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Science 28 October 2005:
Vol. 310. no. 5748, pp. 644 - 648
DOI: 10.1126/science.1117679
Prev | Table of Contents | Next

Research Articles

Recurrent Fusion of TMPRSS2 and ETS Transcription Factor Genes in Prostate Cancer

Scott A. Tomlins,1 Daniel R. Rhodes,1,2 Sven Perner,7,9 Saravana M. Dhanasekaran,1 Rohit Mehra,1 Xiao-Wei Sun,7 Sooryanarayana Varambally,1,6 Xuhong Cao,1 Joelle Tchinda,7 Rainer Kuefer,10 Charles Lee,7 James E. Montie,3,5,6 Rajal B. Shah,1,3,5,6 Kenneth J. Pienta,3,4,5,6 Mark A. Rubin,7,8 Arul M. Chinnaiyan1,2,3,5,6*

Recurrent chromosomal rearrangements have not been well characterized in common carcinomas. We used a bioinformatics approach to discover candidate oncogenic chromosomal aberrations on the basis of outlier gene expression. Two ETS transcription factors, ERG and ETV1, were identified as outliers in prostate cancer. We identified recurrent gene fusions of the 5' untranslated region of TMPRSS2 to ERG or ETV1 in prostate cancer tissues with outlier expression. By using fluorescence in situ hybridization, we demonstrated that 23 of 29 prostate cancer samples harbor rearrangements in ERG or ETV1. Cell line experiments suggest that the androgen-responsive promoter elements of TMPRSS2 mediate the overexpression of ETS family members in prostate cancer. These results have implications in the development of carcinomas and the molecular diagnosis and 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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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
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Starvation Induces Genomic Rearrangements and Starvation-Resilient Phenotypes in Yeast.
S. Coyle and E. Kroll (2008)
Mol. Biol. Evol. 25, 310-318
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Oncogenes and Cancer.
C. M. Croce (2008)
N. Engl. J. Med. 358, 502-511
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Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 Gene Fusions in Prostate Cancer.
B. E. Helgeson, S. A. Tomlins, N. Shah, B. Laxman, Q. Cao, J. R. Prensner, X. Cao, N. Singla, J. E. Montie, S. Varambally, et al. (2008)
Cancer Res. 68, 73-80
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Glutamine tract length of human androgen receptors affects hormone-dependent and -independent prostate cancer in mice.
M. A. Albertelli, O. A. O'Mahony, M. Brogley, J. Tosoian, M. Steinkamp, S. Daignault, K. Wojno, and D. M. Robins (2008)
Hum. Mol. Genet. 17, 98-110
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Detection of TMPRSS2-ERG Translocations in Human Prostate Cancer by Expression Profiling Using GeneChip Human Exon 1.0 ST Arrays.
S. Jhavar, A. Reid, J. Clark, Z. Kote-Jarai, T. Christmas, A. Thompson, C. Woodhouse, C. Ogden, C. Fisher, C. Corbishley, et al. (2008)
J. Mol. Diagn. 10, 50-57
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PADGE: analysis of heterogeneous patterns of differential gene expression.
L. Li, A. Chaudhuri, J. Chant, and Z. Tang (2007)
Physiol Genomics 32, 154-159
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Androgen Receptor Structural and Functional Elements: Role and Regulation in Prostate Cancer.
S. M. Dehm and D. J. Tindall (2007)
Mol. Endocrinol. 21, 2855-2863
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Integrative Microarray Analysis of Pathways Dysregulated in Metastatic Prostate Cancer.
S. R. Setlur, T. E. Royce, A. Sboner, J.-M. Mosquera, F. Demichelis, M. D. Hofer, K. D. Mertz, M. Gerstein, and M. A. Rubin (2007)
Cancer Res. 67, 10296-10303
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Androgen Induction of the Androgen Receptor Coactivator Four and a Half LIM Domain Protein-2: Evidence for a Role for Serum Response Factor in Prostate Cancer.
H. V. Heemers, K. M. Regan, S. M. Dehm, and D. J. Tindall (2007)
Cancer Res. 67, 10592-10599
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TMPRSS2-ETS fusion prostate cancer: biological and clinical implications.
F. Demichelis and M. A Rubin (2007)
J. Clin. Pathol. 60, 1185-1186
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Optimization of primer design for the detection of variable genomic lesions in cancer.
A. Bashir, Y.-T. Liu, B. J. Raphael, D. Carson, and V. Bafna (2007)
Bioinformatics 23, 2807-2815
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Extracting three-way gene interactions from microarray data.
J. Zhang, Y. Ji, and L. Zhang (2007)
Bioinformatics 23, 2903-2909
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Frequency of the TMPRSS2:ERG gene fusion is increased in moderate to poorly differentiated prostate cancers.
A. B Rajput, M. A Miller, A. De Luca, N. Boyd, S. Leung, A. Hurtado-Coll, L. Fazli, E. C Jones, J. B Palmer, M. E Gleave, et al. (2007)
J. Clin. Pathol. 60, 1238-1243
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Genomic Profiling Reveals Alternative Genetic Pathways of Prostate Tumorigenesis.
J. Lapointe, C. Li, C. P. Giacomini, K. Salari, S. Huang, P. Wang, M. Ferrari, T. Hernandez-Boussard, J. D. Brooks, and J. R. Pollack (2007)
Cancer Res. 67, 8504-8510
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Heterogeneity of TMPRSS2 Gene Rearrangements in Multifocal Prostate Adenocarcinoma: Molecular Evidence for an Independent Group of Diseases.
R. Mehra, B. Han, S. A. Tomlins, L. Wang, A. Menon, M. J. Wasco, R. Shen, J. E. Montie, A. M. Chinnaiyan, and R. B. Shah (2007)
Cancer Res. 67, 7991-7995
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Integrative Analysis of Genomic Aberrations Associated with Prostate Cancer Progression.
J. H. Kim, S. M. Dhanasekaran, R. Mehra, S. A. Tomlins, W. Gu, J. Yu, C. Kumar-Sinha, X. Cao, A. Dash, L. Wang, et al. (2007)
Cancer Res. 67, 8229-8239
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Diagnostic Pathology and Laboratory Medicine in the Age of "Omics": A Paper from the 2006 William Beaumont Hospital Symposium on Molecular Pathology.
W. G. Finn (2007)
J. Mol. Diagn. 9, 431-436
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Spectral Karyotyping Detects Chromosome Damage in Bronchial Cells of Smokers and Patients with Cancer.
M. Varella-Garcia, L. Chen, R. L. Powell, F. R. Hirsch, T. C. Kennedy, R. Keith, Y. E. Miller, J. D. Mitchell, and W. A. Franklin (2007)
Am. J. Respir. Crit. Care Med. 176, 505-512
   Abstract »    Full Text »    PDF »
Detection of TMPRSS2-ERG Fusion Transcripts and Prostate Cancer Antigen 3 in Urinary Sediments May Improve Diagnosis of Prostate Cancer.
D. Hessels, F. P. Smit, G. W. Verhaegh, J. A. Witjes, E. B. Cornel, and J. A. Schalken (2007)
Clin. Cancer Res. 13, 5103-5108
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