Abstract

Introduction

The burden of prostate cancer (PCa) on male health is evident as it is one of the leading causes of cancer-related death among men worldwide (¹1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018; 68: 7–30, doi: 10.3322/caac.21442.
https://doi.org/10.3322/caac.21442... ). In Brazil, 14,500 deaths by PCa are registered annually and 68,220 new cases were estimated in 2018 (²2. Instituto Nacional de Câncer Josê Alencar Gomes da Silva. Estimativa 2018: Incidência de câncer no Brasil. Dieguez C, editor. Brasília: Ministério da Saúde, Brasil; 2017. 128 p.). These numbers highlight the need for novel treatment approaches and prevention of PCa.

Although Gleason score system, serum prostate-specific antigen (PSA), and clinical and pathological tumor stage are established tools for grading PCa, they are not capable of distinguishing men with high risk disease from the indolent majority. As a result, patients on active surveillance may lose the correct timing for treatment or suffer from unnecessary side effects of overtreatment (³3. Ullman D, Dorn D, Rais-Bahrami S, Gordetsky J. Clinical utility and biologic implications of phosphatase and tensin homolog (PTEN) and ETS-related gene (ERG) in prostate cancer. Urology 2018; 113: 59–70, doi: 10.1016/j.urology.2017.11.022.
https://doi.org/10.1016/j.urology.2017.1... ). To overcome these issues, a lot of approaches are being explored, such as molecular biomarkers aiming to give information about the tumor biology and help predict the course of the disease. Among these, phosphatase tensin homolog (PTEN), an oncogene suppressor, and TMPRSS2-ERG, a gene rearrangement, are some of the most studied.

PTEN is a tumor suppressor gene commonly inactivated in PCa. Its inactivation rate depends on the method used to assess its status and varies between 10 and 61% (⁴4. Jamaspishvili T, Berman DM, Ross AE, Scher HI, De Marzo AM, Squire JA, et al. Clinical implications of PTEN loss in prostate cancer. Nat Rev Urol 2018; 15: 222–234, doi: 10.1038/nrurol.2018.9.
https://doi.org/10.1038/nrurol.2018.9... ). PTEN loss has been associated with poor prognostic parameters such as higher Gleason score, advanced pathological stage (⁵5. Yoshimoto M, Cunha IW, Coudry RA, Fonseca FP, Torres CH, Soares FA, et al. FISH analysis of 107 prostate cancers shows that PTEN genomic deletion is associated with poor clinical outcome. Br J Cancer 2007; 97: 678–685, doi: 10.1038/sj.bjc.6603924.
https://doi.org/10.1038/sj.bjc.6603924... –⁷7. Chaux A, Peskoe SB, Gonzalez-Roibon N, Schultz L, Albadine R, Hicks J, et al. Loss of PTEN expression is associated with increased risk of recurrence after prostatectomy for clinically localized prostate cancer. Mod Pathol 2012; 25: 1543–1549, doi: 10.1038/modpathol.2012.104.
https://doi.org/10.1038/modpathol.2012.1... ), biochemical recurrence, shortened post-surgical disease-specific survival, shortened metastasis-free survival after radical prostatectomy, and disease-specific survival in castration-resistant PCa (⁸8. Mulholland DJ, Tran LM, Li Y, Cai H, Morim A, Wang S, et al. Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell 2011; 19: 792–804, doi: 10.1016/j.ccr.2011.05.006.
https://doi.org/10.1016/j.ccr.2011.05.00... ,⁹9. Shen MM, Abate-Shen C. Pten inactivation and the emergence of androgen-independent prostate cancer. Cancer Res 2007; 67: 6535–6538, doi: 10.1158/0008-5472.CAN-07-1271.
https://doi.org/10.1158/0008-5472.CAN-07... ). PTEN loss is related to PI3K/mTOR activation, a pathway that could be druggable for developing a potential targeted therapy, as in other malignancies such as lung cancer (¹⁰10. Perreault S, Chandrasekhar J, Cui ZH, Evarts J, Hao J, Kaplan JA, et al. Discovery of a phosphoinositide 3-Kinase (PI3K) beta/delta Inhibitor for the treatment of phosphatase and tensin homolog (PTEN) deficient tumors: building PI3Kbeta potency in a PI3Kdelta-selective template by targeting nonconserved Asp856. J Med Chem 2017; 60: 1555–1567, doi: 10.1021/acs.jmedchem.6b01821.
https://doi.org/10.1021/acs.jmedchem.6b0... ,¹¹11. de Bono JS, De Giorgi U, Rodrigues DN, Massard C, Bracarda S, Font A, et al. Randomized phase II study of akt blockade with or without ipatasertib in abiraterone-treated patients with metastatic prostate cancer with and without PTEN loss. Clin Cancer Res 2019; 25: 928–936, doi: 10.1158/1078-0432.CCR-18-0981.
https://doi.org/10.1158/1078-0432.CCR-18... ).

The fusion between ETS-related gene (ERG) and androgen-regulated transcription factor, TMPRSS2, is the most prevalent genomic alteration in PCa, occurring in approximately half of PCa cases (¹²12. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005; 310: 644–648, doi: 10.1126/science.1117679.
https://doi.org/10.1126/science.1117679... ,¹³13. Rodrigues DN, Boysen G, Sumanasuriya S, Seed G, Marzo AM, de Bono J. The molecular underpinnings of prostate cancer: impacts on management and pathology practice. J Pathol 2017; 241: 173–182, doi: 10.1002/path.4826.
https://doi.org/10.1002/path.4826... ). This rearrangement has been associated to a poor prognosis (¹⁴14. Demichelis F, Fall K, Perner S, Andren O, Schmidt F, Setlur SR, et al. TMPRSS2: ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene 2007; 26: 4596–4599, doi: 10.1038/sj.onc.1210237.
https://doi.org/10.1038/sj.onc.1210237... ,¹⁵15. Mehra R, Tomlins SA, Yu J, Cao X, Wang L, Menon A, et al. Characterization of TMPRSS2-ETS gene aberrations in androgen-independent metastatic prostate cancer. Cancer Res 2008; 68: 3584–3590, doi: 10.1158/0008-5472.CAN-07-6154.
https://doi.org/10.1158/0008-5472.CAN-07... ) and could be a potential biomarker for neoplastic lesions such as high-grade prostatic intraepithelial neoplasia (HGPIN) and adenocarcinomas (¹⁶16. Tomlins SA, Palanisamy N, Siddiqui J, Chinnaiyan AM, Kunju LP. Antibody-based detection of ERG rearrangements in prostate core biopsies, including diagnostically challenging cases: ERG staining in prostate core biopsies. Arch Pathol Lab Med 2012; 136: 935–946, doi: 10.5858/arpa.2011-0424-OA.
https://doi.org/10.5858/arpa.2011-0424-O... ,¹⁷17. Shah RB, Tadros Y, Brummell B, Zhou M. The diagnostic use of ERG in resolving an "atypical glands suspicious for cancer" diagnosis in prostate biopsies beyond that provided by basal cell and alpha-methylacyl-CoA-racemase markers. Hum Pathol 2013; 44: 786–794, doi: 10.1016/j.humpath.2012.06.024.
https://doi.org/10.1016/j.humpath.2012.0... ).

The characterization of molecular subtypes could be useful in understanding the differences in the course of PCa. However, the frequency of those subtypes varies among races adding more complexity to the understanding of the disease (¹⁸18. Powell IJ, Dyson G, Land S, Ruterbusch J, Bock CH, Lenk S, et al. Genes associated with prostate cancer are differentially expressed in African American and European American men. Cancer Epidemiol Biomarkers Prev 2013; 22: 891–897, doi: 10.1158/1055-9965.EPI-12-1238.
https://doi.org/10.1158/1055-9965.EPI-12... ,¹⁹19. Tan DS, Mok TS, Rebbeck TR. Cancer genomics: diversity and disparity across ethnicity and geography. J Clin Oncol 2016; 34: 91–101, doi: 10.1200/JCO.2015.62.0096.
https://doi.org/10.1200/JCO.2015.62.0096... ). Knowing the frequencies of these alterations and how they are involved with each other will provide valuable insights about the pathobiology of PCa, a knowledge that could be translated into better clinical practice.

In this study, we examined the expression of ERG and the loss of PTEN in 119 PCa patients from a large pathology laboratory in Northeastern Brazil and investigated the association between these biomarkers and clinicopathological features of the cases.

Material and Methods

Clinical sample selection

After approval by the Unichristus Ethics Committee (CAAE 61472016.3.0000.5049), a total of 97 radical prostatectomies (RP) with the diagnosis of usual acinar adenocarcinoma, performed between 2013 and 2016 and totally sampled in paraffin blocks, were randomly selected from the files of a reference pathology laboratory in the city of Fortaleza. Available clinical information and histopathological reports were reviewed. To enrich the study cohort, subjects with higher Gleason scores (Gleason ≥8) from 22 transurethral resections of the prostate (TURP) were also included in the study. No patient had history of neoadjuvant treatment. Cases with diagnosis of ductal adenocarcinoma and small cell neuroendocrine carcinoma were not included. All hematoxylin and eosin (HE) slides were reevaluated by 2 pathologists (CLM and FT) for choosing index tumor nodules in RP and the highest Gleason score foci in TURP for tissue microarray (TMA) construction. All clinicopathological information was obtained from the medical requisition forms.

TMA construction

Two punches (2 mm cores) were taken from 8 paraffin-embedded tissue blocks from the dominant tumor nodule in RP and from tumor foci in TURP, sampled in duplicate. Benign prostate tissue from other RPs not included in this study were placed on the corner of each TMA to be used as external control.

Immunohistochemical analysis

Two 4-mm consecutive sections were cut from each TMA block and mounted on charged microscopy glass slides for immunohistochemical staining for PTEN and ERG protein expression.

PTEN immunohistochemistry (IHC) was performed on the Ventana BenchMark^® platform (Ventana Medical Systems, USA) using rabbit monoclonal primary anti-PTEN antibody (Clone SP218; Roche Diagnostics, UK). PTEN protein status was visually scored. A tissue core was considered to have PTEN protein loss if the intensity of cytoplasmic and nuclear staining was markedly decreased or entirely negative across >10% of tumor cells compared to surrounding benign glands and/or stroma, which provided internal positive controls. If PTEN was lost in >10 and <100% of the tumor cells sampled in a given core, the core was annotated as showing heterogeneous PTEN loss (²⁰20. Lotan TL, Wei W, Morais CL, Hawley ST, Fazli L, Hurtado-Coll A, et al. PTEN loss as determined by clinical-grade immunohistochemistry assay is associated with worse recurrence-free survival in prostate cancer. Eur Urol Focus 2016; 2: 180–188, doi: 10.1016/j.euf.2015.07.005.
https://doi.org/10.1016/j.euf.2015.07.00... ). Alternatively, if the core showed PTEN loss in 100% of sampled tumor glands, the core was annotated as showing homogeneous PTEN loss. From 119 samples used in our study, 14 were excluded for technical problems that made it impossible to evaluate the marker (cores fell out from the TMA, no tumor sample, and difficulty in determining the score due to strong background staining). For statistical analysis, each patient's tumor sample was scored for PTEN loss by summarizing the scores of the sampled cores.

ERG IHC was performed on the BenchMark ULTRA automated IHC/ISH staining platform (Ventana Medical Systems) using a rabbit monoclonal anti-ERG antibody (Clone EP111, USA). ERG protein status was visually determined and scored as positive if any tumor cells demonstrated nuclear ERG staining. Endothelial cells were used as internal controls. The same criteria as PTEN was conducted for ERG, with samples for the presence or absence of ERG expression.

Statistical analysis

Statistical analyses were performed using GraphPad Prism version 6.0 (GraphPad, USA). Correlations between categorical data variables were analyzed using Fisher's exact test or Person's chi-squared test. Quantitative variables with parametric distribution were analyzed using Student's t-test and analysis of variance (ANOVA), and quantitative variables with non-parametric distribution were analyzed using Kruskal-Wallis and Mann Whitney tests. For all analyses, a P value <0.05 was considered to be statistically significant.

Results

The study comprised 119 subjects, including 97 (82%) RP and 22 (18%) TURP specimens. The mean age was 71 years (range 51-98 years). Only 13 patients had pre-treatment PSA serum levels, with a median of 8.5 ng/mL, 31 (26%) showed a Gleason score ≤6, 50 (42%) had a Gleason score of 7, and 38 (32%) had a Gleason score ≥8. When using prognostic grade groups (GG) (²¹21. Pierorazio PM, Walsh PC, Partin AW, Epstein JI. Prognostic Gleason grade grouping: data based on the modified Gleason scoring system. BJU Int 2013; 111: 753–760, doi: 10.1111/j.1464-410X.2012.11611.x.
https://doi.org/10.1111/j.1464-410X.2012... ), 31 (26%) were in GG1, 29 (24%) in GG2, 21 (18%) in GG3, 12 (10%) in GG4, and 26 (22%) in GG5.

Median prostate weight and tumor volume were 45 g and 20%, respectively. Extraprostatic extension, HGPIN, and seminal vesicle involvement were observed in 35 (36%), 86 (89%), and 8 (8%) cases, respectively. Final pathologic staging classified 57 (59%) cases as T2 N0/Nx and 40 (41%) as T3 N0/N1/Nx (Table 1).

ERG was positive in 41% (48/117) of samples and was significantly associated with lower prostate weight (P=0.008) and Gleason score (P=0.040). There were no other important associations between ERG and the other clinicopathological features as shown in Table 2. PTEN loss was observed in 38% (40/105) of cases. Half of them showed heterogeneous loss pattern (20/40) (Figures 1 and 2). No associations with all clinicopathological features were demonstrated as shown in Table 3.

Figure 1
PTEN immunohistochemistry in prostate tissue showing several staining patterns on tissue microarray sections. A, Cribriform pattern with Gleason score 4+4 and positive cytoplasmic expression. B, Loose glands with Gleason Score 3+3 and cytoplasmic expression. C, Homogeneous PTEN loss on a Gleason score 3+3 tumor. D, Heterogeneous PTEN loss on Gleason Score 3+4 prostate tumor. Magnification bar: 20 μm.

Figure 2
ETS-related gene (ERG) immunohistochemistry. A, Nuclear ERG positivity in prostate cancer. B, Negative expression in prostate cancer with positive nuclear internal control in endothelial cells. Magnification bar: 20 μm.

ERG and PTEN associations

When PTEN and ERG were analyzed in conjunction (Table 4), PTEN loss was observed in 32% (20/63) of samples without expression of ERG protein, while among samples expressing ERG, PTEN loss was observed in 48% (19/40). However, the augmented frequency of PTEN loss among ERG-positive samples was not significant (P=0.1447) (Table 4)

When all possible combinations between ERG and PTEN were considered, it was observed that a positive ERG expression overlapping with intact PTEN (ERG+/PTEN+) were significantly associated with lower Gleason scores (P=0.0131) and lower prognostic groups (P=0.0369). Prostate weight also showed statistical significance (P=0.0123) with ERG/PTEN profiling, demonstrating significantly lower weight in the ERG+/PTEN+ group.

Discussion

Despite the progress in proteomic, genomic, and other omics data we have experienced over the last decades, PCa treatment is still guided mainly by pathologic grade, final stage, and serum PSA. The absence of specific biomarkers solely capable of providing information on the overall PCa outcome makes distinction between patients with aggressive and indolent disease challenging.

In addition, considering the relevance of race/ethnicity to the outcome of the disease, we studied the utility of two biomarkers, PTEN and ERG, in a population of PCa patients from Northeastern Brazil, a diverse geographical region with no previous study. In the present study, we evaluated ERG by IHC, a method that highly correlates with fluorescent in situ hybridization (FISH) as demonstrated by previous reports (²²22. Minner S, Enodien M, Sirma H, Luebke AM, Krohn A, Mayer PS, et al. ERG status is unrelated to PSA recurrence in radically operated prostate cancer in the absence of antihormonal therapy. Clin Cancer Res 2011; 17: 5878–5888, doi: 10.1158/1078-0432.CCR-11-1251.
https://doi.org/10.1158/1078-0432.CCR-11... ,²³23. Pettersson A, Graff RE, Bauer SR, Pitt MJ, Lis RT, Stack EC, et al. The TMPRSS2: ERG rearrangement, ERG expression, and prostate cancer outcomes: a cohort study and meta-analysis. Cancer Epidemiol Biomarkers Prev 2012; 21: 1497–1509, doi: 10.1158/1055-9965.EPI-12-0042.
https://doi.org/10.1158/1055-9965.EPI-12... ). We found that ERG was expressed in 41.0% of cases, a rate that is in agreement with other previous reports (¹²12. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005; 310: 644–648, doi: 10.1126/science.1117679.
https://doi.org/10.1126/science.1117679... ,²⁴24. Shah RB, Bentley J, Jeffery Z, DeMarzo AM. Heterogeneity of PTEN and ERG expression in prostate cancer on core needle biopsies: implications for cancer risk stratification and biomarker sampling. Hum Pathol 2015; 46: 698–706, doi: 10.1016/j.humpath.2015.01.008.
https://doi.org/10.1016/j.humpath.2015.0... ,²⁵25. Bostrom PJ, Bjartell AS, Catto JW, Eggener SE, Lilja H, Loeb S, et al. Genomic predictors of outcome in prostate cancer. Eur Urol 2015; 68: 1033–1044, doi: 10.1016/j.eururo.2015.04.008.
https://doi.org/10.1016/j.eururo.2015.04... ), including a study of the frequency of TMPRSS2-ERG rearrangement in a PCa Southern Brazilian population (²⁶26. Yoshimoto M, Joshua AM, Cunha IW, Coudry RA, Fonseca FP, Ludkovski O, et al. Absence of TMPRSS2: ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome. Mod Pathol 2008; 21: 1451–1460, doi: 10.1038/modpathol.2008.96.
https://doi.org/10.1038/modpathol.2008.9... ).

Although our findings have shown that ERG-positive cases were associated with lower Gleason score and lower prostate weight, the literature is conflicting and shows varying associations between TMPRSS2-ERG rearrangements and clinicopathological variables. For instance, while one study has shown that patients who expressed ERG fusion protein in prostate tissue (evaluated by FISH) were more prone to present higher Gleason score and PCa-specific death (¹⁴14. Demichelis F, Fall K, Perner S, Andren O, Schmidt F, Setlur SR, et al. TMPRSS2: ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene 2007; 26: 4596–4599, doi: 10.1038/sj.onc.1210237.
https://doi.org/10.1038/sj.onc.1210237... ), other studies showed lack of association between ERG expression and pathologic parameters (²⁷27. Rubio-Briones J, Fernandez-Serra A, Calatrava A, Garcia-Casado Z, Rubio L, Bonillo MA, et al. Clinical implications of TMPRSS2-ERG gene fusion expression in patients with prostate cancer treated with radical prostatectomy. J Urol 2010; 183: 2054–2061, doi: 10.1016/j.juro.2009.12.096.
https://doi.org/10.1016/j.juro.2009.12.0... ,²⁸28. Esgueva R, Perner S, C JL, Scheble V, Stephan C, Lein M, et al. Prevalence of TMPRSS2-ERG and SLC45A3-ERG gene fusions in a large prostatectomy cohort. Mod Pathol 2010; 23: 539–46, doi: 10.1038/modpathol.2009.193.
https://doi.org/10.1038/modpathol.2009.1... ).

Some studies have assessed the importance of the loss of the oncogene PTEN to the prognosis of PCa. By using IHC, Lotan et al. showed that PTEN loss highly correlated with pathologic staging (41% samples with PTEN loss were pT3bN0) and Gleason scores between 8–10 (⁶6. Lotan TL, Gurel B, Sutcliffe S, Esopi D, Liu W, Xu J, et al. PTEN protein loss by immunostaining: analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients. Clin Cancer Res 2011; 17: 6563–6573, doi: 10.1158/1078-0432.CCR-11-1244.
https://doi.org/10.1158/1078-0432.CCR-11... ). Also, by using IHC, Ahearn et al. (²⁹29. Ahearn TU, Pettersson A, Ebot EM, Gerke T, Graff RE, Morais CL, et al. A prospective investigation of PTEN loss and ERG expression in lethal prostate cancer. J Natl Cancer Inst 2016; 108. pii: djv346, doi: 10.1093/jnci/djv346.
https://doi.org/10.1093/jnci/djv346... ) found that 25% of PTEN loss in PCa samples were associated with advanced pathologic stage and higher Gleason scores in a population of Caucasian Americans. Our results showed that PTEN loss occurred in 38% of PCa samples with a distribution of homogeneous and heterogeneous pattern close to 50%. Although PTEN loss showed a discrete tendency to be associated with tumor volume (P=0.0659), lymphovascular invasion (P=0.0710), and staging (P=0.0773), these associations did not reach statistical significance. The absence of statistical importance might be explained in part by the small sample size, as well as by heterogeneity of the studied population. Furthermore, false-negative results could also cause misinterpretation of the final count of PTEN loss.

Studies with murine models have suggested the existence of synergy between PTEN loss and ERG contributing to the oncogenesis of PCa (³3. Ullman D, Dorn D, Rais-Bahrami S, Gordetsky J. Clinical utility and biologic implications of phosphatase and tensin homolog (PTEN) and ETS-related gene (ERG) in prostate cancer. Urology 2018; 113: 59–70, doi: 10.1016/j.urology.2017.11.022.
https://doi.org/10.1016/j.urology.2017.1... ,³⁰30. Carver BS, Tran J, Gopalan A, Chen Z, Shaikh S, Carracedo A, et al. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat Genet 2009; 41: 619–624, doi: 10.1038/ng.370.
https://doi.org/10.1038/ng.370... ), but in humans, this association is still a matter of debate. In a cohort of RP, Yoshimoto et al. showed that PTEN deletion with the simultaneous presence of TMPRSS2-ERG abnormalities was associated with shorter time to biochemical recurrence of PCa (²⁶26. Yoshimoto M, Joshua AM, Cunha IW, Coudry RA, Fonseca FP, Ludkovski O, et al. Absence of TMPRSS2: ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome. Mod Pathol 2008; 21: 1451–1460, doi: 10.1038/modpathol.2008.96.
https://doi.org/10.1038/modpathol.2008.9... ). Ahearn et al. (²⁹29. Ahearn TU, Pettersson A, Ebot EM, Gerke T, Graff RE, Morais CL, et al. A prospective investigation of PTEN loss and ERG expression in lethal prostate cancer. J Natl Cancer Inst 2016; 108. pii: djv346, doi: 10.1093/jnci/djv346.
https://doi.org/10.1093/jnci/djv346... ) evaluated ERG and PTEN by IHC and showed that only the cases with PTEN loss/positive ERG were associated with increased lethality. In the present study, we noted a discrete trend in the frequency of PTEN loss to be higher among those samples with ERG-positive than among ERG-negative samples (48 vs 32%). The association of ERG+/PTEN+ samples with lower Gleason score/lower GG found by the present study might indicate a group with a favorable prognosis, but again the absence of clinical follow-up precludes this conclusion.

Diverse molecular subtypes of prostate cancer could contribute to different clinical behaviors and the prevalence of molecular subtypes might vary according to racial and ethnic background (¹⁸18. Powell IJ, Dyson G, Land S, Ruterbusch J, Bock CH, Lenk S, et al. Genes associated with prostate cancer are differentially expressed in African American and European American men. Cancer Epidemiol Biomarkers Prev 2013; 22: 891–897, doi: 10.1158/1055-9965.EPI-12-1238.
https://doi.org/10.1158/1055-9965.EPI-12... ,¹⁹19. Tan DS, Mok TS, Rebbeck TR. Cancer genomics: diversity and disparity across ethnicity and geography. J Clin Oncol 2016; 34: 91–101, doi: 10.1200/JCO.2015.62.0096.
https://doi.org/10.1200/JCO.2015.62.0096... ). Thus, Tosoian et al. (³¹31. Tosoian JJ, Almutairi F, Morais CL, Glavaris S, Hicks J, Sundi D, et al. Prevalence and prognostic significance of PTEN loss in African-American and European-American men undergoing radical prostatectomy. Eur Urol 2017; 71: 697–700, doi: 10.1016/j.eururo.2016.07.026.
https://doi.org/10.1016/j.eururo.2016.07... ) examined PTEN/ERG status by IHC in self-identified African-Americans (AA) undergoing RP and matched these cases to European-American (EA) patients by pathologic parameters. The rate of PTEN loss was significantly lower in AA compared to EA prostate cancer, similar to the lower rate of ERG expression. Particularly, PTEN loss was observed in 33% ERG-positive tumors, compared to 14% ERG-negative tumors, demonstrating a more than two-fold increase in PTEN loss when ERG expression was present, similar in both groups.

The present study had some limitations. The most relevant was the lack of clinical follow-up information regarding final outcomes, especially biochemical recurrence and disease-specific survival data. Studies evaluating ERG expression in surgically treated patients have shown an association of ERG and longer progression-free survival. It is also important to mention that since it was a single institutional retrospective study, the possibility of bias cannot be excluded.

In summary, we report the frequency of the biomarkers PTEN and ERG in a population of 119 PCa patients from Northeastern Brazil, a population not yet evaluated with these molecular tools. The frequency of ERG expression was 47.5% and PTEN loss 38.1%. Samples with positive ERG expression overlapping with positive PTEN were associated with lower Gleason score and with lower Grade group. The future development of PCa molecular profiling associated with the knowledge of the disease in specific populations could help in stratifying specific risk groups, leading to a more personalized therapeutic decision. Further studies are encouraged in order to integrate molecular studies with clinical information and, in this way, understand how these biomarkers correlate with the overall PCa outcomes.

Acknowledgments

We thank the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for providing financial support for this study.

References

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