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Recurrent Fusion of TMPRSS2 and ETS Transcription Factor Genes in Prostate Cancer
Scott A. Tomlins,1Daniel R. Rhodes,1,2Sven Perner,7,9Saravana M. Dhanasekaran,1Rohit Mehra,1Xiao-Wei Sun,7Sooryanarayana Varambally,1,6Xuhong Cao,1Joelle Tchinda,7Rainer Kuefer,10Charles Lee,7James E. Montie,3,5,6Rajal B. Shah,1,3,5,6Kenneth J. Pienta,3,4,5,6Mark A. Rubin,7,8Arul M. Chinnaiyan1,2,3,5,6*
Recurrent chromosomal rearrangements have not been well characterizedin common carcinomas. We used a bioinformatics approach to discovercandidate oncogenic chromosomal aberrations on the basis ofoutlier gene expression. Two ETS transcription factors, ERGand ETV1, were identified as outliers in prostate cancer. Weidentified recurrent gene fusions of the 5' untranslated regionof TMPRSS2 to ERG or ETV1 in prostate cancer tissues with outlierexpression. By using fluorescence in situ hybridization, wedemonstrated that 23 of 29 prostate cancer samples harbor rearrangementsin ERG or ETV1. Cell line experiments suggest that the androgen-responsivepromoter elements of TMPRSS2 mediate the overexpression of ETSfamily members in prostate cancer. These results have implicationsin the development of carcinomas and the molecular diagnosisand treatment of prostate cancer.
1 Department of Pathology, University of Michigan Medical School, 1301 Catherine Street, Ann Arbor, MI 48109–0602, USA. 2 Bioinformatics Program, University of Michigan Medical School, 1301 Catherine Street, Ann Arbor, MI 48109–0602, USA. 3 Department of Urology, University of Michigan Medical School, 1301 Catherine Street, Ann Arbor, MI 48109–0602, USA. 4 Department of Internal Medicine, University of Michigan Medical School, 1301 Catherine Street, Ann Arbor, MI 48109–0602, USA. 5 Michigan Urology Center, University of Michigan Medical School, 1301 Catherine Street, Ann Arbor, MI 48109–0602, USA. 6 Comprehensive Cancer Center, University of Michigan Medical School, 1301 Catherine Street, Ann Arbor, MI 48109–0602, USA. 7 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. 8 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. 9 Department of Pathology, Harvard Medical School, Boston, MA 02115, USA. 10 Department of Urology, Faculty of Medicine, University of Ulm, Ulm 89075, Germany.
* To whom correspondence should be addressed. E-mail: arul{at}umich.edu
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Steroid Receptor Coactivator-3/AIB1 Promotes Cell Migration and Invasiveness through Focal Adhesion Turnover and Matrix Metalloproteinase Expression.
J. Yan, H. Erdem, R. Li, Y. Cai, G. Ayala, M. Ittmann, L.-y. Yu-Lee, S. Y. Tsai, and M.-J. Tsai (2008)
Cancer Res.
68, 5460-5468
|Abstract »|Full Text »|PDF »
MOST: detecting cancer differential gene expression.
Estrogen-Dependent Signaling in a Molecularly Distinct Subclass of Aggressive Prostate Cancer.
S. R. Setlur, K. D. Mertz, Y. Hoshida, F. Demichelis, M. Lupien, S. Perner, A. Sboner, Y. Pawitan, O. Andren, L. A. Johnson, et al. (2008)
J Natl Cancer Inst
100, 815-825
|Abstract »|Full Text »|PDF »
Characterization of TMPRSS2-ERG Fusion High-Grade Prostatic Intraepithelial Neoplasia and Potential Clinical Implications.
J.-M. Mosquera, S. Perner, E. M. Genega, M. Sanda, M. D. Hofer, K. D. Mertz, P. L. Paris, J. Simko, T. A. Bismar, G. Ayala, et al. (2008)
Clin. Cancer Res.
14, 3380-3385
|Abstract »|Full Text »|PDF »
TMPRSS2:ERG Fusion Identifies a Subgroup of Prostate Cancers with a Favorable Prognosis.
O. R. Saramaki, A. E. Harjula, P. M. Martikainen, R. L. Vessella, T. L.J. Tammela, and T. Visakorpi (2008)
Clin. Cancer Res.
14, 3395-3400
|Abstract »|Full Text »|PDF »
Characterization of TMPRSS2-ETS Gene Aberrations in Androgen-Independent Metastatic Prostate Cancer.
R. Mehra, S. A. Tomlins, J. Yu, X. Cao, L. Wang, A. Menon, M. A. Rubin, K. J. Pienta, R. B. Shah, and A. M. Chinnaiyan (2008)
Cancer Res.
68, 3584-3590
|Abstract »|Full Text »|PDF »
Two Unique Novel Prostate-Specific and Androgen-Regulated Fusion Partners of ETV4 in Prostate Cancer.
K. G. Hermans, A. A. Bressers, H. A. van der Korput, N. F. Dits, G. Jenster, and J. Trapman (2008)
Cancer Res.
68, 3094-3098
|Abstract »|Full Text »|PDF »
Functions of Normal and Malignant Prostatic Stem/Progenitor Cells in Tissue Regeneration and Cancer Progression and Novel Targeting Therapies.
M. Mimeault, P. P. Mehta, R. Hauke, and S. K. Batra (2008)
Endocr. Rev.
29, 234-252
|Abstract »|Full Text »|PDF »
Detection of chromosome changes in pathology archives: an application of microwave-assisted fluorescence in situ hybridization to human carcinogenesis studies.
Identification of Prognostic Biomarkers for Prostate Cancer.
F. Kosari, J. M. A. Munz, C. D. Savci-Heijink, C. Spiro, E. W. Klee, D. M. Kube, L. Tillmans, J. Slezak, R. J. Karnes, J. C. Cheville, et al. (2008)
Clin. Cancer Res.
14, 1734-1743
|Abstract »|Full Text »|PDF »
Inhibition of the Ras-Net (Elk-3) Pathway by a Novel Pyrazole that Affects Microtubules.
C. Wasylyk, H. Zheng, C. Castell, L. Debussche, M.-C. Multon, and B. Wasylyk (2008)
Cancer Res.
68, 1275-1283
|Abstract »|Full Text »|PDF »
Humoral Response Profiling Reveals Pathways to Prostate Cancer Progression.
B. S. Taylor, M. Pal, J. Yu, B. Laxman, S. Kalyana-Sundaram, R. Zhao, A. Menon, J. T. Wei, A. I. Nesvizhskii, D. Ghosh, et al. (2008)
Mol. Cell. Proteomics
7, 600-611
|Abstract »|Full Text »|PDF »
WDR19 Expression is Increased in Prostate Cancer Compared with Normal Cells, but Low-Intensity Expression in Cancers is Associated with Shorter Time to Biochemical Failures and Local Recurrence.
B. Lin, A. G. Utleg, K. Gravdal, J. T. White, O. J. Halvorsen, W. Lu, L. D. True, R. Vessella, P. H. Lange, P. S. Nelson, et al. (2008)
Clin. Cancer Res.
14, 1397-1406
|Abstract »|Full Text »|PDF »
A causal role for ERG in neoplastic transformation of prostate epithelium.
O. Klezovitch, M. Risk, I. Coleman, J. M. Lucas, M. Null, L. D. True, P. S. Nelson, and V. Vasioukhin (2008)
PNAS
105, 2105-2110
|Abstract »|Full Text »|PDF »
A First-Generation Multiplex Biomarker Analysis of Urine for the Early Detection of Prostate Cancer.
B. Laxman, D. S. Morris, J. Yu, J. Siddiqui, J. Cao, R. Mehra, R. J. Lonigro, A. Tsodikov, J. T. Wei, S. A. Tomlins, et al. (2008)
Cancer Res.
68, 645-649
|Abstract »|Full Text »|PDF »
Interplay of Nuclear Factor-{kappa}B and B-myb in the Negative Regulation of Androgen Receptor Expression by Tumor Necrosis Factor {alpha}.
S. Ko, L. Shi, S. Kim, C. S. Song, and B. Chatterjee (2008)
Mol. Endocrinol.
22, 273-286
|Abstract »|Full Text »|PDF »
Starvation Induces Genomic Rearrangements and Starvation-Resilient Phenotypes in Yeast.
