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J Clin Invest. 2018 Jan 2;128(1):381-386. doi: 10.1172/JCI96551. Epub 2017 Dec 4.

SPOP mutation drives prostate neoplasia without stabilizing oncogenic transcription factor ERG.

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Department of Urology, New York Presbyterian Hospital.
HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine.
Sandra and Edward Meyer Cancer Center, and.
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA.
The Caryl and Israel Englander Institute for Precision Medicine of Weill Cornell Medicine, and New York-Presbyterian Hospital, New York, New York, USA.
Human Oncology and Pathogenesis Program, and.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York, USA.
Department of BioMedical Research, University of Bern, Bern, Switzerland.


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.


Oncogenes; Oncology

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