LAUSR

131Background: The mutational landscapes of primary and metastatic PCa have been robustly analyzed in multiple whole exome sequencing (WES) studies. We hypothesized that an aggregate, uniform analysis of all data generated to date would enable discovery of new significantly mutated genes and pathways not previously associated with PCa, and shed more light onto the genetic differences between primary and metastatic PCa. Methods: We assembled and uniformly analyzed a cohort of 1,021 tumor and matched germline primary and metastatic PCa whole exomes (686 primary, 335 metastatic), and performed mutational significance analysis using statistical and biological approaches to determine which genes and pathways are recurrently altered. Results: We identified 117 significantly mutated genes (Mutsig q<0.1) in PCa, which included many novel genes and pathways. These include epigenetic modifiers [KMT2C (6%), KMT2D (6%), and KDM6A (2.7%)], regulators of the SWI/SNF complex [SMARCA1 (1.1%), ARID1A (1.5%), ARID1B (1.3%)...