Since its discovery in 2005, the common gene fusion TMPRSS2:ERG
has been extensively studied as a possible biomarker for prostate cancer progression with mixed results (11
). We analyzed data from the largest cohort study with lethal disease as an endpoint, and found no association between ERG overexpression and risk of lethal prostate cancer. The meta-analysis yielded similarly null results for the analysis of fusion status and biochemical recurrence. These findings suggest that the TMPRSS2:ERG
fusion is not a strong predictive marker of disease outcome among men with prostate cancer treated with radical prostatectomy.
Among men treated with radical prostatectomy, both in the cohort study and in the meta-analysis, ERG overexpression or positive TMPRSS2:ERG fusion status was associated with a more advanced tumor stage. Among these men, the positive association with stage but not with recurrence or death from prostate cancer would be possible if presence of the fusion in prostate tumors were associated with local tumor growth rather than metastatic spread. Then in men treated with radical prostatectomy, who are most often treated before the tumor has spread beyond the prostate capsule, the fusion would not predict outcome.
The prevalence of TMPRSS2:ERG
varied according to several factors. In the meta-analysis, the prevalence of the fusion was 49% in tissue from radical prostatectomy samples and only 30% in tissue from TURP samples. This difference may reflect previous findings that the fusion is less common in transition zone tumors (from which most tumors found in TURP samples presumably originate) (55
) than in peripheral zone tumors (55
). It also supports the notion that prostate cancers originating from the two zones may be genetically or biologically distinct (55
). The prevalence of the fusion further differed by continent of the patient cohort; it was 23% in Asian cohorts, and roughly 50% in European and North American cohorts. Several factors could explain these differences, including varying distributions of genetic or lifestyle factors associated with the risk of developing fusion negative versus positive prostate cancer. We also found that in radical prostatectomy samples the prevalence of the fusion was higher in studies using RT-PCR (52%) or IHC (52%) to assess TMPRSS2:ERG
fusion status, relative to studies using FISH (42%). The results indicate that some, if not all, methods may misclassify TMPRSS2:ERG
fusion status to some degree.
Findings from some previous studies suggest that TMPRSS2:ERG
may be associated with worse outcomes among patients managed with watchful waiting following a diagnosis of prostate cancer by TURP (10
). Demichelis, Fall, and colleagues found an almost three-fold increased risk of distant metastases and prostate cancer death among men who were fusion positive versus negative (11
). This finding was later replicated in a large case-control study by the same group using an “extreme” case design of lethal and indolent prostate cancers (77
). In another TURP cohort, Attard and colleagues found that men who harbor a fusion occurring by deletion specifically were at an increased risk of death compared to men with fusion negative prostate cancer (10
). Only three TURP cohorts (including 90 men from our cohort study) were available for our analysis investigating the association between TMPRSS2:ERG
and lethal prostate cancer. There were similarly few studies providing data on tumor grade and stage in this patient group. Even so, the results align with the hypothesis that TMPRSS2:ERG
occurs at a lower frequency but is associated with a more aggressive phenotype in patients undergoing watchful waiting after TURP. It is possible that TMPRSS2:ERG
is associated with progression in this particular patient group because tumors occurring in the transition zone are biologically or genetically different from tumors occurring in the peripheral zone. It is also possible, given that peripheral zone tumors have been associated with poorer prognosis compared to transition zone tumors (78
), that positive fusion status in TURP samples is simply a marker of peripheral zone tumor origin for that subset of cancers. Yet another explanation is that TMPRSS2:ERG
indeed is a prognostic marker in prostate cancer. If TMPRSS2:ERG
is a marker of local tumor growth rather than metastatic spread, in the absence of therapy, men with fusion positive tumors should have a poorer prognosis than men with tumors not harboring the fusion. A large-scale biopsy study among men with and without initial therapy is needed to answer this question.
It has been suggested that cancers harboring gene fusions occurring by deletion have worse prognosis than those occurring by translocation, possibly because the ~3 Mb between TMPRSS2
on chromosome 21 contain influential tumor suppressor genes (6
fusions occurring through deletion would thus be coupled with down-regulation of tumor suppressor genes as well as up-regulation of an oncogene. Our meta-analysis did not support this hypothesis. We did not find significant associations between TMPRSS2:ERG
positive by translocation or positive by deletion cancers (both versus TMPRSS2:ERG
negative cancers) and outcomes. These results should be interpreted with caution, however, as the number of studies for which we had data in the appropriate format limited our analyses.
It is possible that our cohort study was limited by the use of an indirect method, immunohistochemical expression of ERG, to assess fusion status. A small proportion (~10%) of tumors that overexpress ERG may harbor a fusion between ERG
and genes other than TMPRSS2
, including SLC45A3
. If it is TMPRSS2:ERG
specifically rather than ERG overexpression that is associated with prostate cancer progression, this exposure misclassification would likely have led to attenuation of the risk estimates. The meta-analysis, however, yielded similar results among those assayed by FISH and RT-PCR, indicating that our use of an IHC assay unlikely accounted for our null findings. Another limitation is that we could not examine whether specific subtypes of the fusion are associated with progression. For example, prior studies have suggested that certain fusion transcript variants (13
) and increased copy number of the rearrangement (10
) are associated with outcomes. We did not address some additional important questions, including whether or not other ETS fusion partners of TMPRSS2
, among them ETV1, ETV4
, and ETV5,
are associated with prostate cancer progression.
The meta-analysis was limited by the data available in the appropriate format; there were some studies that reported on relevant endpoints from which we were unable to acquire data eligible for our analyses. Importantly, the meta-analysis was limited by the small number of studies examining lethal prostate cancer. The results from these studies were furthermore highly heterogeneous, as reflected by the wide confidence interval of the pooled risk ratio. More studies examining lethal prostate cancer are needed. The meta-analysis also included few studies on the risk of prostate cancer progression following hormonal treatment, radiation therapy, or chemotherapy, subgroups in which TMPRSS2:ERG
may be a predictive marker (80
This study has important strengths. Our analysis includes the largest prospective prostatectomy cohort examining the association between TMPRSS2:ERG
and lethal prostate cancer published to-date (80% power to detect a relative risk of 1.5 assuming a 10% risk of lethal disease among the unexposed). This is important since biochemical recurrence is an imprecise predictor of prostate cancer death (82
). The meta-analysis supplied increased power primarily to analyses of TMPRSS2:ERG
status in relation to tumor stage, Gleason score, biochemical recurrence, and mean age at diagnosis. That the results from the cohort study and meta-analysis were similar among men treated with radical prostatectomy reinforces the validity of the findings in the cohort study. In addition, one large nested case-control study ineligible for the meta-analysis also found no significant association between fusion status and biochemical recurrence or clinical progression (24
In summary, the results from this cohort study and meta-analysis suggest that among men undergoing radical prostatectomy, TMPRSS2:ERG fusion status is not a strong predictor of prostate cancer recurrence or cancer-specific mortality. It is at the same time clear that the role of TMPRSS2:ERG in prostate cancer pathogenesis and progression is only starting to emerge. Particular subtypes of the fusion, fusion status in specific subgroups of patients, and interaction of the fusion with other factors such as specific genetic events or treatment regimens could ultimately prove important for treatment choices and prognosis. Notably, whether or not the TMPRSS2:ERG fusion is a prognostic marker in men with prostate cancer left untreated, or if the fusion is a predictive marker of outcome among men treated with radiation or chemotherapy, are important questions that remain largely unstudied and unanswered.