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: 4.13). 06/2012; 21(9):1497-509. DOI: 10.1158/1055-9965.EPI-12-0042
Source: PubMed


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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Available from: Richard Flavin, Jan 15, 2016
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    • "In particular, the TMPRSS2- ERG fusion is the most common molecular alteration in prostate cancer (Tomlins et al., 2005), being found in between 40% and 50% of prostate tumor foci, translating to more than 100,000 cases annually in the United States (Tomlins et al., 2009). Nevertheless , among treated prostate cancers, and despite extensive study, affected individuals with fusion-bearing tumors do not appear to have a significantly different prognosis following prostatectomy than those without (Gopalan et al., 2009; Pettersson et al., 2012). Prostate cancers also have varying degrees of DNA copy-number alteration; indolent and low-Gleason tumors have few alterations, whereas more aggressive primary and metastatic tumors have extensive burdens of copy-number alteration genome wide (Taylor et al., 2010; Hieronymus et al., 2014; Lalonde et al., 2014). "
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    ABSTRACT: Summary There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, and FLI1) or mutations (SPOP, FOXA1, and IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1 mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner, with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects.
    Full-text · Article · Nov 2015 · Cell
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    • "reported a strong association between expression of TMPRSS2 fusion with members of the ETS family of genes and PCa aggressiveness , and the interest about TMPRSS2 : ERG fusion protein was increasingly growing . However , more recent studies reported conflicting results about the role of such chromosomal rearrangement and a recent meta - analysis ( Pettersson et al . 2012 ) concluded that TMPRSS2 : ERG expression is associated with tumor stage but is a weak parameter in predicting recurrence or mortal - ity . In accordance with such conclusion and with previous studies of our group ( Bonaccorsi et al . 2009 ) , we show here that mRNA expression of TMPRSS2 : ERG fusion gene in FFPE needle biopsy specimens"
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    ABSTRACT: To evaluate biomarkers involved in biological pathways for prostate cancer (PCa) progression, measured in biopsy specimens, in order to distinguish patients at higher risk for fatal PCa and thus improve the initial management of disease. Retrospective case-control study. In 129 PCa patients who underwent ultrasound-guided needle prostate biopsy and subsequent radical prostatectomy from 1987 to 1999 at the University Hospital of Careggi, we evaluated: (1) mRNA expression of the serine 2 (TMPRSS2): erythroblastosis virus E26 oncogene homolog (ERG); (2) expression of matrix metalloproteinases (MMP)-2 and 9 (epithelial and stromal); (3) expression of androgen receptor; (4) expression of prognostic marker Ki67 (MIB1); (5) presence and typing of human papilloma virus; (6) DNA methylation of CpG islands of several genes involved in PCa progression. The cohort consists of 38 cases (patients with PCa and died of PCa within 10 years from diagnosis) and 91 controls (patients with PCa but alive 10 years after diagnosis). Gleason bioptic score, epithelial MMP expression and SERPINB5 methylation correlated with statistically significant increase in death risk OR. Compared with patients with high level of MMP, patients with low level of MMP had OR for specific death 4.78 times higher (p = 0.0066). After adjustment for age and Gleason score, none of the investigated biomarkers showed increased OR for PCa death. Our preliminary results suggest that evaluation, in prostate biopsy specimens, of a panel of biomarkers known to be involved in PCa progression is poorly indicative of tumor outcome.
    Full-text · Article · Jul 2015 · Journal of Cancer Research and Clinical Oncology
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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.
    Full-text · Article · Nov 2014 · European Urology
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