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Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets

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posted on 01.10.2020 by David C Wedge, Gunes Gundem, Thomas Mitchell, Dan J Woodcock, Inigo Martincorena, Mohammed Ghori, Jorge Zamora, Adam Butler, Hayley Whitaker, Zsofia Kote-Jarai, Ludmil B Alexandrov, Peter Van Loo, Charlie E Massie, Stefan Dentro, Anne Y Warren, Clare Verrill, Dan M Berney, Nening Dennis, Sue Merson, Steve Hawkins, William Howat, Yong-Jie Lu, Adam Lambert, Jonathan Kay, Barbara Kremeyer, Katalin Karaszi, Hayley Luxton, Niedzica Camacho, Luke Marsden, Sandra Edwards, Lucy Matthews, Valeria Bo, Daniel Leongamornlert, Stuart McLaren, Anthony Ng, Yongwei Yu, Hongwei Zhang, Tokhir Dadaev, Sarah Thomas, Douglas F Easton, Mahbubl Ahmed, Elizabeth Bancroft, Cyril Fisher, Naomi Livni, David Nicol, Simon Tavaré, Pelvender Gill, Christopher Greenman, Vincent Khoo, Nicholas Van As, Pardeep Kumar, Christopher Ogden, Declan Cahill, Alan Thompson, Erik Mayer, Edward Rowe, Tim Dudderidge, Vincent Gnanapragasam, Nimish C Shah, Keiran Raine, David Jones, Andrew Menzies, Lucy Stebbings, Jon Teague, Steven Hazell, Cathy Corbishley, CAMCAP Study Group, Johann de Bono, Gerhardt Attard, William Isaacs, Tapio Visakorpi, Michael Fraser, Paul C Boutros, Robert G Bristow, Paul Workman, Chris Sander, The TCGA Consortium, Freddie C Hamdy, Andrew Futreal, Ultan McDermott, Bissan Al-Lazikani, Andrew G Lynch, G Steven Bova, Christopher S Foster, Daniel S Brewer, David E Neal, Colin S Cooper, Rosalind A Eeles
Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials.

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