The long tail of oncogenic drivers in prostate cancer

Comprehensive genomic characterization of prostate cancer has identified recurrent alterations in androgen signaling, DNA repair, and PI3K among others. However, larger and uniform genomic analysis may reveal additional recurrently mutated genes at lower frequencies. Here we aggregate and uniformly analyze exome sequencing data from 1013 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 reveals a set of genomic markers that may inform risk stratification.