title: The evolutionary history of lethal metastatic prostate cancer.
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.
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Gunes
authors.initials: G
authors.lastname: Gundem
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.|Department of Human Genetics, KU Leuven, Herestraat 49 Box 602, B-3000 Leuven, Belgium.|Cancer Research UK London Research Institute, London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Van Loo
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kremeyer
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Ludmil B
authors.initials: LB
authors.lastname: Alexandrov
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Jose M C
authors.initials: JMC
authors.lastname: Tubio
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Elli
authors.initials: E
authors.lastname: Papaemmanuil
authors.affiliation: Norwich Medical School and Department of Biological Sciences, University of East Anglia, Norwich, UK.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Brewer
authors.affiliation: Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
authors.forename: Heini M L
authors.initials: HML
authors.lastname: Kallio
authors.affiliation: Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Högnäs
authors.affiliation: Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Annala
authors.affiliation: Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
authors.forename: Kati
authors.initials: K
authors.lastname: Kivinummi
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Goody
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Calli
authors.initials: C
authors.lastname: Latimer
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: O'Meara
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Dawson
authors.affiliation: The James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: William
authors.initials: W
authors.lastname: Isaacs
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, MD, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Emmert-Buck
authors.affiliation: Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Nykter
authors.affiliation: University of Liverpool and HCA Pathology Laboratories, London, UK.|Senior Principal Investigators of the Cancer Research UK funded ICGC Prostate Cancer Project.
authors.forename: Christopher
authors.initials: C
authors.lastname: Foster
authors.affiliation: Division of Genetics and Epidemiology, The Institute Of Cancer Research, London, UK.
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Kote-Jarai
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.|Senior Principal Investigators of the Cancer Research UK funded ICGC Prostate Cancer Project.
authors.forename: Douglas
authors.initials: D
authors.lastname: Easton
authors.affiliation: Uro-oncology Research Group, Cancer Research UK Cambridge Research Institute, Cambridge, UK.
authors.forename: Hayley C
authors.initials: HC
authors.lastname: Whitaker
authors.affiliation: Uro-oncology Research Group, Cancer Research UK Cambridge Research Institute, Cambridge, UK.|Department of Surgical Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.|Senior Principal Investigators of the Cancer Research UK funded ICGC Prostate Cancer Project.
authors.forename: David E
authors.initials: DE
authors.lastname: Neal
authors.affiliation: Division of Genetics and Epidemiology, The Institute Of Cancer Research, London, UK.|Norwich Medical School and Department of Biological Sciences, University of East Anglia, Norwich, UK.|Senior Principal Investigators of the Cancer Research UK funded ICGC Prostate Cancer Project.
authors.forename: Colin S
authors.initials: CS
authors.lastname: Cooper
authors.affiliation: Division of Genetics and Epidemiology, The Institute Of Cancer Research, London, UK.|Royal Marsden NHS Foundation Trust, London and Sutton, UK.|Senior Principal Investigators of the Cancer Research UK funded ICGC Prostate Cancer Project.
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Eeles
authors.affiliation: Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.|Senior Principal Investigators of the Cancer Research UK funded ICGC Prostate Cancer Project.
authors.forename: Ultan
authors.initials: U
authors.lastname: McDermott
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Wedge
authors.affiliation: Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.|Senior Principal Investigators of the Cancer Research UK funded ICGC Prostate Cancer Project.
authors.forename: G Steven
authors.initials: GS
authors.lastname: Bova
mesh_terms: D000728:Androgens / Q000172:deficiency; D019070:Cell Lineage / Q000235:genetics; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D018450:Disease Progression; D044127:Epigenesis, Genetic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000728:Androgens; D011944:Receptors, Androgen
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