Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue

Colin Cooper, Rosalind A. Eeles, David C. Wedge, Peter Van Loo, Gunes Gundem, Ludmil B. Alexandrov, Barbara Kreymer, Adam Butler, Andrew Lynch, Sandra E. Edwards, Niedzica Camacho, Charlie E. Massie, Zsofia Kote-Jarai, Nening Dennis, Sue Merson, Daniel A. Leongamornlert, Jorge Zamora, Jonathan Kay, Hayley J. Luxton, Cathy CorbishleySarah Thomas, Serena Nik-Zainal, Sarah O'Meara, Lucy Matthews, Jeremy Clark, Rachel Hurst, Richard Mithen (IFR), Rob Bristow (Ontario Cancer Inst. CA), Paul C. Boutros, Michael Fraser, Susanna Cooke, Keiran Raine, David Jones, Andrew Menzies, Lucy Stebbings, Jon Hinton, Jon Teague, Stuart Mclaren, Laura Mudie, Claire Hardy, Elizabeth Anderson, Olivia Joseph, Victoria Goody, Ben Robinson, Mark Maddison, Stephen J. Gamble, Christopher Greenman, Dan Berney, Steven Hazell, Naomi Livni, Cyril Fisher, Christopher Ogden, Pardeep Kumar, Alan Thompson, Christopher J. Woodhouse, David Nicol, Erik Mayer, Tim Dudderidge, Nimish Shah, Vincent Gnanapragasam, Thierry Voet, Peter Campbell, P. Andrew Futreal, Douglas F. Easton, Anne Y. Warren, Christopher S. Foster, Michael R. Stratton, Hayley C. Whitaker, Ultan McDermott, Daniel Brewer, David E. Neal

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Abstract

Whole genome DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of on- going abnormal mutational processes, consistent with field-effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissue or between different ERG-lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.
Original languageEnglish
Pages (from-to)367–372
Number of pages6
JournalNature Genetics
Volume47
Early online date2 Mar 2015
DOIs
Publication statusPublished - Apr 2015

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