|Phylum||Male organs:Prostate:Prostate tumors:t(8;21)(q24;q22)|
|Note||NDRG1 (N-myc downstream regulated 1) was identified as a 5' fusion partner to ERG (v-ets erythroblastosis virus E26 oncogene homolog (avian)) by use of next-generation RNA sequencing (Pflueger et al., 2009).|
|Clinics and Pathology|
|Note|| Prostate cancer is a hormonally sensitive cancer at early stages and eventually becomes hormonally independent as it progresses to castration-resistant prostate cancer (CRPCa). All 5' fusion partners to ERG described in prostate cancer to date (TMPRSS2, SLC45A3, NDRG1, HERPUD1, FKBP5) are known androgen-regulated genes. By utilizing androgen-responsive promoters as 5' partners, the fusion event drives the upregulation of the oncogene ERG.|
Estrogen signaling on TMPRSS2 (Setlur et al., 2008), SLC45A3 and NDRG1 (Pflueger et al., 2009) has been observed as an additional level of hormonal regulation. This aspect of ERG fusions in prostate cancer becomes more important in sight of the androgen hormone ablation treatment, leading to CRPCa.
|Epidemiology|| To date, two studies describe NDRG1-ERG fusion in a total of 3 prostate cancer cases with clinically localized disease (Pflueger et al., 2009; Esgueva et al., 2010). Pflueger et al. and Esgueva et al. estimate NDGR1 to be the 5' fusion partner in up to 5% of ERG-rearranged prostate cancer. In direct comparison, TMPRSS2 is the 5' fusion partner in a majority (~78-82%) of ERG-rearranged prostate cancer cases. SLC45A3 is the 5' partner to ERG in ~6-7% of rearrangement positive prostate cancer. Singular reports exist of a nonrecurring ERG fusion with HERPUD1 (Maher et al., 2009) and FKBP5 (Pflueger et al., 2011), respectively. |
None of the well known prostate cancer cell lines (LNCaP, VCaP, 22Rv1, PC-3, NCI-H660 and DU145) harbor an NDRG1-ERG fusion (Pflueger et al., 2009).
|Genes involved and Proteins|
|Note||NDRG1 (N-myc downstream regulated 1) is a multifunctional protein that is ubiquitously expressed in several tissues. It likely exerts its function cell type and tissue specific. It's described to act in stress response pathways, golgi transport, cell cycle regulation and mitosis. It is hypothesized that it has a tumor-suppressive function in epithelial cells since lower expression levels have been observed in adenocarcinoma compared to normal tissue. Defects in this gene are found in a subtype of the Charcot-Marie-Tooth disease type 4D (CMT4D), a peripheral neuropathy.|
|Note||ERG (v-ets erythroblastosis virus E26 oncogene like (avian)) is a member of the ETS family of transcription factors. It is implicated in lymphoid cell development and endothelial cell differentiation, among other less well described functions in mitogenic signal transduction pathways, platelet activation, DNA methylation, angiogenesis etc. Elevated ERG levels are observed in several disease conditions (i.e. several cancers, Alzheimer's disease, Down syndrome etc.). Its role in oncogenesis is well established since fusions between several genes and ERG are characteristic for Ewing sarcoma, acute myeloid leukemia and prostate cancer.|
|Result of the chromosomal anomaly|
|Schematic representation of the NDRG1-ERG fusion in prostate cancer.|
|Transcript|| The fusion breakpoint(s) on DNA level are unknown. However, there are at least 2 distinct transcript isoforms described (Pflueger et al., 2009) (see figure above): |
FJ627786: NDRG1 (NM_006096) exon 3 joined with ERG (NM_004449) exon 6.
FJ627787: NDRG1 (NM_006096) exon 2 joined with ERG (NM_004449) exon 6.
The exon junctions of NDRG1-ERG isoforms are utilizing the same splice sites as the respective wild-type mRNAs possibly indicating the involvement of alternative splicing processes to produce distinct transcript isoforms.
|Description|| Unlike TMPRSS2-ERG and SLC45A3-ERG, the NDRG1-ERG gene fusion transcripts are in frame, meaning that NDRG1 contributes 33 (FJ627786) and 21 (FJ627787) amino acids, respectively, to an NDRG1-ERG fusion protein (Pflueger et al., 2009). An antibody specific to NDRG1-ERG fusion protein does not exist yet. Hence, the expression of a fusion protein was indirectly verified by monitoring elevated ERG protein expression in cell lines that were transiently transfected with NDRG1-ERG expression vectors. |
In invasion assays, it was observed that NDRG1-ERG confers increased invasiveness (unpublished results).
Additional functions of the NDRG1-ERG fusion proteins have not been eluded further and it is unclear if they exert similar or differing functions compared to the N-terminally truncated ERG protein encoded by the TMPRSS2-ERG and SLC45A3-ERG fusions (Tomlins et al., 2008; Klezovitch et al., 2008).
|A causal role for ERG in neoplastic transformation of prostate epithelium.|
|Klezovitch O, Risk M, Coleman I, Lucas JM, Null M, True LD, Nelson PS, Vasioukhin V.|
|Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2105-10. Epub 2008 Feb 1.|
|Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer.|
|Setlur SR, Mertz KD, Hoshida Y, Demichelis F, Lupien M, Perner S, Sboner A, Pawitan Y, Andren O, Johnson LA, Tang J, Adami HO, Calza S, Chinnaiyan AM, Rhodes D, Tomlins S, Fall K, Mucci LA, Kantoff PW, Stampfer MJ, Andersson SO, Varenhorst E, Johansson JE, Brown M, Golub TR, Rubin MA.|
|J Natl Cancer Inst. 2008 Jun 4;100(11):815-25. Epub 2008 May 27.|
|Role of the TMPRSS2-ERG gene fusion in prostate cancer.|
|Tomlins SA, Laxman B, Varambally S, Cao X, Yu J, Helgeson BE, Cao Q, Prensner JR, Rubin MA, Shah RB, Mehra R, Chinnaiyan AM.|
|Neoplasia. 2008 Feb;10(2):177-88.|
|Chimeric transcript discovery by paired-end transcriptome sequencing.|
|Maher CA, Palanisamy N, Brenner JC, Cao X, Kalyana-Sundaram S, Luo S, Khrebtukova I, Barrette TR, Grasso C, Yu J, Lonigro RJ, Schroth G, Kumar-Sinha C, Chinnaiyan AM.|
|Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12353-8. Epub 2009 Jul 10.|
|N-myc downstream regulated gene 1 (NDRG1) is fused to ERG in prostate cancer.|
|Pflueger D, Rickman DS, Sboner A, Perner S, LaFargue CJ, Svensson MA, Moss BJ, Kitabayashi N, Pan Y, de la Taille A, Kuefer R, Tewari AK, Demichelis F, Chee MS, Gerstein MB, Rubin MA.|
|Neoplasia. 2009 Aug;11(8):804-11.|
|Prevalence of TMPRSS2-ERG and SLC45A3-ERG gene fusions in a large prostatectomy cohort.|
|Esgueva R, Perner S, J LaFargue C, Scheble V, Stephan C, Lein M, Fritzsche FR, Dietel M, Kristiansen G, Rubin MA.|
|Mod Pathol. 2010 Apr;23(4):539-46. Epub 2010 Jan 29.|
|Discovery of non-ETS gene fusions in human prostate cancer using next-generation RNA sequencing.|
|Pflueger D, Terry S, Sboner A, Habegger L, Esgueva R, Lin PC, Svensson MA, Kitabayashi N, Moss BJ, MacDonald TY, Cao X, Barrette T, Tewari AK, Chee MS, Chinnaiyan AM, Rickman DS, Demichelis F, Gerstein MB, Rubin MA.|
|Genome Res. 2011 Jan;21(1):56-67. Epub 2010 Oct 29.|
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|University Hospital Zurich, Institute of Surgical Pathology, Schmelzbergstrasse 12, 8091 Zurich, Switzerland|
|This paper should be referenced as such :|
|Pflueger D . t(8;21)(q24;q22) in prostate cancer. Atlas Genet Cytogenet Oncol Haematol. March 2012 .|
URL : http://AtlasGeneticsOncology.org/Tumors/t0821q24q22ProstID6373.html
This paper is referenced by INIST as such :
|http://documents.irevues.inist.fr/bitstream/handle/2042/47498/03-2012-t0821q24q22ProstID6373.pdf [ Bibliographic record ]|
|© Atlas of Genetics and Cytogenetics in Oncology and Haematology||indexed on : Sat Mar 9 12:39:34 CET 2013|
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