Abstract 1108: SPOP mutation leads to genomic instability in prostate cancer

Background: Genomic instability is a fundamental feature of human cancer, and DNA repair defects resulting in impaired genome maintenance promote pathogenesis of many types of cancers. In prostate cancer, structural genomic rearrangements, including translocations and copy number aberrations, are a key mechanism driving tumorigenesis. Recently, whole genome sequencing revealed a striking abundance, complexity, and heterogeneity of genomic rearrangements, potentially suggesting distinct mechanisms of instability in different molecular classes of prostate cancer. However, the somatic alterations underlying these phenomena remain largely undefined. Recurrent mutations in SPOP, the substrate-recognition component of an E3-ubiquitin ligase, represent the most common point mutations in primary prostate cancer, occurring in about 10% of tumors. SPOP mutations define a distinct molecular class of prostate cancer; they are mutually exclusive with TMPRSS2-ERG fusions, but harbor distinct patterns of copy number aberrations. Here, we report that SPOP mutant prostate cancers also harbor increased numbers of genomic rearrangements, and functional data suggest that SPOP mutation alters repair of DNA double strand breaks (DSB). Methods: We systematically investigated somatic alterations associated with genomic rearrangements, using a composite data set of 402 clinically localized prostate cancers. Functional analyses in vitro and in vivo were used to define pathways affected, and interrogate DNA repair phenotypes. Results: In human prostate cancers, SPOP mutation is an early event specifically associated with increased intrachromosomal genomic rearrangements. Using a zebrafish model, SPOP mutation results in a transcriptional response consistent with BRCA1 inactivation, implicating altered repair of DSB. In vitro data suggest that SPOP participates in repair of DSB, and SPOP mutation impairs homology-directed repair (HDR), instead promoting error-prone non-homologous end joining (NHEJ). Finally, SPOP mutation sensitizes prostate cancer cells to DNA damaging therapeutic agents such as PARP inhibitors. Conclusions: These results implicate SPOP as a novel participant in DSB repair, suggest that SPOP mutation drives prostate tumorigenesis in part through genomic instability, and indicate that SPOP mutant prostate cancer may be selectively responsive to DNA damaging therapeutics. Citation Format: Gunther Boysen, Christopher E. Barbieri, Davide Prandi, Sung-Suk Chae, Srilakshm