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.
Loss of a whole chromosome S or a deletion of its long arm (5q) is a recurring abnormality in malignant myeloid neoplasms. To determine the location of genes on Sq that may be involved in leukemogenesis, we examined the deleted chromosome 5 homologs in a series of 135 patients with malignant myeloid diseases. By comparing the breakpoints, we identified a small segment of 5q, consisting of band 5q31, that was deleted in each patient. This segment has been termed the critical region. Distal Sq contains a number of genes encoding growth factors, hormone receptors, and proteins involved in signal transduction or transcriptional regulation. These include several genes that are good candidates for a tumorsuppressor gene, as well as the genes encoding five hematopoietic growth factors (CSF2, IL3, IL4, IL5, and IL9). By using fluorescence in situ hybridization, we have refrned the localization of these genes to 5q31.1 and have determined the order of these genes and of other markers within 5q31. By hybridizing probes to metaphase cells with overlapping deletions involving 5q31, we have narrowed the critical region to a smail segment of 5q31 containing the EGRI gene. The five hematopoietic growth factor genes and seven other genes are excluded from this region. The EGRI gene was not deleted in nine other patients with acute myeloid leukemia who did not have abnormalities of chromosome 5. By physical mapping, the minimum size of the critical region was estimated to be 2.8 megabases. This cytogenetic map of 5q31, together with the molecular characterization of the critical region, will facilitate the identification of a putative tumor-suppressor gene in this band.Recurring chromosomal rearrangements are characteristic of human malignant diseases, particularly the leukemias and lymphomas (1) (93%o) had a clonal chromosomal abnormality and 97 (75%) had loss or deletion of chromosome 5 and/or 7. Among these 97 patients, 21 had loss of chromosome 5, 26 had a del(5q), 8 had loss of 5q following unbalanced translocations, 51 had loss of chromosome 7, 11 had a del(7q), and 12 had loss of 7q as a result of an unbalanced translocation. Thirty-one patients had abnormalities of both chromosomes 5 and 7. Overall, 55 patients (43%) had abnormalities of chromosome 5. A del(5q) was the most common structural aberration in our series.In addition to t-MDS/t-AML, a -5/del(Sq) has also been observed in the malignant cells of 10%o ofpatients with AML de novo and in 15% ofpatients who have MDS arising de novo (8). Many of these patients have had significant occupational exposure to potential environmental carcinogens, suggesting that abnormalities of chromosome 5 or 7 may be a marker of mutagen-induced leukemia. A distinct clinical syndrome associated with a del(5q) is seen in a subset ofpatients with MDS de novo. Clinically, this disorder, termed the "5q-syndrome," is characterized by refractory anemia (RA). These patients having a del(Sq) as the sole abnormality tend to have a relatively mild course that usually does not progress to ...
Although common in hematologic and mesenchymal malignancies, recurrent gene fusions have not been well characterized in epithelial carcinomas. Recently, using a novel bioinformatic approach, we identified recurrent gene fusions between TMPRSS2 and the ETS family members ERG or ETV1 in the majority of prostate cancers. Here, we interrogated the expression of all ETS family members in prostate cancer profiling studies and identified marked overexpression of ETV4 in 2 of 98 cases. In one such case, we confirmed the overexpression of ETV4 using quantitative PCR, and by rapid amplification of cDNA ends, quantitative PCR, and fluorescence in situ hybridization, we show that the TMPRSS2 (21q22) and ETV4 (17q21) loci are fused in this case. This result defines a third molecular subtype of prostate cancer and supports the hypothesis that dysregulation of ETS family members through fusions with TMRPSS2 may be an initiating event in prostate cancer development. (Cancer Res 2006; 66(7): 3396-400)
Two genes have been implicated in leukemias of patients with ab l of chromosome 3, band q26: EVII, which can be activated over long dances by chromosomal rearrangements involving 3q26, and EAP, a ribosomal gene that fuses withAMLI in a therapy-related myelodysplasia patient with a t(3;21)(q26.2;q22). AMLI was identified by its involvement in the t(8;21)(q22;q22) of acute myelod leukemia. Here we report the consistent identification of fusion transcripts between AMLI and EAP or between AMLI and previously unidentified sequences that we named MDSI (MDSassociated sequences) in the leukemic cells of four patients with therapy-related myelodysplala/acute myeloid leukemia and in one patient with chronic myelogenous leukemia in blast crisis, all of whom had a t(3;21). In addition, we have identified a third chimeric transcript, AMLI /EVI, in one ofthe therapyrelated acute myeloid leukemia patients.-field gel electrophoresis established the order of the genes as EAP, the most telomeric, and EVII, the most centromeric, gene. The results indicate that translocations could involve multiple genes and affect gene expression over long distances.The molecular analysis of recurring chromosomal translocations in leukemias has led to the identification of protooncogenes located at the translocation breakpoint that are activated either by altered expression or by gene fusion. One of the most common translocations in acute myeloid leukemia is the t(8;21)(q22;q22), which has recently been shown to involve the AMLI gene at 21q22 (1) fused to the ETO gene at 8q22 (2, 3). AMLI is identical' to the murine transcription factor pebp2a and the DNA-binding subunit of the human transcription core factor CBF (1, 4). The human and murine AMLi polypeptides are 99% homologous in their first 242 residues, but they differ in overall size. pebp2a encodes a predicted polypeptide of 452 residues containing the DNAbinding and dimerization region encoded by the Drosophila melanogaster runt (run) homology segment at the N terminus (2, 5), as well as a region rich in serine, threonine, and proline, suggestive of a transcription activation domain at the C terminus (4). The sequence ofthe human AMLI cDNA is 250 residues shorter than that of pebp2a and lacks the serine-, threonine-, and proline-rich region. It probably represents a spliced isoform of the mRNA consisting mostly of the run homology segment.Chromosome 21, band q22, is also involved in the t(3;21)(q26.2;q22) in therapy-related acute myeloid leukemia/myelodysplasia (t-AML/t-MDS) or chronic myelogenous leukemia in blast crisis (CML-BC) (6, 7). Recent studies have shown that this translocation involves the AMLJ gene and a gene at 3q26, which is EAP (8, 9). EAP codes for a small (129 amino acids) ribosomal protein, L22, and belongs to a large family of genes. Although EAP is highly conserved and abundantly expressed in all tissues (10, 11) and in hematopoietic cell lines (9), it is not known whether the allele at 3q26 is the one that is expressed. In t(3;21), the translocation results in th...
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