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Deep Insight Section
Review
TMPRSS2:ETS gene fusions in prostate cancer
Julia L Williams, Maisa Yoshimoto, Alexander H Boag, Jeremy A Squire, Paul C Park
Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada (JLW,
MY, AHB, JAS), Kingston General Hospital, 76 Stuart Street, Douglas 4, Room 8-431, Kingston, Ontario,
K7L 2V7 Canada (PCP)
Published in Atlas Database: December 2010
Online updated version : http://AtlasGeneticsOncology.org/Deep/TMPRSS2ERGinCancerID20091.html
DOI: 10.4267/2042/46008
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Table of Contents
I. Background
I.i. Prostate cancer oncogenomics
II. Discovery of TMPRSS2:ETS fusion genes in prostate cancer
III. Frequency of TMPRSS2:ETS gene fusions in prostate cancer
IV. TMPRSS2:ETS gene fusions: genes and protein structure
IV.i. TMPRSS2 and the androgen receptor
IV.ii. ETS transcription factors
V. Fusion variants
VI. Detection and classification
VI.i. FISH
VI.ii. Other methods of detection
VII. Fusion gene formation and chromosomal instability
VIII. Heterogeneity of multifocal disease
IX. Prognostic significance
X. Clinical utility
XI. Role of ETS in prostate tumourigenesis: Driver?
XII. Concluding remarks
Clinicopathological criteria, including Gleason grading,
are not sufficient to differentiate men whose tumours
require immediate and aggressive therapy from those
that would suffice with vigilant clinical observation,
thereby causing the latter group enormous amounts of
unnecessary treatment (Yao and Lu-Yao, 2002). In this
regard, the emerging data on the genetics of CaP hold
great promise not only in stratifying this heterogeneous
group of patients, but also in providing the groundwork
for future development of targeted therapy.
I. Background
Prostate cancer (CaP) is the most commonly diagnosed
male malignancy and a leading cause of cancer deaths
in developed countries. With one in six men diagnosed,
CaP remains a serious global public health issue (Jemal
et al., 2008). CaP is a clinically heterogeneous disease,
with manifestations ranging from a rapid and often fatal
progression, to the typical, indolent disease which
remains relatively insignificant to a patient's health.
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qPCR analysis. Subsequent studies showed that the
frequency of the TMPRSS2:ERG fusion gene (or ERG
rearrangement) is exceptionally variable and
inconsistent in the literature, ranging from 27% to 79%
in radical prostatectomy (RP) and biopsy samples,
generally from prostate-specific antigen (PSA)
screened cohorts (Tomlins et al., 2005; Yoshimoto et
al., 2008; Mehra et al., 2007b; Watson et al., 2009;
Barwick et al., 2010; Magi-Galluzzi et al., 2010).
Some of the discrepancies in frequency relate to
differences in the patient cohort (race as well as global
geographical location or PSA-screened versus
population based) or the type of specimen examined, as
well as the technique used to detect the fusion gene.
This concept is clearly illustrated when comparing
population based cohorts, which have a lower reported
frequency of 15-35%, as compared to RP cohorts
(Attard et al., 2008a; Demichelis et al., 2007; Fitzgerald
et al., 2008). The TMPRSS2:ERG gene fusion is found
in approximately half of Caucasian patients, with a
lower reported frequency in African-American men and
is less common in Asian cohorts (Mosquera et al.,
2009; Magi-Galluzzi et al., 2010; Lee K et al., 2010;
Miyagi et al., 2010). An excellent example of
discrepancies based on patient populations was
demonstrated in a study that compared patients from
the United Kingdom (UK) and China, wherein 41.3%
of the UK patients but only 7.5% of Chinese cohort
were found to harbour ERG rearrangements detected
by FISH (Mao et al., 2010). The recent, contradicting
report that 90% of the Chinese RP specimens
harboured ETS rearrangements further emphasize the
multifactorial nature of the variability in the frequency
of this gene fusion (Sun et al., 2010).
TMPRSS2:ERG gene fusions are reported in 10-21%
of high-grade prostatic intraepithelial neoplastic
(HGPIN) lesions, but are identified almost exclusively
adjacent to fusion-positive cancer (Cerveira et al.,
2006; Perner et al., 2007; Carver et al., 2009b; Han et
al., 2009; Zhang et al., 2010; Mosquera et al., 2008).
Benign prostatic hyperplasia (BPH) and normal
epithelium are negative for ERG rearrangements and
fusion transcripts, with the exception of the report by
Clark and colleagues (Rajput et al., 2007; Wang et al.,
2006; Cerveira et al., 2006; Clark et al., 2007; Perner et
al., 2007; Dai et al., 2008; Han et al., 2009; Mosquera
et al., 2009; Zhang et al., 2010; Sun et al., 2010; Lu et
al., 2009). This study found that eight of 17 (47%)
normal epithelial samples adjacent to fusion-positive
CaP were also positive for TMPRSS2:ERG
rearrangements and found a 6% fusion-positive rate in
BPH samples (Clark et al., 2007). Hormone refractory
and/or metastatic CaP exhibits less variability in the
occurrence of TMPRSS2:ERG rearrangements with
reported frequencies ranging from 29-59% (Perner et
al., 2007; Mehra et al., 2008; Gopalan et al., 2009; Han
et al., 2009; Boormans et al., 2010; Saramaki et al.,
2008; Attard et al., 2009; Stott et al., 2010).
Additionally, minute prostatic adenocarcinoma, a form
I. i. Prostate cancer oncogenomics
Advances in cytogenetics and genomics facilitated the
characterization of common genomic alterations in
CaP, which are predominantly characterized by
deletions (10q, PTEN; 13q, RB1; 8p, NKX3.1 (a
prostate-specific tumour suppressor); 5q; 2q; 17p; and
less commonly 6q; 7p; 16q; 18q) with only a small
number of recurrent gains (8q, MYC; and chromosome
7). More complex patterns as well as an accumulation
in the number of genomic gains and amplifications
(Xq11.2-q12, androgen receptor (AR)) emerge as the
disease advances. Genomic rearrangements leading to
the formation of TMPRSS2:ETS gene fusions and
deletion of the PTEN tumour suppressor are the two
most frequent alterations observed in CaP (Tomlins et
al., 2005; Yoshimoto et al., 2007; Yoshimoto et al.,
2008). The TMPRSS2:ERG gene fusion is the principle
genomic alteration and a characteristic signature in
approximately half of prostatic malignancies.
II. Discovery of TMPRSS2:ETS
fusion genes in prostate cancer
The discovery of the TMPRSS2:ERG gene fusion
exemplifies the current shift in the strategy in cancer
genomics from experimental to bioinformatics
approaches. By surveying 132 gene-expression CaP
datasets from the Oncomine database (Compendia
Bioscience) using the data transformation algorithm
cancer outlier profile analysis (COPA), Chinnaiyan and
colleagues identified genes with aberrant expression
profiles in a subset of samples (Tomlins et al., 2005).
COPA allowed the systematic investigation of cancerrelated genes known to participate in chromosomal
rearrangements in haematological malignancies and
sarcomas. Two mutually exclusive Erythroblastosis
virus E26 transformation-specific (ETS) transcription
factors, ETS variant 1 (ETV1, 7p21.3) and ETS-related
gene (ERG, 21q22.2), were identified as high-ranking
outliers in several independent gene-expression
profiling datasets. Exon-walking quantitative PCR
(qPCR) of patient samples found the 3' regions of ERG
and ETV1 to be overexpressed but the corresponding 5'
regions were absent. 5' RNA ligase-mediated rapid
amplification of cDNA ends identified the 5' end of
these transcripts as the promoter sequences belonging
to
the
prostate-specific,
androgen
regulated
transmembrane protease, serine II (TMPRSS2,
21q22.3).
III. Frequency of TMPRSS2:ETS
gene fusions in prostate cancer
This breakthrough study reported that 79% of radical
prostatectomy (RP) samples harboured a fusion of the
5' untranslated region (UTR) of TMPRSS2 with the
coding sequences of either ERG or ETV1 (Tomlins et
al., 2005). Interestingly, just months prior, Petrovics et
al. (2005) reported that ERG was the most commonly
overexpressed oncogene in CaP by microarray and
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of CaP that is considered less clinically significant,
harbours ETS fusions in approximately half of reported
cases, underscoring the necessity of examining all
prostatic malignancies for aggressive features such as
the fusion gene (Albadine et al., 2009).
Investigators have also evaluated this rearrangement in
the peripheral and transitional zones of the prostate.
Nearly half of the peripheral tumours (43.3%) derived
from RP samples were ERG rearrangement positive,
whereas all 30 corresponding transitional tumours
displayed a normal ERG locus by FISH (Guo et al.,
2009). In contrast, other studies found TMPRSS2:ERG
(13.3%) and ERG rearrangements (11.9%) are present
in transitional zone tumours, despite being identified at
a lower rate compared to peripheral zone lesions
(Bismar and Trpkov, 2010; Falzarano et al., 2010).
These data illustrate the enormous variability in the
frequency of TMPRSS2:ERG fusion positivity with
respect to the cohort, disease stage, origin of sample as
well as the method of detection.
Interestingly, a comprehensive study of patient samples
from 54 tumour types, including sarcomas and
haematological malignancies, for ETS gene fusions and
ERG rearrangements by FISH found these alterations
to be exclusive to CaP samples (Scheble et al., 2010).
The same result was obtained when RT-PCR was
performed
to
detect
TMPRSS2:ERG
and
TMPRSS2:ETV1 fusion transcripts in gastric and
colorectal carcinomas (Yoo et al., 2007). These
findings provide strong evidence that TMPRSS2:ETS
gene fusions are specific to CaP.
to the growth and development of the prostate gland
but also play an important role in the initiation and
progression of CaP (Balk et al., 2008). It is well
established that despite chemical castration the AR
functions to drive CaP, likely through a variety of
mechanisms such as hypersensitivity to low levels of
androgens, activation in absence of, or via
unconventional ligands, or amplification of the AR
gene locus, resulting in elevated levels of AR protein.
All of these mechanisms could potentially allow AR
activation in the presence of low androgen
concentration (Ai et al., 2009; Kawata et al., 2010; Vis
and Schroder, 2009). Consequently, TMPRSS2 in turn
plays an important role in CaP progression in spite of
hormonal ablation regimens as its promoter region
drives the expression of the fused ETS gene.
IV. ii. ETS transcription factors
Twenty-seven human ETS transcription factor family
members have been identified, all of which share a
conserved DNA binding domain that recognizes unique
sequences containing GGA(A/T) (Nye et al., 1992).
ERG (21q22.2) is the ETS transcription factor most
commonly known to participate in CaP gene fusions.
The ERG gene contains 11 exons, with the
transcriptional start site in exon 3. The ERG protein can
interact with ETS members as well as other
transcription factors, such as Jun and Fos, through its
protein-protein interacting domain, SAM-PNT (Carrere
et al., 1998; Verger et al., 2001; Basuyaux et al., 1997).
The conserved ETS DNA binding domain permits
binding to purine rich DNA sequences (Reddy et al.,
1991; Reddy et al., 1987), and in this manner, exert its
effects in numerous cellular processes including
membrane remodelling, angiogenesis, differentiation,
proliferation, and tumourigenesis (Carver et al., 2009a;
Kruse et al., 2009; Oikawa et al., 2003; Randi et al.,
2009; Ellett et al., 2009; Birdsey et al., 2008;
Mclaughlin et al., 2001; Sato et al., 2001). Emerging
evidence suggests that formation of the fusion gene
may promote prostatic tumourigenesis, progression,
and invasive disease and is associated with CaP-related
mortality (Demichelis et al., 2007; Klezovitch et al.,
2008; Wang et al., 2008; Hawksworth et al., 2010).
Functionally, ERG overexpression in CaP is highly
implicated in promoting motility and invasiveness
(Perner et al., 2007; Singh et al., 2002; Trojanowska et
al., 2000; Tomlins et al., 2008a; Sreekumar et al., 2009;
Schulz et al., 2010). In CaP, ERG expression has been
associated with elevated levels of histone deactylase 1
(HDAC1) and subsequent down regulation of HDAC1
target genes, upregulation of WNT pathway proteins,
and inhibition of apoptotic signalling (Iljin et al., 2006).
HDAC1 upregulation is common in CaP, but was
found to be uniformly increased in ERG rearranged
tumours (Iljin et al., 2006; Bjorkman et al., 2008).
Activation of the WNT pathway leads to transcription
of numerous genes involved in tumourigenesis,
including AR, MYC, JUN, cyclinD1, BMP4 and
IV. TMPRSS2:ETS gene fusions:
genes and protein structure
IV. i. TMPRSS2 and the androgen receptor
TMPRSS2, a 70 KDa serine protease family member is
associated with physiological and pathological
processes such as digestion, tissue remodelling, blood
coagulation, fertility, inflammatory responses, tumour
cell invasion and apoptosis. The normal function of this
protein is not yet known but is composed of a type II
transmembrane domain, receptor class A low density
lipoprotein domain, scavenger receptor cysteine-rich
domain, protease domain, and cytoplasmic domain
(Paoloni-Giacobino et al., 1997). The 32 KDa serine
protease domain undergoes autocleaveage, secretion
into the prostate epithelia and interacts with cell surface
proteins, the extracellular matrix and proteins of
neighbouring cells (Vaarala et al., 2001; Wilson et al.,
2005; Afar et al., 2001). The TMPRSS2 (21q22.3) gene
is composed of 14 exons, with protein coding
sequences only in the latter half. Importantly,
TMPRSS2 harbours androgen responsive elements
(ARE) in its 5' UTR. Prostate epithelial cells express
TMPRSS2 at higher levels relative to other tissues,
while TMPRSS2 gene expression is further elevated in
CaP relative to BPH and normal prostatic epithelium
(Afar et al., 2001). Androgens and the AR are essential
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MMP7 (Terry et al., 2006; Schweizer et al., 2008).
Highlighting the importance of WNT pathway
activation in fusion-positive CaP is the resultant
increase in AR transcription and expression levels.
Consequently transcription of the fusion gene is
increased, further amplifying ERG expression.
Moreover, beta-catenin and the AR interact in an
androgen-dependent manner to regulate AR target
genes, whereas in androgen-insensitive tumours, both
beta-catenin and AR target genes are expressed
(Schweizer et al., 2008).
ERG overexpression has recently been shown to
activate C-MYC and result in its overexpression. These
experiments revealed that C-MYC is activated by ERG
and together their co-overexpression results in the
suppression of prostate-epithelial differentiation genes
and shorter time to biochemical recurrence
(Hawksworth et al., 2010; Sun et al., 2008). ERG can
also induce ICAM2 expression, resulting in AKT
activation via PDK1 and subsequent inhibition of BAD
leading to suppression of apoptotic signals (Mclaughlin
et al., 2001). In addition, ERG can bind BRCA1, a coactivator of the AR, and together were shown to
regulate IGFR expression (Chai et al., 2001; Schayek et
al., 2009). IGFR expression eventually leads to
activation of AKT upon IGFR ligand-binding. ERG
regulates MMPs thus influencing extracellular matrix
(ECM) remodelling and the invasive potential of the
cell (Ellett et al., 2009; Hawksworth et al., 2010; Singh
et al., 2002; Schulz et al., 2010). Recently, Carver and
colleagues have identified ETS binding sites in the
promoter regions of CXCR4 and ADAMTS1, two
genes involved in cellular motility and invasion (Carver
et al., 2009a). Furthermore, it was shown that ERG
directly upregulates the expression level of CXCR4 and
ADAMTS1 (Carver et al., 2009b). Together, these
studies provide a compelling evidence for a central,
functional role of the fusion gene in the biology of
prostatic carcinoma.
intensive study examining ETV1 rearrangements found
that only 9 of 23 samples had previously identified 5'
partners, demonstrating the dramatic variability in
fusion partners pairing with ETS transcription factors
other than ERG (Attard et al., 2008b). The combined
frequency of the remaining fusion variants accounts for
approximately 10% of cases.
Five prime partners are divided into classes based on
their tissue specificity and sensitivity to androgens
(Tomlins et al., 2007). Class I is reserved for
TMPRSS2; Class II represents other prostate-specific
androgen inducible 5' UTR or endogenous retroviral
elements; Class III represents the prostate-specific but
androgen repressed partners; Class IV represents the
non-tissue-specific promoters that are ubiquitously
expressed, (i.e. house-keeping genes-this class often
forms a chimeric or fusion protein, unlike the previous
divisions of gene fusions); and finally Class V consists
of ETV1-specific rearrangements, including the
localization of the entire ETV1 locus to prostate
specific locus, 14q13.3-14q21.1 (Tomlins et al., 2007;
Attard et al., 2008b). To date only a single study has
identified fusion genes in CaP devoid of ETS
transcription factor participation (Palanisamy et al.,
2010).
VI. Detection and classification
VI. i. FISH
Two strategies for FISH experiments are frequently
used to detect the TMPRSS2:ERG fusion gene in CaP.
The three-colour break-apart strategy, developed by
Yoshimoto et al. (2006), uses differentially labelled
bacterial artificial chromosome (BAC) clones as probes
for the 3' (RP11-476D17) and 5' (RP11-95I21)
segments of ERG with an additional BAC probe
specific for the 5' region of TMPRSS2 (RP11-535H11)
or for the transcriptional regulatory sequences
(telomeric) of TMPRSS2 (RP11-35C4, RP11-891L10;
RP11-260O11; Figure 1) (Yoshimoto et al., 2006).
Using this probe configuration enables not only the
detection of ERG rearrangement, but also allows
confirmation that ERG's coding sequences are
juxtaposed to the transcriptional regulatory region of
TMPRSS2.
Moreover,
the
mechanism
of
rearrangement can also be deduced by this approach
(Yoshimoto et al., 2006; Yoshimoto et al., 2007).
Characterization of rearrangement method is essential
as differential clinical impacts are observed with the
various mechanisms resulting in ETS gene fusions.
V. Fusion variants
The TMPRSS2:ERG fusion gene constitutes the
majority (>85%) of ETS rearrangements in CaP, likely
owing to their close proximity (2.7 Mb) and identical
orientation on chromosome 21. Although, the
remainder of this review will predominately focus on
the
TMPRSS2:ERG
rearrangement,
numerous
alternative ETS members also can fuse to TMPRSS2,
albeit at a much lower frequency. Similarly, variability
in 5' partners have also been identified (Table 1). An
1Table 1
5' partner
Class
3' partner
Initial reference
TMPRSS2
I
ERG
Tomlins et al.(2005)
TMPRSS2
I
ETV1
Tomlins et al. (2005)
TMPRSS2
I
ETV4
Tomlins et al. (2006)
HERV-K_22q11.23
II
ETV1
Tomlins et al. (2007)
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SLC45A3
II
ETV1
Tomlins et al (2007)
C15orf21
III
ETV1
Tomlins et al. (2007)
HNRPA2B1
IV
ETV1
Tomlins et al. (2007)
KLK2
II
ETV4
Hermans et al. (2008a)
CANT1
II
ETV4
Hermans et al. (2008a)
ACSL3
II
ETV1
Attard et al. (2008b)
SLC45A3
II
ERG
Han et al. (2008)
FLJ35294
II
ETV1
Han et al. (2008)
DDX5
IV
ETV1
Han et al. (2008)
TMPRSS2
I
ETV5
Helgeson et al. (2008)
SLC45A3
II
ETV5
Helgeson et al. (2008)
EST14
II
ETV1
Hermans et al. (2008b)
HERVK17
II
ETV1
Hermans et al. (2008b)
FOXP1
II
ETV1
Hermans et al. (2008b)
SLC45A3
II
ELK4
Rickman et al. (2009)
NDRG1
II
ERG
Pflueger et al. (2009)
SLC45A3
ETS neg
BRAF*
Palanisamy et al. (2010)
ESRP1
ETS neg
RAF1*
Palanisamy et al. (2010)
*Only 3' partners identified to date that are not a member of the ETS transcription factor family.
Figure 1: In house BAC probe configuration for three-colour break-apart TMPRSS2:ERG gene fusion FISH
This schematic ideogram depicts the positions of differentially labelled bacterial artificial chromosome (BAC) clones specific for 3' and 5'
regions of the ERG gene (RP11-476D17 in spectrum orange and RP11-95I21 in spectrum green, respectively), within the 21q22.2-3
region. Telomeric to this, the TMPRSS2 gene locus is represented by RP11-535H11 (spectrum red) which spans the gene, or by three
BAC clones downstream (telomeric) of the TMPRSS2 gene (RP11-35C4, RP11-891L10 and RP11-260O11 in spectrum aqua). This
probe design permits the accurate identification of TMPRSS2:ERG gene fusions as well as ERG rearrangements independent of fusion
with TMPRSS2 fusion.
Work by Attard and colleagues classified the
TMPRSS2:ERG rearrangement mechanisms according
to the pattern of interphase FISH signals (Attard et al.,
2008a). Class N describes the normal ERG locus,
therefore co-localization of the two ERG probe signals
in close proximity to the TMPRSS2 signal (less than
one signal diameter) (Figure 2A). The majority of
fusion-positive cases present with a heterozygous
deletion at cytoband 21q22.2-3, termed Class Edel
(Figure 2B). The deletion typically spans ERG, exons
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1-3 and a partial deletion of exon 4, the known
intervening genes (based on RefSeq Genes:
NCRNA00114,
ETS2,
PSMG1,
BRWD1,
NCRNA00257, HMGN1, WRB, LCA5L, SH3BGR,
C21orf88, B3GALT5, IGSF5, PCP4, DSCAM,
C21orf130, MIR3197, BACE2, PLAC4, FAM3B,
MX2, and MX1) and the coding exons of TMPRSS2.
The three-colour FISH of an Edel rearrangement
displays co-localization of the 3' ERG and TMPRSS2
signals, and absence of the 5' ERG signal. Less
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Williams JL, et al.
frequently a genomic rearrangement leading to
insertion of those sequences elsewhere in the genome
to an unknown chromosome location can occur
resulting in the separation of the 5' ERG signals from
the co-localization of the 3' ERG and TMPRSS2
signals, thus described as ERG split or Class Esplit
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(Figure 2C). In both types of TMPRSS2:ERG
rearrangements the unaffected chromosome 21
generally display a Class N signal configuration.
Finally, additional copies of TMPRSS2:ERG gene
fusions is identified as Class 2+Edel (Attard et al.,
2008a).
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Williams JL, et al.
Figure 2: Classification of TMPRSS2:ERG gene fusion by interphase FISH.
Prostate cancer patient samples were hybridized with the three-colour probe set, described in Figure 1, and counterstained with DAPI.
The nuclei of interest (in dashed boxes) are magnified in the insets. A) Class N, where no ERG rearrangement has occurred. Colocalization of 3' and 5' ERG probes (often visualized as a yellow signal), with the 5' TMPRSS2 BAC probe signals (red) indicates a
normal Chr21q22.2-3 locus. Frequently, the signals for the TMPRSS2 probe, situated 2.7 Mb away from the ERG locus, may be
separated from the ERG signals by up to one probe signal width. B) Class Edel is characterized by the co-localization of 3' ERG probe to
the TMPRSS2 probe signals, and the absence of the 5' ERG signal. This represents rearrangement with the loss of the intervening
sequence. The unaffected Chr21 displays Class N configuration. C) Class Esplit is characterized by the co-localization of the 3' ERG and
TMPRSS2 signals, with the retention of the 5' ERG signal elsewhere in the nucleus. The unaffected Chr21 displays Class N
configuration.
The second strategy employs a two-colour break-apart
FISH design to identify rearrangements in specific ETS
genes (Mehra et al., 2007; Zhang et al., 2010). By this
method, confirmation of fusion between two genes and
identification of the specific 5' partner is not possible
because the probes are specific for a single gene, and
therefore, this strategy is an indirect method for the
detection of fusion genes in CaP.
VI.ii. Other methods of detection
RT-PCR is another technique frequently employed to
determine the fusion status of prostatic tissue samples.
However, this approach is limited to the detection of
the hybrid transcripts, and is unable to obtain important
cytogenetic information such as the genomic
mechanism that generated the gene fusion (Edel vs
Esplit). To date, as many as 17 fusion transcripts and
splice variations have been characterized, the most
common fusion transcript is composed of exon 1 of
TMPRSS2 fused to exon 4 of ERG (T1:E4 (Wang et
al., 2006; Jhavar et al., 2008)). The majority of the
remaining transcripts result in truncation of the ERG
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protein product by 39-99 amino acids, while the few
that initiate translation from the native start codon in
exon 3 produce full length ERG (Tomlins et al., 2005;
Soller et al., 2006; Wang et al., 2006; Clark et al.,
2007; Clark et al., 2008a). One of the transcripts
produces a genuine TMPRSS2:ERG fusion protein and
eight contain premature stop codons and are unlikely to
result in ERG overexpression (Tomlins et al., 2005;
Soller et al., 2006; Wang et al., 2006; Clark et al.,
2007; Clark et al., 2008a). These studies further
revealed that elaborate heterogeneity exists in hybrid
transcripts present, between foci and within individual
tumour foci of the same patient. Variability in the
translation start site consequentially affects the size of
the mRNA transcript (373-885 bp) and therefore the
protein product potentially modifying the functional
capacity of the gene fusion product (Wang et al., 2006).
Distinct transcript variants display differential
prognostic influence based on the resultant biological
activities (Hermans et al., 2009; Wang et al., 2008). A
significant challenge remains in relating the clinical
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TMPRSS2:ETS gene fusions in prostate cancer
Williams JL, et al.
by sequencing, revealed the presence of consensus
sequences homologous to the human Alu-Sq and AluSp subfamily (Liu et al., 2006). The presence of these
consensus sequences within intronic regions correlated
with the presence of the fusion gene and may be a
factor contributing to the deletion at 21q22.2-3,
resulting in the fusion gene. More recently, genotyping
of familial CaP revealed that the fusion gene associates
with polymorphisms in DNA repair genes, specifically
POLI and ESCO1 (Luedeke et al., 2009).
Using FISH, the AR was shown to induce
chromosomal proximity of TMPRSS2 and ERG by
binding to the promoter region of TMPRSS2 (Mani et
al., 2009). Subsequently, LnCaP cells were irradiated to
induce double-strand breaks inducing the formation of
the
TMPRSS2:ERG
gene
fusion
upon
dihydrotestosterone stimulation in the previously
fusion-negative cell line (Mani et al., 2009). The DNAbound AR is also implicated in chromatin architecture
modifications that can cause double-strand breaks,
commonly repaired by non homologous end joining
machinery, and may result in the formation of gene
fusions (Lin et al., 2009). Also recently, androgen
signalling was shown to recruit topoisomerase II beta
with the AR to the breakpoints resulting
TMPRSS2:ERG fusion genes (Haffner et al., 2009).
Undoubtedly, specific nucleotide sequences within the
21q22.2-3 region are of great importance and further
elucidation as to their role in the formation of gene
fusions is essential. The TMPRSS2:ERG gene fusion is
an unique model to query sequence level
polymorphisms that may lead to the formation of intrachromosomal rearrangements largely due to the close
proximity and orientation of the involved genes as well
as the high rate of recurrence.
Chromosomal instability, defined as the formation of
novel chromosome alterations and rearrangements at an
elevated rate, compared to normal cells may also be a
factor contributing to the formation of ETS gene
fusions in CaP. It is well established that deletion of the
tumour suppressor PTEN (10q23.31), a common
genomic aberration in CaP, results in an elevated level
of chromosomal instability through activation of AKT.
One of sequelae of this change is the phosphorylation
and inhibition of the cell cycle check point kinase 1
(Chk1), an important kinase preventing cell cycle
progression in response to DNA damage (Puc et al.,
2005; Sanchez et al., 1997). Furthermore, nuclear
PTEN interacts with kinetochore proteins and induces
the expression of RAD51, a protein required to reduce
the incidence of spontaneous double-strand breaks
(Shen et al., 2007). PTEN deficiency ultimately alters
multiple cell cycle checkpoints, which could potentially
delay DNA damage repair and/or chromosome
segregation (Gupta et al., 2009). Overall, PTEN has a
variety of roles in maintaining chromosomal stability
and integrity, and the recurrent PTEN loss in CaP may
represent an important trigger in the events leading to
the formation of TMPRSS2:ETS gene fusions.
prognosis to the fusion gene and will be addressed in
the subsequent section.
Indirect methods suggestive of gene fusions in CaP are
being employed to broadly determine ETS
rearrangement status with perhaps the anticipation of
implementing a high-throughput method of detection.
Analysis of array comparative genomic hybridization
(aCGH) data, specifically the 21q22.2-3 region may
permit identification of Class Edel TMPRSS2:ERG
gene fusions (Watson et al., 2009; Ishkanian et al.,
2009). Class Esplit retains the intervening sequences
within the nuclei, in a copy neutral manner and
consequently aCGH cannot identify this rearrangement.
Overexpression of ETS transcription factors by gene
expression microarrays may also imply an ETS
rearrangement has occurred. Due to inconclusive
results, FISH or RT-PCR assays are necessary to
validate microarray findings pertaining to the ETS gene
fusions. A novel multiplexing technology recently
developed uses nanostructured microelectrodes
integrated onto a chip and has the capability to detect
disease-specific biomarkers, including differentiation
of various fusion transcripts (Fang et al., 2009). More
recently, immunohistochemistry (IHC) is also being
explored as a means to detect the fusion by ERG
protein overexpression, in the absence of confirming
fusion at the genomic or transcript level (Furusato et
al., 2010; Park et al., 2010). Of the numerous direct
(three-colour FISH, RT-PCR) and indirect (two-colour
FISH, microarrays, IHC) methods employed to
determine fusion status to date, the three-colour FISH
yields the most cytogenetic and genomic information.
In addition, to identifying the fusion status and class,
the inherent cell-by-cell analysis addresses the
heterogeneous nature of the disease, and provides a
biological context for such information.
VII. Fusion gene formation and
chromosomal instability
There is increasing research interest and effort focusing
on the genomic events and attributes that lead to the
formation of ETS gene fusions. A complex
TMPRSS2:ERG rearrangement found in a single
patient was meticulously examined and described by
Yoshimoto et al. (2007). This patient had a
microdeletion of the sequences from 5' ERG to and
including the TMPRSS2 coding sequences with a
concurrent translocation of the region immediately
telomeric of 5' untranslated TMPRSS2 sequences. A
detailed multicolour FISH assay mapped the region
between ERG and TMPRSS2, revealing the complexity
of chromosomal rearrangements that can lead to the
formation of fusion genes in CaP. This case
demonstrates the valuable information available
through the use of complex multicolour FISH assays.
The molecular mechanisms that underlie this recurrent
translocation are just beginning to be understood. For
example, fine mapping of the deletion breakpoints
located within the ERG and TMPRSS2 loci, followed
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suggests a trend towards unfavourable factors outcome
in CaP progression. Notably, an interesting comparison
of two studies looking at conservatively managed men
had opposing results from an association with CaPspecific death (Demichelis et al., 2007) to no reduction
in CaP-specific survival for patients harbouring this
rearrangement (Fitzgerald et al., 2008).
The role of deletion (Edel) or retention (Esplit) of
intervening sequences in tumour biology has also been
scrutinized with relatively uniform results suggesting
that Edel is not only the more prevalent mechanism but
is also associated with more aggressive disease
(Mwamukonda et al., 2010; Attard et al., 2008a; Mehra
et al., 2008). Edel was associated with worse prostatespecific survival and shorter time to biochemical
recurrence than Class Esplit (Yoshimoto et al., 2006;
Attard et al., 2008a). While, Class 2+Edel was
associated with lethal disease and significantly worse
clinical outcome, particularly when combined with
prostate-specific
clinicopathological
criteria
(Yoshimoto et al., 2006; Attard et al., 2008a). Another
study also demonstrated that Edel rearrangements have
a more aggressive tendency since all fusion-positive
androgen-independent metastases had lost 5' ERG
sequences (Mehra et al., 2008) and Edel was associated
with clinically aggressive features of progression
(Perner et al., 2006). These findings are consistent with
elevated ERG expression and led investigators to
speculate that the loss of 5' ERG is associated with
aggressive CaP.
It must be considered that the commonly deleted 2.7
Mb between ERG and TMPRSS2 could contain
important tumour suppressor genes (Yoshimoto et al.,
2006) and its loss in the Edel rearrangement leads to
haploinsufficiency of a tumour suppressor gene that
underlies the aggressive clinical course. One gene
candidate for this effect within this region, HMGN1, a
nucleosome binding protein has previously been
associated with CaP progression (Birger et al., 2005).
In agreement with this view, the Esplit rearrangement
has not yet been shown to associate with any particular
clinical outcome to date. However, given the low
frequency of this event (~10% of TMPRSS2:ERG
rearrangements), Esplit rearrangements cannot be
excluded as a measure of prognosis until further studies
are completed (Attard et al., 2008a).
On the other hand, one investigation demonstrated no
statistically
significant
association
with
clinicopathological criteria and Edel or Esplit, but
evidence did suggest 2+Edel is a factor contributing to
CaP-specific mortality (Fitzgerald et al., 2008).
Conversely, TMPRSS2:ERG rearrangement alone were
associated with lower histological grade, but no other
clinical features or CaP-specific death (Gopalan et al.,
2009). However, the same group also found that copy
number increases (CNI) of the ERG locus with or
without TMPRSS2:ERG gene fusions was associated
with high grade and advanced stage, while cancers with
CNI and 2+Edel rearrangements tended to be more
VIII. Heterogeneity of multifocal
disease
CaP, one of the most heterogeneous epithelial
carcinomas, is also notoriously multifocal in nature. As
a multifocal disease, CaP permits the investigation and
comparison of recurrent genomic events within distinct
foci of individual patients. In 32 RP specimens with
spatially distinct foci, ERG rearrangement status was
examined using two-colour FISH (Barry et al., 2007).
Nineteen samples displayed interfocal homogeneity,
with 80% of the samples negative for ERG
rearrangement. The remaining 13 samples exhibited
interfocal heterogeneity but intrafocal homogeneity,
with two samples harbouring three separate foci each
with a different rearrangement status: Class N, Edel
and Esplit. Similarly, whole mount examination of RP
specimens for fusion transcripts yielded multiple fusion
transcripts in individual CaP foci with an identical
hybrid transcript profile in the adjacent HGPIN
(Furusato et al., 2008). Two other studies examining
fusion transcript variants found different transcript
hybrids in discrete regions of a single prostate (Wang et
al., 2006; Clark et al., 2007). Multiple TMPRSS2:ETS
gene fusion-positive foci may arise independently and
exhibit interfocal heterogeneity. Investigation of ERG
rearrangement in multifocal CaP and corresponding
metastases provides a glimpse of the potential
biological impact of this aberration in the context of
disease progression (Perner et al., 2009). This study
reported that the metastatic lesion was always positive
for ERG rearrangement through the same mechanism
(Edel vs Esplit) as that present in at least one of the
prostatic tumour foci (not necessarily the index focus).
The authors suggest that this rearrangement may be a
factor contributing to the development of metastases,
regardless of clinicopathological criteria of the
individual foci.
IX. Prognostic significance
There exists appreciable controversy with respect to the
prognostic significance of the TMPRSS2:ERG gene
fusion in CaP, with studies suggesting that the fusion
gene has a favourable (Winnes et al., 2007; Petrovics et
al., 2005; Winnes et al., 2007; Saramaki et al., 2008),
unfavourable (Yoshimoto et al., 2008; Mehra et al.,
2007a; Perner et al., 2006; Wang et al., 2006; Nam et
al., 2007a; Nam et al., 2007b; Attard et al., 2008a;
Mehra et al., 2008; Reid et al., 2010; Demichelis et al.,
2007; Rostad et al., 2009; Lapointe et al., 2007a) or no
association (Mehra et al., 2008; Yoshimoto et al., 2006;
Neill et al., 2007; Fletcher et al., 2008; Dai et al., 2008;
Furusato et al., 2008; Darnel et al., 2009; Gopalan et
al., 2009; Rubio-Briones et al., 2010; Fitzgerald et al.,
2008; Lee et al., 2010; Sun et al., 2010; Rouzier et al.,
2008) with clinical outcomes. When no association
between clinicopathological criteria and the presence of
the fusion gene was found, it was often attributable to
small sample sizes. The most compelling evidence
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Williams JL, et al.
comprehensive evaluation of biopsy or RP specimens
providing well-informed judgments on diagnosis,
prognosis and treatment decisions.
In an attempt to optimize the clinical utility of this
biomarker, investigators are turning to less invasive
survey modes, such as urine specimens and circulating
tumour cells (CTCs). Post-digital rectal exam (DRE)
urine analyzed by qRT-PCR found 17.2% positive rate
for ERG overexpression. Subsequent examination of
the corresponding biopsy samples from the same cohort
revealed a 40% positive rate (Rice et al., 2010). The
clinical yield of this assay can be improved, as
indicated by another study which found a 69% positive
rate following prostatic message versus only 24% when
no prostatic message was performed before collecting
the urine samples (Rostad et al., 2009). Two additional
studies report similar results (42% and 59%) of fusionpositive transcripts in post-DRE urine (Hessels et al.,
2007; Laxman et al., 2006). Expressed prostatic
secretion has also been a successful specimen for the
non-invasive detection of fusion transcripts (Clark et
al., 2008b). These studies demonstrate the potential for
ETS gene fusion detection using non-invasive
approaches following physical evaluation of the
prostate by DRE, adding valuable information to
disease stratification prior to radical treatments. A
handful of studies have also used FISH to detect ERG
rearrangement in CTCs in effort to monitor disease
recurrence or treatment efficacy (Mao et al., 2008;
Attard et al., 2009; Stott et al., 2010).
clinically aggressive (Fine et al., 2010). While the
above results are conflicting to the previous studies that
showed no association with extra copies of the
unrearranged ERG locus (Attard et al., 2008a), the
difference may be due to the deletion of the intervening
genes potentially generating a more aggressive
tumourigenic phenotype.
SPINK1 (5q32) is a gene identified in a more recent
COPA meta-analysis as being overexpressed in 10% of
CaP, all of which are exclusively ETS fusion negative
(Tomlins et al., 2008b). For this reason, SPINK1
expression and the TMPRSS2:ERG fusion gene were
evaluated to determine their relative significance as
prognostic biomarkers in biopsy samples from
hormonally treated men (Leinonen et al., 2010). In this
cohort, the fusion gene was associated with Ki-67
staining, age at diagnosis and tumour area, but not with
any prostate-specific clinicopathological criteria
(Leinonen et al., 2010). On the other hand, cases that
overexpressed SPINK1 had a significantly shorter time
to biochemical recurrence, but no association with any
other criteria.
X. Clinical utility
Promptly following the emergence of adverse clinical
correlations of fusion-positive CaP Mosquera and
colleagues evaluated a series of CaP cases to determine
if there was a morphological phenotype associated with
this genomic alteration (Mosquera et al., 2007).
Blinded to ERG rearrangement status, the group
identified five histologic criteria that were significantly
related to ERG rearrangement positive samples: bluetinged mucin, cribriform growth, macronucleoli,
intraductal tumour spread, and signet-ring cell features.
Only 24% of ERG rearranged samples did not identify
with any of the above mentioned morphological
features and 93% of samples with three features were
positive for ERG rearrangement. The authors speculate
that the morphological characteristics shared by ERG
rearranged tumours could result from ETS dysregulated
pathways and could be utilized in the routine
assessment performed by pathologists. More recently,
the same group published a similar set of
morphological features with the addition of collagenous
micronodules (Mosquera et al., 2009). A significant
association between perineural invasion, blue-tinged
mucin, and intraductal tumor spread with a positive
gene fusion status has been documented (Nigwekar et
al., 2008), while another study confirmed the
association that ETS fusion-positive CaP samples were
more likely mucin-positive than mucin-negative (Tu et
al., 2007). These results should be taken, however, in
the context of somewhat contradictory reports, such
that the TMPRSS2:ERG gene fusion correlates with
low Gleason grade and is inversely related to highgrade morphological features. These studies hold
promise that morphological markers routinely
examined by pathologists could be coupled with the
current clinicopathological criteria for a more
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(8)
XI. Role of ETS in prostate
tumourigenesis: Driver?
Discrepancies regarding the fusion gene are not limited
to its diagnostic potential and prognostic significance.
Controversy also exists in the sequence of genomic and
molecular alterations in CaP initiation and progression.
Several groups speculate that the formation of the
TMPRSS2:ERG fusion gene is required for CaP
initiation in ETS positive CaP tumours, with other
aberrations occuring later in the course of disease
advancement and metastasis (Perner et al., 2007;
Tomlins et al., 2007; Attard et al., 2009). Recently,
Attard and colleagues demonstrated that CTCs from
individual castration-resistant CaP patients were either
clonally positive or negative for ERG rearrangement,
however, loss of PTEN and increase in AR gene copy
number was heterogeneous in the CTCs derived from a
single patient (Attard et al., 2009). These results
suggest that the formation of the fusion gene occurred
before PTEN loss and gain of the AR locus. However,
this study was performed on a very small cohort of
castration-resistant CaP and may not necessarily reflect
the sequence of accumulating genomic alterations in
CaP.
TMPRSS2:ETS fusion status in HGPIN occurs at a low
frequency, and almost exclusively only when
juxtaposed to fusion-positive CaP. These HGPIN
lesions, however, do not exhibit the chromosomal copy
708
TMPRSS2:ETS gene fusions in prostate cancer
Williams JL, et al.
factors downstream of AKT as a result of PTEN
deficiency, but on their own are not sufficient to
provoke the transition from benign to neoplastic. The
implication is not that PTEN loss is the driver in CaP,
but that ETS gene fusions are enhancer alterations
significantly affecting cellular processes further
progressing prostatic tumourigenesis when the
background is primed first by a driver event capable of
initiating sufficient dysregulation leading to the
development of a preneoplastic lesion. However,
because PTEN loss and the presence of the fusion gene
are significantly associated events in CaP (Yoshimoto
et al., 2008; Carver et al., 2009a; Han et al., 2009; King
et al., 2009; Bismar et al., 2010) it is likely that PTEN
inactivation may be an important driver lesion for
fusion-positive CaP. Together the driver event and ETS
overexpression lead to a significantly aggressive and
invasive lesion. Therefore, elucidation of the cellular
pathways affected by ETS overexpression is
fundamental to the comprehension of the aggressive
nature observed in the majority of fusion-positive CaP,
and to developing novel therapeutic strategies to
specifically target this subset of CaP.
XII. Concluding remarks
Difficulty in assigning prognostic significance,
diagnostic and therapeutic utility to ETS gene fusions is
a result of a myriad of factors including, the
heterogeneity of the disease, the mechanism of
rearrangement (Edel vs Esplit), the technique used to
assess the presence of the fusion as well as the cohort
examined. Nevertheless, continued controversy
between positive and negative clinical associations of
the gene fusion dictates further studies are required
using larger cohorts to determine the absolute potential
of this genomic aberration as a biomarker for CaP
diagnostic utility, prognostic significance, and
stratification of patients to aid in treatment decisions.
Furthermore, comprehension of the pathways affected
by ETS overexpression will aid in the potential of
implementing ETS specific therapies to target this
aggressive subtype of CaP and benefit many patients.
number changes seen in 42% of the paired CaP as
assessed by CGH (Cerveira et al., 2006). These results
propose that formation of the fusion gene may precede
chromosomal-level alterations and is consistent with
the literature indicating that few gross chromosome- or
arm-level chromosomal copy alterations are present in
localized CaP. Another study investigating a range of
prostate tissues comprising benign, precursor,
malignant and metastatic samples found that the
majority of patient samples examined showed
homogeneity with respect to fusion status and
mechanism (Edel vs Esplit). The presence of fusionpositive HGPIN was interpreted as additional evidence
that this entity is a true-precursor to CaP, a notion that
has eluded indisputable proof (Perner et al., 2007). In
contrast, a recent study that examined both PTEN
genomic loss and fusion status by FISH observed
PTEN loss in benign and HGPIN lesions, while ERG
rearrangement was identified in HGPIN, albeit at a
lower frequency than PTEN loss, and absent in BPH
lesions (Bismar et al., 2010). Maintaining this model of
progression and accumulation of genomic changes in
CaP it is possible that heterozygous loss of PTEN may
be a 'driver lesion', in a subset of CaP, and PTEN
haploinsufficiency may facilitate the selective
formation of the fusion gene (Figure 3).
TMPRSS2:ERG gene fusion may occur as a secondary
alteration and may function as an 'enhancer' permitting
the cell to achieve a higher level of aggressiveness and
invasiveness. When this sequence of events was
emulated in transgenic mice, ERG overexpression
resulted in marked acceleration of preneoplastic lesions
to invasive CaP on a Pten deleted background, but ERG
overexpression alone simply displayed slight atypical
histology compared to control mice (Carver et al.,
2009a; Carver et al., 2009b). In vitro experiments using
cell lines demonstrated ERG overexpression provided
enhanced motility without affecting proliferation, in
agreement with Tomlins et al. (2007); Carver et al.
(2009b). These findings corroborate the view that
effectors of ERG overexpression affect cellular
processes which are complimentary to unregulated
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(8)
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TMPRSS2:ETS gene fusions in prostate cancer
Williams JL, et al.
Figure 3: Model of prostate cancer progression showing ETS gene fusions as an enhancer lesion.
Cooperation of unregulated pathways downstream of PTEN with effectors of ERG overexpression is likely a crucial event in the
progression of an invasive and aggressive prostatic adenocarcinoma. Heterozygous genomic deletion of PTEN in benign prostatic
precursors may represent an early event, and act as a driver lesion leading to proliferation, survival and genomic instability-all initial
requisites of cancer. As a consequence of such heightened genomic instability, PTEN haploinsufficiency may facilitate the selective
formation of the fusion gene with consequent acquisition of additional invasive properties. The presence of both rearrangements within a
lesion is associated with accelerated disease progression and poor prognosis, indicating that synergistic molecular interactions exist
between their complementary pathways. Continuing instability generates genotypic heterogeneity and diversity, such that subclones
bearing PTEN homozygous deletions and amplified AR loci have further selective advantage for aggressive tumour progression,
androgen escape and metastases.
Atlas Genet Cytogenet Oncol Haematol. 2011; 15(8)
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Yao SL, Lu-Yao G. Understanding and appreciating
overdiagnosis in the PSA era. J Natl Cancer Inst. 2002 Jul
3;94(13):958-60
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