, induces a stress response that activates the p53
then it would seem that these tissues would quickly pathway to block cell cycle progression. Cellular stress
become populated with aneuploid cells, yet this does could be caused by imbalances in protein expression
not occur. In most healthy somatic tissues (exceptions caused by improper dosage for genes on the aneusomic
being megakaryocytes, hepatocytes, and some neu- chromosome (Thompson and Compton 2010). Evi-
rons), aneuploid cells do not proliferate efficiently and dence for protein expression imbalances was recently
the overall karyotype of the cell population remains provided through proteomic analyses of aneuploid
diploid. However, cancer cells are highly aneuploid strains of budding yeast (Pavelka et al. 2010).
with numerous copy number alterations (Fig. 1) and Mutation of p53 is not the only way to gain
do not appear to suffer a limitation in proliferation. tolerance for an aneuploid genome as aneuploid
This suggests that mechanisms exist to prevent neurons and polyploid/aneuploid hepatocytes are
aneuploid cell proliferation and cancer cells must likely to be wild type for p53 (Rehen et al. 2001;
overcome this mechanism to propagate efficiently Duncan et al. 2010). Also, some aneuploid tumors are
following chromosome mis-segregation. wild type for p53, and aneuploid embryonic cells
One candidate that would suppress aneuploid cell divide for many generations before embryonic lethality
growth is the tumor suppressor p53. Support for this (http://www.sanger.ac.uk/perl/genetics/CGP/cosmic;
hypothesis comes from the strong positive correlation Dobles et al. 2000; Kalitsis et al. 2000). There are
between mutation of p53 and aneuploid tumors (De multiple ways to inhibit the p53 pathway without
Angelis et al. 1993; Meling et al. 1993; Campomenosi directly mutating the p53 gene including MDM2/
et al. 1998; Duensing and Duensing 2005; Schjolberg MDM4 overexpression, deletion or promoter hyper-
et al. 2009). In addition, p53 mutations often occur methylation of p14ARF, inhibition of upstream activa-
before aneuploidy (Blount et al. 1994), p53 is tors such as p38 stress kinase or inhibition of
inactivated at the same time as aneuploidization in downstream targets (Esteller et al. 2000; Toledo and
the immortalization process (Harvey et al. 1993), and Wahl 2006; Mikhailov et al. 2007; Ventura et al. 2007;
somatic tissues in p53 null mice have elevated levels of Vousden and Lu 2007). In the context of cancer cells, it
aneuploidy (Fukasawa et al. 1997). Direct evidence is likely that tolerance for aneuploidy is provided by
linking p53 to aneuploidy intolerance comes from either direct mutation of p53 or the disruption of the
experiments where diploid colorectal cancer cells were p53 pathway through these other routes since the p53
induced to mis-segregate chromosomes by elevating pathway is disrupted in most human cancers. In
levels of merotely. Aneuploid cells that formed in these contrast, it is unlikely that aneuploid neurons,
440 S.L. Thompson, D.A. Compton

hepatocytes, and embryonic cells have lost p53 PTEN (Baker et al. 2009). Likewise, mice heterozy-
function, suggesting that alternative mechanisms gous for CENPE with p19/ARF deleted or treated with
for aneuploidy tolerance exist. Intriguingly, normal DNA damage inducing DMBA had decreased rates of
hepatocytes are polyploid and frequently aneuploid tumor formation (Weaver et al. 2007). These results
because they mis-segregate chromosomes at high again point to tissue context as an important compo-
rates (Duncan et al. 2010). Since aneuploidy and nent for cellular transformation. An alternative hypoth-
CIN appear to play a role in tumorigenesis, it esis is that aneuploidy imbalances the dosage of the
remains unknown how genomically unstable hepa- gene products on the aneusomic chromosome which
tocytes evade oncogenic transformation. can be hundreds of proteins. Dosage changes in several
Whether whole chromosome aneuploidy and partial cell cycle regulators may have large consequences on
aneuploidy caused by translocation are causes or the cells’ commitment to cell cycle progression.
consequences of deregulated cell growth and cancer However, this model seems inconsistent with mouse
has been a matter of debate for decades. A significant models that harbor heterozygous mutations in check-
amount of work has gone into the generation of mouse point genes but show no increase in rates of tumor
models of aneuploidy/CIN where chromosome mis- formation despite equivalent levels of aneuploidy and
segregation is induced by partial inhibition of the mitotic presumably similar rates of chromosome mis-
checkpoint. Many of these mouse models including segregation as other mouse models for aneuploidy. If
heterozygous deletions of Mad1, Mad2, and CENP-E, imbalances in protein levels were sufficient for cell
and hypomorph alleles of Bub1 develop tumors late in transformation, then Bub1 heterozygous mice should
life, supporting a causative role for aneuploidy in have an equivalent rate of tumor formation to CENP-E
tumorigenesis (recently reviewed in Foijer et al. 2008; heterozygous mice because the two strains contain
Holland and Cleveland 2009). However, some mouse similar levels of aneuploidy, but they do not (Jegana-
models of aneuploidy/CIN do not develop tumors than et al. 2007; Weaver et al. 2007). Lastly, it has been
despite evidence for aneuploidy in tissues. This proposed that aneuploidy causes a “mutator” pheno-
indicates that tissue context is an important contribut- type: imbalances in the levels of proteins involved in
ing factor to the susceptibility of cells to transformation DNA replication and repair could undermine genome
induced by aneuploidy. Moreover, this underscores the fidelity and an increase the DNA mutation rate
importance of designing experiments in mouse models (Duesberg et al. 2000; Duesberg and Li 2003). Solid
where the rate of chromosome mis-segregation can be tumor formation requires approximately four to seven
quantified and the roles of aneuploidy and CIN can be mutations in tumor suppressors and oncogenes in order
determined independently. to escape proliferation restraints. Large-scale gene
The most likely cause of transformation induced by sequencing studies suggest even more pathways must
CIN is through loss of heterozygosity for a tumor be disrupted, as tumors possess mutations in genes
suppressor or amplification of an activated oncogene. involved in nearly all of 12 critical regulatory signal
Chromosome loss has been shown to reveal recessive transduction pathways (Jones et al. 2008). Support for
mutations in tumor suppressors (Cavenee et al. 1983), this hypothesis comes from the fact that solid cancers
and the late appearance of tumors in mouse models of are almost always aneuploid, with the exception being
aneuploidy hints that other mutations must be present tumors with mutations in genes involved in nucleotide
for aneuploidy to promote tumorigenesis. Recent excision repair (NER) or mismatch repair (MMR).
mouse models combining mitotic segregation defects Tumors with disrupted NER or MMR pathways have
with heterozygosity for tumor suppressors support this elevated rates of mutation called microsatellite insta-
hypothesis. Reduced Bub1 levels combined with bility (MIN). MIN cancer cells are often near diploid
heterozygous deletion of p53 or the ApcMIN allele led and possess fewer structural rearrangements than their
to accelerated rates of tumor formation compared to aneuploid counterparts (Lengauer et al. 1997; Abdel-
mice heterozygous for the tumor suppressor without Rahman et al. 2001). In MIN cells, aneuploidy is not a
chromosome segregation defects (Baker et al. 2009). requirement for tumorigenesis; however, non-MIN
However, reduced segregation fidelity had no impact solid tumors cells are rarely ever diploid, which
on tumors formed in mice heterozygous for Rb, and suggests a necessity for aneuploidy to generate muta-
decreased tumor formation in mice heterozygous for tions in cells with intact NER and MMR pathways.
Chromosome aberrations in cancer cells 441

In addition to the potential to promote tumor References

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