Journal
NATURE COMMUNICATIONS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms7605
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Funding
- National Health and Medical Research Council, Australia, University of Melbourne (Melville Hughes Scholarship)
- Royal Australasian College of Surgeons
- Faculty of Medicine, Dentistry and Health Sciences at the University of Melbourne
- Carlo Vaccari Scholarship
- APCR
- NHMRC [1024081, 1047581]
- Australian Department of Health and Aging to the Epworth Cancer Centre, Epworth Hospital
- Victoria Research Laboratory of National ICT Australia (NICTA)
- University of Melbourne, Australia
- Australian Government through the Department of Communications
- Australian Research Council
- Adden-brooke's Charitable Trust Clinical Research Training Fellowship
- NIHR Cambridge Biomedical Research Centre
- Cambridge Cancer Centre and Human Research Tissue Bank
- National Nuclear Security Administration of the US Department of Energy
- Cambridge Institute Genomics Core
- Australian Genomics Research Facility
- Cancer Research UK [C14303/A17197]
- Cancer Research UK [20240] Funding Source: researchfish
- The Francis Crick Institute [10202] Funding Source: researchfish
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Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.
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