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Causes and consequences of aneuploidy in cancer

Nature Reviews Genetics volume 13, pages 189–203 (2012)Cite this article

Subjects

Key Points

  • Genomic instability, including whole-chromosome aneuploidy, is a hallmark of cancer.

  • The disruption of multiple pathways, including defects in kinetochore–microtubule attachments and dynamics, centrosome number, spindle assembly checkpoint (SAC) and chromosome cohesion, can lead to aneuploidy.

  • Aneuploidy is generally detrimental in non-transformed cells and can result in imbalances at the level of the transcriptome and proteome.

  • A key question and area of research is how cells can adapt to tolerate aneuploidy.

  • Aneuploidy can be an effective mechanism to generate phenotypic variation and adaptation under a selective pressure.

  • Aneuploidy can both promote and inhibit tumorigenesis.

  • Aneuploidy is a highly attractive target in cancer therapy.

  • Therapeutics that target aneuploidy could either target aneuploidy generally or target specific recurrent aneuploidies that are associated with certain cancers.

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 less well-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 of developing aneuploidy-specific therapies.

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Figure 1: Chromosomal instability.
Figure 2: Pathways to aneuploidy.
Figure 3: Proteotoxic stress.
Figure 4: Aneuploidy-specifc therapeutic strategies.

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Acknowledgements

We apologize to the authors whose work was not discussed or cited owing to space limitations. The authors are grateful to members of the Pellman laboratory, in particular Hubo Li, for helpful discussions. The authors thank Z. Storchova, A. Amon and R. Li for sharing results before publication. The authors thank E. Ivanova for providing the SKY karyotype for Fig. 1.

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Authors and Affiliations

  1. Department of Pediatric Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, 02115, Massachusetts, USA

    David J. Gordon, Benjamin Resio & David Pellman

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  1. David J. Gordon
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  2. Benjamin Resio
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  3. David Pellman
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Correspondence to David Pellman.

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FURTHER INFORMATION

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ClinicalTrials.gov

Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer

Statistical Associations in Cancer Karyotypes (STACK)

Glossary

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.

Kinetochore

A large protein complex that assembles at centromeres. It is composed of inner and outer regions that contain >80 proteins, which are required for spindle attachment, chromosome movement and regulation of the mitotic checkpoint.

Centrosome

An organelle that serves as the main microtubule-organizing centre of the cell, as well as a regulator of cell cycle progression.

Spindle assembly checkpoint

(SAC). A highly conserved surveillance mechanism in mitosis and meiosis that minimizes chromosome loss by preventing chromosomes from initiating anaphase until all kinetochores have successfully captured spindle microtubules.

Merotelic attachments

Abnormal kinetochore–microtubule attachments that occur when a single kinetochore attaches to microtubules that arise from both poles of the spindle.

Mosaic variegated aneuploidy

A rare, recessive condition that is characterized by growth restriction, microcephaly, childhood cancer and constitutional mosaicism for chromosomal gains and losses.

Co-culture

A cell culture containing a mixture of two different cell types.

Proteasome inhibitors

A class of drugs, including MG132 and bortezomib, that block the action of proteasomes, which are cellular complexes involved in protein degradation.

Dosage compensation

The counterbalancing of gene and protein imbalances that arise from unequal numbers of chromosomes, such as sex chromosomes in normal cells or potentially any chromosome in aneuploid cells.

Environmental stress response

(ESR). A gene set signature defined in yeast that has been grown under stressful conditions and at slow growth rates.

Proteotoxic stress

Results from the accumulation of unfolded, misfolded and aggregated proteins in a cell.

Robertsonian translocation

A chromosomal abnormality in which two acrocentric chromosomes become joined by a common centromere.

Reactive oxygen species

(ROS). Ions or small molecules — including oxygen ions, free radicals, inorganic peroxides and organic peroxides — that are highly reactive owing to the presence of unpaired valence shell electrons. They are a by-product of the normal metabolism of oxygen and have important roles in cell signalling. Increased levels owing to environmental stress can result in damage to cells.

Mutator phenotype

The loss-of-function of one gene, such as one for the repair of damaged DNA, that greatly increases the mutation rates at other loci.

Chromosome congression

The process of aligning chromosomes on the spindle during mitosis.

Oncogene addiction

The dependence of a cancer cell on one overactive gene or pathway for survival, growth and proliferation.

Synthetic lethality

Two genes are synthetic lethal if mutation of either alone is compatible with viability, but mutation of both leads to cell death.

AICAR

Short for 5-aminoimidazole-4-carboxamide ribonucleotide, this is an activator of AMP-activated protein kinase (AMPK), which is a metabolic master regulator that is activated in times of reduced energy availability.

HSP90 inhibitor

A class of drugs, including 17-allylaminogeldanamycin (17-AAG), that inhibit the function of the molecular chaperone heat shock protein 90 (HSP90), which is involved in protein folding.

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Gordon, D., Resio, B. & Pellman, D. Causes and consequences of aneuploidy in cancer. Nat Rev Genet 13, 189–203 (2012). https://doi.org/10.1038/nrg3123

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