Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer - Nature
- ️Chinnaiyan, Arul M.
- ️Thu Aug 02 2007
- Letter
- Published: 02 August 2007
- Bharathi Laxman1 na1,
- Saravana M. Dhanasekaran1 na1,
- Beth E. Helgeson1,
- Xuhong Cao1,
- David S. Morris2,
- Anjana Menon1,
- Xiaojun Jing1,
- Qi Cao1,
- Bo Han1,
- Jindan Yu1,
- Lei Wang1,
- James E. Montie2,4,
- Mark A. Rubin5,6,
- Kenneth J. Pienta2,3,4,
- Diane Roulston1,
- Rajal B. Shah1,2,4,
- Sooryanarayana Varambally1,4,
- Rohit Mehra1,4 &
- …
- Arul M. Chinnaiyan1,2,4
Nature volume 448, pages 595–599 (2007)Cite this article
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Abstract
Recently, we identified recurrent gene fusions involving the 5′ untranslated region of the androgen-regulated gene TMPRSS2 and the ETS (E26 transformation-specific) family genes ERG, ETV1 or ETV4 in most prostate cancers1,2. Whereas TMPRSS2–ERG fusions are predominant, fewer TMPRSS2–ETV1 cases have been identified than expected on the basis of the frequency of high (outlier) expression of ETV1 (refs 3–13). Here we explore the mechanism of ETV1 outlier expression in human prostate tumours and prostate cancer cell lines. We identified previously unknown 5′ fusion partners in prostate tumours with ETV1 outlier expression, including untranslated regions from a prostate-specific androgen-induced gene (SLC45A3) and an endogenous retroviral element (HERV-K_22q11.23), a prostate-specific androgen-repressed gene (C15orf21), and a strongly expressed housekeeping gene (HNRPA2B1). To study aberrant activation of ETV1, we identified two prostate cancer cell lines, LNCaP and MDA-PCa 2B, that had ETV1 outlier expression. Through distinct mechanisms, the entire ETV1 locus (7p21) is rearranged to a 1.5-megabase prostate-specific region at 14q13.3–14q21.1 in both LNCaP cells (cryptic insertion) and MDA-PCa 2B cells (balanced translocation). Because the common factor of these rearrangements is aberrant ETV1 overexpression, we recapitulated this event in vitro and in vivo, demonstrating that ETV1 overexpression in benign prostate cells and in the mouse prostate confers neoplastic phenotypes. Identification of distinct classes of ETS gene rearrangements demonstrates that dormant oncogenes can be activated in prostate cancer by juxtaposition to tissue-specific or ubiquitously active genomic loci. Subversion of active genomic regulatory elements may serve as a more generalized mechanism for carcinoma development. Furthermore, the identification of androgen-repressed and insensitive 5′ fusion partners may have implications for the anti-androgen treatment of advanced prostate cancer.
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Change history
08 October 2007
The original publication of this paper had the incorrect name 'Presner' in the Acknowledgements. This was corrected to 'Prenser' on 8 Oct 2007
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Acknowledgements
We thank D. Rhodes, S. Kalyana-Sundaram and T. Barrette for support of the OCM, L. Smith for cytogenetics assistance, E. Keller and J. Macoska for prostate cancer cell lines, J. Moran for discussions regarding endogenous retroviral elements, J. Prensner for technical assistance, and R. Craig and L. Stoolman for the FACS analysis. We thank the UM Transgenic Animal Model Core for generating transgenic mice and the UM Vector core for virus generation. This work was supported in part by Department of Defense (to R.M., A.M.C. and S.V.), the National Institutes of Health (to K.J.P., A.M.C., R.B.S., K.J.P. and A.M.C.), the Early Detection Research Network (to A.M.C.), the Prostate Cancer Foundation (to A.M.C.), and Gen-Probe Incorporated (to A.M.C.). A.M.C. is supported by a Clinical Translational Research Award from the Burroughs Wellcome Foundation. S.A.T. is supported by a Rackham Predoctoral Fellowship. K.J.P. is supported as an American Cancer Society Clinical Research Professor. S.A.T. is a Fellow of the Medical Scientist Training Program.
The primary microarray data have been deposited in NCBI’s Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) under the GEO series accession numbers GSE7701 and GSE7702. Sequences of the ETV1 fusion transcript junctions identified by RACE have been deposited in GenBank under accession numbers EF632109–EF632112.
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Author notes
Scott A. Tomlins, Bharathi Laxman and Saravana M. Dhanasekaran: These authors contributed equally to this work.
Authors and Affiliations
Department of Pathology, Michigan Center for Translational Pathology,
Scott A. Tomlins, Bharathi Laxman, Saravana M. Dhanasekaran, Beth E. Helgeson, Xuhong Cao, Anjana Menon, Xiaojun Jing, Qi Cao, Bo Han, Jindan Yu, Lei Wang, Diane Roulston, Rajal B. Shah, Sooryanarayana Varambally, Rohit Mehra & Arul M. Chinnaiyan
Department of Urology,,
David S. Morris, James E. Montie, Kenneth J. Pienta, Rajal B. Shah & Arul M. Chinnaiyan
Department of Internal Medicine, and,
Kenneth J. Pienta
Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA,
James E. Montie, Kenneth J. Pienta, Rajal B. Shah, Sooryanarayana Varambally, Rohit Mehra & Arul M. Chinnaiyan
Department of Pathology, Brigham and Women’s Hospital,
Mark A. Rubin
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA,
Mark A. Rubin
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Correspondence to Arul M. Chinnaiyan.
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Competing interests
The University of Michigan has filed for a patent on the detection of gene fusions in prostate cancer, on which S.A.T., R.M., M.A.R. and A.M.C. are co-inventors. The diagnostic field of use has been licensed to GenProbe Inc. A.M.C. also has a sponsored research agreement with GenProbe; however, GenProbe has had no role in the design or experimentation of this study, nor has it participated in the writing of the manuscript. Oncomine and the OCM are freely available to the academic community. The commerical rights to Oncomine and OCM have been licensed to Compendia Bioscience, which A.M.C. cofounded.
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Tomlins, S., Laxman, B., Dhanasekaran, S. et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature 448, 595–599 (2007). https://doi.org/10.1038/nature06024
Received: 27 April 2007
Accepted: 16 June 2007
Issue Date: 02 August 2007
DOI: https://doi.org/10.1038/nature06024