Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer

Abstract

Recently, we identified recurrent gene fusions involving the 5' untranslated region of the androgen-regulated gene TMPRSS2 and the ETS (E26 transformation-specific) family genes ERG, ETV1 or ETV4 in most prostate cancers. 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 5' 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 5' fusion partners may have implications for the anti-androgen treatment of advanced prostate cancer.

ERG immunohistochemistry is not predictive for PSA recurrence, local recurrence or overall survival after radical prostatectomy for prostate cancer

“…It cannot distinguish whether fusion to TMPRSS2 or another fusion partner causes ERG overexpression. 9,34,35 Likewise, with immunohistochemistry no distinction can be made between genomic deletion, translocation or duplication leading to ERG overexpression. While immunohistochemical analysis was performed by visual semiquantitative scoring by two independent researchers and not by automated imaging, we have previously shown that semiquantitative scoring correlated with quantitative ERG mRNA levels.…”

Next-generation transcriptome assembly

“…Detection of trans-spliced genes has been shown to be critical for understanding the genetic pathways involved in some cancers 56 , such as prostate cancer 57 .…”

miR-148a is an androgen-responsive microRNA that promotes LNCaP prostate cell growth by repressing its target CAND1 expression

“…[8][9][10] Integrative transcriptome sequencing in prostate cancer cells could detect gene fusions, 11 including known prostate cancer-specific rearrangements TMPRSS2-ERG/ETV1. 12 Recently, miRNA profiling has been reported to be informative and predictive in some malignancies, including prostate cancer. [13][14][15] Systematic identification of disease-associated miRNAs will be useful for finding good indicators for prostate cancer management, although a consensus has not been yet achieved in terms of a prostate cancerrelated miRNA signature.…”