Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer
Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer
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DOI：
10.1038/nature06024
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发表时间：
2007-08-02
期刊：
影响因子：
64.8
通讯作者：
Chinnaiyan, Arul M.
中科院分区：
文献类型：
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作者：
Tomlins, Scott A.;Laxman, Bharathi;Chinnaiyan, Arul M.
最近，我们在大多数前列腺癌(1，2)中发现了涉及雄激素调节基因TMPRSS2的59个非翻译区和E26转化特异性(E26)家族基因ERG、ETV1或ETV4的复发基因融合。虽然TMPRSS2 ERG融合占主导地位，但根据ETV1高(异常)表达的频率，TMPRSS2-ETV1病例比预期的要少(参考文献3-13)。在这里，我们探索了ETV1在人类前列腺癌和前列腺癌细胞系中异常表达的机制。我们在前列腺癌中发现了59个以前未知的ETV1异常表达的融合伙伴，包括前列腺特异性雄激素诱导基因(SLC45A3)和内源性逆转录病毒元件(HERV-K_22q11.23)的非翻译区，前列腺特异性雄激素抑制基因(C15orf21)和强表达的管家基因(HNRPA2B1)。为了研究ETV1的异常激活，我们鉴定了两个前列腺癌细胞系LNCaP和MDA-PCA2B，它们都有ETV1的异常表达。通过不同的机制，在LNCaP细胞(隐蔽插入)和MDA-PCa 2B细胞(平衡易位)中，整个ETV1基因座(7p21)被重排到14q13.3-14q21.1处的1.5兆碱基的前列腺特异性区域。由于这些重排的共同因素是ETV1的异常过表达，我们在体外和体内总结了这一事件，表明ETV1在良性前列腺细胞和小鼠前列腺中的过度表达赋予了肿瘤表型。不同类别的ETS基因重排的鉴定表明，在前列腺癌中，休眠的癌基因可以通过并置到组织特定的或普遍活跃的基因组位点而被激活。活性基因组调控元件的颠覆可能是肿瘤发生的一种更普遍的机制。此外，识别雄激素抑制和不敏感的59个融合伙伴可能对晚期前列腺癌的抗雄激素治疗有意义。
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.