Download Solid Tumour Section t(8;21)(q24;q22) in prostate cancer Atlas of Genetics and Cytogenetics

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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)
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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)
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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
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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
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Perner S, Sboner A, Pawitan Y, Andrén O, Johnson LA, Tang
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Pflueger D, Terry S, Sboner A, Habegger L, Esgueva R, Lin
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Cao X, Barrette T, Tewari AK, Chee MS, Chinnaiyan AM,
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of non-ETS gene fusions in human prostate cancer using nextgeneration RNA sequencing. Genome Res. 2011 Jan;21(1):5667
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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.
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