The relationship of TMPRSS2-ERG gene fusion between primary and metastatic prostate cancers

doi:10.1016/j.humpath.2011.06.018

Human Pathology

Volume 43, Issue 5, May 2012, Pages 644-649

https://doi.org/10.1016/j.humpath.2011.06.018 Get rights and content

Summary

Recent studies have revealed the presence of TMPRSS2-ERG gene fusion in both primary and metastatic prostate cancers. However, the relationship between primary and corresponding metastatic prostate cancers with respect to the status of this gene fusion remains unclear. Using fluorescence in situ hybridization, we evaluated the rearrangement of the ERG gene in the radical prostatectomy specimens and corresponding lymph node metastases from 19 patients with prostate cancer. The mean age of the patients was 61 years, and the median Gleason score in the radical prostatectomy specimens was 7 (4 + 3). Prostate cancer was unifocal in 6 cases and multifocal in 13 cases, including 10 with 2 foci and 3 with 3 foci. In the primary prostate cancers, rearrangement of the ERG gene was observed in 13 cases and associated with deletion of the 5′ ERG gene in 8 cases. In the metastases, the ERG rearrangement was present in 10 cases and associated with deletion of the 5′ ERG gene in 6 cases. In unifocal prostate cancers, the status of the ERG rearrangement was concordant between the primary prostate cancer and metastasis in 5 of 6 cases. In multifocal prostate cancer, despite a significant interfocal discordance, the status of the ERG rearrangement was concordant between the index (largest) primary tumor focus and metastasis in all 13 cases. Our study demonstrates a close relationship of the TMPRSS2-ERG gene fusion status between primary and metastatic prostate cancer. The concordance of the ERG gene rearrangement status between the index primary tumor focus and metastasis suggests that metastasis most likely arises from the index tumor focus in multifocal prostate cancer.

Introduction

Recent studies have demonstrated a unique recurrent gene fusion in most prostate cancers (PCAs) [1], [2], [3]. This gene fusion is characterized by fusion of the 5′ region of the TMPRSS2 (Transmembrane protease serine 2) gene with the 3′ region of the ERG gene (ETS related gene). TMPRSS2 is regulated by androgen in the prostate [4], and ERG, a member of the ETS (E-twenty-six) family, is an oncogene [5]. The TMPRSS2-ERG gene fusion leads to aberrant function of ERG in the prostate, which is believed to be involved in the oncogenesis of PCA [1]. Other members of the ETS family, such as ETV1 (ETS variant), ETV4, and ETV5, also fuse with the 5′ end of TMPRSS2, although at a much lower frequency [6], [7]. Likewise, other genes, such as SLC45A3 (Solute carrier family 45 member 3) and NDRG1 (N-myc downstream regulated gene 1), may fuse with the 3′ region of ETS [8], [9]. Nonetheless, the TMPRSS2-ERG gene fusion accounts for most recurrent gene fusions in PCA [10].

The TMPRSS2-ERG gene fusion is also highly prevalent in metastatic PCA [11], [12]. Mehra et al [11] found that all the TMPRSS2-ERG gene fusions in metastatic PCA was associated with deletion of the 5′ end of ERG gene. Furthermore, multiple metastases from an individual patient shared the same pattern of TMPRSS2-ERG gene fusion, suggesting that metastases developed because of clonal expansion of a single focus of primary PCA. However, the relationship of TMPRSS2-ERG gene fusion between primary and metastatic PCA remains unclear. In the current study, we compared the gene fusion status (presence or absence) between primary PCA in radical prostatectomy (RP) specimens and their corresponding metastases in lymph nodes.

Section snippets

Case selection and pathologic evaluation

With the approval of institutional review board, we retrospectively searched our pathology file at The University of Texas MD Anderson Cancer Center and selected 19 patients who underwent RP and pelvic lymph nodes dissection from 2003 to 2009. All patients had primary PCA in the RP specimens and metastatic PCA in the pelvic lymph nodes. No patient had received treatment of PCA before RP. Pathologic features were collected from histologic examination of the specimens. In the RP specimens, each

Results

The average age of patients was 61 years (range, 43-76 years). In the RP specimens, the PCA was unifocal in 6 cases and multifocal in 13 cases (Table 1). In the RP specimens, 23 tumor foci were in the peripheral zone, and 8 foci were in the transition zone. Two tumor foci involved multiple zones, and their zonal origin was considered undetermined. The RPs with unifocal PCA had a median Gleason score of 9 (4 + 5) (range, 7-9), and the mean tumor volume was 7.45 cm³ (range, 2.80-12.16 cm³). The

Discussion

Our study demonstrates a close relationship between primary and metastatic PCA with respect to the status of TMPRSS2-ERG gene fusion. Like primary PCA in our study, most metastatic PCAs carried the TMPRSS2-ERG gene fusion, which was associated with either deletion or translocation of the 5′ ERG gene. Furthermore, we compared the gene fusion status between the metastasis and its corresponding primary PCA in the RP specimen. In patients with unifocal disease in the RP specimen, the TMPRSS2-ERG

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Indications and limits of ablative therapies in prostate cancer
2017, Progres en Urologie
Établir un état des lieux des indications et des limites actuelles des traitements ablatifs in situ dans le cancer de la prostate localisé.
Une recherche bibliographique à partir de Medline (http://www.ncbi.nlm.nih.gov) et Embase (http://www.embase.com) a été réalisée et les articles ont été sélectionnés sur leur méthodologie, leur langue de publication (anglais/français) et leur pertinence. Après sélection, 107 articles ont été analysés.
L’objectif de concilier la réduction des effets secondaires et le maintien d’une efficacité carcinologique a conduit au développement récent de traitements ablatifs, divers dans leurs principes et dans leurs indications. Malgré cette hétérogénéité, un certain nombre d’indications préférentielles apparaissent : cancer de prostate unilatéral de risque faible (mais avec volume tumoral significatif récusant donc l’indication de surveillance active) ou surtout de risque intermédiaire (actuellement sans grade 4 majoritaire, point toujours objet de discussion) ; traitement de la lésion principale (« index lésion »), en quadrant ou en hémi-ablation, s’appuyant sur les résultats des biopsies et de l’IRM multiparamétrique. À ces éléments s’ajoutent les limites liées aux spécificités des énergies employées, notamment en ce qui concerne le volume de la glande prostatique ou la localisation tumorale.
Les thérapies ablatives, appuyées sur l’imagerie (IRM ou techniques innovantes), les biopsies et le développement de nouvelles énergies, sont amenées à prendre une place importante dans la prise en charge du cancer de prostate localisé. Les multiples études internationales en cours permettront aux panels d’experts de préciser et d’optimiser le consensus sur les indications de ces traitements.
To perform a state of the art about indications and limits of ablative therapies for localized prostate cancer.
A review of the scientific literature was performed in Medline database (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) using different associations of keywords. Publications obtained were selected based on methodology, language and relevance. After selection, 107 articles were analysed.
The objective to combine reduction of side effects and oncological control has induced recent development of several ablative therapies. Beyond this heterogeneity, some preferential indications appear: unilateral cancer of low risk (but with significant volume, excluding active surveillance) or intermediate risk (excluding majority of grade 4); treatment targeted the index lesion, by quarter or hemi-ablation, based on biopsy and mpMRI. In addition, indications must considered specific limits of each energy, such as gland volume and tumor localization.
Based on new imaging and biopsy, ablative therapies will probably increased its role in the future in management of localize prostate cancer. The multiple ongoing trials will certainly be helpful to better define their indications and limits.
Focal therapy in prostate cancer: A review of seven common controversies
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Citation Excerpt :
Likewise, the importance of TMPRSS2-ERG fusion in prostate cancer has been documented for some time [15]. More relevant to this arena however, is the concordant presence of this abnormality in both the index lesion and lymph node metastases [16] and multiple metastases exhibiting TMPRSS2 aberrations of indistinct molecular subtypes [17]. We can conclude from these observations that metastatic deposits in prostate cancer originate from a single precursor cancer cell [14,16,17] and that these are most likely to arise from the index lesion in multifocal disease [16].
Radical treatments such as prostatectomy and radiotherapy have demonstrated success in terms of biochemical and disease-specific survival for localised prostate cancer. However, whilst the end goal of any cancer treatment is to control or cure disease it must also do so by minimising any side effects that may be experienced by the patient. Focal therapy as a concept aims to redress this established therapeutic ratio by treating areas of the prostate affected by significant disease as opposed to treating the entire gland. However, there are a number of common criticisms of focal therapy – we deem the seven sins – that require further interrogation.
The prognostic role of ERG immunopositivity in prostatic acinar adenocarcinoma: A study including 454 cases and review of the literature
2014, Human Pathology
Citation Excerpt :
Recently, it has been shown that poly(ADP-ribosome) polymerase 1 inhibitor selectively represses the growth of ERG-positive, but not ERG-negative, prostate cancer xenografts, rendering TMPRSS2/ERG fusion a potential molecular therapeutic target for prostate cancer [81]. The reported incidence of TMPRSS2/ERG fusion in prostate adenocarcinoma ranges from 20% to 68% in RP and biopsy specimens [3-24] and from 0 to 29% in incidental tumors detected in TURP specimens [4,5,13,25-30]. This wide range of incidence is influenced by multiple factors including study design, detection methods (PCR, FISH, or IHC), patients' ethnic background, intratumoral immunoheterogeneity of ERG, interobserver and interstudy variability of stain interpretation, the clone of the ERG antibody used, and the molecular difference between transitional and peripheral zone tumors [11,13,24,50-52,76,83-85].
TMPRSS2/ERG fusion is among the most frequent genetic anomalies in prostate adenocarcinomas. Although positive immunostaining for ERG has been shown to tightly correlate with ERG fusion status, the clinical and prognostic significance of a positive ERG stain remains undetermined. The significance of ERG immunostaining in 454 consecutive prostate adenocarcinomas from radical prostatectomies (RPs) using tissue microarrays, herein, is evaluated. A separate set of 59 cases of incidental prostate adenocarcinoma detected on transurethral resection of prostate with a Gleason score of 6 was also included. ERG translocation was significantly more common in peripheral zone cancer in comparison with cancer of the transitional zone (33% in RP versus 5% in transurethral resection of prostate specimens). In the RP cohort, although ERG positivity was significantly associated with younger age at presentation and lower prostate-specific antigen values, it showed no association with Gleason score or with pathologic stage. In multivariate analysis, biochemical recurrence was only associated with the final RP Gleason score and elevated prostate-specific antigen levels and was unrelated to neither ERG positivity or to its staining intensity. In our hands, ERG positivity was unrelated to either aggressive local tumor characteristics or a worse outcome. Our results, as well as an extensive review of the related literature showing conflicting findings, seem to indicate that ERG immunopositivity cannot be considered as an important prognostic factor in prostate cancer.
Frequent TMPRSS2-ERG rearrangement in prostatic small cell carcinoma detected by fluorescence in situ hybridization: The superiority of fluorescence in situ hybridization over ERG immunohistochemistry
2013, Human Pathology
Citation Excerpt :
It is lacking in carcinomas of other organs, including small cell carcinomas of the urinary bladder and lung [3,8,15], and only very rarely present in benign prostatic tissue [16]. Additionally, the gene fusion status of the primary tumor is often retained in metastases [17]. Thus, identification of the TMPRSS2-ERG fusion in a metastatic tumor would be a reliable method of determining prostatic origin.
Small cell carcinoma of the prostate is both morphologically and immunohistochemically similar to small cell carcinoma of other organs such as the urinary bladder or lung. TMPRSS2-ERG gene fusion appears to be a highly specific alteration in prostatic carcinoma that is frequently shared by small cell carcinoma. In adenocarcinoma, immunohistochemistry for the ERG protein product has been reported to correlate well with the presence of the gene fusion, although in prostatic small cell carcinoma, this relationship is not completely understood. We evaluated 54 cases of small cell carcinoma of the prostate and compared TMPRSS2-ERG gene fusion status by fluorescence in situ hybridization (FISH) to immunohistochemical staining with antibody to ERG. Of 54 cases of prostatic small cell carcinoma, 26 (48%) were positive for TMPRSS2-ERG gene fusion by FISH and 12 (22%) showed overexpression of ERG protein by immunohistochemistry. Of the 26 cases positive by FISH, 11 were also positive for ERG protein by immunohistochemistry. One tumor was positive by immunohistochemistry but negative by FISH. Urinary bladder small cell carcinoma (n = 25) showed negative results by both methods; however, 2 of 14 small cell carcinomas of other organs (lung, head, and neck) showed positive immunohistochemistry but negative FISH. Positive staining for ERG by immunohistochemistry is present in a subset of prostatic small cell carcinomas and correlates with the presence of TMPRSS2-ERG gene fusion. Therefore, it may be useful in confirming prostatic origin when molecular testing is not accessible. However, sensitivity and specificity of ERG immunohistochemistry in small cell carcinoma are decreased compared to FISH.
Focal therapy for prostate cancer: Rationale and treatment opportunities
2013, Clinical Oncology
Citation Excerpt :
In the presence of multifocal disease, the index lesion has been shown to determine the clinical progression of disease [26–29]. Molecular genetics studies suggest that a single tumour focus is responsible for metastasis and disease progression and that this focus is the index lesion [30,31]. The critical tumour volume that correlates to a ‘clinically significant’ lesion that will probably contribute to disease progression, has often been proposed as 0.5 ml [32,33].
Focal therapy is an emerging treatment modality for localised prostate cancer that aims to reduce the morbidity seen with radical therapy, while maintaining cancer control. Focal therapy treatment strategies minimise damage to non-cancerous tissue, with priority given to the sparing of key structures such as the neurovascular bundles, external sphincter, bladder neck and rectum. There are a number of ablative technologies that can deliver energy to destroy cancer cells as part of a focal therapy strategy. The most widely investigated are cryotherapy and high-intensity focussed ultrasound. Existing radical therapies, such as brachytherapy and external beam radiotherapy, also have the potential to be applied in a focal manner. The functional outcomes of focal therapy from several phase I and II trials have been encouraging, with low rates of urinary incontinence and erectile dysfunction. Robust medium- and long-term cancer control outcomes are currently lacking. Controversies in focal therapy remain, notably treatment paradigms based on the index lesion hypothesis, appropriate patient selection for focal therapy and how the efficacy of focal therapy should be assessed. This review articles discusses the current status of focal therapy, highlighting controversies and emerging strategies that can influence treatment outcomes for the future.
Oncological and functional outcome after partial prostate HIFU ablation with Focal-One<sup>®</sup>: a prospective single-center study
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^☆: We have no conflict of interest to declare. This research is supported in part by the National Institutes of Health through MD Anderson’s Cancer Center Support grant CA016672.

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Original contributionThe relationship of TMPRSS2-ERG gene fusion between primary and metastatic prostate cancers☆

Summary

Introduction

Section snippets

Case selection and pathologic evaluation

Results

Discussion

Mod Pathol

Gene

Urology

Mod Pathol

Urology

Mod Pathol

Mod Pathol

Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer

Science

Diversity of TMPRSS2-ERG fusion transcripts in the human prostate

Oncogene

Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2

Cancer Res

TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer

Cancer Res

Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusions in prostate cancer

Cancer Res

Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer

Nature

Original contribution
The relationship of TMPRSS2-ERG gene fusion between primary and metastatic prostate cancers☆