The epidemiology of PCA in Middle Eastern Arab populations are not well studied in contrast to North America and Western Europe. This is likely due to the absence of established PSA screening, lack of population-based registries, and existence of prospective oncology databases [41].
In this study, we assessed a large and more homogenous cohort of 340 radical prostatectomy and documented ERG expression to be present in 42% of PCA cases in Middle Eastern Arab population with prognostic implication in association to PTEN loss and SPINK1 expression.
Although the rate of ERG expression detected in this study is at lower end of that observed in in North America and Western Europe, which is documented generally around 45%-50% [42], it is still significantly higher than those reported in Asian and African American populations of about 15% and 27% respectively [43, 44].
One earlier study by Aldaoud et al. reported on ERG expression in Middle Eastern population suggested the incidence to be lower among Arab population at 33.2% compared to North American and European population and the study failed to document any prognostic value or association to Gleason grade grouping [21]. The reason for such discrepancy in incidence between our study and that of Aldaoud et al, is that they reported ERG incidence in mixed cases spanning peripheral zone (assessed through needle biopsy) and transition zone (assess by TURP). This is significant issue, as it is well known and documented by our group and others that ERG expression is significantly higher in peripheral zone tumors compared to those in transition zone [3], hence, combining both zones for reporting ERG incidence will artificially suggest lower incidence of ERG.
Loss of PTEN expression is well known to be associated with disease progression and patient’s prognosis in several cancers and has also been implicated as potential targets for PI3K related therapies [21] and PTEN loss, as assessed by a validated and simple IHC protocol, was documented to be associated with a two-fold increase in risk of lethal progression independent of clinical-pathologic parameters [26]. Another study performed by Shan, et al in Arab men with PCA confirmed that PTEN is downregulated and associated with disease progression in PCA [45]. In the current study, the rate of PTEN loss was noted within the same range compared to Caucasian and African American cohorts, however, we did not observe significant association between loss of PTEN expression and increased Gleason grade grouping as suggested in North American and Western populations (p=0.11),
Previous reports in Western and European cohorts suggested significant interplay between ERG positivity and PTEN loss with potential clinical value in various clinical scenarios. However, the prognostic value of combined ERG and PTEN have yielded mixed results. A study from Brazil showed that tumors which are PTEN deleted and ERG gene rearranged were more likely to exhibit biochemical relapse after radical prostatectomy relative to those with no genomic alterations for ERG and PTEN (i.e., not ERG rearranged and PTEN deleted). However, several subsequent studies in North American and European cohorts documented that prostate tumors with PTEN genomic alteration without ERG rearrangements (i.e., those with PTEN deletion or loss of protein expression) are associated with worse clinical outcome [26, 46, 47]. Our results in Middle Eastern cohort document higher BCR in PTEN neg/ERG pos tumors similar to the initial data from Brazil.
Similar to earlier reports in Western cohorts, we observed higher frequency of ERG expression in lower grade group 1-3 vs 4-5 (p=0.04). However, contrary to Western and European cohorts, our results in this Middle Eastern cohort, ERG positive foci were not enriched for PTEN genomic deletions as reflected by absence of PTEN staining, but showed non-significant trend (p=0.06).
Most studies reported that SPINK1 protein is detected in about 9% of PCA cases of Caucasian cohorts vs 23% in African American with some suggestion of prognostic value[44, 48]. In our study, SPINK1 protein expression was noted at much lower incidence of only 4% which is significantly lower than those reported in Western population above. However, we did not observe any prognostic association for SPINK1 which may be due to the fact of lower-case number overall.
Previous studies found SPINK1 protein expression to be inversely associated with PTEN gene deletion and exclusive of loss of PTEN intensity [27] and positively associated with higher PTEN protein expression[49]. In this study we also observed notable inverse relation between PTEN negative intensity and SPINK positivity.
Although some recent studies have reported co-expression of ERG and SPINK1 in up to 4% of prostate cancers[27, 41, 49], the majority of reports confirm ERG and SPINK1 being mutually exclusive[34], which was also noted in our study.
The above results indicate that molecular landscape of PCA in Middle Eastern population differs from other races. This might be explained by genetic differences, environmental, lifestyle and dietary factors, especially since it has been reported that gut microbiome reflective of diet may have a role on gene expression and cancer risk cancers[50].
The clinical value of our study stems from the fact that pathological staging system and Gleason score do not explain racial difference in PCA outcomes. Therefore, such markers may have a role in the future in personalizing prognosis estimates for patients and guide novel targeted treatment.