Comprehensive genomic characterization of prostate cancer has identified recurrent alterations in genes involved in androgen signaling, DNA repair, and PI3K signaling, among others. However, larger and uniform genomic analysis may identify additional recurrently mutated genes at lower frequencies. Here we aggregate and uniformly analyze exome sequencing data from 1,013 prostate cancers. We identify and validate a new class of E26 transformation-specific (ETS)-fusion-negative tumors defined by mutations in epigenetic regulators, as well as alterations in pathways not previously implicated in prostate cancer, such as the spliceosome pathway. We find that the incidence of significantly mutated genes (SMGs) follows a long-tail distribution, with many genes mutated in less than 3% of cases. We identify a total of 97 SMGs, including 70 not previously implicated in prostate cancer, such as the ubiquitin ligase CUL3 and the transcription factor SPEN. Finally, comparing primary and metastatic prostate cancer identifies a set of genomic markers that may inform risk stratification.
Nature genetics. 2018 Apr 02 [Epub]
Joshua Armenia, Stephanie A M Wankowicz, David Liu, Jianjiong Gao, Ritika Kundra, Ed Reznik, Walid K Chatila, Debyani Chakravarty, G Celine Han, Ilsa Coleman, Bruce Montgomery, Colin Pritchard, Colm Morrissey, Christopher E Barbieri, Himisha Beltran, Andrea Sboner, Zafeiris Zafeiriou, Susana Miranda, Craig M Bielski, Alexander V Penson, Charlotte Tolonen, Franklin W Huang, Dan Robinson, Yi Mi Wu, Robert Lonigro, Levi A Garraway, Francesca Demichelis, Philip W Kantoff, Mary-Ellen Taplin, Wassim Abida, Barry S Taylor, Howard I Scher, Peter S Nelson, Johann S de Bono, Mark A Rubin, Charles L Sawyers, Arul M Chinnaiyan, PCF/SU2C International Prostate Cancer Dream Team , Nikolaus Schultz, Eliezer M Van Allen
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Department of Medicine, University of Washington, Seattle, WA, USA., Department of Laboratory Medicine, University of Washington, Seattle, WA, USA., Department of Urology, University of Washington, Seattle, WA, USA., Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA., Department of Medicine, Division of Medical Oncology, Weill Cornell Medicine, New York, NY, USA., Biomarkers Team, Division of Clinical Studies, The Institute of Cancer Research and Royal Marsden Hospital, London, UK., Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA., Centre for Integrated Biology, University of Trento, Trento, Italy., Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. ., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. .