Prostate: Carcinoma with t(8;21)(q24;q22) NDRG1/ERG

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Prostate: Carcinoma with t(8;21)(q24;q22) NDRG1/ERG

Written	2012-03	Dorothee Pflueger
		University Hospital Zurich, Institute of Surgical Pathology, Schmelzbergstrasse 12, 8091 Zurich, Switzerland

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Identity

ICD-Topo C619 PROSTATE GLAN

ICD-Morpho 8140/3 Adenocarcinoma, NOS

Atlas_Id 6373

Phylum Male organs: Prostate::Prostate tumor

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 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

Gene Name 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.

Gene Name 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.

Result of the chromosomal anomaly

Hybrid Gene

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.

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 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).

Bibliography

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.

PMID 20118910

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.

PMID 18245377

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.

PMID 19592507

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.

PMID 21036922

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.

PMID 18505969

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.

PMID 18283340

Citation

This paper 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.

Free journal version : [ pdf ] [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/t0821q24q22ProstID6373.html

Translocations implicated (Data extracted from papers in the Atlas)

t(8;21)(q24;q22) NDRG1/ERG

External links

Mitelman database t(8;21)(q24;q22) NDRG1/ERG [Case List]    t(8;21)(q24;q22) NDRG1/ERG [Association List] Mitelman database (CGAP - NCBI)

arrayMap Topo ( C61) arrayMap ((UZH-SIB Zurich) [auto + random 100 samples .. if exist ] [tabulated segments]

COSMIC_fusion NDRG1 (8q24.22) ERG (21q22.2)    [fusion1133] [fusion1134] [fusion1135] [fusion1136] [fusion1146]
Mitelman database NDRG1/ERG[MCList]    NDRG1 (8q24.22) ERG (21q22.2)

Mitelman database NDRG1/ERG[MCList]    NDRG1 (8q24.22) ERG (21q22.2)   t(8;21)(q24;q22)

TCGA_Fusion NDRG1/ERG    NDRG1 (8q24.22) ERG (21q22.2)

TICdb NDRG1/ERG    NDRG1 (8q24.22) ERG (21q22.2)

Disease database Prostate: Carcinoma with t(8;21)(q24;q22) NDRG1/ERG

REVIEW articles automatic search in PubMed

Last year articles automatic search in PubMed

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For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.

ICD-Topo	C619 PROSTATE GLAN
ICD-Morpho	8140/3 Adenocarcinoma, NOS
Atlas_Id	6373
Phylum	Male organs: Prostate::Prostate tumor

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).

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 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).

Gene Name	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.

Gene Name	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.

Hybrid Gene


	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.
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 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).

Mitelman database	t(8;21)(q24;q22) NDRG1/ERG [Case List] t(8;21)(q24;q22) NDRG1/ERG [Association List] Mitelman database (CGAP - NCBI)
arrayMap	Topo ( C61) arrayMap ((UZH-SIB Zurich) [auto + random 100 samples .. if exist ] [tabulated segments]

COSMIC_fusion	NDRG1 (8q24.22) ERG (21q22.2) [fusion1133] [fusion1134] [fusion1135] [fusion1136] [fusion1146]
Mitelman database	NDRG1/ERG[MCList] NDRG1 (8q24.22) ERG (21q22.2)
Mitelman database	NDRG1/ERG[MCList] NDRG1 (8q24.22) ERG (21q22.2) t(8;21)(q24;q22)
TCGA_Fusion	NDRG1/ERG NDRG1 (8q24.22) ERG (21q22.2)
TICdb	NDRG1/ERG NDRG1 (8q24.22) ERG (21q22.2)

Disease database	Prostate: Carcinoma with t(8;21)(q24;q22) NDRG1/ERG

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed