Aneuploidia En El Cancer

REVIEWS

Causes and consequences of
aneuploidy in cancer
David J. Gordon, Benjamin Resio and David Pellman

Abstract | Genetic instability, which includes both numerical and structural chromosomal
abnormalities, is a hallmark of cancer. Whereas the structural chromosome rearrangements
have received substantial attention, the role of whole-chromosome aneuploidy in
cancer is much lesswell-understood. Here we review recent progress in understanding
the roles of whole-chromosome aneuploidy in cancer, including the mechanistic causes
of aneuploidy, the cellular responses to chromosome gains or losses and how cells
might adapt to tolerate these usually detrimental alterations. We also explore the role
of aneuploidy in cellular transformation and discuss the possibility ofdeveloping
aneuploidy-specific therapies.
Aneuploidy
The presence of an abnormal
number of chromosomes,
either more or less than the
diploid number. Aneuploidy
is associated with cell and
organismal inviability, cancer
and birth defects.

Chromosomal instability
(CIN). A persistently high
rate of gain and loss of
chromosomes.

Department of Pediatric
Oncology, Dana-Farber
CancerInstitute,
44 Binney Street, Boston,
Massachusetts 02115, USA.
Correspondence to D.P. 
e-mail: david_pellman@dfci.
harvard.edu
doi:10.1038/nrg3123
Published online
24 January 2012

Numerical and structural chromosome abnormalities
are the most obvious and most distinguishing characteristics of cancer genomes (FIG. 1). In recent years, we
have learned important details about how structural
orsegmental rearrangements can have an impact on
tumour development through the activation of oncogenes and the inactivation of tumour suppressors1. By
contrast, the role of numerical, whole-chromosome
aneuploidy during tumour development is considerably less
well-understood2,3. As a point of nomenclature, we shall
hereafter refer to whole-chromosome aneuploidy as just
‘aneuploidy’. Asdiscussed below, numerous animal models, as well as a human cancer predisposition syndrome,
make it clear that aneuploidy can predispose to tumour
development, and the underlying mechanisms that
drive tumorigenesis are now an active area of research4,5.
There has been an intense focus on the causes and
consequences of chromosomal instability (CIN), because
it is a common feature of many cancers6–8.However, it
i s important to distinguish aneuploidy (the ‘state’
of the karyotype) from CIN (the ‘rate’ of karyotypic
change). Although CIN leads to aneuploidy, not all
aneuploid cells exhibit CIN; some cells are aneuploid
with a uniform, stable karyotype — a phenomenon
that has received much less attention than CIN. Recent
large-scale DNA copy number analyses highlight how
commonrecurrent aneuploidy is in human cancer 9.
The genes and pathways that are deregulated by
whole-chromosome aneuploidy are largely unknown,
and the impact of these genomic alterations may be
complex 2. Unlike balanced translocations, for which
the breakpoint regions can be cloned and sequenced,

the genes on the aneuploid chromosomes that con tribute to tumorigenesis are more difficult to identifyowing to the large genomic regions that are affected
and the potential requirement for multiple altered
genes to act cooperatively. However, understanding
the role of aneuploidy in specific cancers is crucial for
understanding disease pathogenesis and may also lead
to new avenues for treatment.
This Review focuses on recent progress in understanding how aneuploidy contributes to thephenotypes
of human cancers. We discuss recent progress in defining how tumour cells develop CIN. We describe how
aneuploidy is usually detrimental to cellular and organismal survival owing to the resultant gene expression
imbalances, and we discuss the specific adaptations that
cells might need to tolerate it. Given that aneuploidy is
not just tolerated but is remarkably common in cancer,
we...