# Aneuploidy and chromosomal instability as the cause of cancer

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## TL;DR

The oldest theory of cancer, from Theodor Boveri in 1914: tumours arise from cells with the wrong number or arrangement of chromosomes. Peter Duesberg revived it in the 1990s as an alternative to gene mutations. Most solid tumours are indeed aneuploid and chromosome shattering can create several drivers at once, but chromosomal chaos is now read as an accelerator of evolution, not the sole cause.

## Summary

The claim. Cancer is caused by abnormal chromosome number and structure. Boveri argued from sea urchin eggs with extra centrosomes that an unbalanced chromosome set produces malignant growth; von Hansemann had described abnormal mitoses in carcinomas in 1890. Duesberg's strong form (1998 onward) held that aneuploidy, by changing the dosage of thousands of genes at once and destabilising further divisions, is sufficient and that gene mutations are incidental; he denied that oncogenes cause cancer. The modern form treats chromosomal instability as an ongoing rate of gain and loss that fuels heterogeneity, resistance and metastasis.

Who and when. Boveri, Zur Frage der Entstehung maligner Tumoren, 1914 (translated by Harris in 2008). Duesberg, Rausch, Rasnick and Hehlmann, PNAS 1998. Stephens, Campbell and colleagues described chromothripsis, tens to hundreds of rearrangements acquired in a single catastrophic event, in 2011; Cortés-Ciriano and colleagues found it in a large fraction of 2,658 whole genomes in 2020. Bakhoum and Cantley (2018) and Sansregret, Vanhaesebroeck and Swanton (2018) reviewed chromosomal instability as a driver of tumour biology.

Evidence for. Most solid tumours are aneuploid and the Philadelphia chromosome was the first consistent cancer lesion found. Chromosomal instability correlates with poor prognosis, metastasis and drug resistance, and it generates the copy-number heterogeneity that clonal evolution feeds on. Chromothripsis can amplify oncogenes on extrachromosomal DNA and delete suppressors in one step. People with Down syndrome have a much higher risk of childhood leukaemia. Whole-genome doubling is a common early event that tolerates subsequent chromosome loss. Chromosome missegregation activates cGAS-STING and drives inflammatory signalling and invasion.

Evidence against and limits. Aneuploidy on its own usually slows proliferation and can suppress tumours, as Weaver and Cleveland showed in mice in 2007. Many leukaemias and some solid tumours are near-diploid and are driven by single point mutations or fusions. Duesberg's rejection of oncogenes was refuted by the response of BCR::ABL1 leukaemia to imatinib and of EGFR-mutant lung cancer to EGFR inhibitors. Which specific gains and losses matter is only now being mapped.

Predictions that held or failed. Held: chromosomal instability predicts heterogeneity and resistance and is measurable in circulating DNA; chromothripsis is real and common. Failed: the strong form that aneuploidy rather than gene mutation is the cause; the prediction that aneuploid cells cannot depend on a single gene.

Therapies that came from it. Taxanes and vinca alkaloids act on mitosis, though they predate the theory. Drugs that exploit the vulnerability of chromosomally unstable cells (KIF18A inhibitors, spindle checkpoint and PLK inhibitors) are in early trials. Karyotyping and copy-number profiling remain diagnostic and prognostic in leukaemias and myeloma. The theory was framed against the somatic mutation theory and now feeds clonal evolution, of which chromosomal instability is a major engine.

Status: partly confirmed. Chromosomal instability and chromothripsis are established causes of cancer progression and an enabling characteristic in the hallmarks; the claim that aneuploidy rather than gene mutation is the origin of cancer is superseded.

## Fields

- Kind: Term
- Last checked: 2026-09-17
- Also known as: aneuploidy theory; chromosomal theory of cancer; Boveri hypothesis; Duesberg aneuploidy hypothesis; chromosomal instability theory; chromothripsis
- Tags: theory

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Chromosome_instability
- Boveri, Concerning the origin of malignant tumours, translated and annotated by Henry Harris (Journal of Cell Science 2008): https://doi.org/10.1242/jcs.025742
- Duesberg et al., Genetic instability of cancer cells is proportional to their degree of aneuploidy (PNAS 1998): https://doi.org/10.1073/pnas.95.23.13692
- Stephens et al., Massive genomic rearrangement acquired in a single catastrophic event during cancer development (Cell 2011): https://doi.org/10.1016/j.cell.2010.11.055
- Cortés-Ciriano et al., Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing (Nature Genetics 2020): https://doi.org/10.1038/s41588-019-0576-7
- Bakhoum and Cantley, The multifaceted role of chromosomal instability in cancer and its microenvironment (Cell 2018): https://doi.org/10.1016/j.cell.2018.08.027
- Weaver et al., Aneuploidy acts both oncogenically and as a tumor suppressor (Cancer Cell 2007): https://doi.org/10.1016/j.ccr.2006.12.003

## Connected records

- pathways: [cGAS-STING innate sensing](https://onco.cc/pathways/cgas-sting/), [Chromosomal instability & aneuploidy](https://onco.cc/pathways/chromosomal-instability/), [Mitosis & the spindle assembly checkpoint](https://onco.cc/pathways/mitotic-spindle-checkpoint/), [The cell-cycle engine (cyclins & CDKs)](https://onco.cc/pathways/cell-cycle-engine-cdks/), [Theories of cancer: how the ideas connect](https://onco.cc/pathways/theories-of-cancer/)
- terms: [Clonal evolution and the ecological view of cancer](https://onco.cc/terms/clonal-evolution-theory/), [Enabling characteristic: genome instability and mutation](https://onco.cc/terms/genome-instability-mutation/), [Hallmarks of cancer as a synthesis of the theories](https://onco.cc/terms/hallmarks-synthesis/), [Somatic mutation theory of cancer](https://onco.cc/terms/somatic-mutation-theory/), [Whole-genome doubling (WGD)](https://onco.cc/terms/whole-genome-doubling/)
- targets: [BCR::ABL1 (Philadelphia chromosome)](https://onco.cc/targets/bcr-abl/)
- cancers: [Acute lymphoblastic leukaemia](https://onco.cc/cancers/all-leukemia/), [Chronic myeloid leukaemia (CML)](https://onco.cc/cancers/cml/)
- technologies: [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- drugs: [Docetaxel](https://onco.cc/drugs/docetaxel/), [Imatinib](https://onco.cc/drugs/imatinib/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/)
- people: [Charles Swanton](https://onco.cc/people/charles-swanton/), [Michael Stratton](https://onco.cc/people/michael-stratton/)

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