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Nat Genet DOI:10.1038/s41588-018-0078-z

The long tail of oncogenic drivers in prostate cancer.

Publication TypeJournal Article
Year of Publication2018
AuthorsArmenia, J, Wankowicz, SAM, Liu, D, Gao, J, Kundra, R, Reznik, E, Chatila, WK, Chakravarty, D, G Han, C, Coleman, I, Montgomery, B, Pritchard, C, Morrissey, C, Barbieri, CE, Beltran, H, Sboner, A, Zafeiriou, Z, Miranda, S, Bielski, CM, Penson, AV, Tolonen, C, Huang, FW, Robinson, D, Wu, YMi, Lonigro, R, Garraway, LA, Demichelis, F, Kantoff, PW, Taplin, M-E, Abida, W, Taylor, BS, Scher, HI, Nelson, PS, de Bono, JS, Rubin, MA, Sawyers, CL, Chinnaiyan, AM, Schultz, N, Van Allen, EM
Corporate AuthorsPCF/SU2C International Prostate Cancer Dream Team
JournalNat Genet
Date Published2018 05
KeywordsAndrogens, Carcinogenesis, Cullin Proteins, Epigenesis, Genetic, Exome, Homeodomain Proteins, Humans, Male, Mutation, Oncogenes, Phosphatidylinositol 3-Kinases, Prostatic Neoplasms, Spliceosomes, Transcription Factors

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.


Alternate JournalNat Genet
PubMed ID29610475
PubMed Central IDPMC6107367
Grant ListP50 CA090381 / CA / NCI NIH HHS / United States
R01 CA193837 / CA / NCI NIH HHS / United States
P50 CA097186 / CA / NCI NIH HHS / United States
K08 CA188615 / CA / NCI NIH HHS / United States
P50 CA092629 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA155169 / CA / NCI NIH HHS / United States
U54 CA224079 / CA / NCI NIH HHS / United States