Cancer is driven by multiple types of genetic alterations, which range in size from point mutations to whole-chromosome gains and losses, known as aneuploidy. Chromosome instability, the process that gives rise to aneuploidy, can promote tumorigenesis by increasing genetic heterogeneity and promoting tumour evolution. However, much less is known about how aneuploidy itself contributes to tumour formation and progression. Unlike some pan-cancer oncogenes and tumour suppressor genes that drive transformation in virtually all cell types and cellular contexts, aneuploidy is not a universal promoter of tumorigenesis. Instead, recent studies suggest that aneuploidy is a context-dependent, cancer-type-specific oncogenic event that may have clinical relevance as a prognostic marker and as a potential therapeutic target.
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The authors thank Iris Fung for her assistance with figure design. The work by U.B.-D. described in this Review was supported by the European Molecular Biology Organization Long-Term Fellowship and by the Human Frontier Science Program Postdoctoral Fellowship. U.B.-D. is an Azrieli Faculty Fellow. The work by the Amon lab described in this Review was supported by NIH grants CA206157 and GM118066. A.A. is an investigator of the Howard Hughes Medical Institute and the Paul F. Glenn Centre for Biology of Ageing Research at MIT. The authors apologize to the authors of many important publications not cited due to space limitations.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Nature Reviews Genetics thanks F. Foijer, T. Ried and other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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A chromosome number that is not a multiple of the haploid complement. In cancer genomics, the term often includes copy number alterations of chromosome arms. Note that the mechanisms that lead to whole-chromosome mis-segregation are very different from those that cause arm-level copy number changes.
The set of all chromosomes. The haploid complement consists of one chromosome each, the diploid of two, and so forth.
- Chromosome instability
(CIN). A high rate of chromosome mis-segregation that gives rise to aneuploidy.
- Microcell-mediated chromosome transfer
A technique to transfer a chromosome from a donor cell line to a recipient cell line.
- Cre–Lox recombination
A technique to introduce deletions, insertions, translocations or inversions at specific chromosomal locations.
- CRISPR–Cas9 gene editing
A technique to introduce precise genetic alterations, ranging in size from point mutations to the deletion of entire chromosome arms.
- Prognostic value
The degree to which a biomarker provides information about the patients’ overall survival, regardless of therapy.
A chromosome number that is an exact multiple of the haploid complement. Diploid, triploid, tetraploid and polyploid cells are all euploid.
- Epithelial-to-mesenchymal transition
(EMT). A process by which epithelial cells lose their epithelial identity and adopt the properties of mesenchymal cells. They lose their ability to form cell–cell adhesion and gain migratory and invasive properties.
A euploid genome comprising more than two sets of chromosomes.
- Human leukocyte antigen complex
A gene complex that encodes the major histocompatibility complex proteins and is responsible for regulation of the immune system.
- Single-nucleotide polymorphism arrays
A DNA microarray that is used to detect genetic variation (including copy number alterations) on a genome-wide scale.
- Comparative genomic hybridization arrays
A molecular technique to detect copy number alterations on a genome-wide scale and with high resolution.
- Predictive value
The degree to which a biomarker provides information about the effect of a therapeutic intervention.
- The Cancer Genome Atlas
(TCGA). A cancer genomics repository that contains sequence information for over 20,000 primary cancers and matched normal samples across 33 cancer types.
- CNA burden
The prevalence of copy number alterations (CNAs) within a tumour, commonly defined by the proportion of the genome that is affected by CNAs.
- Overall survival
The length of time from diagnosis or start of treatment during which patients remain alive.
- Disease-specific survival
The length of time from diagnosis or start of treatment during which patients have not died from that specific disease.
- Recurrence-free survival
The length of time from treatment during which no sign of cancer is found.
- Progression-free survival
The length of time from treatment during which patients live with a disease but it does not get worse.
- Microsatellite instability
Predisposition of a cell to mutations (hypermutability) due to impaired DNA mismatch repair.
- Prostate-specific antigen
(PSA). A protein produced by prostate cells. Its levels in the blood are elevated in prostate cancer. PSA is therefore used as a prostate cancer screening tool.
- Gleason score
A commonly used system to stage prostate cancers, based on their pathological features.
- Pap smears
The Papanicolaou test, a commonly used histological method to screen for cervical cancer.
- Hyperdiploid MM
A subtype of multiple myeloma (MM) that is characterized by trisomy of eight specific chromosomes (3, 5, 7, 9, 11, 15, 19 and 21).
- Non-hyperdiploid MM
A subtype of multiple myeloma (MM) that can be further subdivided into hypodiploid (≤44 chromosomes), pseudodiploid (45–46 chromosomes) and near-tetraploid (>75 chromosomes) subtypes.
- Hyperdiploid ALL
A subtype of acute lymphoblastic lymphoma (ALL) that is characterized by a chromosome count of 51–65, often involving one additional copy of chromosomes X, 4, 6, 10, 14, 17 and 18, and two additional copies of chromosome 21.
- Hypodiploid ALL
A subtype of acute lymphoblastic lymphoma (ALL) that can be further divided into near-haploid (24–31 chromosomes), low-hypodiploid (32–39 chromosomes) and high-hypodiploid (40–43 chromosomes) subtypes.
The shattering of an individual chromosome into many pieces and its religation in random order, with amplification of some segments (those that provide a growth advantage, including oncogenes) and loss of others (for example, tumour suppressors).
- Intratumour heterogeneity
(ITH). Genomic and/or phenotypic cell-to-cell variability within a tumour.
Chromosomal regions that are conserved between two species.
A state in which deletion of one copy of a gene in a diploid organism results in a phenotype.
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Ben-David, U., Amon, A. Context is everything: aneuploidy in cancer. Nat Rev Genet 21, 44–62 (2020). https://doi.org/10.1038/s41576-019-0171-x
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