Tomlins et al.1
first reported the recurrent genetic fusion of TMPRSS2
. ERG, a member of the ETS family of transcription factors, has been associated with normal developmental processes, such as mesoderm formation, among others.16
In contrast to mesenchymal tumors, the recurrent genetic fusion that occurs during tumorigenesis is very rare in carcinomas. Furthermore, the TMPRSS2-ERG
fusion may serve to explain the mechanism underlying oncogenic protein overexpression, although this case is not yet fully investigated.17
Since the discovery of the TMPRSS2-ERG
fusion, several groups have examined its clinical implications for the prognosis of prostate adenocarcinoma. However, because of the variability of study cohorts, clinical endpoints and the methods for gene fusion detection, the relationship between gene fusion and clinical outcome has been variably described. Barwick et al.18
reported that the TMPRSS2-ERG
fusion is associated with the prognosis of biochemical recurrence in multiple cohorts. On the other hand, Hermans et al.19
concluded that a favorable prognosis is significantly related to the TMPRSS2-ERG
gene fusion. Several articles demonstrated that TMPRSS2-ERG
gene fusion expression is an independent predictor of poor outcome in prostate cancer patients.20
However, other studies have indicated that the ERG
gene fusion has no significant clinical implications or prognostic value.22
In our study, the ERG positive rate was 24.4%, which is relatively lower than those reported in western population-based studies. Nevertheless, it has been observed that the frequency of the TMPRSS2-ERG
gene fusion ranges widely from 15.3% to over 70% depending on the detection method and the study groups.2
In a study involving the Japanese population, a relatively lower rate of ERG positivity has been reported (20.1% and 28%).5
Thus, in view of the present as well as the previous findings, it can be suggested that East Asian prostate cancer patients have a lower ERG-positive rate.
The associations between TMPRSS2-ERG
gene fusion status and clinicopathologic parameters have varied between studies. While Attard et al.7
found higher ERG
gene fusion rate in tumor cells with a higher Gleason grade, some groups reported no significant association between the Gleason pattern and ERG
More recent studies, however, have shown that a lower Gleason grade is associated with a higher ERG
gene fusion rate.26
Notably, our results coincide with the findings of these recent studies.
Several previous reports also showed that a higher PSA level and a higher pT stage were positively associated with ERG fusion rate.3
However, more recent studies identified lack of significant association between a T stage and a PSA level.28
We conclude that only primary Gleason patterns and Gleason scores are associated with a ERG-positive rate. Previous studies have also reported varied relationship between ERG
gene fusion status and the histologic tumor pattern. Mosquera et al.24
found that the ERG
gene fusion is more frequently observed in higher grade features of prostate cancer. However, another study noted that the ERG-positive rate is higher in Gleason pattern 3 tumors than in Gleason pattern 4 and 5 tumors.28
Our ERG immunohistochemical results showed a higher ERG-positive rate in tumors with Gleason pattern 3 which is represented by discrete glandular units. Moreover, although not statistically significant (p=0.071), a lower ERG-positive rate was observed in Gleason pattern 4 tumors containing large cribriform glands than in tumors without them. Furthermore, a number of studies have reported that heterogeneous ERG immunostaining was observed in the same tumor.12
In this study, we also observed heterogeneous ERG staining in 25 cases.
We previously reported the relationship between ERG
gene rearrangement status and FISH analysis in the same cohort.4
As such, we can compare the present immunohistochemical staining results to those of the FISH. Compared with the results on FISH, the sensitivity of ERG immunohistochemical staining is 89.8%, and the specificity is 96.4%.
In summary, using ERG immunohistochemical staining on TMA, we found the ERG-positive rate in Korean prostate cancer cases to be 24.4%. It is significantly higher in tumors with a lower Gleason grade represented by discrete glandular units, and in cases displaying a lower primary Gleason grade and a lower Gleason score. Nevertheless, this rate is relatively lower than those observed in studies involving western populations.