The long tail of oncogenic drivers in prostate cancer. - PubMed - NCBI
Nat Genet. 2018 Apr 2. doi: 10.1038/s41588-018-0078-z. [Epub ahead of print]
The long tail of oncogenic drivers in prostate cancer.
Armenia J1,2,
Wankowicz SAM3,4,
Liu D3,4,
Gao J1,2,
Kundra R1,2,
Reznik E1,2,
Chatila WK1,2,
Chakravarty D1,2,
Han GC3,4,
Coleman I5,
Montgomery B6,
Pritchard C7,
Morrissey C8,
Barbieri CE9,
Beltran H10,11,12,
Sboner A9,
Zafeiriou Z13,
Miranda S13,
Bielski CM1,2,
Penson AV1,2,
Tolonen C4,
Huang FW3,4,
Robinson D14,
Wu YM14,
Lonigro R14,
Garraway LA3,4,
Demichelis F15,
Kantoff PW16,
Taplin ME3,
Abida W16,
Taylor BS1,2,17,
Scher HI16,
Nelson PS5,6,
de Bono JS13,
Rubin MA9,11,12,
Sawyers CL1,
Chinnaiyan AM14;
PCF/SU2C International Prostate Cancer Dream Team,
Schultz N18,19,20,
Van Allen EM21,22;
PCF/SU2C International Prostate Cancer Dream Team.
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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