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

Abstract

Background Whether the genomic rearrangement TMPRSS2:ERG has prognostic value in prostate cancer is unclear. Methods 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. Results 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 (HR: 0.99; 95% 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 (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). Conclusions 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.

Genomic Predictors of Outcome in Prostate Cancer

“…In contrast, one study demonstrated lower BCR risk after RP among patients with the TMPRSS2:ERG fusion [25]. Overall, a metaanalysis including 5074 men following RP found no significant association with BCR or lethal disease [24]. One study investigated the outcome after intensitymodulated radiation therapy but found no association between fusion status and BCR.…”

“…Ten studies reported the prognostic value of the gene fusion in radical prostatectomy (RP) cohorts [19][20][21][22][23][24][25][26][27][28]. In 6 of the 10 studies, TMPRSS2:ERG fusion status was not associated with outcome after surgery [19,21,22,24,27,29].…”

“…Ten studies reported the prognostic value of the gene fusion in radical prostatectomy (RP) cohorts [19][20][21][22][23][24][25][26][27][28]. In 6 of the 10 studies, TMPRSS2:ERG fusion status was not associated with outcome after surgery [19,21,22,24,27,29]. In one Urine-detected rearrangement associated with positive repeat biopsy aCGH = array comparative genomic hybridization; ADT = androgen-deprivation therapy; AS = active surveillance; BCR = biochemical recurrence; CRPC = castration-resistant prostate cancer; DSS = disease-specific survival; FISH = fluorescence in situ hybridization; HR = hazard ratio; IHC = immunohistochemistry; IMRT = intensity-modulated radiation therapy; NA = not applicable; NR = not reported; OS = overall survival; PCa = prostate cancer; PSA = prostate-specific antigen; RT-PCR = reverse transcriptase polymerase chain reaction; RP = radical prostatectomy; SNP = single nucleotide polymorphism; TURP = transurethral resection of prostate; WW = watchful waiting.…”

A Prospective Investigation of PTEN Loss and ERG Expression in Lethal Prostate Cancer

“…Approximately half of US prostate cancer cases are positive for the TMPRSS2:ERG gene fusion (21), an event that can also be detected using a validated IHC assay (22). Tumor fusion status is not associated with lethal progression in most studies (22), but our group recently presented the first evidence that tumor fusion status may modify the association of prostate cancer risk factors with lethal prostate cancer progression (23).…”

ETS fusion genes in prostate cancer

“…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 . 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 metastasesand 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).…”