The evolutionary history of lethal metastatic prostate cancer

Gundem, Gunes, Van Loo, Peter, Kremeyer, Barbara, Alexandrov, Ludmil B., Tubio, Jose M. C., Papaemmanuil, Elli, Brewer, Daniel ORCID:, Kallio, Heini, Högnäs, Högnäs, Annala, Matti, Kivinummi, Kati, Goody, Victoria, Latimer, Calli, O'Meara, Sarah, Dawson, Kevin, Isaacs, William, Emmert-Buck, Michael R., Nykter, Matti, Foster, Christopher S., Kote-Jarai, Zsofia, Easton, Douglas F., Whitaker, Hayley C., Neal, David E., Cooper, Colin S. ORCID:, Eeles, Rosalind A., Visakorpi, Tapio, Campbell, Peter, McDermott, Ultan, Wedge, David C. and Bova, G. Steven and ICGC Prostate UK Group* (2015) The evolutionary history of lethal metastatic prostate cancer. Nature, 520 (7547). 353–357. ISSN 1476-4687

[thumbnail of Author Final Version]
PDF (Author Final Version) - Accepted Version
Download (5MB) | Preview


Cancers emerge from an on-going Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and inter-clonal cooperation between multiple subclones. In this study, we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole genome sequencing, we characterised multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen deprivation therapy in prostate cancer.

Item Type: Article
Additional Information: Correction to: Nature Published online 1 April 2015. In the Supplementary Information of this Article, some errors were made in compiling the Supplementary Data file called ‘Supplementary Variant Lists’. In the first worksheet (entitled ‘subs’) the clusters to which some single nucleotide variants (SNVs) were assigned were not reported and were replaced with ‘NA’ for ‘not available’. The correct cluster numbers have now been inserted. Three mutations occurring in tumour A32 were incorrectly assigned to cluster 3 and have now been correctly assigned to cluster 2. Duplicate entries were present for some mutations in A32. These duplicate entries have now been removed. In the fourth worksheet (entitled ‘copy_number’) incorrect copy number information was reported for sample A31-c. The previous information, implying that A31-c was primarily diploid, has now been replaced with the copy number call used within the Article, which indicates that A31-c is primarily tetraploid. The Supplementary Information to this Amendment contains the corrected Excel file ‘Supplementary Variant Lists’. These corrections do not change the authors’ interpretation of the findings. The original Article has not been corrected.
Uncontrolled Keywords: cancer genomics,metastasis,tumour heterogeneity,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies
Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User: Pure Connector
Date Deposited: 24 Jul 2015 21:11
Last Modified: 19 Oct 2023 01:25
DOI: 10.1038/nature14347

Actions (login required)

View Item View Item