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.
Nature. 2015 Apr 16;520(7547):353-357. doi: 10.1038/nature14347. Epub 2015 Apr 1.
Gundem G1, Van Loo P1,2,3, Kremeyer B1, Alexandrov LB1, Tubio JMC1, Papaemmanuil E1, Brewer DS4, Kallio HML5, Högnäs G5, Annala M5, Kivinummi K5, Goody V1, Latimer C1, O'Meara S1, Dawson KJ1, Isaacs W6, Emmert-Buck MR7, Nykter M5, Foster C#8,9, Kote-Jarai Z10, Easton D#11,9, Whitaker HC12; ICGC Prostate Group, Neal DE12,13,9, Cooper CS10,4,9, Eeles RA10,14,9, Visakorpi T5, Campbell PJ1, McDermott U#1,9, Wedge DC#1, Bova GS#5,9.
1. Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
2. Department of Human Genetics, KU Leuven, Herestraat 49 Box 602, B-3000 Leuven, Belgium.
3. Cancer Research UK London Research Institute, London, UK.
4. Norwich Medical School and Department of Biological Sciences, University of East Anglia, Norwich, UK.
5. Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
6. The James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA.
7. Laboratory of Pathology, National Cancer Institute, National Institutes of Health, MD, USA.
8. University of Liverpool and HCA Pathology Laboratories, London, UK.
9. Senior Principal Investigators of the Cancer Research UK funded ICGC Prostate Cancer Project.
10. Division of Genetics and Epidemiology, The Institute Of Cancer Research, London, UK.
11. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
12. Uro-oncology Research Group, Cancer Research UK Cambridge Research Institute, Cambridge, UK.
13 .Department of Surgical Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
14. Royal Marsden NHS Foundation Trust, London and Sutton, UK.
#. Contributed equally