MP66-01 SPOP MUTATION LEADS TO GENOMIC INSTABILITY IN PROSTATE CANCER (2015)

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2015MP66-01 SPOP MUTATION LEADS TO GENOMIC INSTABILITY IN PROSTATE CANCER Christopher Barbieri, Gunther Boysen, Davide Prandi, Sung-Suk Chae, Arun Dahiya, Srilakshmi Nataraj, Mirjam Blattner, Clarisse Marotz, Limei Xu, Julie Huang, Paola Lecca, Sagar Chhangawala, Pengbo Zhou, Andrea Sboner, Francesca Demichelis, Yariv Houvras, and Mark Rubin Christopher BarbieriChristopher Barbieri More articles by this author , Gunther BoysenGunther Boysen More articles by this author , Davide PrandiDavide Prandi More articles by this author , Sung-Suk ChaeSung-Suk Chae More articles by this author , Arun DahiyaArun Dahiya More articles by this author , Srilakshmi NatarajSrilakshmi Nataraj More articles by this author , Mirjam BlattnerMirjam Blattner More articles by this author , Clarisse MarotzClarisse Marotz More articles by this author , Limei XuLimei Xu More articles by this author , Julie HuangJulie Huang More articles by this author , Paola LeccaPaola Lecca More articles by this author , Sagar ChhangawalaSagar Chhangawala More articles by this author , Pengbo ZhouPengbo Zhou More articles by this author , Andrea SbonerAndrea Sboner More articles by this author , Francesca DemichelisFrancesca Demichelis More articles by this author , Yariv HouvrasYariv Houvras More articles by this author , and Mark RubinMark Rubin More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2354AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES 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. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e816 Peer Review Report Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christopher Barbieri More articles by this author Gunther Boysen More articles by this author Davide Prandi More articles by this author Sung-Suk Chae More articles by this author Arun Dahiya More articles by this author Srilakshmi Nataraj More articles by this author Mirjam Blattner More articles by this author Clarisse Marotz More articles by this author Limei Xu More articles by this author Julie Huang More articles by this author Paola Lecca More articles by this author Sagar Chhangawala More articles by this author Pengbo Zhou More articles by this author Andrea Sboner More articles by this author Francesca Demichelis More articles by this author Yariv Houvras More articles by this author Mark Rubin More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...