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Nature. 2015 Apr 16;520(7547):353-7. doi: 10.1038/nature14347. Epub 2015 Apr 1.

The evolutionary history of lethal metastatic prostate cancer.

Author information

1
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
2
1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Department of Human Genetics, KU Leuven, Herestraat 49 Box 602, B-3000 Leuven, Belgium [3] Cancer Research UK London Research Institute, London WC2A 3LY, UK.
3
1] Norwich Medical School and Department of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK [2] The Genome Analysis Centre, Norwich NR4 7UH, UK.
4
Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, Tampere FI-33520, Finland.
5
The James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, USA.
6
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Maryland 20892, USA.
7
University of Liverpool and HCA Pathology Laboratories, London WC1E 6JA, UK.
8
Division of Genetics and Epidemiology, The Institute Of Cancer Research, London SW7 3RP, UK.
9
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
10
Uro-oncology Research Group, Cancer Research UK Cambridge Institute, Cambridge CB2 0RE, UK.
11
1] Uro-oncology Research Group, Cancer Research UK Cambridge Institute, Cambridge CB2 0RE, UK [2] Department of Surgical Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
12
1] Norwich Medical School and Department of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK [2] Division of Genetics and Epidemiology, The Institute Of Cancer Research, London SW7 3RP, UK.
13
1] Division of Genetics and Epidemiology, The Institute Of Cancer Research, London SW7 3RP, UK [2] Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK; and Sutton SM2 5PT, UK.

Abstract

Cancers emerge from an ongoing 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 interclonal cooperation between multiple subclones. Here 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 characterized 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.

PMID:
25830880
PMCID:
PMC4413032
DOI:
10.1038/nature14347
[Indexed for MEDLINE]
Free PMC Article
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