ETS fusion genes in prostate cancer

in Endocrine-Related Cancer
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Delila Gasi Tandefelt Departments of Pathology, Urology, Erasmus University Medical Centre, PO Box 2040, 2000 CA Rotterdam, The Netherlands

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Joost Boormans Departments of Pathology, Urology, Erasmus University Medical Centre, PO Box 2040, 2000 CA Rotterdam, The Netherlands

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Karin Hermans Departments of Pathology, Urology, Erasmus University Medical Centre, PO Box 2040, 2000 CA Rotterdam, The Netherlands

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Jan Trapman Departments of Pathology, Urology, Erasmus University Medical Centre, PO Box 2040, 2000 CA Rotterdam, The Netherlands

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Prostate cancer is very common in elderly men in developed countries. Unravelling the molecular and biological processes that contribute to tumor development and progressive growth, including its heterogeneity, is a challenging task. The fusion of the genes ERG and TMPRSS2 is the most frequent genomic alteration in prostate cancer. ERG is an oncogene that encodes a member of the family of ETS transcription factors. At lower frequency, other members of this gene family are also rearranged and overexpressed in prostate cancer. TMPRSS2 is an androgen-regulated gene that is preferentially expressed in the prostate. Most of the less frequent ETS fusion partners are also androgen-regulated and prostate-specific. During the last few years, novel concepts of the process of gene fusion have emerged, and initial experimental results explaining the function of the ETS genes ERG and ETV1 in prostate cancer have been published. In this review, we focus on the most relevant ETS gene fusions and summarize the current knowledge of the role of ETS transcription factors in prostate cancer. Finally, we discuss the clinical relevance of TMRPSS2–ERG and other ETS gene fusions in prostate cancer.

Abstract

Prostate cancer is very common in elderly men in developed countries. Unravelling the molecular and biological processes that contribute to tumor development and progressive growth, including its heterogeneity, is a challenging task. The fusion of the genes ERG and TMPRSS2 is the most frequent genomic alteration in prostate cancer. ERG is an oncogene that encodes a member of the family of ETS transcription factors. At lower frequency, other members of this gene family are also rearranged and overexpressed in prostate cancer. TMPRSS2 is an androgen-regulated gene that is preferentially expressed in the prostate. Most of the less frequent ETS fusion partners are also androgen-regulated and prostate-specific. During the last few years, novel concepts of the process of gene fusion have emerged, and initial experimental results explaining the function of the ETS genes ERG and ETV1 in prostate cancer have been published. In this review, we focus on the most relevant ETS gene fusions and summarize the current knowledge of the role of ETS transcription factors in prostate cancer. Finally, we discuss the clinical relevance of TMRPSS2–ERG and other ETS gene fusions in prostate cancer.

Introduction

Prostate cancer is the most frequent malignancy and the second most common cause of cancer-related death in men in the USA and in other countries with a Western lifestyle (Siegel et al. 2013). Almost all prostate cancers are adenocarcinomas and it is generally accepted that prostate cancers develop from a precursor stage denoted as prostate intraepithelial neoplasia (PIN; DeMarzo et al. 2003). Growth patterns of tumors can be very different and heterogeneous, reflected in the so-called Gleason grade (Lotan & Epstein 2010). Similar to other tumors, prostate cancer growth is driven by the accumulation of genetic and epigenetic alterations. One of the earliest genetic alterations in prostate cancer is overexpression of the ERG oncogene, which occurs in over 50% of prostate cancers (Tomlins et al. 2005, Hermans et al. 2006, 2009, Soller et al. 2006). The overexpression of ERG is in the majority of tumors driven by fusion of the ERG gene with transmembrane protease, serine 2 (TMPRSS2), a prostate-specific and androgen-regulated gene that maps very close to ERG on the same chromosome. This gene fusion has never been found in normal prostate but is present in tumor adjacent to PIN (Cerveira et al. 2006, Mosquera et al. 2008, Park et al. 2010, van Leenders et al. 2011). ERG is a member of the large family of ETS transcription factors (Hollenhorst et al. 2011).

Localized prostate cancer can be cured by surgical removal of the prostate or by local radiotherapy, but approximately 30% of treated patients show recurrences. It is well established that the growth of prostate cancer depends on male steroid hormones, androgens. Therefore, the treatment of choice of metastasized prostate cancer is one of various types of endocrine therapy, all aiming at the inhibition of the function of the androgen receptor (AR), the intracellular molecular target of androgens (Feldman & Feldman 2001, Scher & Sawyers 2005, Lonergan & Tindall 2011). The AR is a member of the family of ligand-dependent nuclear receptor transcription factors. Although many prostate tumors show an initial response to endocrine therapy, within 1–3 years essentially all tumors become resistant to the therapy and patients develop a disease now described as castration-resistant prostate cancer (CRPC). Remarkably, in CRPC the AR still plays a prominent role. Androgen signaling in CRPC can be modified by many different mechanisms, including amplification and mutation of the AR gene.

In this review, the role of ERG and other ETS transcription factors in prostate cancer is described. The focus is on the mechanism of ETS overexpression and on the clinical relevance of ERG and other ETS genes.

Functions of ETS transcription factors

The founding member of the ETS family of transcription factors, v-ets, was originally discovered as part of the GAG–MYB–ETS fusion protein of the transforming virus E26 that induces leukemia in chickens. The ETS family is composed of approximately 27 members, that all share high homology in their evolutionary conserved DNA-binding domain, the ETS domain, that is in the C-terminal part of the protein. Homology in other parts of the proteins is limited (Fig. 1; Oikinawa & Yamada 2003, Seth & Watson 2005, Hollenhorst et al. 2011).

Figure 1
Figure 1

Schematic presentation of the ETS transcription factors ERG, ETV1, and truncated ETV1. ETS, ETS DNA-binding domain; PNT, pointed protein–protein interaction domain; TAD, acidic transactivation domain.

Citation: Endocrine-Related Cancer 21, 3; 10.1530/ERC-13-0390

The 85-amino-acid ETS domain forms a helix–turn–helix DNA-binding structure that recognizes a GGAA/T core consensus sequence, the ETS binding site, in the regulatory regions of target genes. Small differences in the composition of flanking sequences of the binding site contribute to the specificity of ETS binding (Wei et al. 2010, Hollenhorst et al. 2011). A second conserved domain present in a subset of ETS factors is the pointed domain (PNT). This 65–85 amino acid helix–loop–helix domain functions in protein–protein interactions. In addition to the ETS- and PNT-domains, activation and repression domains have been postulated for most ETS factors.

On the basis of their overall structural composition and on the homology in the ETS domain, ETS transcription factors can be separated in ∼11 subfamilies (Oikinawa & Yamada 2003, Hollenhorst et al. 2011). ERG is, together with FLI1, a member of the ERG-subfamily and ETV1, ETV4, and ETV5 are the members of PEA3-subfamily that contain an N-terminal acidic transactivation domain (TAD; Oh et al. 2012). ETS proteins can function not only as transcription activators but also as repressors. Many directly or indirectly ETS-regulated genes have been defined. Recently, the first Chromatin immunoprecipitation (ChIP)-chip and ChIP-seq data have been published that identify and compare the binding sites of different ETS transcription factors in different cell lines and tissues (Wei et al. 2010, Hollenhorst et al. 2011). A wide variety of overlapping and more specific binding sites have been documented.

ETS transcription factors can play crucial roles in many biological processes, including cellular proliferation, differentiation, apoptosis, tissue remodeling, angiogenesis, metastasis, and transformation. Deregulated expression of ETS genes has been described in leukemia's and solid tumors (Seth & Watson 2005). Moreover, overexpression of ETS genes, most commonly ETS1, ETS2, ETV1, and ETV4 has been observed in breast, colon, lung, and prostate cancers. In general, overexpression of ETS genes was associated with advanced stage of the disease. More recently, it has been found that ETV1 in concert with activating KIT mutations plays a prominent role in gastrointestinal stromal tumors (Chi et al. 2010). As mentioned earlier, ERG is the most frequently overexpressed ETS gene in prostate cancer. ERG overexpression is found in both early- and late-stage prostate cancer (CRPC) (Tomlins et al. 2005, Soller et al. 2006, Hermans et al. 2009).

Fusion of TMPRSS2 to ERG and other ETS gene fusions in prostate cancer

ETS genes are frequently involved in gene fusions, resulting in the synthesis of chimerical proteins or altered expression of the ETS protein. ETS fusion genes have been detected in Ewing's sarcoma and in leukemia (Bohlander 2005, Khoury 2005, Hollenhorst et al. 2011). Fusion of the Ewing's sarcoma gene (EWS) to FLI1 occurs in over 90% of Ewing's sarcoma. This gene fusion leads to the production of a chimerical protein, linking the N-terminal region of EWS to the ETS-domain of FLI1. EWS–ERG fusions are detected in approximately 5% of Ewing's sarcoma. In rare cases EWS is linked to other ETS genes. The first exons of EWS encode a strong transactivation domain. The chimerical protein produced not only modulates the expression of ETS target genes, but probably also induces the expression of novel genes. In leukemia many different fusion genes involving the ETS gene TEL (ETV6) have been described.

In 2005, frequent overexpression of ERG in prostate cancer was observed (Petrovics et al. 2005). Later that year, it was discovered that the mechanism underlying this overexpression was the recurrent genomic rearrangement between the first exon(s) of TMPRSS2 and the ERG oncogenes (Fig. 2; Tomlins et al. 2005). This latter finding was rapidly confirmed and extended by others, and it is now generally accepted that over half of prostate cancers harbor the TMPRSS2–ERG gene fusion as the most frequent genomic alteration (Kumar-Sinha et al. 2008; Table 1).

Figure 2
Figure 2

Schematic presentation of the TMPRSS2–ERG fusion on chromosome band 21q22.

Citation: Endocrine-Related Cancer 21, 3; 10.1530/ERC-13-0390

Table 1

ETS gene fusions in prostate cancer

5′ Fusion partnerProstate specificAndrogen regulatedETS partnerFrequency (%)
TMPRRS2 (chr 21q)++ERG (chr 21q)50
SLC45A3 (chr 1q)++<1
NDRG1 (chr 8)+/−+<1
SLC45A3 (chr 1q)++FLI1<1
TMPRRS2 (chr 21q)++ETV1 (chr 7p)<1
SLC45A3 (chr 1q)++<1
FOXP1 (chr 3p)NDND<1
EST14 (chr 14q)++<1
HERVK17 (chr 17p)+<1
HERV-K_22q11.23++<1
C15ORF21 (chr 15q)++ (down)<1
HNRPA2B1 (chr 7p)−−<1
ACSL3 (chr 2q)+/−+<1
TMPRRS2 (chr 21q)++ETV4 (chr 17q)<1
KLK2 (chr 19p)++<1
CANT (chr 17q)++<1
DDX5 (chr 17q)−−<1
TMPRRS2 (chr 21q)++ETV5 (chr 3q)<1
SLC45A3 (chr 1q)++<1
aSLC45A3 (chr 1q)++ELK4 (chr 1q)<1

ND, not determined.

Read-through transcript.

TMPRSS2 is an androgen-regulated gene that is preferentially expressed in the prostate (Hermans et al. 2009). TMPRSS2 is located on chromosomal band 21q22. ERG maps also 21q22 in the same orientation, at a distance of approximately 3 Mb (Fig. 2). The fusion of the androgen- and prostate-specific regulating sequences and first exon(s) of TMPRSS2 to the coding sequences of ERG resulted in the androgen-regulated overexpression of ERG. Fusion of TMPRSS2 to ERG can occur by two mechanisms: the genomic region between the two genes can be lost by interstitial deletion, which is the case in approximately 60% of the fusion-positive tumors, or it can be the result of more complex genomic rearrangements involving chromosome 21q22 and presumably other chromosomes (Hermans et al. 2006, Perner et al. 2006). TMPRSS2–ERG has never been detected in normal prostate or in benign prostatic hyperplasia (Cerveira et al. 2006, Park et al. 2010, van Leenders et al. 2011). So, TMPRSS2–ERG is a very specific prostate cancer biomarker, although TMPRSS2–ERG has been found in approximately 20% of PIN lesions (Cerveira et al. 2006, Mosquera et al. 2008). More recently, ERG overexpression has been detected by immunohistochemistry in a much higher percentage of PIN (Park et al. 2010, van Leenders et al. 2011). So, the formation of TMPRSS2–ERG is an early event in prostate carcinogenesis. It remains to be established whether the gene fusion plays a role in PIN to cancer progression or can even play a role in earlier stages of prostate cancer development. At a low frequency, ERG overexpression is not caused by fusion to TMPRSS2, but by fusion to SLC45A3 or NDRG1, two other androgen-regulated genes that are preferentially expressed in the prostate (Table 1; Esgueva et al. 2010). These two fusion partners do not map to 21q22, indicating that chromosomal proximity is important but not essential for the fusion event.

ETV1 is overexpressed in 5–10% of prostate cancers (Tomlins et al. 2005, Hermans et al. 2008a). ETV1 gene fusions lead to overexpression of a truncated ETV1 protein that lacks the N-terminal TAD domain (Fig. 1). In a low percentage of tumors, structurally and functionally related ETV4 or ETV5 is overexpressed due to gene fusion (Tomlins et al. 2006, Helgeson et al. 2008, Hermans et al. 2008b). ETS gene fusions in prostate cancer seem mutually exclusive, but in multifocal disease more than one fusion event can be found. ERG is predominantly fused to TMPRSS2, but ETV1, ETV4, and ETV5 have multiple fusion partners that all are located on different chromosomes (Table 1; Tomlins et al. 2006, 2007, Attard et al. 2008a, Han et al. 2008, Helgeson et al. 2008, Hermans et al. 2008a,b, Clark & Cooper 2009, Rubin et al. 2011). Interestingly, two of the fusion partners are endogenous retroviral HERV-K sequences that are apparently insignificant in the normal prostate. A gene encoding a non-coding RNA, denoted EST14, can also be a more frequent fusion partner.

Most of the fusion partners of the ETS genes ETV1, ETV4 and ETV5 are androgen-upregulated and display prostate-specific expression (Table 1). There are, however, exceptions. The ETV1 fusion partner C15ORF21 is downregulated by androgens and HNRPA2B1 and DDX5 are housekeeping genes. Remarkably, expression of HNRPA2B1 is regulated by a dual-specific CG-rich promoter that cannot be methylated and always maintains an open chromatin structure (Antoniou et al. 2003, Lindahl-Allen & Antoniou 2007).

ETV1 is overexpressed not only as a fusion gene but also as a full-length mRNA, due to translocation of the complete gene (Tomlins et al. 2007, Hermans et al. 2008a, Gasi et al. 2011). Several full-length ETV1 translocations are to a specific region of chromosome 14 that also contains EST14. Recently, we mapped a full-length ETV1 translocation to chromosome 4 (Gasi et al. 2011), but for most translocations of the complete gene the chromosomal region of translocation has not yet been studied. Identification of the characteristics of these regions will be very helpful in addressing the question as to whether or not there are common mechanisms of full-length ETV1 overexpression. In a small percentage of prostate tumors, the ETS gene ELK4 is overexpressed due to cis-splicing of the flanking SLC45A3 gene (Rickman et al. 2009, Zhang et al. 2012). The finding that the expression of ETS transcription factors is mutually exclusive in clinical prostate cancers might not necessarily indicate a similar function. In a small proportion of ETS-negative samples, overexpression of SPINK1 has been described, and more recently, a mutually exclusive mutation of SPOP has been identified (Tomlins et al. 2008a, Barbieri et al. 2012). However, a direct association between ETS genes and SPINK1 or SPOP has not yet been found.

Mechanism of gene fusion

Probably, the genomic proximity of TMPRSS2 and ERG is an important determinant in explaining the high frequency of TMPRSS2–ERG fusion as compared with other ETS gene fusions. Although all other ETS gene fusion events are between genes that map on different chromosomes or at a long distance on the same chromosome, it has been postulated that these ETS fusions might also be facilitated by nuclear proximity of the fusion partners. This is presumed to be accomplished by looping out of genomic regions under certain cell growth conditions, facilitating the expression of the fusion partners (Lin et al. 2009, 2012, Mani et al. 2009).

As described earlier, most ETS-fusion partners share the properties of androgen-upregulated and prostate-specific expression. So, the mechanisms of regulation of expression of the fusion partner seem to be a second important determinant in the fusion event (Lin et al. 2009, 2012, Mani et al. 2009). Regulation of expression might contribute to nuclear proximity. It has also been postulated that binding of an activated AR to genes encoding fusion partners plays an active role in the fusion process. Evidence has been provided that the AR is instrumental in induction of genomic breaks by recruiting enzymes such as topoisomerase II β, or cytidine deaminase (CDA), and ORF2 endonuclease (Lin et al. 2009, 2012, Haffner et al. 2010, 2011). However, the experimental conditions used to investigate the mechanisms of chromosomal proximity and of induced DNA damage were rather complex, and follow-up studies should confirm and extend these earlier observations.

Biological and molecular functions of ETS proteins in prostate cancer

The main function of ERG and other ETS proteins in prostate cancer is not well understood. ETS overexpression alone seems insufficient to induce prostate cancer. In vitro studies showed that overexpression of ERG or ETV1 in immortalized, non-tumorigenic epithelial prostate cells increased cell migration and invasion (Tomlins et al. 2007, 2008b, Hermans et al. 2008a, Klezovitch et al. 2008, Wang et al. 2008), and knockdown of ERG or ETV1 in prostate cancer cell lines slowed invasion (Tomlins et al. 2007, 2008b, Sun et al. 2008, Wang et al. 2008).

In genetically modified mice (GEMs), overexpression of ERG or ETV1 resulted in the development of PIN but not of invasive cancer (Klezovitch et al. 2008, Tomlins et al. 2008b). However, in other studies, TMPRSS2–ERG GEMs did not even develop PIN. Among the progeny from crossbreeding Erg mice with Pten-knockout mice, PIN and micro-invasive cancer were observed (Carver et al. 2009, King et al. 2009, Baena et al. 2013, Chen et al. 2013). Witte and colleagues provided additional evidence that ERG can cooperate with several different oncogenes or tumor suppressor genes in the development of mouse prostate tumors (Zong et al. 2009).

By comparison of global gene expression data for clinical prostate cancer samples with and without ERG overexpression, pathways associated with ERG overexpression have been identified. Data obtained by Iljin et al. (2006) indicated a role of the WNT pathway in ERG-associated prostate cancer and showed high expression of HDAC1 in ERG-overexpressing tumor samples. Also, activation of the transforming growth factor β (TGFβ) pathway has been associated with ERG overexpression (Brase et al. 2011). Although the data reported in different studies are variable, a consistent association with ERG overexpression, of more than ten genes, including CACNA1D, TDRD1, PLA2G7, and NCALD, has been found (Iljin et al. 2006, Jhavar et al. 2008, Taylor et al. 2010, Brase et al. 2011, Boormans et al. 2013). This does not mean that these genes are direct ERG target genes. They might be indirectly regulated by ERG or they might represent a common prostate cell type in which TMPRSS2–ERG fusion occurred. Recently, TDRD1 has been identified as the first directly ERG-regulated gene (Paulo et al. 2012, Boormans et al. 2013). The mechanism of expression of other ERG-associated genes remains to be investigated.

Important initial results regarding the molecular effect of ERG overexpression in prostate cancer have been published (Yu et al. 2010). It has been shown by whole-genome ChIP-seq that there is overlap between genomic regions that bind AR and ERG. As a result, ERG overexpression can interfere with and modify the expression of AR-regulated genes. A model has been proposed in which ERG overexpression inhibits AR-regulated differentiation and stimulates dedifferentiation mediated by the H3K27 methyltransferase polycomb gene EZH2. In a Pten knockout GEM prostate cancer model, ERG overexpression changed the AR cistrome (Chen et al. 2013).

Our knowledge of the biological and molecular effects of ETV1 overexpression in prostate cancer is more limited. As described earlier, due to gene fusion, ETV1 can be overexpressed as a truncated protein lacking the N-terminal TAD domain (dETV1) (Fig. 1), or as a full-length protein, due to translocation of the complete gene to a different genomic region (Hermans et al. 2008a, Gasi et al. 2011). In in vitro studies, full-length ETV1 is a strong transcriptional activator, but dETV1 is much less active. Although both variants similarly induce migration and invasion in non-tumor prostate cells, only the full-length protein seems capable of inducing anchorage-independent growth in in vitro assays (Hermans et al. 2008a).

The relatively low percentage of clinical prostate cancer samples with ETV1 overexpression complicates the elucidation of the possible role of these different forms in prostate cancer growth. Although MMPs and the UPA/UPAR system have been described as ETV1-associated genes, a clear global picture of ETV1-regulated gene expression is still lacking (de Launoit et al. 2006, Hermans et al. 2008a).

An important remaining question is whether ERG and ETV1 affect prostate cancer development by the same mechanism. This might not be the case, although ERG and ETV1 are both members of the same ETS family. ERG and ETV1 at least partially interact with overlapping binding sites, but might have different effects on target gene expression. ERG negatively regulates AR-regulated gene expression and ETV1 has the opposite effect (Baena et al. 2013). As an example, although ERG inhibits PSA expression, ETVI seems to stimulate PSA expression (Shin et al. 2009, Yu et al. 2010). Paulo et al. (2012) recently suggested that there are both specific and shared targets of ETV1 and ERG. Applying unsupervised clustering of mRNA from primary clinical samples, we observed that ETV1-positive and ERG-positive tumor samples clustered separately (Boormans et al. 2013, Gasi Tandefelt et al. 2013). So, molecular evidence for a common mechanism of ERG and ETV1 in human prostate cancer is limited.

Heterogeneity of prostate cancer

Because localized prostate cancer can be a multifocal disease, tumors have been tested for ETS gene fusions in different cancerous foci within one prostate. In approximately half of the cases, individual tumor foci differed according to the presence of ETS rearrangements or fusion mechanism (deletion or translocation; Barry et al. 2007, Mehra et al. 2007). Because ERG gene fusion is an early event, it confirmed and extended the general assumption that the majority of men develop multiple cancers in their prostate. Metastatic prostate cancer foci in one individual, however, displayed identical ETS rearrangement, showing that only one tumor focus seeded metastatic deposits (Mehra et al. 2008, Liu et al. 2009, Guo et al. 2012).

ETS fusions as diagnostic and prognostic markers of prostate cancer

Because ERG fusion transcripts are present in approximately 50% of prostate tumors, it is obvious that the presence of ERG fusion transcripts in prostate tissue or in urine or overexpression of ERG protein detected by immunostaining in prostate biopsies can be an important robust diagnostic marker of prostate cancer in a large subgroup of patients. Absence of ERG is not informative. The prognostic significance of TMPRSS2–ERG gene fusion is controversial and contradictory results have been reported (Table 2). The discrepancies might be the result of the differences in the patient populations studied, the techniques used to detect gene fusions and the effect of treatment on the examined tumor samples. Originally, Petrovics et al. (2005) found that patients with high expression levels of ERG showed a slower progression than patients with tumors without ERG overexpression. After the discovery of recurrent gene fusions TMPRSS2–ERG was more frequently to be found correlated with poor clinical outcome (Table 2; Wang et al. 2006, Demichelis et al. 2007, Nam et al. 2007, Attard et al. 2008b, Perner et al. 2006). However, this was not confirmed in other studies (Lapointe et al. 2007, Saramaki et al. 2008, Gopalan et al. 2009). It also was suggested that a subgroup of patients who had gene fusion with an interstitial deletion between TMPRSS2 and ERG (so called ‘class Edel’) had poorer clinical outcome than gene-fusion-negative patients or than patients with TMPRSS2–ERG gene fusion without loss of the genomic region between the two genes (Attard et al. 2008b). Alternatively, it is possible that the poor survival associated with a copy number increase of chromosome 21 reflected generalized aneuploidy and genomic instability. We showed that patients expressing TMPRSS2–ERG fusion transcripts starting at an alternative first exon had better outcomes after radical prostatectomy than patients carrying tumors that only expressed TMPRSS2(exon1)–ERG (Hermans et al. 2009) and confirmed this finding in a completely independent patient cohort (Boormans et al. 2011). In the largest series reported thus far, more than 1100 radical prostatectomy specimens were evaluated for ERG overexpression using immunohistochemistry (Pettersson et al. 2012) and ERG overexpression was studied in correlation with biochemical recurrence and metastases- and cancer-specific survival. In the study population, 49% of the patients overexpressed ERG and although this overexpression was associated with a higher pathological T-stage, no association was found between ERG overexpression and survival in this cohort (median follow-up 12.6 years). In addition, the authors carried out a meta-analysis including analysis of prostate tissues or urine samples from more than 10 000 patients. The vast majority of the cases were primary tumors. Again no association between ERG overexpression and/or TMPRSS2–ERG gene fusion and clinical outcome was observed.

Table 2

Original studies on clinical relevance of TMPRSS2–ERG fusion gene in prostate cancer

ReferencenTissueTechniqueTMPRSS2–ERG (%)Follow-up (median)Fusion-positive vs fusion-negative cases
(A) Cancer-specific (CSS) and overall survival (OS)
 Gopalan et al. (2009)521RPFISH427.9 yearsNo difference in OS (univariate level)
 FitzGerald et al. (2008)214RP/TURPFISH35.512.3 yearsNo difference in CSS (multivariate level)
 Attard et al. (2008b)445TURP/biopsiesFISH307.5 yearsPoorer CSS and OS (multivariate level)
 Demichelis et al. (2007)111TURP/Millin prostatectomyFISH159.1 yearsPoorer CSS (univariate level)
(B) PSA recurrence-free survival (PRFS)
 Petrovics et al. (2005)114RPQuantitative RT-PCR62aNSLonger PRFS (univariate level)
 Saramaki et al. (2008)150RPFISH335.5 yearsLonger PRFS (multivariate level)
 Nam et al. (2007)165RPRT-PCR421.7 yearsPoorer PRFS (multivariate level)
 Perner et al. (2006)118RPFISH49NS–b
 Wang et al. (2006)59RPRT-PCR59NS–c
 Lapointe et al. (2007)63RP LNRT-PCR702.0 yearsNo difference in PRFS
 Hermans et al. (2009)67RPQuantitative RT-PCR6610.2 yearsNo difference in PRFSd

RP, radical prostatectomy; FISH, fluorescence in situ hybridization; TURP, transurethral resection of the prostate; LN, lymph node.

ERG overexpression.

Higher recurrence rate, no survival analysis.

More early recurrences, no survival analysis.

Longer BRFS for TMPRSS2(exon0)–ERG (multivariate level).

In almost all studies exploring the correlation between ERG gene fusion and clinical outcome, ERG status was assessed on surgically treated specimens. Data on association of TMPRSSS2–ERG expression and response to a specific non-surgical treatment are limited. We studied 71 hormone-naïve prostate cancer lymph node metastases. Although you might expect an important role for TMPRSS2-ERG in the success of endocrine treatment because of the androgen-regulation of TMPSS2 expression, in this group of patients no association between TMPRSS2-ERG expression and time to development of castration resistant disease was detected (Boormans et al. 2010). ERG-positive tumors in CRPC patients who were treated with the inhibitor of testosterone synthesis abiraterone acetate were more frequent in patients who responded well to the therapy than in patients who did not show a good response (Attard et al. 2009). ERG status alone was not sufficient to explain sensitivity to abiraterone, but these results indicated that ETS gene fusions remained dependent on androgen signalling, despite the castration-resistant stage of the disease. Whether gene fusion status of the tumor has implications for the timing and the choice of endocrine therapy remains to be clarified further.

Although TMPRSS2–ERG overexpression might not be a tumor progression marker, it remains a strong novel therapeutic target because of its prostate cancer specificity and its overexpression in many stages of tumor development. So far, no specific inhibitors of ERG function have been described. In a recent report two independent cohorts of over 100 patients were treated with external beam radiotherapy (Dal Pra et al. 2013). Although preclinical studies predicted that TMPRSS2–ERG tumors might be more sensitive to radiation (Brenner et al. 2011), the presence of the gene fusion showed no association with biochemical recurrence-free survival in the clinical study. So, a simple extrapolation of experimental data to the clinical setting seems not to be possible and other factors not included in the clinical analyses so far contribute to clinical behavior.

In a recent study, we have identified in a group of prostate cancer patients who showed ERG overexpression in the tumor, two subgroups with very different clinical outcomes (Gasi Tandefelt et al. 2013). A 36-gene signature was generated that could predict rapid clinical progression in this group of ERG-positive patients. Using this predictor it was not possible to separate ERG-negative patients into two clinically relevant subgroups. We presumed that the ERG-positive patient group was more homogeneous, facilitating the identification of groups of genes that cooperate with ERG in tumor progression. No doubt, the ERG-negative group was genetically more heterogeneous, making selection of subgroups more difficult. In ETS-negative samples, there is evidence that SPINK1 overexpression was an independent predictor of clinical progression (Tomlins et al. 2008a).

Concluding remarks

The finding of ETS gene fusions in prostate cancer has been a major step in increasing our knowledge of the molecular and biological mechanisms of development and progressive growth of the disease. The postulated mechanisms of gene fusion and molecular function of ETS genes are of high general interest. Further exploration of proposed mechanisms will contribute to understanding of the processes of genomic rearrangements and oncogene heterogeneity in general. The gene fusions are also of the utmost importance in clinical prostate cancer. At the moment, ERG overexpression is already instrumental in the diagnosis of the disease. Moreover, elucidation of the mechanisms of ETS gene expression and function increases the opportunity for finding new therapeutic targets for early and late stage prostate cancer (CRPC).

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.

Funding

The study was supported by a grant from the Dutch Cancer Society Koningin Wilhelmina Fonds (KWF) and by the Marie Curie grant ‘Cancure’ from the European Union.

References

  • Antoniou M, Harland L, Mustoe T, Williams S, Holdstock J, Yague E, Mulcahy T, Griffiths M, Edwards S & Ioannou PA et al. 2003 Transgenes encompassing dual-promotor CpG islands from the human TBP and HNRPA2B1 loci are resistant to heterochromatin-mediated silencing. Genomics 82 269–279. (doi:10.1016/S0888-7543(03)00107-1).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Attard G, Clark J, Ambroisine L, Mills IG, Fisher G, Flohr P, Reid A, Edwards S, Kovacs G & Berney D et al. 2008a Heterogeneity and clinical significance of ETV1 translocations in human prostate cancer. British Journal of Cancer 99 314–320. (doi:10.1038/sj.bjc.6604472).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Attard G, Clark J, Ambroisine L, Fisher G, Kovacs G, Flohr P, Berney D, Foster CS, Fletcher A & Gerald WL et al. 2008b Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene 27 253–263. (doi:10.1038/sj.onc.1210640).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Attard G, Swennenhuis JF, Olmos D, Reid AH, Vickers E, A'Hern R, Levink R, Coumans F, Moreira J & Riisnaes R et al. 2009 Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Research 69 2912–2918. (doi:10.1158/0008-5472.CAN-08-3667).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Baena E, Shao Z, Linn DE, Glass K, Hamblen MJ, Fujiwara Y, Kim J, Nguyen M, Zhang X & Godinho FJ et al. 2013 ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients. Genes and Development 27 683–698. (doi:10.1101/gad.211011.112).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blater M, Theurillat J-P, White TA, Stojanov P, Van Allen E & Stransky N et al. 2012 Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nature Genetics 44 685–689. (doi:10.1038/ng.2279).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Barry M, Perner S, Demichelis F & Rubin MA 2007 TMPRSS2–ERG fusion heterogeneity in multifocal prostate cancer: clinical and biologic implications. Urology 70 630–633. (doi:10.1016/j.urology.2007.08.032).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bohlander SK 2005 ETV6: a versatile player in leukemogenesis. Seminars in Cancer Biology 15 162–174. (doi:10.1016/j.semcancer.2005.01.008).

  • Boormans JL, Hermans KG, Made J, van Leenders GJ, Wildhagen MF, Collette L, Schroder FH, Trapman J & Verhagen PC 2010 Expression of androgen-regulated fusion gene TMPRSS2–ERG does not predict response to endocrine treatment in hormone-naïve, node-positive prostate cancer. European Urology 57 830–835. (doi:10.1016/j.eururo.2009.08.013).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Boormans JL, Porkka K, Visakorpi T & Trapman J 2011 Confirmation of the association of TMPRSS2(exon 0):ERG expression and a favorable prognosis of primary prostate cancer. European Urology 60 183–184. (doi:10.1016/j.eururo.2011.03.028).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Boormans JL, Korsten H, Made AC, van Leenders GJ, de Vos CV, Jenster G & Trapman J 2013 Identification of TDRD1 as a direct target gene of ERG in primary prostate cancer. International Journal of Cancer 133 335–346. (doi:10.1002/ijc.28025).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brase JC, Johannes M, Mannsperger H, Fälth M, Metzger J, Kacprzyk LA, Andrasiuk T, Gade S, Meister M & Sirma H et al. 2011 TMPRSS2–ERG-specific transcriptional modulation is associated with prostate cancer biomarkers and TGF-β signaling. BMC Cancer 11 507. (doi:10.1186/1471-2407-11-507).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brenner JC, Ateeq B, Li Y, Yocum AK, Cao Q, Asangani IA, Patel S, Wang X, Liang H & Yu J et al. 2011 Mechanistic rationale for inhibition of poly(ADP-ribose)polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell 19 664–678. (doi:10.1016/j.ccr.2011.04.010).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Carver BS, Tran J, Gopalan A, Chen Z, Shaikh S, Carracedo A, Alimonti A, Nardella C, Varmeh S & Scardino PT et al. 2009 Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nature Genetics 41 619–624. (doi:10.1038/ng.370).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cerveira N, Ribeiro FR, Peixoto A, Costa V, Henrique R, Jeronimo C & Teixeira MR 2006 TMPRSS2–ERG gene fusion causing ERG overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions. Neoplasia 8 826–832. (doi:10.1593/neo.06427).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chen Y, Chi P, Rockowitz S, Iaquinta PJ, Shamu T, Shukla S, Gao D, Sirota I, Carver BS & Wongvipat J et al. 2013 ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss. Nature Medicine 19 1023–1029. (doi:10.1038/nm.3216).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chi P, Chen Y, Zhang L, Guo X, Wongvipat J, Shamu T, Fletcher JA, Dewell S, Maki RG & Zheng D et al. 2010 ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumors. Nature 467 849–853. (doi:10.1038/nature09409).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Clark JP & Cooper CS 2009 ETS gene fusions in prostate cancer. Nature Reviews. Urology 6 429–439. (doi:10.1038/nrurol.2009.127).

  • Dal Pra A, Lalonde E, Sykes E, Warde F, Ishkanian A, Meng A, Maloff C, Srigley J, Joshua AM & Petrovics G et al. 2013 TMPRSS2–ERG status is not prognostic following prostate cancer radiotherapy: implications for fusion status and DSB repair. Clinical Cancer Research 19 5202–5209. (doi:10.1158/1078-0432.CCR-13-1049).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • DeMarzo AM, Nelson WG, Isaacs WB & Epstein JI 2003 Pathological and molecular aspects of prostate cancer. Lancet 361 955–964. (doi:10.1016/S0140-6736(03)12779-1).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Demichelis F, Fall K, Perner S, Andrén O, Schmidt F, Setlur SR, Hoshida Y, Mosquera JM, Pawitan Y & Lee C et al. 2007 TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene 26 4596–4599. (doi:10.1038/sj.onc.1210237).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Esgueva R, Perner S, LaFargue CJ, Scheble V, Stephan C, Lein M, Fritzsche FR, Dietel M, Kristiansen G & Rubin MA 2010 Prevalence of TMPRSS2–ERG and SLC45A3–ERG gene fusions in a large prostatectomy cohort. Modern Pathology 23 539–546. (doi:10.1038/modpathol.2009.193).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Feldman BJ & Feldman D 2001 The development of androgen-independent prostate cancer. Nature Reviews. Cancer 1 34–45. (doi:10.1038/35094009).

  • FitzGerald LM, Agalliu I, Johnson K, Miller MA, Kwon EM, Hurtado-Coll A, Fazli L, Rajput AB & Gleave ME et al. 2008 Association of TMPRSS2-ERG gene fusion with clinical characteristics and outcomes: results from a population-based study of prostate cancer. BMC Cancer 8 230. (doi:10.1186/1471-2407-8-230).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gasi D, van der Korput HA, Douben HC, de Klein A, de Ridder CM, van Weerden WM & Trapman J 2011 Overexpression of full-length ETV1 transcripts in clinical prostate cancer due to gene translocation. PLoS ONE 6 e16332. (doi:10.1371/journal.pone.0016332).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gasi Tandefelt D, Boormans JL, van der Korput HA, Jenster G & Trapman J 2013 A 36-gene signature predicts clinical progression in a subgroup of ERG-positive prostate cancers. European Urology 64 941–950. (doi:10.1016/j.eururo.2013.02.039).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gopalan A, Leversha MA, Satagopan JM, Zhou Q, Al-Ahmadie HA, Fine SW, Eastham JA, Scardino PT, Scher HI & Tickoo SK et al. 2009 TMPRSS2–ERG gene fusion is not associated with outcome in patients treated by prostatectomy. Cancer Research 69 1400–1406. (doi:10.1158/0008-5472.CAN-08-2467).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Guo CC, Wang Y, Xiao L, Troncoso P & Czerniak B 2012 The relationship of TMPRSS2–ERG gene fusion between primary and metastatic prostate cancers. Human Pathology 43 644–649. (doi:10.1016/j.humpath.2011.06.018).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Haffner MC, Aryee MJ, Toubaji A, Esopi DM, Albadine R, Gurel B, Isaacs WB, Bova GS, Liu J & Meeker AK et al. 2010 Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nature Genetics 42 668–675. (doi:10.1038/ng.613).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Haffner MC, De Marzo AM, Meeker AK, Nelson WG & Yegnasubramanian S 2011 Transcription-induced DNA double strand breaks: Both oncogenic force and potential therapeutic target? Clinical Cancer Research 17 3858–3864. (doi:10.1158/1078-0432.CCR-10-2044).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Han B, Mehra R, Dhanasekaran SM, Yu J, Menon A, Lonigro RJ, Wang X, Gong Y, Wang L & Shankar S et al. 2008 A fluorescence in situ hybridization screen for E26 transformation-specific aberrations: identification of DDX5–ETV4 fusion protein in prostate cancer. Cancer Research 68 7629–7637. (doi:10.1158/0008-5472.CAN-08-2014).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Helgeson BE, Tomlins SA, Shah N, Laxman B, Cao Q, Prensner JR, Cao X, Singla N, Montie JE & Varambally S et al. 2008 Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusions in prostate cancer. Cancer Research 68 73–80. (doi:10.1158/0008-5472.CAN-07-5352).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hermans KG, van Marion R, van Dekken H, Jenster G, van Weerden WM & Trapman J 2006 TMPRSS2:ERG fusion by translocation or interstitial deletion is highly relevant in androgen-dependent prostate cancer, but is bypassed in late-stage androgen receptor-negative prostate cancer. Cancer Research 66 10658–10663. (doi:10.1158/0008-5472.CAN-06-1871).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hermans KG, van der Korput HA, van Marion R, van de Wijngaart DJ, Ziel-van der Made A, Dits NF, Boormans JL, van der Kwast TH, van Dekken H & Bangma CH et al. 2008a Truncated ETV1, fused to novel tissue-specific genes, and full-length ETV1 in prostate cancer. Cancer Research 68 7541–7549. (doi:10.1158/0008-5472.CAN-07-5930).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hermans KG, Bressers AA, van der Korput HA, Dits NF, Jenster G & Trapman J 2008b Two novel prostate-specific and androgen-regulated fusion partners of ETV4 in prostate cancer. Cancer Research 68 3094–3098. (doi:10.1158/0008-5472.CAN-08-0198).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hermans KG, Boormans JL, Gasi D, van Leenders GJ, Jenster G, Verhagen PC & Trapman J 2009 Overexpression of prostate-specific TMPRSS2(exon 0)–ERG fusion transcripts corresponds with favorable prognosis of prostate cancer. Clinical Cancer Research 15 6398–6403. (doi:10.1158/1078-0432.CCR-09-1176).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hollenhorst PC, McIntosh LP & Grave BJ 2011 Genomic and biochemical insights into the specificity of ETS transcription factors. Annual Review of Biochemistry 80 437–471. (doi:10.1146/annurev.biochem.79.081507.103945).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Iljin K, Wolf M, Edgren H, Gupta S, Kilpinen S, Skotheim RI, Peltola M, Smit F, Verhaegh G & Schalken J et al. 2006 TMPRSS2 fusions with oncogenic ETS factors in prostate cancer involve unbalanced genomic rearrangements and are associated with HDAC1 and epigenetic reprogramming. Cancer Research 66 10242–10246. (doi:10.1158/0008-5472.CAN-06-1986).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jhavar S, Reid A, Clark J, Kote-Jarai Z, Christmas T, Thompson A, Woodhouse C, Ogden C, Fisher C & Corbishley C et al. 2008 Association of TMPRSS2–ERG gene fusion in human prostate cancer by expression profiling using GeneChip Human Exon 1.0 ST arrays. Journal of Molecular Diagnostics 10 50–57. (doi:10.2353/jmoldx.2008.070085).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Khoury JD 2005 Ewing sarcoma family of tumors. Advances in Anatomic Pathology 12 212–220. (doi:10.1097/01.pap.0000175114.55541.52).

  • King JC, Xu J, Wongvipat J, Hieronymus H, Carver BS, Leung DH, Taylor BS, Sander C, Cardiff RD & Couto SS et al. 2009 Cooperativity of TMPRSS2–ERG with PI3-kinase pathway activation in prostate oncogenesis. Nature Genetics 41 524–526. (doi:10.1038/ng.371).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Klezovitch O, Risk M, Coleman I, Lucas JM, Null M, True LD, Nelson PS & Vasioukhin V 2008 A causal role for ERG in neoplastic transformation of prostate epithelium. PNAS 105 2105–2110. (doi:10.1073/pnas.0711711105).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kumar-Sinha C, Tomlins SA & Chinnaiyan AM 2008 Recurrent gene fusions in prostate cancer. Nature Reviews. Cancer 8 497–511. (doi:10.1038/nrc2402).

  • Lapointe J, Kim YH, Miller MA, Li C, Kaygusuz G, van de Rijn M, Huntsman DG, Brooks JD & Pollack JR 2007 A variant TMPRSS2 isoform and ERG fusion product in prostate cancer with implications for molecular diagnosis. Modern Pathology 20 467–473. (doi:10.1038/modpathol.3800759).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • de Launoit Y, Baert JL, Chotteau-Lelievre A, Monte D, Coutte L, Mauen S, Firlej V, Degerny C & Verreman K 2006 The Ets transcription factors of the PEA3 group: transcriptional regulators in metastasis. Biochimica et Biophysica Acta 1766 79–87. (doi:10.1016/j.bbcan.2006.02.002).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • van Leenders GJ, Boormans JL, Vissers CJ, Hoogland AM, Bressers AA, Furusato B & Trapman J 2011 Antibody EPR3864 is specific for ERG genomic fusions in prostate cancer: implications for pathological practice. Modern Pathology 24 1128–1138. (doi:10.1038/modpathol.2011.65).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin C, Yang L, Tanasa B, Hutt K, Ju B-G, Ohgi KA, Zang J, Rose DW, Fu X-D & Glass CK et al. 2009 Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer. Cell 139 1069–1083. (doi:10.1016/j.cell.2009.11.030).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin C, Yang L & Rosenfeld MG 2012 Molecular logic underlying chromosomal translocations, random or non-random? Advances in Cancer Research 113 241–279. (doi:10.1016/B978-0-12-394280-7.00015-4).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lindahl-Allen M & Antoniou M 2007 Correlation of DNA methylation with histone modifications across the HNRPA2B1-CBX3 ubiquitously-acting chromatin open element (UCOE). Epigenetics 2 227–236. (doi:10.4161/epi.2.4.5231).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu W, Laitinen S, Khan S, Vihinen M, Kowalski J, Yu G, Chen L, Ewing CM, Eisenberger MA & Carducci MA et al. 2009 Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nature Medicine 15 559–565. (doi:10.1038/nm.1944).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lonergan PE & Tindall DJ 2011 Androgen receptor signalling in prostate cancer development and progression. Journal of Carcinogenesis 10 20. (doi:10.4103/1477-3163.83937).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lotan TL & Epstein JI 2010 Clinical implications of changing definitions within the Gleason grading system. Nature Reviews. Urology 7 136–142. (doi:10.1038/nrurol.2010.9).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mani R-S, Tomlins SA, Callahan K, Ghosh A, Nyati MK, Varambally S, Palanisamy N & Cinnaiyan AM 2009 Induced chromosomal proximity and gene fusions in prostate cancer. Science 326 1230. (doi:10.1126/science.1178124).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mehra R, Han B, Tomlins SA, Wang L, Menon A, Wasco MJ, Shen R, Montie JE, Chinnaiyan AM & Shah RB 2007 Heterogeneity of TMPRSS2 gene rearrangements in multifocal prostate adenocarcinoma: molecular evidence for an independent group of diseases. Cancer Research 67 7991–7995. (doi:10.1158/0008-5472.CAN-07-2043).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mehra R, Tomlins SA, Yu J, Cao X, Wang L, Menon A, Rubin MA, Pienta KJ, Shah RB & Chinnaiyan AM 2008 Characterization of TMPRSS2–ETS gene aberrations in androgen-independent metastatic prostate cancer. Cancer Research 68 3584–3590. (doi:10.1158/0008-5472.CAN-07-6154).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mosquera JM, Perner S, Genega EM, Sanda M, Hofer MD, Mertz KD, Paris PL, Simko J, Bismar TA & Ayala G et al. 2008 Characterization of TMPRSS2–ERG fusion in high-grade prostatic intraepithelial neoplasia and potential clinical implications. Clinical Cancer Research 14 3380–3385. (doi:10.1158/1078-0432.CCR-07-5194).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nam RK, Sugar L, Yang W, Srivastava S, Klotz LH, Yang LY, Staminirovic A, Encioiu E, Neill M & Loblaw DA et al. 2007 Expression of the TMPRSS2:ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer. British Journal of Cancer 97 1690–1695. (doi:10.1038/sj.bjc.6604054).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Oh S, Shin S & Janknecht R 2012 ETV1, 4 and 5: an oncogenic subfamily of ETS transcription factors. Biochimica et Biophysica Acta 1826 1–12. (doi:10.1016/j.bbcan.2012.02.002).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Oikinawa T & Yamada T 2003 Molecular biology of the Ets family of transcription factors. Gene 303 11–34. (doi:10.1016/S0378-1119(02)01156-3).

  • Park K, Tomlins SA, Mudaliar KM, Chiu YL, Esqueva R, Mehra R, Suleman K, Varembally S, Brenner JC & MacDonald T et al. 2010 Antibody-based detection of ERG rearrangement-positive prostate cancer. Neoplasia 12 590–598. (doi:10.1593/neo.10726).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Paulo P, Ribiero FR, Santos J, Mesquita D, Almeida M, Barros-Silva JD, Itkonen H, Henrique R, Jeronimo C & Sveen A et al. 2012 Molecular subtyping of primary prostate cancer reveals specific and shared target genes of different ETS rearrangements. Neoplasia 14 600–611. (doi:10.1593/neo.12600).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Perner S, Demichelis F, Beroukhim R, Schmidt FH, Mosquera JM, Setlur S, Tchinda J, Tomlins SA, Hofer MD & Pienta KG et al. 2006 TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Research 66 8337–8341. (doi:10.1158/0008-5472.CAN-06-1482).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Petrovics G, Liu A, Shaheduzzaman S, Furusato B, Sun C, Chen Y, Nau M, Ravindranath L, Chen Y & Dobi A et al. 2005 Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome. Oncogene 24 3847–3852. (doi:10.1038/sj.onc.1208518).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pettersson A, Graff RE, Bauer SR, Pitt MJ, Lis RT, Stack EC, Martin NE, Kunz L, Penney KL & Ligon AH et al. 2012 The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: a cohort study and meta-analysis. Cancer Epidemiology, Biomarkers & Prevention 21 1497–1509. (doi:10.1158/1055-9965.EPI-12-0042).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rickman DS, Pflueger D, Moss B, VanDoren VE, Chen CX, de la Taille A, Kuefer R, Tewari AK, Setlur SR & Demichelis F et al. 2009 SLC45A3–ELK4 is a novel and frequent erythroblast transformation-specific fusion transcript in prostate cancer. Cancer Research 69 2734–2738. (doi:10.1158/0008-5472.CAN-08-4926).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rubin MA, Maher CA & Chinnaiyan AM 2011 Common gene rearrangements in prostate cancer. Journal of Clinical Oncology 27 3659–3668. (doi:10.1200/JCO.2011.35.1916).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Saramaki OR, Harjula AE, Martikainen PM, Vessella RL, Tammela TL & Visakorpi T 2008 TMPRSS2–ERG fusion identified a subgroup of prostate cancers with a favorable prognosis. Clinical Cancer Research 14 3395–4000. (doi:10.1158/1078-0432.CCR-07-2051).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Scher HI & Sawyers CL 2005 Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen receptor signalling axis. Journal of Clinical Oncology 23 8253–8261. (doi:10.1200/JCO.2005.03.4777).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Seth A & Watson DK 2005 ETS transcription factors and their emerging roles in human cancer. European Journal of Cancer 41 2462–2478. (doi:10.1016/j.ejca.2005.08.013).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Shin S, Kim T-D, Jin F, van Deursen J, Dehm SM, Tindall DJ, Grande JP, Munz J-M, Vasmatzis G & Janknecht R 2009 Induction of prostatic intraepithelial neoplasia and modulation of androgen receptor by ETS variant 1/ETS-related protein 81. Cancer Research 69 8102–8110. (doi:10.1158/0008-5472.CAN-09-0941).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Siegel R, Naishadham D & Jemal A 2013 Cancer statistics, 2012. CA: A Cancer Journal for Clinicians 63 11–30. (doi:10.3322/caac.21166).

  • Soller MJ, Isaksson M, Elfving P, Soller W, Lundgren R & Panagopoulos I 2006 Confirmation of the high frequency of the TMPRSS2/ERG fusion gene in prostate cancer. Genes, Chromosomes & Cancer 45 717–719. (doi:10.1002/gcc.20329).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sun C, Dobi A, Mohamed A, Li H, Thangapazham RL, Furusato B, Shaheduzzaman S, Tan SH, Vaidyanathan G & Whitman E et al. 2008 TMPRSS2–ERG fusion, a common genomic alteration in prostate cancer activates C-MYC and abrogates prostate epithelial differentiation. Oncogene 27 5348–5353. (doi:10.1038/onc.2008.183).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kausik P, Cerami E & Reva B et al. 2010 Integrative genomic profiling of human prostate cancer. Cancer Cell 18 1–12. (doi:10.1016/j.ccr.2010.05.026).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J & Kuefer R et al. 2005 Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310 644–648. (doi:10.1126/science.1117679).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tomlins SA, Mehra R, Rhodes DR, Smith LR, Roulston D, Helgeson BE, Cao X, Wei JT, Rubin MA & Shah RB et al. 2006 TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer. Cancer Research 66 3396–3400. (doi:10.1158/0008-5472.CAN-06-0168).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tomlins SA, Laxman B, Dhanasekaran SM, Helgeson BE, Cao X, Morris DS, Menon A, Jing X, Cao Q & Han B et al. 2007 Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature 448 595–599. (doi:10.1038/nature06024).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tomlins SA, Rhodes DR, Yu J, Varambally S, Mehra R, Perner S, Demichelis F, Helgeson BE, Laxman B & Morris DS et al. 2008a The role of SPINK1 in ETS rearrangement negative prostate cancers. Cancer Cell 13 519–528. (doi:10.1016/j.ccr.2008.04.016).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tomlins SA, Laxman B, Varambally S, Cao X, Yu J, Helgeson BE, Cao Q, Prensner JR, Rubin MA, Shah RB & Mehra R et al. 2008b Role of the TMPRSS2–ERG gene fusion in prostate cancer. Neoplasia 10 177–188. (doi:10.1593/neo.07822).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang J, Cai Y, Ren C & Ittman M 2006 Expression of variant TMPRSS2–ERG mRNAs is associated with aggressive prostate cancer. Cancer Research 66 8347–8351. (doi:10.1158/0008-5472.CAN-06-1966).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang J, Cai Y, Yu W, Ren C, Spencer DM & Ittmann M 2008 Pleiotropic biological activities of alternatively spliced TMPRSS2/ERG fusion gene transcripts. Cancer Research 68 8516–8524. (doi:10.1158/0008-5472.CAN-08-1147).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wei G-H, Badis G, Berger MF, Kivioja T, Palin K, Enge M, Bonke M, Jolma A, Varjosalo M & Gehrke AR et al. 2010 Genome-wide analysis of ETS-family DNA-binding in vitro and in vivo. EMBO Journal 29 2147–2160. (doi:10.1038/emboj.2010.106).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yu J, Yu J, Mani RS, Cao Q, Brenner CJ, Cao X, Wang X, Wu L, Li J & Hu M et al. 2010 An integrated network of androgen receptor, polycomb, and TMPRSS2–ERG gene fusions in prostate cancer progression. Cancer Cell 17 443–454. (doi:10.1016/j.ccr.2010.03.018).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhang Y, Gong M, Yuan H, Park HG, Frierson HF & Li H 2012 Chimeric transcript generated by cis-splicing of adjacent genes regulates prostate cancer cell proliferation. Cancer Discovery 2 598–607. (doi:10.1158/2159-8290.CD-12-0042).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zong Y, Goldstein AS, Lawson DA, Teitell MA & Witte ON 2009 ETS family transcription factors collaborate with alternative signaling pathways to induced carcinoma from adult murine prostate cells. PNAS 106 12465–12470. (doi:10.1073/pnas.0905931106).

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    • Search Google Scholar
    • Export Citation

 

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  • Schematic presentation of the ETS transcription factors ERG, ETV1, and truncated ETV1. ETS, ETS DNA-binding domain; PNT, pointed protein–protein interaction domain; TAD, acidic transactivation domain.

  • Schematic presentation of the TMPRSS2–ERG fusion on chromosome band 21q22.

  • Antoniou M, Harland L, Mustoe T, Williams S, Holdstock J, Yague E, Mulcahy T, Griffiths M, Edwards S & Ioannou PA et al. 2003 Transgenes encompassing dual-promotor CpG islands from the human TBP and HNRPA2B1 loci are resistant to heterochromatin-mediated silencing. Genomics 82 269–279. (doi:10.1016/S0888-7543(03)00107-1).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Attard G, Clark J, Ambroisine L, Mills IG, Fisher G, Flohr P, Reid A, Edwards S, Kovacs G & Berney D et al. 2008a Heterogeneity and clinical significance of ETV1 translocations in human prostate cancer. British Journal of Cancer 99 314–320. (doi:10.1038/sj.bjc.6604472).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Attard G, Clark J, Ambroisine L, Fisher G, Kovacs G, Flohr P, Berney D, Foster CS, Fletcher A & Gerald WL et al. 2008b Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene 27 253–263. (doi:10.1038/sj.onc.1210640).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Attard G, Swennenhuis JF, Olmos D, Reid AH, Vickers E, A'Hern R, Levink R, Coumans F, Moreira J & Riisnaes R et al. 2009 Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Research 69 2912–2918. (doi:10.1158/0008-5472.CAN-08-3667).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Baena E, Shao Z, Linn DE, Glass K, Hamblen MJ, Fujiwara Y, Kim J, Nguyen M, Zhang X & Godinho FJ et al. 2013 ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients. Genes and Development 27 683–698. (doi:10.1101/gad.211011.112).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blater M, Theurillat J-P, White TA, Stojanov P, Van Allen E & Stransky N et al. 2012 Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nature Genetics 44 685–689. (doi:10.1038/ng.2279).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Barry M, Perner S, Demichelis F & Rubin MA 2007 TMPRSS2–ERG fusion heterogeneity in multifocal prostate cancer: clinical and biologic implications. Urology 70 630–633. (doi:10.1016/j.urology.2007.08.032).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bohlander SK 2005 ETV6: a versatile player in leukemogenesis. Seminars in Cancer Biology 15 162–174. (doi:10.1016/j.semcancer.2005.01.008).

  • Boormans JL, Hermans KG, Made J, van Leenders GJ, Wildhagen MF, Collette L, Schroder FH, Trapman J & Verhagen PC 2010 Expression of androgen-regulated fusion gene TMPRSS2–ERG does not predict response to endocrine treatment in hormone-naïve, node-positive prostate cancer. European Urology 57 830–835. (doi:10.1016/j.eururo.2009.08.013).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Boormans JL, Porkka K, Visakorpi T & Trapman J 2011 Confirmation of the association of TMPRSS2(exon 0):ERG expression and a favorable prognosis of primary prostate cancer. European Urology 60 183–184. (doi:10.1016/j.eururo.2011.03.028).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Boormans JL, Korsten H, Made AC, van Leenders GJ, de Vos CV, Jenster G & Trapman J 2013 Identification of TDRD1 as a direct target gene of ERG in primary prostate cancer. International Journal of Cancer 133 335–346. (doi:10.1002/ijc.28025).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brase JC, Johannes M, Mannsperger H, Fälth M, Metzger J, Kacprzyk LA, Andrasiuk T, Gade S, Meister M & Sirma H et al. 2011 TMPRSS2–ERG-specific transcriptional modulation is associated with prostate cancer biomarkers and TGF-β signaling. BMC Cancer 11 507. (doi:10.1186/1471-2407-11-507).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brenner JC, Ateeq B, Li Y, Yocum AK, Cao Q, Asangani IA, Patel S, Wang X, Liang H & Yu J et al. 2011 Mechanistic rationale for inhibition of poly(ADP-ribose)polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell 19 664–678. (doi:10.1016/j.ccr.2011.04.010).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Carver BS, Tran J, Gopalan A, Chen Z, Shaikh S, Carracedo A, Alimonti A, Nardella C, Varmeh S & Scardino PT et al. 2009 Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nature Genetics 41 619–624. (doi:10.1038/ng.370).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cerveira N, Ribeiro FR, Peixoto A, Costa V, Henrique R, Jeronimo C & Teixeira MR 2006 TMPRSS2–ERG gene fusion causing ERG overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions. Neoplasia 8 826–832. (doi:10.1593/neo.06427).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chen Y, Chi P, Rockowitz S, Iaquinta PJ, Shamu T, Shukla S, Gao D, Sirota I, Carver BS & Wongvipat J et al. 2013 ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss. Nature Medicine 19 1023–1029. (doi:10.1038/nm.3216).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chi P, Chen Y, Zhang L, Guo X, Wongvipat J, Shamu T, Fletcher JA, Dewell S, Maki RG & Zheng D et al. 2010 ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumors. Nature 467 849–853. (doi:10.1038/nature09409).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Clark JP & Cooper CS 2009 ETS gene fusions in prostate cancer. Nature Reviews. Urology 6 429–439. (doi:10.1038/nrurol.2009.127).

  • Dal Pra A, Lalonde E, Sykes E, Warde F, Ishkanian A, Meng A, Maloff C, Srigley J, Joshua AM & Petrovics G et al. 2013 TMPRSS2–ERG status is not prognostic following prostate cancer radiotherapy: implications for fusion status and DSB repair. Clinical Cancer Research 19 5202–5209. (doi:10.1158/1078-0432.CCR-13-1049).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • DeMarzo AM, Nelson WG, Isaacs WB & Epstein JI 2003 Pathological and molecular aspects of prostate cancer. Lancet 361 955–964. (doi:10.1016/S0140-6736(03)12779-1).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Demichelis F, Fall K, Perner S, Andrén O, Schmidt F, Setlur SR, Hoshida Y, Mosquera JM, Pawitan Y & Lee C et al. 2007 TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene 26 4596–4599. (doi:10.1038/sj.onc.1210237).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Esgueva R, Perner S, LaFargue CJ, Scheble V, Stephan C, Lein M, Fritzsche FR, Dietel M, Kristiansen G & Rubin MA 2010 Prevalence of TMPRSS2–ERG and SLC45A3–ERG gene fusions in a large prostatectomy cohort. Modern Pathology 23 539–546. (doi:10.1038/modpathol.2009.193).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Feldman BJ & Feldman D 2001 The development of androgen-independent prostate cancer. Nature Reviews. Cancer 1 34–45. (doi:10.1038/35094009).

  • FitzGerald LM, Agalliu I, Johnson K, Miller MA, Kwon EM, Hurtado-Coll A, Fazli L, Rajput AB & Gleave ME et al. 2008 Association of TMPRSS2-ERG gene fusion with clinical characteristics and outcomes: results from a population-based study of prostate cancer. BMC Cancer 8 230. (doi:10.1186/1471-2407-8-230).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gasi D, van der Korput HA, Douben HC, de Klein A, de Ridder CM, van Weerden WM & Trapman J 2011 Overexpression of full-length ETV1 transcripts in clinical prostate cancer due to gene translocation. PLoS ONE 6 e16332. (doi:10.1371/journal.pone.0016332).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gasi Tandefelt D, Boormans JL, van der Korput HA, Jenster G & Trapman J 2013 A 36-gene signature predicts clinical progression in a subgroup of ERG-positive prostate cancers. European Urology 64 941–950. (doi:10.1016/j.eururo.2013.02.039).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gopalan A, Leversha MA, Satagopan JM, Zhou Q, Al-Ahmadie HA, Fine SW, Eastham JA, Scardino PT, Scher HI & Tickoo SK et al. 2009 TMPRSS2–ERG gene fusion is not associated with outcome in patients treated by prostatectomy. Cancer Research 69 1400–1406. (doi:10.1158/0008-5472.CAN-08-2467).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Guo CC, Wang Y, Xiao L, Troncoso P & Czerniak B 2012 The relationship of TMPRSS2–ERG gene fusion between primary and metastatic prostate cancers. Human Pathology 43 644–649. (doi:10.1016/j.humpath.2011.06.018).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Haffner MC, Aryee MJ, Toubaji A, Esopi DM, Albadine R, Gurel B, Isaacs WB, Bova GS, Liu J & Meeker AK et al. 2010 Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nature Genetics 42 668–675. (doi:10.1038/ng.613).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Haffner MC, De Marzo AM, Meeker AK, Nelson WG & Yegnasubramanian S 2011 Transcription-induced DNA double strand breaks: Both oncogenic force and potential therapeutic target? Clinical Cancer Research 17 3858–3864. (doi:10.1158/1078-0432.CCR-10-2044).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Han B, Mehra R, Dhanasekaran SM, Yu J, Menon A, Lonigro RJ, Wang X, Gong Y, Wang L & Shankar S et al. 2008 A fluorescence in situ hybridization screen for E26 transformation-specific aberrations: identification of DDX5–ETV4 fusion protein in prostate cancer. Cancer Research 68 7629–7637. (doi:10.1158/0008-5472.CAN-08-2014).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Helgeson BE, Tomlins SA, Shah N, Laxman B, Cao Q, Prensner JR, Cao X, Singla N, Montie JE & Varambally S et al. 2008 Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusions in prostate cancer. Cancer Research 68 73–80. (doi:10.1158/0008-5472.CAN-07-5352).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hermans KG, van Marion R, van Dekken H, Jenster G, van Weerden WM & Trapman J 2006 TMPRSS2:ERG fusion by translocation or interstitial deletion is highly relevant in androgen-dependent prostate cancer, but is bypassed in late-stage androgen receptor-negative prostate cancer. Cancer Research 66 10658–10663. (doi:10.1158/0008-5472.CAN-06-1871).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hermans KG, van der Korput HA, van Marion R, van de Wijngaart DJ, Ziel-van der Made A, Dits NF, Boormans JL, van der Kwast TH, van Dekken H & Bangma CH et al. 2008a Truncated ETV1, fused to novel tissue-specific genes, and full-length ETV1 in prostate cancer. Cancer Research 68 7541–7549. (doi:10.1158/0008-5472.CAN-07-5930).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hermans KG, Bressers AA, van der Korput HA, Dits NF, Jenster G & Trapman J 2008b Two novel prostate-specific and androgen-regulated fusion partners of ETV4 in prostate cancer. Cancer Research 68 3094–3098. (doi:10.1158/0008-5472.CAN-08-0198).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hermans KG, Boormans JL, Gasi D, van Leenders GJ, Jenster G, Verhagen PC & Trapman J 2009 Overexpression of prostate-specific TMPRSS2(exon 0)–ERG fusion transcripts corresponds with favorable prognosis of prostate cancer. Clinical Cancer Research 15 6398–6403. (doi:10.1158/1078-0432.CCR-09-1176).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hollenhorst PC, McIntosh LP & Grave BJ 2011 Genomic and biochemical insights into the specificity of ETS transcription factors. Annual Review of Biochemistry 80 437–471. (doi:10.1146/annurev.biochem.79.081507.103945).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Iljin K, Wolf M, Edgren H, Gupta S, Kilpinen S, Skotheim RI, Peltola M, Smit F, Verhaegh G & Schalken J et al. 2006 TMPRSS2 fusions with oncogenic ETS factors in prostate cancer involve unbalanced genomic rearrangements and are associated with HDAC1 and epigenetic reprogramming. Cancer Research 66 10242–10246. (doi:10.1158/0008-5472.CAN-06-1986).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jhavar S, Reid A, Clark J, Kote-Jarai Z, Christmas T, Thompson A, Woodhouse C, Ogden C, Fisher C & Corbishley C et al. 2008 Association of TMPRSS2–ERG gene fusion in human prostate cancer by expression profiling using GeneChip Human Exon 1.0 ST arrays. Journal of Molecular Diagnostics 10 50–57. (doi:10.2353/jmoldx.2008.070085).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Khoury JD 2005 Ewing sarcoma family of tumors. Advances in Anatomic Pathology 12 212–220. (doi:10.1097/01.pap.0000175114.55541.52).

  • King JC, Xu J, Wongvipat J, Hieronymus H, Carver BS, Leung DH, Taylor BS, Sander C, Cardiff RD & Couto SS et al. 2009 Cooperativity of TMPRSS2–ERG with PI3-kinase pathway activation in prostate oncogenesis. Nature Genetics 41 524–526. (doi:10.1038/ng.371).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Klezovitch O, Risk M, Coleman I, Lucas JM, Null M, True LD, Nelson PS & Vasioukhin V 2008 A causal role for ERG in neoplastic transformation of prostate epithelium. PNAS 105 2105–2110. (doi:10.1073/pnas.0711711105).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kumar-Sinha C, Tomlins SA & Chinnaiyan AM 2008 Recurrent gene fusions in prostate cancer. Nature Reviews. Cancer 8 497–511. (doi:10.1038/nrc2402).

  • Lapointe J, Kim YH, Miller MA, Li C, Kaygusuz G, van de Rijn M, Huntsman DG, Brooks JD & Pollack JR 2007 A variant TMPRSS2 isoform and ERG fusion product in prostate cancer with implications for molecular diagnosis. Modern Pathology 20 467–473. (doi:10.1038/modpathol.3800759).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • de Launoit Y, Baert JL, Chotteau-Lelievre A, Monte D, Coutte L, Mauen S, Firlej V, Degerny C & Verreman K 2006 The Ets transcription factors of the PEA3 group: transcriptional regulators in metastasis. Biochimica et Biophysica Acta 1766 79–87. (doi:10.1016/j.bbcan.2006.02.002).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • van Leenders GJ, Boormans JL, Vissers CJ, Hoogland AM, Bressers AA, Furusato B & Trapman J 2011 Antibody EPR3864 is specific for ERG genomic fusions in prostate cancer: implications for pathological practice. Modern Pathology 24 1128–1138. (doi:10.1038/modpathol.2011.65).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin C, Yang L, Tanasa B, Hutt K, Ju B-G, Ohgi KA, Zang J, Rose DW, Fu X-D & Glass CK et al. 2009 Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer. Cell 139 1069–1083. (doi:10.1016/j.cell.2009.11.030).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin C, Yang L & Rosenfeld MG 2012 Molecular logic underlying chromosomal translocations, random or non-random? Advances in Cancer Research 113 241–279. (doi:10.1016/B978-0-12-394280-7.00015-4).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lindahl-Allen M & Antoniou M 2007 Correlation of DNA methylation with histone modifications across the HNRPA2B1-CBX3 ubiquitously-acting chromatin open element (UCOE). Epigenetics 2 227–236. (doi:10.4161/epi.2.4.5231).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu W, Laitinen S, Khan S, Vihinen M, Kowalski J, Yu G, Chen L, Ewing CM, Eisenberger MA & Carducci MA et al. 2009 Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nature Medicine 15 559–565. (doi:10.1038/nm.1944).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lonergan PE & Tindall DJ 2011 Androgen receptor signalling in prostate cancer development and progression. Journal of Carcinogenesis 10 20. (doi:10.4103/1477-3163.83937).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lotan TL & Epstein JI 2010 Clinical implications of changing definitions within the Gleason grading system. Nature Reviews. Urology 7 136–142. (doi:10.1038/nrurol.2010.9).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mani R-S, Tomlins SA, Callahan K, Ghosh A, Nyati MK, Varambally S, Palanisamy N & Cinnaiyan AM 2009 Induced chromosomal proximity and gene fusions in prostate cancer. Science 326 1230. (doi:10.1126/science.1178124).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mehra R, Han B, Tomlins SA, Wang L, Menon A, Wasco MJ, Shen R, Montie JE, Chinnaiyan AM & Shah RB 2007 Heterogeneity of TMPRSS2 gene rearrangements in multifocal prostate adenocarcinoma: molecular evidence for an independent group of diseases. Cancer Research 67 7991–7995. (doi:10.1158/0008-5472.CAN-07-2043).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mehra R, Tomlins SA, Yu J, Cao X, Wang L, Menon A, Rubin MA, Pienta KJ, Shah RB & Chinnaiyan AM 2008 Characterization of TMPRSS2–ETS gene aberrations in androgen-independent metastatic prostate cancer. Cancer Research 68 3584–3590. (doi:10.1158/0008-5472.CAN-07-6154).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mosquera JM, Perner S, Genega EM, Sanda M, Hofer MD, Mertz KD, Paris PL, Simko J, Bismar TA & Ayala G et al. 2008 Characterization of TMPRSS2–ERG fusion in high-grade prostatic intraepithelial neoplasia and potential clinical implications. Clinical Cancer Research 14 3380–3385. (doi:10.1158/1078-0432.CCR-07-5194).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nam RK, Sugar L, Yang W, Srivastava S, Klotz LH, Yang LY, Staminirovic A, Encioiu E, Neill M & Loblaw DA et al. 2007 Expression of the TMPRSS2:ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer. British Journal of Cancer 97 1690–1695. (doi:10.1038/sj.bjc.6604054).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Oh S, Shin S & Janknecht R 2012 ETV1, 4 and 5: an oncogenic subfamily of ETS transcription factors. Biochimica et Biophysica Acta 1826 1–12. (doi:10.1016/j.bbcan.2012.02.002).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Oikinawa T & Yamada T 2003 Molecular biology of the Ets family of transcription factors. Gene 303 11–34. (doi:10.1016/S0378-1119(02)01156-3).

  • Park K, Tomlins SA, Mudaliar KM, Chiu YL, Esqueva R, Mehra R, Suleman K, Varembally S, Brenner JC & MacDonald T et al. 2010 Antibody-based detection of ERG rearrangement-positive prostate cancer. Neoplasia 12 590–598. (doi:10.1593/neo.10726).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Paulo P, Ribiero FR, Santos J, Mesquita D, Almeida M, Barros-Silva JD, Itkonen H, Henrique R, Jeronimo C & Sveen A et al. 2012 Molecular subtyping of primary prostate cancer reveals specific and shared target genes of different ETS rearrangements. Neoplasia 14 600–611. (doi:10.1593/neo.12600).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Perner S, Demichelis F, Beroukhim R, Schmidt FH, Mosquera JM, Setlur S, Tchinda J, Tomlins SA, Hofer MD & Pienta KG et al. 2006 TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Research 66 8337–8341. (doi:10.1158/0008-5472.CAN-06-1482).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Petrovics G, Liu A, Shaheduzzaman S, Furusato B, Sun C, Chen Y, Nau M, Ravindranath L, Chen Y & Dobi A et al. 2005 Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome. Oncogene 24 3847–3852. (doi:10.1038/sj.onc.1208518).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pettersson A, Graff RE, Bauer SR, Pitt MJ, Lis RT, Stack EC, Martin NE, Kunz L, Penney KL & Ligon AH et al. 2012 The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: a cohort study and meta-analysis. Cancer Epidemiology, Biomarkers & Prevention 21 1497–1509. (doi:10.1158/1055-9965.EPI-12-0042).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rickman DS, Pflueger D, Moss B, VanDoren VE, Chen CX, de la Taille A, Kuefer R, Tewari AK, Setlur SR & Demichelis F et al. 2009 SLC45A3–ELK4 is a novel and frequent erythroblast transformation-specific fusion transcript in prostate cancer. Cancer Research 69 2734–2738. (doi:10.1158/0008-5472.CAN-08-4926).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rubin MA, Maher CA & Chinnaiyan AM 2011 Common gene rearrangements in prostate cancer. Journal of Clinical Oncology 27 3659–3668. (doi:10.1200/JCO.2011.35.1916).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Saramaki OR, Harjula AE, Martikainen PM, Vessella RL, Tammela TL & Visakorpi T 2008 TMPRSS2–ERG fusion identified a subgroup of prostate cancers with a favorable prognosis. Clinical Cancer Research 14 3395–4000. (doi:10.1158/1078-0432.CCR-07-2051).

    • PubMed