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Cooperativity of TMPRSS2-ERG with PI3-kinase pathway activation in prostate oncogenesis

Nature Genetics volume 41, pages 524–526 (2009)Cite this article

Abstract

The TMPRSS2-ERG fusion, present in approximately 50% of prostate cancers, is less common in prostatic intraepithelial neoplasia (PIN), raising questions about whether TMPRSS2-ERG contributes to disease initiation. We identified the translational start site of a common TMPRSS2-ERG fusion and showed that transgenic TMPRSS2-ERG mice develop PIN, but only in the context of PI3-kinase pathway activation. TMPRSS2-ERG–positive human tumors are also enriched for PTEN loss, suggesting cooperation in prostate tumorigenesis.

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Figure 1: TMPRSS2-ERG fusion transcript produces a truncated ERG protein product.
Figure 2: TMPRSS2-ERG fusion and PI3K-pathway activation are cooperative events in prostate cancer.

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Acknowledgements

J.C.K. is supported by a NIH/NCI Ruth L. Kirschstein NRSA (7F32CA113132). C.L.S. is supported by the Howard Hughes Medical Institute and the Doris Duke Foundation. B.S.T. is supported by a MSKCC Geoffrey Beene Cancer Research Center fellowship. We thank K. Yen, N. Clegg, Y. Chen, T. Shamu and the MSKCC CMG, Proteomics, and Molecular Cytology Core Facilities for technical help and/or discussions. We also thank P.P. Pandolfi (Beth Israel Deaconess Medical Center, Harvard University) for sharing unpublished results and V. Vasioukhin (Fred Hutchinson Cancer Research Center) for providing transgenic prostate lobes.

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Authors and Affiliations

  1. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Jennifer C King, Jin Xu, John Wongvipat, Haley Hieronymus, Brett S Carver, David H Leung, William L Gerald & Charles L Sawyers

  2. Computational and Systems Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Barry S Taylor & Chris Sander

  3. Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, USA

    Barry S Taylor

  4. Department of Pathology and Laboratory Medicine, Center for Comparative Medicine, University of California, Davis, California, USA

    Robert D Cardiff

  5. Laboratory of Comparative Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Suzana S Couto

  6. Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Charles L Sawyers

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  1. Jennifer C King
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Contributions

J.C.K., J.X., J.W., D.H.L., B.S.C. and C.L.S. designed, created and characterized the transgenic animals. S.S.C. and R.D.C. performed the pathological analysis. J.X. and C.L.S. identified the potential start site. H.H., B.S.T., C.S. and W.L.G. performed and analyzed the CGH and exon array experiments. J.C.K. and C.L.S. wrote the initial draft of the manuscript and all authors contributed to the final version.

Corresponding author

Correspondence to Charles L Sawyers.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2, Supplementary Methods (PDF 961 kb)

Supplementary Table 1

aCGH data (XLS 96 kb)

Supplementary Table 2

Raw expression data (XLS 461 kb)

Supplementary Table 3

Log transformed ERG core expression data (XLS 107 kb)

Supplementary Table 4

Merged expression data (XLS 38 kb)

Supplementary Table 5

Discretized aCGH and expression data (XLS 36 kb)

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King, J., Xu, J., Wongvipat, J. et al. Cooperativity of TMPRSS2-ERG with PI3-kinase pathway activation in prostate oncogenesis. Nat Genet 41, 524–526 (2009). https://doi.org/10.1038/ng.371

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