Abstract
Chromosomal instability (CIN) refers to an increased propensity of cells to acquire structural and numerical chromosomal abnormalities during cell division, which contributes to tumour genetic heterogeneity. CIN has long been recognized as a hallmark of cancer, and evidence over the past decade has strongly linked CIN to tumour evolution, metastasis, immune evasion and treatment resistance. Until recently, the mechanisms by which CIN propels cancer progression have remained elusive. Beyond the generation of genomic copy number heterogeneity, recent work has unveiled additional tumour-promoting consequences of abnormal chromosome segregation. These mechanisms include complex chromosomal rearrangements, epigenetic reprogramming and the induction of cancer cell-intrinsic inflammation, emphasizing the multifaceted role of CIN in cancer.
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Acknowledgements
The authors thank all members of the Bakhoum laboratory for discussion and comments. The authors thank the National Institutes of Health (NIH)/National Cancer Institute (NCI) (grant nos. P50CA247749, DP5OD026395, R01CA256188, R01CA280572, P30CA008748), the Department of Defense Era of Hope Award, the Burroughs Wellcome Fund, the Mark Foundation for Cancer Research, the Pershing Square Sohn Cancer Research Alliance, the Starr Cancer Consortium, and the Mary Kay Ash Foundation for funding to S.F.B.
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X.C., A.S.A., J.L. and S.F.B. researched the literature and wrote the article. M.D. created the figures and provided conceptual input. All authors substantially contributed to discussions of the content and reviewed and/or edited the manuscript before submission.
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S.F.B. holds a patent related to some of the work described targeting chromosomal instability (CIN) and the cGAS–STING pathway in advanced cancer; and owns equity in, receives compensation from, serves as a consultant for and serves on the Scientific Advisory Board (SAB) and Board of Directors (BOD) of Volastra Therapeutics Inc., and serves on the SAB of Meliora Therapeutics. The other authors declare no competing interests.
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Glossary
- Breakage–fusion–bridge cycles
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Cycles beginning with the breakage of chromosomes, followed by end-to-end fusions that form dicentric chromosomes. These dicentric chromosomes break again during cell division, perpetuating cycles of breakage and fusion. This process leads to complex chromosomal rearrangements, contributing to genomic instability.
- cGAS–STING pathway
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The cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway is a critical component of the innate immune response. It plays a vital role in antiviral defence, antitumour immunity and the detection of cellular stress or damage.
- Chromosomal instability
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(CIN). Above normal rates of chromosome segregation errors leading to cellular populations with genomic heterogeneity and diverse karyotypes.
- Chromosome bridges
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(Also known as chromatin bridges). Strings of chromatin connecting the two segregating masses of chromosomes in anaphase or daughter nuclei in cytokinesis.
- Chromothripsis
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A complex chromosomal rearrangement pattern associated with genomic gains, losses, inversion and duplications and that is typically restricted to one chromosome or a chromosome arm.
- Dosage compensation
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A mechanism by which a cell could maintain the stoichiometry of expressed proteins despite changes in underlying gene copy number.
- Extrachromosomal DNA
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(ecDNA). Circular pieces of the genome that form a chromosome that often contains oncogenes or other genomic loci that are subject to selection. Historically, ecDNA has been referred to as a double-minute chromosome given its appearance during conventional karyotyping preparation.
- Loss of heterozygosity
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A genetic phenomenon characterized by the loss or reduction of one allele of a specific gene or genetic locus in a diploid organism.
- Micronuclei
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Small membrane-bounded compartments outside the primary nucleus that often contain one or more chromosomes, or parts thereof.
- Neochromosomes
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Abnormal chromosomes that can be circular or linear and that contain either rearranged segments of a single chromosome or pieces from multiple chromosomes.
- Selection
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In the context of cancer, refers to the process by which certain cancer cells within a heterogeneous tumour population are favoured for survival and proliferation due to their acquisition of specific mutations or other genomic alterations based on various factors in the tumour microenvironment.
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Chen, X., Agustinus, A.S., Li, J. et al. Chromosomal instability as a driver of cancer progression. Nat Rev Genet 26, 31–46 (2025). https://doi.org/10.1038/s41576-024-00761-7
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DOI: https://doi.org/10.1038/s41576-024-00761-7
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