# The evolutionary history of lethal metastatic prostate cancer

Source: https://onco.cc/key-papers/paper-gundem-evolutionary-history-lethal-metastatic-prostate-nature-2015/  
OnCo record `paper-gundem-evolutionary-history-lethal-metastatic-prostate-nature-2015` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

By sequencing many separate deposits from ten men who died of prostate cancer, this study reconstructed how the cancer travelled. Metastases seeded other metastases, and often did it in groups of cells rather than one at a time.

## Summary

Gunes Gundem, David Wedge, Peter Campbell, Scott Bova and the International Cancer Genome Consortium Prostate Group used whole-genome sequencing of multiple metastases from ten men with androgen-deprived metastatic prostate cancer and reconstructed the subclonal architecture across sites.

The standard model of metastasis is that each deposit descends from one cell that left the primary tumour. This work found that metastasis-to-metastasis spread is common, either by a daughter metastasis being seeded from a parent one, or, in five of the ten men, by multiple tumour clones moving between metastatic sites together. It also found a pattern in what is mutated where: tumour suppressor lesions occur as single events, whereas androgen receptor pathway mutations arise convergently and repeatedly in different metastases, which is evolution being watched under the same selective pressure in parallel.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Also known as: Gundem 2015; metastasis-to-metastasis spread prostate; polyclonal seeding prostate cancer
- Tags: prostate-evidence
- Journal: Nature
- Year: 2015
- DOI: 10.1038/nature14347
- Authors: Gundem G, Van Loo P, Kremeyer B, et al.
- Findings: Whole-genome sequencing of multiple metastases from ten patients showed that metastasis-to-metastasis spread is common, through de novo monoclonal seeding of daughter metastases or, in five cases, through transfer of multiple tumour clones between metastatic sites.; Lesions affecting tumour suppressor genes usually occurred as single events.; Mutations in genes involved in androgen receptor signalling commonly involved multiple convergent events in different metastases.; The results provide evidence for polyclonal seeding in human malignancy, previously demonstrated mainly in mouse models.
- What it means: Metastatic prostate cancer is a communicating population, not a set of independent colonies, which is an argument for treating the whole body rather than chasing individual deposits, and an argument that resistance to androgen receptor drugs will emerge in several places at once because it emerges convergently.
- Caveats: Ten men, all with androgen-deprived disease, from a research autopsy and biopsy programme; the generality of the seeding patterns is not established.; Phylogenetic reconstruction from bulk sequencing infers the history rather than observing it, and depends on the clonal deconvolution method used.; No treatment implication has yet been tested prospectively; the finding argues against, rather than disproves, metastasis-directed therapy in polymetastatic disease.

## Sources

- Nature 2015: https://doi.org/10.1038/nature14347
- PubMed: https://pubmed.ncbi.nlm.nih.gov/25830880/

## Connected records

- key papers: [Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer](https://onco.cc/key-papers/paper-zhang-nat-commun/), [Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial](https://onco.cc/key-papers/paper-phillips-jama-oncol/), [Punctuated evolution of prostate cancer genomes](https://onco.cc/key-papers/paper-baca-punctuated-evolution-chromoplexy-cell-2013/)
- ideas: [A test to tell true oligometastatic disease from hidden widespread spread](https://onco.cc/ideas/idea-bio2-oligometastatic-signature/)
- roadmaps: [Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch](https://onco.cc/roadmaps/prostate-roadmap/)
- cancers: [Metastatic castration-resistant prostate cancer](https://onco.cc/cancers/prostate-mcrpc/), [Prostate cancer](https://onco.cc/cancers/prostate/)
- fronts: [Diagnostics & Biomarkers](https://onco.cc/fronts/diagnostics/)
- targets: [Androgen receptor](https://onco.cc/targets/androgen-receptor/), [TP53](https://onco.cc/targets/tp53/)
- terms: [Bone metastases and skeletal-related events](https://onco.cc/terms/bone-metastases/), [Chromoplexy](https://onco.cc/terms/chromoplexy/), [Oligometastatic disease](https://onco.cc/terms/oligometastatic/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Metastasis is understood least and studied last](https://onco.cc/bottlenecks/b-metastasis-biology/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)
- journals: [Nature](https://onco.cc/journals/nature/)

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