SPOP Mutation Drives Prostate Neoplasia Without Stabilizing Oncogenic Transcription Factor ERG

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2017 Dec 5

PMID 29202479

Citations 22

Authors

Jonathan Shoag

Deli Liu

Mirjam Blattner

Andrea Sboner

Kyung Park

Lesa Deonarine

Brian D Robinson

Juan Miguel Mosquera

Yu Chen

Mark A Rubin

Christopher E Barbieri

Affiliations

Soon will be listed here.

Abstract

Nearly 50% of prostate cancers harbor gene fusions that lead to overexpression of the transcription factor ERG, while a mutually exclusive 10% of prostate cancers harbor recurrent mutations in the gene encoding the E3 ubiquitin ligase SPOP. Recent reports suggest that SPOP acts as a ubiquitin ligase for ERG and propose that ERG stabilization is the oncogenic effector of SPOP mutation. Here, we used human prostate cancer samples and showed that the vast majority of human SPOP-mutant cancers do not express ERG. Comparison of SPOP-mutant and ERG-fusion organoid models showed evidence of divergent, rather than common, transcriptional programs. Furthermore, expression of prostate cancer-associated SPOP mutations in genetically engineered mouse models of SPOP-mutant prostate cancer did not result in the expression of ERG protein in histologically normal prostate glands, high-grade prostatic intraepithelial neoplasia, invasive adenocarcinoma, or prostate organoids. In summary, we found no evidence that ERG is an effector of SPOP mutation in human prostate cancer or mouse models.

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References

Boysen G, Barbieri C, Prandi D, Blattner M, Chae S, Dahija A . SPOP mutation leads to genomic instability in prostate cancer. Elife. 2015; 4. PMC: 4621745. DOI: 10.7554/eLife.09207. View

An J, Ren S, Murphy S, Dalangood S, Chang C, Pang X . Truncated ERG Oncoproteins from TMPRSS2-ERG Fusions Are Resistant to SPOP-Mediated Proteasome Degradation. Mol Cell. 2015; 59(6):904-16. DOI: 10.1016/j.molcel.2015.07.025. View

Gan W, Dai X, Lunardi A, Li Z, Inuzuka H, Liu P . SPOP Promotes Ubiquitination and Degradation of the ERG Oncoprotein to Suppress Prostate Cancer Progression. Mol Cell. 2015; 59(6):917-30. PMC: 4575912. DOI: 10.1016/j.molcel.2015.07.026. View

Karthaus W, Iaquinta P, Drost J, Gracanin A, van Boxtel R, Wongvipat J . Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell. 2014; 159(1):163-175. PMC: 4772677. DOI: 10.1016/j.cell.2014.08.017. View

Wise A, Stamey T, McNeal J, Clayton J . Morphologic and clinical significance of multifocal prostate cancers in radical prostatectomy specimens. Urology. 2002; 60(2):264-9. DOI: 10.1016/s0090-4295(02)01728-4. View

Tomlins S, Bjartell A, Chinnaiyan A, Jenster G, Nam R, Rubin M . ETS gene fusions in prostate cancer: from discovery to daily clinical practice. Eur Urol. 2009; 56(2):275-86. DOI: 10.1016/j.eururo.2009.04.036. View

van Leenders G, Boormans J, Vissers C, Hoogland A, Bressers A, Furusato B . Antibody EPR3864 is specific for ERG genomic fusions in prostate cancer: implications for pathological practice. Mod Pathol. 2011; 24(8):1128-38. DOI: 10.1038/modpathol.2011.65. View

Chaux A, Albadine R, Toubaji A, Hicks J, Meeker A, Platz E . Immunohistochemistry for ERG expression as a surrogate for TMPRSS2-ERG fusion detection in prostatic adenocarcinomas. Am J Surg Pathol. 2011; 35(7):1014-20. PMC: 3505676. DOI: 10.1097/PAS.0b013e31821e8761. View

Barry M, Perner S, Demichelis F, Rubin M . TMPRSS2-ERG fusion heterogeneity in multifocal prostate cancer: clinical and biologic implications. Urology. 2007; 70(4):630-3. PMC: 3198826. DOI: 10.1016/j.urology.2007.08.032. View

10.

Schaefer G, Mosquera J, Ramoner R, Park K, Romanel A, Steiner E . Distinct ERG rearrangement prevalence in prostate cancer: higher frequency in young age and in low PSA prostate cancer. Prostate Cancer Prostatic Dis. 2013; 16(2):132-8. PMC: 3655380. DOI: 10.1038/pcan.2013.4. View

11.

. The Molecular Taxonomy of Primary Prostate Cancer. Cell. 2015; 163(4):1011-25. PMC: 4695400. DOI: 10.1016/j.cell.2015.10.025. View

12.

Park K, Tomlins S, Mudaliar K, Chiu Y, Esgueva R, Mehra R . Antibody-based detection of ERG rearrangement-positive prostate cancer. Neoplasia. 2010; 12(7):590-8. PMC: 2907585. DOI: 10.1593/neo.10726. View

13.

Shoag J, Barbieri C . Clinical variability and molecular heterogeneity in prostate cancer. Asian J Androl. 2016; 18(4):543-8. PMC: 4955177. DOI: 10.4103/1008-682X.178852. View

14.

Duan S, Pagano M . SPOP Mutations or ERG Rearrangements Result in Enhanced Levels of ERG to Promote Cell Invasion in Prostate Cancer. Mol Cell. 2015; 59(6):883-4. PMC: 4948578. DOI: 10.1016/j.molcel.2015.09.003. View

15.

Villers A, McNeal J, Freiha F, Stamey T . Multiple cancers in the prostate. Morphologic features of clinically recognized versus incidental tumors. Cancer. 1992; 70(9):2313-8. DOI: 10.1002/1097-0142(19921101)70:9<2313::aid-cncr2820700917>3.0.co;2-t. View

16.

Tomlins S, Palanisamy N, Siddiqui J, Chinnaiyan A, Kunju L . Antibody-based detection of ERG rearrangements in prostate core biopsies, including diagnostically challenging cases: ERG staining in prostate core biopsies. Arch Pathol Lab Med. 2012; 136(8):935-46. PMC: 3667408. DOI: 10.5858/arpa.2011-0424-OA. View

17.

Barbieri C, Baca S, Lawrence M, Demichelis F, Blattner M, Theurillat J . Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet. 2012; 44(6):685-9. PMC: 3673022. DOI: 10.1038/ng.2279. View

18.

Blattner M, Lee D, OReilly C, Park K, MacDonald T, Khani F . SPOP mutations in prostate cancer across demographically diverse patient cohorts. Neoplasia. 2014; 16(1):14-20. PMC: 3924544. DOI: 10.1593/neo.131704. View

19.

Baca S, Prandi D, Lawrence M, Mosquera J, Romanel A, Drier Y . Punctuated evolution of prostate cancer genomes. Cell. 2013; 153(3):666-77. PMC: 3690918. DOI: 10.1016/j.cell.2013.03.021. View

20.

Liu H, Shi J, Wilkerson M, Yang X, Lin F . Immunohistochemical evaluation of ERG expression in various benign and malignant tissues. Ann Clin Lab Sci. 2013; 43(1):3-9. View