The evolutionary history of lethal metastatic prostate cancer
Gunes Gundem, Peter Van Loo, Barbara Kremeyer, Ludmil B Alexandrov, Jose M C Tubio, Elli Papaemmanuil, Daniel S Brewer, Heini M L Kallio, Gunilla Högnäs, Matti Annala, Kati Kivinummi, Victoria Goody, Calli Latimer, Sarah O'Meara, Kevin J Dawson, William Isaacs, Michael R Emmert-Buck, Matti Nykter, Christopher Foster, Zsofia Kote-Jarai, Douglas Easton, Hayley C Whitaker, ICGC Prostate Group, David E Neal, Colin S Cooper, Rosalind A Eeles, Tapio Visakorpi, Peter J Campbell, Ultan McDermott, David C Wedge, G Steven Bova, Colin S Cooper, Rosalind A Eeles, G Steven Bova, Douglas Easton, Christopher Foster, Andrew Futreal, Ultan McDermott, David E Neal, Michael Stratton, Daniel S Brewer, Adam P Butler, Gunes Gundem, Freddie Hamdy, Yong-Jie Lu, Andrew G Lynch, Charlie E Massie, Anthony Ng, Peter Van Loo, David C Wedge, Hayley C Whitaker, Yongwei Yu, Hongwei Zhang, Ludmil B Alexandrov, Elizabeth Bancroft, Dan Berney, Niedzica Camacho, Cathy Corbishley, Tokhir Dadaev, Nening Dennis, Tim Dudderidge, Sandra Edwards, Cyril Fisher, Jilur Ghori, Vincent J Gnanapragasam, Christopher Greenman, Steve Hawkins, Steven Hazell, Will Howat, Katalin Karaszi, Jonathan Kay, Zsofia Kote-Jarai, Barbara Kremeyer, Pardeep Kumar, Adam Lambert, Daniel Leongamornlert, Naomi Livni, Hayley Luxton, Lucy Matthews, Erik Mayer, Susan Merson, David Nicol, Christopher Ogden, Sarah O'Meara, Gill Pelvender, John Radcliffe, Nimish C Shah, Simon Tavare, Sarah Thomas, Alan Thompson, Claire Verrill, Anne Warren, Jorge Zamora, Gunes Gundem, Peter Van Loo, Barbara Kremeyer, Ludmil B Alexandrov, Jose M C Tubio, Elli Papaemmanuil, Daniel S Brewer, Heini M L Kallio, Gunilla Högnäs, Matti Annala, Kati Kivinummi, Victoria Goody, Calli Latimer, Sarah O'Meara, Kevin J Dawson, William Isaacs, Michael R Emmert-Buck, Matti Nykter, Christopher Foster, Zsofia Kote-Jarai, Douglas Easton, Hayley C Whitaker, ICGC Prostate Group, David E Neal, Colin S Cooper, Rosalind A Eeles, Tapio Visakorpi, Peter J Campbell, Ultan McDermott, David C Wedge, G Steven Bova, Colin S Cooper, Rosalind A Eeles, G Steven Bova, Douglas Easton, Christopher Foster, Andrew Futreal, Ultan McDermott, David E Neal, Michael Stratton, Daniel S Brewer, Adam P Butler, Gunes Gundem, Freddie Hamdy, Yong-Jie Lu, Andrew G Lynch, Charlie E Massie, Anthony Ng, Peter Van Loo, David C Wedge, Hayley C Whitaker, Yongwei Yu, Hongwei Zhang, Ludmil B Alexandrov, Elizabeth Bancroft, Dan Berney, Niedzica Camacho, Cathy Corbishley, Tokhir Dadaev, Nening Dennis, Tim Dudderidge, Sandra Edwards, Cyril Fisher, Jilur Ghori, Vincent J Gnanapragasam, Christopher Greenman, Steve Hawkins, Steven Hazell, Will Howat, Katalin Karaszi, Jonathan Kay, Zsofia Kote-Jarai, Barbara Kremeyer, Pardeep Kumar, Adam Lambert, Daniel Leongamornlert, Naomi Livni, Hayley Luxton, Lucy Matthews, Erik Mayer, Susan Merson, David Nicol, Christopher Ogden, Sarah O'Meara, Gill Pelvender, John Radcliffe, Nimish C Shah, Simon Tavare, Sarah Thomas, Alan Thompson, Claire Verrill, Anne Warren, Jorge Zamora
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.
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Source: PubMed