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Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer

Oncogene volume 27, pages 253–263 (2008)Cite this article

Abstract

New predictive markers for managing prostate cancer are urgently required because of the highly variable natural history of this disease. At the time of diagnosis, Gleason score provides the gold standard for assessing the aggressiveness of prostate cancer. However, the recent discovery of TMPRSS2 fusions to the ERG gene in prostate cancer raises the possibility of using alterations at the ERG locus as additional mechanism-based prognostic indicators. Fluorescence in situ hybridization (FISH) assays were used to assess ERG gene status in a cohort of 445 prostate cancers from patients who had been conservatively managed. The FISH assays detected separation of 5′ (labelled green) and 3′ (labelled red) ERG sequences, which is a consequence of the TMPRSS2–ERG fusion, and additionally identify interstitial deletion of genomic sequences between the tandemly located TMPRSS2 and ERG gene sequences on chromosome 21. Cancers lacking ERG alterations exhibited favourable cause-specific survival (90% survival at 8 years). We identify a novel category of prostate cancers, characterized by duplication of the fusion of TMPRSS2 to ERG sequences together with interstitial deletion of sequences 5′ to ERG (called ‘2+Edel’), which by comparison exhibited extremely poor cause-specific survival (hazard ratio=6.10, 95% confidence ratio=3.33–11.15, P<0.001, 25% survival at 8 years). In multivariate analysis, ‘2+Edel’ provided significant prognostic information (P=0.003) in addition to that provided by Gleason score and prostate-specific antigen level at diagnosis. Other individual categories of ERG alteration were associated with intermediate or good prognosis. We conclude that determination of ERG gene status, including duplication of the fusion of TMPRSS2 to ERG sequences in 2+Edel, allows stratification of prostate cancer into distinct survival categories.

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Acknowledgements

This work was funded by Cancer Research UK, National Cancer Research Institute, a specialized program of Research Excellence grant from US National Cancer Institute, Grand Charity of Freemasons, Rosetrees Trust, The Bob Champion Cancer Trust, The Orchid Appeal and David Koch Foundation. Funding bodies had no involvement in the design and conduct of the study, or in collection management, analysis and interpretation of the data or in preparation, review or approval of the manuscript. We thank Christine Bell and Sandra Edwards for help in typing the manuscript and preparing figures and tables.

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Author notes

  1. G Attard and J Clark: Joint first authors.

Authors and Affiliations

  1. Institute of Cancer Research,

    G Attard, J Clark, P Flohr, A Fletcher & C S Cooper

  2. Male Urological Cancer Research Centre, Surrey, UK

    G Attard, J Clark, P Flohr, A Fletcher & C S Cooper

  3. The Royal Marsden NHS Trust Foundation Hospital, Surrey, UK

    G Attard & J S De Bono

  4. Wolfson Institute of Preventive Medicine, University of London, London, UK

    L Ambroisine, G Fisher & J Cuzick

  5. Ruprecht-Karls-Universitat, Medical Faculty, Laboratory of Molecular Oncology, Heidelberg, Germany

    G Kovacs

  6. Department of Histopathology, St Bartholomew's Hospital, London, UK

    D Berney

  7. Department of Pathology, Royal Liverpool University Hospital, Liverpool, UK

    C S Foster

  8. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    W L Gerald & V Reuter

  9. Kings College, Thames Cancer Registry, London, UK

    H Moller

  10. Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    P Scardino

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on behalf of the Transatlantic Prostate Group

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Correspondence to C S Cooper.

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Attard, G., Clark, J., Ambroisine, L. et al. Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene 27, 253–263 (2008). https://doi.org/10.1038/sj.onc.1210640

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