The TMPRSS2:ERG Rearrangement, ERG Expression, and Prostate Cancer Outcomes: A Cohort Study and Meta-analysis

Corresponding Authors: Andreas Pettersson and Rebecca E. Graff, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115. .
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.32). 06/2012; 21(9):1497-509. DOI: 10.1158/1055-9965.EPI-12-0042
Source: PubMed

ABSTRACT Whether the genomic rearrangement transmembrane protease, serine 2 (TMPRSS2):v-ets erythroblastosis virus E26 oncogene homolog (ERG) has prognostic value in prostate cancer is unclear.
Among men with prostate cancer in the prospective Physicians' Health and Health Professionals Follow-Up Studies, we identified rearrangement status by immunohistochemical assessment of ERG protein expression. We used Cox models to examine associations of ERG overexpression with biochemical recurrence and lethal disease (distant metastases or cancer-specific mortality). In a meta-analysis including 47 additional studies, we used random-effects models to estimate associations between rearrangement status and outcomes.
The cohort consisted of 1,180 men treated with radical prostatectomy between 1983 and 2005. During a median follow-up of 12.6 years, 266 men experienced recurrence and 85 men developed lethal disease. We found no significant association between ERG overexpression and biochemical recurrence [hazard ratio (HR), 0.99; 95% confidence interval (CI), 0.78-1.26] or lethal disease (HR, 0.93; 95% CI, 0.61-1.43). The meta-analysis of prostatectomy series included 5,074 men followed for biochemical recurrence (1,623 events), and 2,049 men followed for lethal disease (131 events). TMPRSS2:ERG was associated with stage at diagnosis [risk ratio (RR)(≥T3 vs. T2), 1.23; 95% CI, 1.16-1.30) but not with biochemical recurrence (RR, 1.00; 95% CI, 0.86-1.17) or lethal disease (RR, 0.99; 95% CI, 0.47-2.09).
These results suggest that TMPRSS2:ERG, or ERG overexpression, is associated with tumor stage but does not strongly predict recurrence or mortality among men treated with radical prostatectomy. Impact: This is the largest prospective cohort study to examine associations of ERG overexpression and lethal prostate cancer among men treated with radical prostatectomy. Cancer Epidemiol Biomarkers Prev; 21(9); 1497-509. ©2012 AACR.

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    • "Lin et al. recently reported that TMPRSS2-ERG levels in post-DRE urine were associated with higher tumour volume and GS in subsequent biopsies [6], and data indicate that high values of TMPRSS2-ERG fusion mRNA in expressed prostatic secretion are associated with an increased risk of tumour upgrading and upstaging in AS candidates undergoing immediate RP [23]. This apparent prognostic difference between gene-fusion positivity and negativity in untreated patients has not, however, been found translated into a risk of postsurgical biochemical recurrence [12] [24]. This discrepancy may be explained by differences between the cohorts, pathologic specimens, clinical end points, ERG-fusion detection methods , and tumour multifocality [25]. "
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    ABSTRACT: Background Compelling biomarkers identifying prostate cancer patients with a high risk of progression during active surveillance (AS) are needed. Objective To examine the association between ERG expression at diagnosis and the risk of progression during AS. Design, setting, and participants This study included 265 patients followed on AS with prostate-specific antigen (PSA) measurements, clinical examinations, and 10–12 core rebiopsies from 2002 to 2012 in a prospectively maintained database. ERG immunohistochemical staining was performed on diagnostic paraffin-embedded formalin-fixed sections with a ready-to-use kit (anti-ERG, EPR3864). Men were characterised as ERG positive if a minimum of one tumour focus demonstrated ERG expression. Outcome measurements and statistical analysis Overall AS progression was defined as clinical progression: increased clinical tumour category ≥cT2b by digital rectal examination and ultrasound, and/or histopathologic progression: upgrade of Gleason score, more than three positive cores or bilateral positive cores, and/or PSA progression: PSA doubling time <3 yr. Risk of progression was analysed using multiple cause-specific Cox regression and stratified cumulative incidences (Aalen-Johansen method). Curatively intended treatment, watchful waiting, and death without progression were treated as competing events. Results and limitations A total of 121 of 142 ERG-negative and 96 of 123 ERG-positive patients had complete diagnostic information. In competing risk models, the ERG-positive group showed significantly higher incidences of overall AS progression (p < 0.0001) and of the subgroups PSA progression (p < 0.0001) and histopathologic progression (p < 0.0001). The 2-yr cumulative incidence of overall AS progression was 21.7% (95% confidence interval [CI], 14.3–29.1) in the ERG-negative group compared with 58.6% (95% CI, 48.7–68.5) in the ERG-positive group. ERG positivity was a significant predictor of overall AS progression in multiple Cox regression (hazard ratio: 2.45; 95% CI, 1.62–3.72; p < 0.0001). The main limitation of this study is its observational nature. Conclusions In our study, ERG positivity at diagnosis can be used to estimate the risk of progression during AS. If confirmed, ERG status can be used to individualise AS programmes. Patient summary The tissue biomarker ERG identifies active surveillance patients with an increased risk of disease progression.
    European Urology 11/2014; 66(5). DOI:10.1016/j.eururo.2014.02.058 · 12.48 Impact Factor
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    • "Since TMPRSS2-ERG fusion first reported by Tomlins and colleagues in 2005, its role in PCa oncogenesis, PCa diagnosis and prognosis have been extensively studied. It is widely accepted that TMPRSS2-ERG fusion is PCa specific [5] and can be used to subtype and stratify PCa [18] [19] [20] [21]. However, due to the relative low sensitivity, the value of TMPRSS2-ERG fusion as a PCa diagnostic marker is limited. "
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    ABSTRACT: Erythroblastosis virus E26 related gene (ERG) overexpression is correlated with the TMPRSS2-ERG fusion gene, a rearrangement known to be present in about 50% of cases of prostate cancer. Androgen receptor (AR) is a known regulator of the TMPRSS2 gene. Despite knowledge of this relationship, limited data is available on the specific relationship of AR expression to TMPRSS2-ERG fusion (ERG) status in prostate cancer (PCa). We used multiplexed immunohistochemistry, multispectral imaging technology and tissue microarray (TMA) to elucidate this relationship. Two prostate tissue microarrays were created from two cohorts of hormonal naïve patients’ prostatectomy specimens: progression TMA (pTMA, from 95 PCa patients) and outcome TMA (oTMA, from 183 PCa patients with at least 5-year follow-up information). Each of the two TMAs were triple-stained with ERG, AR and E-cadherin antibodies and visualized with a different chromogen. We found marked difference in AR expression levels between ERG positive (ERG+) and ERG negative (ERG-) prostate cancer. The difference was significant in localized (pT2) prostate cancer. We also found that AR expression levels were significantly higher in PCa tissue compared to benign prostate tissue, with the highest expression levels in ERG+ metastatic cancer. Neither AR nor ERG expression was associated with clinical outcome. Our findings confirm that TMPRSS2-ERG fusion is AR-dependent and is associated with increased AR expression. Our data suggest that the AR pathway may play an important role in the development of ERG+ PCa and ERG status may be useful in stratifying PCa patients for hormonal therapy.
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    • "Reference N Assay Type [74] 344 FISH RP a 454 IHC RP [15] 481 IHC RP [12] 521 FISH RP [8] 540 FISH RP [75] 640 FISH RP [55] 1039 IHC RP [45] 1180 IHC RP [47] 2805 IHC RP "
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    ABSTRACT: 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.
    Human pathology 10/2013; 45(3). DOI:10.1016/j.humpath.2013.10.012 · 2.81 Impact Factor
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