Abstract 3566: The long tail of significantly mutated genes in prostate cancer
Authors: Armenia Joshua , Mullane Stephanie , Gao Jianjiong , Chakravarty Debyani , Kundra Ritika , Huang Franklin , Han Celine , Robinson Dan , Garraway Levi A. , Nelson Peter , Rubin Mark , Taplin Mary-Ellen , Abida Wassim , Sawyers Charles L. , Chinnaiyan Arul M. , Kantoff Philip W. , Bono Johann S. , Schultz Nikolaus , Allen Eliezer M. Van 
Published: July 2017

Abstract
Background: The mutational landscapes of primary and metastatic prostate cancer (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 uniformly analyzed WES data of 1,021 tumor and matched germline primary and metastatic PCa (686 primary, 335 metastatic). We performed mutational significance analysis using statistical and biological approaches to determine recurrently altered genes and pathways.
Results: We identified 117 significantly mutated genes (Mutsig q&lt;0.1) in PCa. These include epigenetic modifiers [KMT2C (6%), KMT2D (6%), and KDM6A (2.7%)] and regulators of the SWI/SNF complex [SMARCA1 (1.1%), ARID1A (1.5%), ARID1B (1.3%), ARID2 (1.3%), and PBRM1 (0.7%)]. Interestingly, genomic alterations in chromatin remodelers (MLL, SWI/SNF) appear to be significantly mutually exclusive with ETS fusions and SPOP mutations (p&lt;0.001, Fisher’s test), indicating that these mutations may represent a novel distinct oncogenic driver in prostate cancer. Among the novel PCa related pathways, the splicing pathway was found to have oncogenic mutations in key drivers such as SF3B1 (1.1%), U2AF1 (0.5%), and FUBP1 (0.4%), a novel splicing regulator involved in the regulation of MDM2 splicing. We also found truncating mutations in SPEN, a hormone inducible transcriptional repressor, in 2.8% of samples, similar to the frequency observed in breast tumors, and these mutations appear to be significantly associated with AR mutations (p=0.01, Fisher’s test).
Our analysis also uncovered mutations in CUL3 (1.3%) and KLHL20, components of an E3-ubiquitin ligase complex that interacts with SPOP to promote the degradation of critical PCa genes (AR, SRC). KLHL20, CUL3, and SPOP mutations are mutually exclusive. Finally, a comparison of primary and metastatic samples identified alterations that are associated with metastatic disease, including AR amplifications and mutations, and loss of TP53, PTEN, and RB1. At lower frequency, metastatic tumors showed enrichment in mutations in MLLs (KMT2C/D), APC, CDK12, BRCA2, CTNNB1, and amplifications of MYC and CCND1.
Conclusions: Through aggregation and uniform genomic analysis, we refined the map of somatic mutations in PCa and identified cancer genes and pathways not previously associated with this disease. Our findings may inform patient stratification and translational investigation.
Citation Format: Joshua Armenia, Stephanie Mullane, Jianjiong Gao, Debyani Chakravarty, Ritika Kundra, Franklin Huang, Celine Han, Dan Robinson, Levi A. Garraway,, Peter Nelson, Mark Rubin, Mary-Ellen Taplin, Wassim Abida, Charles L. Sawyers, Arul M. Chinnaiyan, Philip W. Kantoff, Johann S. Bono, Nikolaus Schultz, Eliezer M. Van Allen. The long tail of significantly mutated genes in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3566. doi:10.1158/1538-7445.AM2017-3566