1314 RECURRENT MUTATIONS IN SPOP DEFINE A DISTINCT MOLECULAR CLASS OF PROSTATE CANCER (2012)

You have accessJournal of UrologyProstate Cancer: Basic Research II1 Apr 20121314 RECURRENT MUTATIONS IN SPOP DEFINE A DISTINCT MOLECULAR CLASS OF PROSTATE CANCER Christopher Barbieri, Sylvan Baca, Francesca Demichelis, Michael Lawrence, Mija Blattner, Jean-Philippe Theurillat, Gunther Boysen, Petar Stojanov, Eli Van Allen, Nico Stransky, Elizabeth Nickerson, Kyung Park, Naoki Kitabayashi, Theresa MacDonald, Terry Vuong, Daniel Auclair, Robert Onofrio, Candace Guiducci, Kristian Cibulskis, Andrey Sivachenko, Scott Carter, Lauren Ambrogio, Melissa Parkin, Thomas White, Gordon Saksena, Douglas Voet, Alex H. Ramos, Wendy Winckler, Wasay Hussain, Jane Wilkinson, Kristin Ardlie, Samprit Banerjee, Jennifer Baldwin, Juan Miguel Mosquera, Stacey B. Gabriel, Philip W. Kantoff, Todd R. Golub, Matthew Meyerson, Eric S. Lander, Gad Getz, Peter Nelson, Levi A. Garraway, Ashutosh Tewari, and Mark A. Rubin Christopher BarbieriChristopher Barbieri New York, NY , Sylvan BacaSylvan Baca Cambridge, MA , Francesca DemichelisFrancesca Demichelis New York, NY , Michael LawrenceMichael Lawrence Cambridge, MA , Mija BlattnerMija Blattner New York, NY , Jean-Philippe TheurillatJean-Philippe Theurillat Cambridge, MA , Gunther BoysenGunther Boysen New York, NY , Petar StojanovPetar Stojanov Cambridge, MA , Eli Van AllenEli Van Allen Cambridge, MA , Nico StranskyNico Stransky Cambridge, MA , Elizabeth NickersonElizabeth Nickerson Cambridge, MA , Kyung ParkKyung Park New York, NY , Naoki KitabayashiNaoki Kitabayashi New York, NY , Theresa MacDonaldTheresa MacDonald New York, NY , Terry VuongTerry Vuong New York, NY , Daniel AuclairDaniel Auclair Cambridge, MA , Robert OnofrioRobert Onofrio Cambridge, MA , Candace GuiducciCandace Guiducci Cambridge, MA , Kristian CibulskisKristian Cibulskis Cambridge, MA , Andrey SivachenkoAndrey Sivachenko Cambridge, MA , Scott CarterScott Carter Cambridge, MA , Lauren AmbrogioLauren Ambrogio Cambridge, MA , Melissa ParkinMelissa Parkin Cambridge, MA , Thomas WhiteThomas White Seattle, WA , Gordon SaksenaGordon Saksena Cambridge, MA , Douglas VoetDouglas Voet Cambridge, MA , Alex H. RamosAlex H. Ramos Cambridge, MA , Wendy WincklerWendy Winckler Cambridge, MA , Wasay HussainWasay Hussain New York, NY , Jane WilkinsonJane Wilkinson Cambridge, MA , Kristin ArdlieKristin Ardlie Cambridge, MA , Samprit BanerjeeSamprit Banerjee New York, NY , Jennifer BaldwinJennifer Baldwin Cambridge, MA , Juan Miguel MosqueraJuan Miguel Mosquera New York, NY , Stacey B. GabrielStacey B. Gabriel Cambridge, MA , Philip W. KantoffPhilip W. Kantoff Boston, MA , Todd R. GolubTodd R. Golub Cambridge, MA , Matthew MeyersonMatthew Meyerson Cambridge, MA , Eric S. LanderEric S. Lander Cambridge, MA , Gad GetzGad Getz Cambridge, MA , Peter NelsonPeter Nelson Seattle, WA , Levi A. GarrawayLevi A. Garraway Cambridge, MA , Ashutosh TewariAshutosh Tewari New York, NY , and Mark A. RubinMark A. Rubin New York, NY View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1661AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prostate cancer is a heterogeneous disease with marked variability in patient outcomes. However, recent advances in molecular characterization raise the possibility that prostate cancer might soon transition from a poorly understood, clinically heterogeneous disease to a collection of homogenous subtypes identifiable by molecular criteria. While structural genomic lesions in prostate cancer are well-characterized, recurrent protein-altering point mutations are rare. Here, we report recurrent missense mutations in SPOP, the substrate recognition component of an E3 ubiquitin ligase, in human prostate cancer. METHODS Somatic single nucleotide variations in the SPOP gene were determined from whole exome DNA-seq, whole transcriptome RNA-seq, and Sanger sequencing from multiple independent cohorts of prostate cancer comprising over 400 patients. ERG rearrangement and PTEN deletion status were determined by FISH, somatic copy number aberrations were analyzed by Affymetrix 6.0 SNP arrays, and the association of SPOP mutation with these molecular characteristics was determined. RESULTS SPOP was the most frequently mutated gene in whole exome sequencing of 111 primary prostate cancers, with missense mutations in 13% of cases. Recurrent missense mutations were found in SPOP in 6-15% of human prostate cancers in multiple independent cohorts. Mutations were found exclusively in the structurally-defined substrate-binding cleft of SPOP; structural analysis suggests that these mutations will affect SPOP function by disrupting SPOP-substrate interaction. Importantly, all SPOP mutations occurred in primary tumors that lacked ERG rearrangement and inactivation of the p53 and PTEN tumor suppressors. Furthermore, these SPOP mutant cancers displayed characteristic somatic copy number aberrations, including deletions at 5q21 and in the 6q14-22 region. CONCLUSIONS Recurrent missense mutations occur in substrate-binding residues of SPOP in 6-15% of human prostate cancer. SPOP mutant tumors lack ERG rearrangement, and lesions in the TP53 and PTEN genes, but harbor characteristic somatic copy number aberrations. These data suggest that mutation of SPOP is a driver lesion that may underlie a specific molecular class of prostate cancer. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e532-e533 Peer Review Report Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christopher Barbieri New York, NY More articles by this author Sylvan Baca Cambridge, MA More articles by this author Francesca Demichelis New York, NY More articles by this author Michael Lawrence Cambridge, MA More articles by this author Mija Blattner New York, NY More articles by this author Jean-Philippe Theurillat Cambridge, MA More articles by this author Gunther Boysen New York, NY More articles by this author Petar Stojanov Cambridge, MA More articles by this author Eli Van Allen Cambridge, MA More articles by this author Nico Stransky Cambridge, MA More articles by this author Elizabeth Nickerson Cambridge, MA More articles by this author Kyung Park New York, NY More articles by this author Naoki Kitabayashi New York, NY More articles by this author Theresa MacDonald New York, NY More articles by this author Terry Vuong New York, NY More articles by this author Daniel Auclair Cambridge, MA More articles by this author Robert Onofrio Cambridge, MA More articles by this author Candace Guiducci Cambridge, MA More articles by this author Kristian Cibulskis Cambridge, MA More articles by this author Andrey Sivachenko Cambridge, MA More articles by this author Scott Carter Cambridge, MA More articles by this author Lauren Ambrogio Cambridge, MA More articles by this author Melissa Parkin Cambridge, MA More articles by this author Thomas White Seattle, WA More articles by this author Gordon Saksena Cambridge, MA More articles by this author Douglas Voet Cambridge, MA More articles by this author Alex H. Ramos Cambridge, MA More articles by this author Wendy Winckler Cambridge, MA More articles by this author Wasay Hussain New York, NY More articles by this author Jane Wilkinson Cambridge, MA More articles by this author Kristin Ardlie Cambridge, MA More articles by this author Samprit Banerjee New York, NY More articles by this author Jennifer Baldwin Cambridge, MA More articles by this author Juan Miguel Mosquera New York, NY More articles by this author Stacey B. Gabriel Cambridge, MA More articles by this author Philip W. Kantoff Boston, MA More articles by this author Todd R. Golub Cambridge, MA More articles by this author Matthew Meyerson Cambridge, MA More articles by this author Eric S. Lander Cambridge, MA More articles by this author Gad Getz Cambridge, MA More articles by this author Peter Nelson Seattle, WA More articles by this author Levi A. Garraway Cambridge, MA More articles by this author Ashutosh Tewari New York, NY More articles by this author Mark A. 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