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| Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer |
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| Author(s): Tomlins SA (Tomlins, Scott A.), Laxman B (Laxman, Bharathi), Dhanasekaran SM (Dhanasekaran, Saravana M.), Helgeson BE (Helgeson, Beth E.), Cao XH (Cao, Xuhong), Morris DS (Morris, David S.), Menon A (Menon, Anjana), Jing XJ (Jing, Xiaojun), Cao Q (Cao, Qi), Han B (Han, Bo), Yu JD (Yu, Jindan), Wang L (Wang, Lei), Montie JE (Montie, James E.), Rubin MA (Rubin, Mark A.), Pienta KJ (Pienta, Kenneth J.), Roulston D (Roulston, Diane), Shah RB (Shah, Rajal B.), Varambally S (Varambally, Sooryanarayana), Mehra R (Mehra, Rohit), Chinnaiyan AM (Chinnaiyan, Arul M.) |
| Source: NATURE Volume: 448 Issue: 7153 Pages: 595-U9 Published: AUG 2 2007 |
| Times Cited: 109 References: 34 |
| Abstract: Recently, we identified recurrent gene fusions involving the 59 untranslated region of the androgen-regulated gene TMPRSS2 and the ETS (E26 transformation-specific) family genes ERG, ETV1 or ETV4 in most prostate cancers(1,2). Whereas TMPRSS2 ERG 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 59 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 59 fusion partners may have implications for the anti-androgen treatment of advanced prostate cancer. |
| Document Type: Article |
| Language: English |
| Reprint Address: Chinnaiyan, AM (reprint author), Univ Michigan, Sch Med, Michigan Ctr Translat Pathol, Dept Pathol, Ann Arbor, MI 48109 USA |
Addresses:
1. Univ Michigan, Sch Med, Michigan Ctr Translat Pathol, Dept Pathol, Ann Arbor, MI 48109 USA
2. Univ Michigan, Sch Med, Dept Urol, Ann Arbor, MI 48109 USA
3. Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA
4. Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA
5. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA |
| Publisher: NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND |
| Subject Category: Multidisciplinary Sciences |
| IDS Number: 195XV |
| ISSN: 0028-0836 |
| DOI: 10.1038/nature06024 |
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