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Grant Details

Grant Number: 7R01CA125612-10 Interpret this number
Primary Investigator: Rubin, Mark
Organization: Universitat Bern
Project Title: Towards Understanding Prostate Cancer Heterogeneity
Fiscal Year: 2017
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Abstract

DESCRIPTION (provided by applicant): Protein-altering point mutations are uncommon in prostate cancer. The overall and protein-altering mutation rate of primary prostate cancer is among the lowest reported, approximately an order of magnitude lower than other cancers. Consistent with this, recurrent protein-altering mutations are rare in prostate cancer. Mutations in AR, PTEN, and AKT1 are among the most common; these occur rarely in primary prostate cancer, with reported frequency around 1%. The SPOP gene (Speckle-type POZ Protein) encodes for the substrate-recognition component of a Cullin3- based E3-ubiquitin ligase. Mutations in SPOP in prostate cancer were recently reported in two systematic sequencing studies. We have identified the presence of recurrent mutations in SPOP in 6-13% of human prostate cancers in multiple independent patient cohorts (Barbieri et al., Nature Genetics 2012). Recurrent missense mutations were found exclusively in the structurally-defined substrate-binding cleft of SPOP, and structural analysis suggests that these mutations will inactivate SPOP function by disrupting SPOP-substrate interaction. Further, we found that loss of SPOP function in prostate cell lines resulted in increased invasion, and altered gene expression; evidence of this expression signature was identified in primary tumors harboring SPOP mutation. Importantly, all SPOP mutations occurred in tumors that were negative for ERG rearrangement and PTEN deletion; these tumors displayed characteristic somatic copy number aberrations. Taken together, these findings support a distinct molecular class of prostate cancer. The overall goal of this proposal is to define the role of SPOP mutations in prostate cancer and elucidate the biology of SPOP mutant prostate cancer as a distinct molecular subclass. We propose three specific Aims that together will examine the substrate specificity of SPOP mutant proteins, test the common SPOP mutations in an in vivo model of prostate cancer, identify cooperating and mutually exclusive genetic events, and examine the impact of SPOP mutation on prostate cancer patients. We will use a combination of biochemical, structural biology, in vivo and molecular biology approaches to study these events in prostate cancer models systems, while also employing large cohorts of primary and metastatic human prostate cancer samples to integrate genetic and epidemiologic analyses. Furthermore, we have assembled an outstanding team of co- investigators with complementary skills and resources to execute these proposed studies.

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Publications

Tumor purity quantification by clonal DNA methylation signatures.
Authors: Benelli M. , Romagnoli D. , Demichelis F. .
Source: Bioinformatics (oxford, England), 2018-05-15 00:00:00.0; 34(10), p. 1642-1649.
PMID: 29325057
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SPOP mutation drives prostate neoplasia without stabilizing oncogenic transcription factor ERG.
Authors: Shoag J. , Liu D. , Blattner M. , Sboner A. , Park K. , Deonarine L. , Robinson B.D. , Mosquera J.M. , Chen Y. , Rubin M.A. , et al. .
Source: The Journal Of Clinical Investigation, 2018-01-02 00:00:00.0; 128(1), p. 381-386.
EPub date: 2017-12-04 00:00:00.0.
PMID: 29202479
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Spop Mutation Drives Prostate Tumorigenesis In vivo Through Coordinate Regulation Of Pi3k/mtor And Ar Signaling
Authors: Blattner M. , Liu D. , Robinson B.D. , Huang D. , Poliakov A. , Gao D. , Nataraj S. , Deonarine L.D. , Augello M.A. , Sailer V. , et al. .
Source: Cancer Cell, 2017-03-13 00:00:00.0; 31(3), p. 436-451.
PMID: 28292441
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The Emergence Of Precision Urologic Oncology: A Collaborative Review On Biomarker-driven Therapeutics
Authors: Barbieri C.E. , Chinnaiyan A.M. , Lerner S.P. , Swanton C. , Rubin M.A. .
Source: European Urology, 2017 Feb; 71(2), p. 237-246.
PMID: 27567210
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A Novel Brain Tumour Model In Zebrafish Reveals The Role Of Yap Activation In Mapk- And Pi3k-induced Malignant Growth
Authors: Mayrhofer M. , Gourain V. , Reischl M. , Affaticati P. , Jenett A. , Joly J.S. , Benelli M. , Demichelis F. , Poliani P.L. , Sieger D. , et al. .
Source: Disease Models & Mechanisms, 2017-01-01 00:00:00.0; 10(1), p. 15-28.
PMID: 27935819
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SPOP mutation leads to genomic instability in prostate cancer.
Authors: Boysen G. , Barbieri C.E. , Prandi D. , Blattner M. , Chae S.S. , Dahija A. , Nataraj S. , Huang D. , Marotz C. , Xu L. , et al. .
Source: Elife, 2015-09-16 00:00:00.0; 4, .
EPub date: 2015-09-16 00:00:00.0.
PMID: 26374986
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Genomic rearrangements in prostate cancer.
Authors: Barbieri C.E. , Rubin M.A. .
Source: Current Opinion In Urology, 2015 Jan; 25(1), p. 71-6.
PMID: 25393273
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Defining Order And Timing Of Mutations During Cancer Progression: The To-dag Probabilistic Graphical Model
Authors: Lecca P. , Casiraghi N. , Demichelis F. .
Source: Frontiers In Genetics, 2015; 6, p. 309.
PMID: 26528329
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Evidence for molecular differences in prostate cancer between African American and Caucasian men.
Authors: Khani F. , Mosquera J.M. , Park K. , Blattner M. , O'Reilly C. , MacDonald T.Y. , Chen Z. , Srivastava A. , Tewari A.K. , Barbieri C.E. , et al. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2014-09-15 00:00:00.0; 20(18), p. 4925-34.
EPub date: 2014-09-15 00:00:00.0.
PMID: 25056375
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Unraveling the clonal hierarchy of somatic genomic aberrations.
Authors: Prandi D. , Baca S.C. , Romanel A. , Barbieri C.E. , Mosquera J.M. , Fontugne J. , Beltran H. , Sboner A. , Garraway L.A. , Rubin M.A. , et al. .
Source: Genome Biology, 2014-08-26 00:00:00.0; 15(8), p. 439.
EPub date: 2014-08-26 00:00:00.0.
PMID: 25160065
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SPOP mutations in prostate cancer across demographically diverse patient cohorts.
Authors: Blattner M. , Lee D.J. , O'Reilly C. , Park K. , MacDonald T.Y. , Khani F. , Turner K.R. , Chiu Y.L. , Wild P.J. , Dolgalev I. , et al. .
Source: Neoplasia (new York, N.y.), 2014 Jan; 16(1), p. 14-20.
PMID: 24563616
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Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells.
Authors: Stoyanova T. , Cooper A.R. , Drake J.M. , Liu X. , Armstrong A.J. , Pienta K.J. , Zhang H. , Kohn D.B. , Huang J. , Witte O.N. , et al. .
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2013-12-10 00:00:00.0; 110(50), p. 20111-6.
EPub date: 2013-12-10 00:00:00.0.
PMID: 24282295
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The mutational landscape of prostate cancer.
Authors: Barbieri C.E. , Bangma C.H. , Bjartell A. , Catto J.W. , Culig Z. , Grönberg H. , Luo J. , Visakorpi T. , Rubin M.A. .
Source: European Urology, 2013 Oct; 64(4), p. 567-76.
PMID: 23759327
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Punctuated evolution of prostate cancer genomes.
Authors: Baca S.C. , Prandi D. , Lawrence M.S. , Mosquera J.M. , Romanel A. , Drier Y. , Park K. , Kitabayashi N. , MacDonald T.Y. , Ghandi M. , et al. .
Source: Cell, 2013-04-25 00:00:00.0; 153(3), p. 666-77.
PMID: 23622249
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Prostate cancer-associated mutations in speckle-type POZ protein (SPOP) regulate steroid receptor coactivator 3 protein turnover.
Authors: Geng C. , He B. , Xu L. , Barbieri C.E. , Eedunuri V.K. , Chew S.A. , Zimmermann M. , Bond R. , Shou J. , Li C. , et al. .
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2013-04-23 00:00:00.0; 110(17), p. 6997-7002.
EPub date: 2013-04-23 00:00:00.0.
PMID: 23559371
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Molecular archeology: unearthing androgen-induced structural rearrangements in prostate cancer genomes.
Authors: Demichelis F. , Garraway L.A. , Rubin M.A. .
Source: Cancer Cell, 2013-02-11 00:00:00.0; 23(2), p. 133-5.
PMID: 23410968
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Oncogenic transcription factors as master regulators of chromatin topology: a new role for ERG in prostate cancer.
Authors: Elemento O. , Rubin M.A. , Rickman D.S. .
Source: Cell Cycle (georgetown, Tex.), 2012-09-15 00:00:00.0; 11(18), p. 3380-3.
EPub date: 2012-09-15 00:00:00.0.
PMID: 22918253
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Oncogene-mediated alterations in chromatin conformation.
Authors: Rickman D.S. , Soong T.D. , Moss B. , Mosquera J.M. , Dlabal J. , Terry S. , MacDonald T.Y. , Tripodi J. , Bunting K. , Najfeld V. , et al. .
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2012-06-05 00:00:00.0; 109(23), p. 9083-8.
EPub date: 2012-06-05 00:00:00.0.
PMID: 22615383
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Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer.
Authors: Barbieri C.E. , Baca S.C. , Lawrence M.S. , Demichelis F. , Blattner M. , Theurillat J.P. , White T.A. , Stojanov P. , Van Allen E. , Stransky N. , et al. .
Source: Nature Genetics, 2012-05-20 00:00:00.0; 44(6), p. 685-9.
EPub date: 2012-05-20 00:00:00.0.
PMID: 22610119
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Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets.
Authors: Beltran H. , Rickman D.S. , Park K. , Chae S.S. , Sboner A. , MacDonald T.Y. , Wang Y. , Sheikh K.L. , Terry S. , Tagawa S.T. , et al. .
Source: Cancer Discovery, 2011 Nov; 1(6), p. 487-95.
PMID: 22389870
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Characterization of KRAS rearrangements in metastatic prostate cancer.
Authors: Wang X.S. , Shankar S. , Dhanasekaran S.M. , Ateeq B. , Sasaki A.T. , Jing X. , Robinson D. , Cao Q. , Prensner J.R. , Yocum A.K. , et al. .
Source: Cancer Discovery, 2011 Jun; 1(1), p. 35-43.
PMID: 22140652
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Testing mutual exclusivity of ETS rearranged prostate cancer.
Authors: Svensson M.A. , LaFargue C.J. , MacDonald T.Y. , Pflueger D. , Kitabayashi N. , Santa-Cruz A.M. , Garsha K.E. , Sathyanarayana U.G. , Riley J.P. , Yun C.S. , et al. .
Source: Laboratory Investigation; A Journal Of Technical Methods And Pathology, 2011 Mar; 91(3), p. 404-12.
PMID: 20975660
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Discovery of non-ETS gene fusions in human prostate cancer using next-generation RNA sequencing.
Authors: Pflueger D. , Terry S. , Sboner A. , Habegger L. , Esgueva R. , Lin P.C. , Svensson M.A. , Kitabayashi N. , Moss B.J. , MacDonald T.Y. , et al. .
Source: Genome Research, 2011 Jan; 21(1), p. 56-67.
PMID: 21036922
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ERG cooperates with androgen receptor in regulating trefoil factor 3 in prostate cancer disease progression.
Authors: Rickman D.S. , Chen Y.B. , Banerjee S. , Pan Y. , Yu J. , Vuong T. , Perner S. , Lafargue C.J. , Mertz K.D. , Setlur S.R. , et al. .
Source: Neoplasia (new York, N.y.), 2010 Dec; 12(12), p. 1031-40.
PMID: 21170267
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Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma.
Authors: Palanisamy N. , Ateeq B. , Kalyana-Sundaram S. , Pflueger D. , Ramnarayanan K. , Shankar S. , Han B. , Cao Q. , Cao X. , Suleman K. , et al. .
Source: Nature Medicine, 2010 Jul; 16(7), p. 793-8.
PMID: 20526349
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Antibody-based detection of ERG rearrangement-positive prostate cancer.
Authors: Park K. , Tomlins S.A. , Mudaliar K.M. , Chiu Y.L. , Esgueva R. , Mehra R. , Suleman K. , Varambally S. , Brenner J.C. , MacDonald T. , et al. .
Source: Neoplasia (new York, N.y.), 2010 Jul; 12(7), p. 590-8.
PMID: 20651988
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ERG rearrangement metastasis patterns in locally advanced prostate cancer.
Authors: Perner S. , Svensson M.A. , Hossain R.R. , Day J.R. , Groskopf J. , Slaughter R.C. , Jarleborn A.R. , Hofer M.D. , Kuefer R. , Demichelis F. , et al. .
Source: Urology, 2010 Apr; 75(4), p. 762-7.
PMID: 20018353
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Prevalence of TMPRSS2-ERG and SLC45A3-ERG gene fusions in a large prostatectomy cohort.
Authors: Esgueva R. , Perner S. , J LaFargue C. , Scheble V. , Stephan C. , Lein M. , Fritzsche F.R. , Dietel M. , Kristiansen G. , Rubin M.A. .
Source: Modern Pathology : An Official Journal Of The United States And Canadian Academy Of Pathology, Inc, 2010 Apr; 23(4), p. 539-46.
PMID: 20118910
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FusionSeq: a modular framework for finding gene fusions by analyzing paired-end RNA-sequencing data.
Authors: Sboner A. , Habegger L. , Pflueger D. , Terry S. , Chen D.Z. , Rozowsky J.S. , Tewari A.K. , Kitabayashi N. , Moss B.J. , Chee M.S. , et al. .
Source: Genome Biology, 2010; 11(10), p. R104.
PMID: 20964841
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N-myc downstream regulated gene 1 (NDRG1) is fused to ERG in prostate cancer.
Authors: Pflueger D. , Rickman D.S. , Sboner A. , Perner S. , LaFargue C.J. , Svensson M.A. , Moss B.J. , Kitabayashi N. , Pan Y. , de la Taille A. , et al. .
Source: Neoplasia (new York, N.y.), 2009 Aug; 11(8), p. 804-11.
PMID: 19649210
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Distinct genomic aberrations associated with ERG rearranged prostate cancer.
Authors: Demichelis F. , Setlur S.R. , Beroukhim R. , Perner S. , Korbel J.O. , Lafargue C.J. , Pflueger D. , Pina C. , Hofer M.D. , Sboner A. , et al. .
Source: Genes, Chromosomes & Cancer, 2009 Apr; 48(4), p. 366-80.
PMID: 19156837
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SLC45A3-ELK4 is a novel and frequent erythroblast transformation-specific fusion transcript in prostate cancer.
Authors: Rickman D.S. , Pflueger D. , Moss B. , VanDoren V.E. , Chen C.X. , de la Taille A. , Kuefer R. , Tewari A.K. , Setlur S.R. , Demichelis F. , et al. .
Source: Cancer Research, 2009-04-01 00:00:00.0; 69(7), p. 2734-8.
EPub date: 2009-04-01 00:00:00.0.
PMID: 19293179
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KLF6-SV1 overexpression accelerates human and mouse prostate cancer progression and metastasis.
Authors: Narla G. , DiFeo A. , Fernandez Y. , Dhanasekaran S. , Huang F. , Sangodkar J. , Hod E. , Leake D. , Friedman S.L. , Hall S.J. , et al. .
Source: The Journal Of Clinical Investigation, 2008 Aug; 118(8), p. 2711-21.
PMID: 18596922
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Molecular alterations in prostate cancer and association with MRI features.
Authors: Lee D. , Fontugne J. , Gumpeni N. , Park K. , MacDonald T.Y. , Robinson B.D. , Sboner A. , Rubin M.A. , Mosquera J.M. , Barbieri C.E. .
Source: Prostate Cancer And Prostatic Diseases, 2017 12; 20(4), p. 430-435.
EPub date: 2017-08-01 00:00:00.0.
PMID: 28762374
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