Recurrent gene fusions in prostate cancer: ETV1 class of fusions

CN02-04

The discovery of BCR-ABL1 gene fusion in chronic myelogenous leukemia helped to understand the role of chromosomal aberrations in carcinogenesis and has also served as a target for effective therapeutic intervention. Recently, we reported the discovery of recurrent gene fusion events in prostate cancer, a common epithelial carcinoma. These gene fusions juxtaposed 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. Characterization of prostate tumors that overexpress ETV1 has now identified several new 5' fusion partners. The list of novel 5’ partners include, 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). Among the two ETV1 overexpressing prostate cancer cell lines, LNCaP and MDA-PCa 2B, we observed a rearrangement of the entire ETV1 locus (7p21) 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). Functional aspects of ETV1 overexpression was studied in vitro and in vivo. In both benign prostate cells and in the mouse prostate ETV1 overexpression confered neoplastic phenotypes. Thus, 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.