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Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer - Nature

  • ️Chinnaiyan, Arul M.
  • ️Thu Aug 02 2007

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 TMPRSS2ERG 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

References

  1. Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005)

    Article  ADS  CAS  Google Scholar 

  2. Tomlins, S. A. et al. TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer. Cancer Res. 66, 3396–3400 (2006)

    Article  CAS  Google Scholar 

  3. Cerveira, N. et al. TMPRSS2–ERG gene fusion causing ERG overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions. Neoplasia 8, 826–832 (2006)

    Article  CAS  Google Scholar 

  4. Glinsky, G. V., Glinskii, A. B., Stephenson, A. J., Hoffman, R. M. & Gerald, W. L. Gene expression profiling predicts clinical outcome of prostate cancer. J. Clin. Invest. 113, 913–923 (2004)

    Article  CAS  Google Scholar 

  5. Hermans, K. G. et al. TMPRSS2:ERG fusion by translocation or interstitial deletion is highly relevant in androgen-dependent prostate cancer, but is bypassed in late-stage androgen receptor-negative prostate cancer. Cancer Res. 66, 10658–10663 (2006)

    Article  CAS  Google Scholar 

  6. Lapointe, J. et al. Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc. Natl Acad. Sci. USA 101, 811–816 (2004)

    Article  ADS  CAS  Google Scholar 

  7. Mehra, R. et al. Comprehensive assessment of TMPRSS2 and ETS family gene aberrations in clinically localized prostate cancer. Mod. Pathol. 6, 1177–1187 (2007)

    Google Scholar 

  8. Perner, S. et al. TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Res. 66, 8337–8341 (2006)

    Article  CAS  Google Scholar 

  9. Soller, M. J. et al. Confirmation of the high frequency of the TMPRSS2/ERG fusion gene in prostate cancer. Genes Chromosom. Cancer 45, 717–719 (2006)

    Article  CAS  Google Scholar 

  10. Tomlins, S. A. et al. Integrative molecular concept modeling of prostate cancer progression. Nature Genet. 39, 41–51 (2007)

    Article  CAS  Google Scholar 

  11. Winnes, M., Lissbrant, E., Damber, J. E. & Stenman, G. Molecular genetic analyses of the TMPRSS2–ERG and TMPRSS2–ETV1 gene fusions in 50 cases of prostate cancer. Oncol. Rep. 17, 1033–1036 (2007)

    CAS  PubMed  Google Scholar 

  12. Yoshimoto, M. et al. Three-color FISH analysis of TMPRSS2/ERG fusions in prostate cancer indicates that genomic microdeletion of chromosome 21 is associated with rearrangement. Neoplasia 8, 465–469 (2006)

    Article  CAS  Google Scholar 

  13. Yu, Y. P. et al. Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J. Clin. Oncol. 22, 2790–2799 (2004)

    Article  CAS  Google Scholar 

  14. Mitelman, F., Johansson, B. & Mertens, F. Fusion genes and rearranged genes as a linear function of chromosome aberrations in cancer. Nature Genet. 36, 331–334 (2004)

    Article  CAS  Google Scholar 

  15. Rowley, J. D. Chromosome translocations: dangerous liaisons revisited. Nature Rev. Cancer 1, 245–250 (2001)

    Article  CAS  Google Scholar 

  16. Lin, B. et al. Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer Res. 59, 4180–4184 (1999)

    CAS  PubMed  Google Scholar 

  17. Mertz, K. D. et al. Molecular characterization of the TMPRSS2–ERG gene fusion in the NCI-H660 prostate cancer cell line—a new perspective for an old model. Neoplasia 9, 200–206 (2007)

    Article  CAS  Google Scholar 

  18. Rabbitts, T. H. Chromosomal translocations in human cancer. Nature 372, 143–149 (1994)

    Article  ADS  CAS  Google Scholar 

  19. Demichelis, F. et al. TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene advance online publication, doi: 10.1038/sj.onc.1210237 (22 January 2007)

  20. van Bokhoven, A. et al. Spectral karyotype (SKY) analysis of human prostate carcinoma cell lines. Prostate 57, 226–244 (2003)

    Article  CAS  Google Scholar 

  21. Cai, C. et al. ETV1 is a novel androgen receptor-regulated gene that mediates prostate cancer cell invasion. Mol. Endocrinol. advance online publication, doi: 10.1210/me.2006-0480 (15 May 2007)

  22. Rhodes, D. R. et al. Molecular concepts analysis links tumors, pathways, mechanisms, and drugs. Neoplasia 9, 443–454 (2007)

    Article  CAS  Google Scholar 

  23. Ellwood-Yen, K. et al. Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell 4, 223–238 (2003)

    Article  CAS  Google Scholar 

  24. Shappell, S. B. et al. Prostate pathology of genetically engineered mice: definitions and classification. The consensus report from the Bar Harbor meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee. Cancer Res. 64, 2270–2305 (2004)

    Article  CAS  Google Scholar 

  25. Suzukawa, K. et al. Identification of a breakpoint cluster region 3′ of the ribophorin I gene at 3q21 associated with the transcriptional activation of the EVI1 gene in acute myelogenous leukemias with inv(3)(q21q26). Blood 84, 2681–2688 (1994)

    CAS  PubMed  Google Scholar 

  26. Wieser, R. Rearrangements of chromosome band 3q21 in myeloid leukemia. Leuk. Lymphoma 43, 59–65 (2002)

    Article  CAS  Google Scholar 

  27. Rhodes, D. R. et al. Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia 9, 166–180 (2007)

    Article  CAS  Google Scholar 

  28. Beheshti, B., Karaskova, J., Park, P. C., Squire, J. A. & Beatty, B. G. Identification of a high frequency of chromosomal rearrangements in the centromeric regions of prostate cancer cell lines by sequential giemsa banding and spectral karyotyping. Mol. Diagn. 5, 23–32 (2000)

    Article  CAS  Google Scholar 

  29. Rubin, M. A. et al. Rapid (“warm”) autopsy study for procurement of metastatic prostate cancer. Clin. Cancer Res. 6, 1038–1045 (2000)

    CAS  PubMed  Google Scholar 

  30. Korenchuk, S. et al. VCaP, a cell-based model system of human prostate cancer. In Vivo 15, 163–168 (2001)

    CAS  PubMed  Google Scholar 

  31. Vandesompele, J. et al. Accurate normalization of real-time quantitative RT–PCR data by geometric averaging of multiple internal control genes. Genome Biol. 3, RESEARCH0034 (2002)

    Article  Google Scholar 

  32. Specht, K. et al. Quantitative gene expression analysis in microdissected archival formalin-fixed and paraffin-embedded tumor tissue. Am. J. Pathol. 158, 419–429 (2001)

    Article  CAS  Google Scholar 

  33. Stauffer, Y., Theiler, G., Sperisen, P., Lebedev, Y. & Jongeneel, C. V. Digital expression profiles of human endogenous retroviral families in normal and cancerous tissues. Cancer Immun. 4, 2 (2004)

    PubMed  Google Scholar 

  34. Wiemels, J. L. & Greaves, M. Structure and possible mechanisms of TEL–AML1 gene fusions in childhood acute lymphoblastic leukemia. Cancer Res. 59, 4075–4082 (1999)

    CAS  PubMed  Google Scholar 

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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

  1. Scott A. Tomlins, Bharathi Laxman and Saravana M. Dhanasekaran: These authors contributed equally to this work.

Authors and Affiliations

  1. 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

  2. Department of Urology,,

    David S. Morris, James E. Montie, Kenneth J. Pienta, Rajal B. Shah & Arul M. Chinnaiyan

  3. Department of Internal Medicine, and,

    Kenneth J. Pienta

  4. 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

  5. Department of Pathology, Brigham and Women’s Hospital,

    Mark A. Rubin

  6. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA,

    Mark A. Rubin

Authors

  1. Scott A. Tomlins

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  2. Bharathi Laxman

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  3. Saravana M. Dhanasekaran

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  4. Beth E. Helgeson

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  5. Xuhong Cao

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  6. David S. Morris

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  7. Anjana Menon

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  8. Xiaojun Jing

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  9. Qi Cao

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  10. Bo Han

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  11. Jindan Yu

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  12. Lei Wang

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  13. James E. Montie

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  14. Mark A. Rubin

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  15. Kenneth J. Pienta

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  16. Diane Roulston

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  17. Rajal B. Shah

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  18. Sooryanarayana Varambally

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  19. Rohit Mehra

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  20. Arul M. Chinnaiyan

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Corresponding author

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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Supplementary Information

This file contains Supplementary Figures 1-16 with Legends, Supplementary Tables 1-5, Supplementary Discussion and additional references. (PDF 3607 kb)

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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

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  • Received: 27 April 2007

  • Accepted: 16 June 2007

  • Issue Date: 02 August 2007

  • DOI: https://doi.org/10.1038/nature06024

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