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Atlas of Genetics and Cytogenetics in Oncology and Haematology INIST-CNRS OPEN ACCESS JOURNAL Solid Tumour Section Short Communication t(8;21)(q24;q22) in prostate cancer Dorothee Pflueger University Hospital Zurich, Institute of Surgical Pathology, Schmelzbergstrasse 12, 8091 Zurich, Switzerland (DP) Published in Atlas Database: March 2012 Online updated version : http://AtlasGeneticsOncology.org/Tumors/t0821q24q22ProstID6373.html DOI: 10.4267/2042/47498 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology 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 ERGrearranged 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). Identity 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 Disease Prostate cancer 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 androgenregulated 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. Genes involved and proteins NDRG1 Location 8q24.22 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. Epidemiology To date, two studies describe NDRG1-ERG fusion in a total of 3 prostate cancer cases with clinically localized Atlas Genet Cytogenet Oncol Haematol. 2012; 16(8) 591 t(8;21)(q24;q22) in prostate cancer Pflueger D Schematic representation of the NDRG1-ERG fusion in prostate cancer. 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 wildtype mRNAs possibly indicating the involvement of alternative splicing processes to produce distinct transcript isoforms. ERG Location 21q22.2 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. Fusion Protein 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 Result of the chromosomal anomaly Hybrid Gene Transcript The fusion breakpoint(s) on DNA level are unknown. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(8) 592 t(8;21)(q24;q22) in prostate cancer Pflueger D Maher CA, Palanisamy N, Brenner JC, Cao X, KalyanaSundaram S, Luo S, Khrebtukova I, Barrette TR, Grasso C, Yu J, Lonigro RJ, Schroth G, Kumar-Sinha C, Chinnaiyan AM. Chimeric transcript discovery by paired-end transcriptome sequencing. Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12353-8 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). 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. N-myc downstream regulated gene 1 (NDRG1) is fused to ERG in prostate cancer. Neoplasia. 2009 Aug;11(8):804-11 References Klezovitch O, Risk M, Coleman I, Lucas JM, Null M, True LD, Nelson PS, Vasioukhin V. A causal role for ERG in neoplastic transformation of prostate epithelium. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2105-10 Esgueva R, Perner S, J LaFargue C, Scheble V, Stephan C, Lein M, Fritzsche FR, Dietel M, Kristiansen G, Rubin MA. Prevalence of TMPRSS2-ERG and SLC45A3-ERG gene fusions in a large prostatectomy cohort. Mod Pathol. 2010 Apr;23(4):539-46 Setlur SR, Mertz KD, Hoshida Y, Demichelis F, Lupien M, Perner S, Sboner A, Pawitan Y, Andrén 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. Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer. J Natl Cancer Inst. 2008 Jun 4;100(11):815-25 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. Discovery of non-ETS gene fusions in human prostate cancer using nextgeneration RNA sequencing. Genome Res. 2011 Jan;21(1):5667 Tomlins SA, Laxman B, Varambally S, Cao X, Yu J, Helgeson BE, Cao Q, Prensner JR, Rubin MA, Shah RB, Mehra R, Chinnaiyan AM. Role of the TMPRSS2-ERG gene fusion in prostate cancer. Neoplasia. 2008 Feb;10(2):177-88 Atlas Genet Cytogenet Oncol Haematol. 2012; 16(8) This article should be referenced as such: Pflueger D. t(8;21)(q24;q22) in prostate cancer. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(8):591-593. 593