Abstract LB-246: Recurrent inactivating mutations in SPOP define a molecular subset of prostate cancer

Abstract

Abstract Considerable evidence exists that prostate cancer is driven by cardinal genetic alterations that activate oncogenes and inactivate tumor suppressors. Recently, recurrent fusions involving members of the ETS transcription factor family have been implicated in the majority of prostate cancer. In addition, several studies have shown that prostate cancers can be classified by genome-wide analysis of somatic copy-number aberration, or transcriptome-wide analysis of gene expression profiles. These discoveries raise the possibility that prostate cancer may soon transition from a poorly understood, clinically heterogeneous disease to a collection of homogenous subtypes identifiable by molecular criteria. However, the limited number of known driver alterations in prostate cancer currently limits this effort. Here, we report the presence of recurrent mutations in human prostate cancer in SPOP, the substrate-recognition component of an E3-ubiquitin ligase. Recurrent missense mutations in SPOP were discovered by whole genome DNA sequencing (DNA-seq) and whole transcription RNA sequencing (RNA-seq). SPOP mutations were found in approximately 10% of prostate cancers in multiple independent patient cohorts. All mutations were heterozygous, and were found exclusively in the structurally-defined substrate-binding cleft of SPOP. Structural analysis suggests that these mutations inactivate SPOP function by disrupting SPOP-substrate interaction, and loss of SPOP function in prostate cell lines resulted in increased invasion. Prostate cancers harboring SPOP mutations displayed characteristic somatic genomic aberrations. However, all tumors with SPOP mutations lacked both ERG rearrangement and deletion of PTEN, two of the most common genetic alterations in human prostate cancer. We conclude from these results that recurrent mutations in SPOP define a distinct molecular subclass of prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-246. doi:10.1158/1538-7445.AM2011-LB-246