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Nat Genet. 2018 May;50(5):645-651. doi: 10.1038/s41588-018-0078-z. Epub 2018 Apr 2.

The long tail of oncogenic drivers in prostate cancer.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
4
Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
5
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
6
Department of Medicine, University of Washington, Seattle, WA, USA.
7
Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
8
Department of Urology, University of Washington, Seattle, WA, USA.
9
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
10
Department of Medicine, Division of Medical Oncology, Weill Cornell Medicine, New York, NY, USA.
11
Englander Institute for Precision Medicine, Weill Cornell Medical College-New York Presbyterian Hospital, New York, NY, USA.
12
Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College, New York, NY, USA.
13
Biomarkers Team, Division of Clinical Studies, The Institute of Cancer Research and Royal Marsden Hospital, London, UK.
14
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
15
Centre for Integrated Biology, University of Trento, Trento, Italy.
16
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
17
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
18
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. schultzn@mskcc.org.
19
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. schultzn@mskcc.org.
20
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. schultzn@mskcc.org.
21
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. eliezerm_vanallen@dfci.harvard.edu.
22
Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. eliezerm_vanallen@dfci.harvard.edu.

Abstract

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.

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