Open Access

Association Between ERG/PTEN Genes and Pathologic Parameters of Prostate Cancer With an Emphasis on Gleason Score: A Literature Review

SPINOS THEODOROS 1
GEORGIOU ALEXANDROS 1
VOULGARI OLGA 1
GOUTAS DIMITRIOS 1
LAZARIS ANDREAS C. 1
THYMARA IRINI 1
KAVANTZAS NIKOLAOS 1
  &  
THOMOPOULOU GEORGIA-ELENI 2

1First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

2Cytopathology Department, “Attikon” University General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

Cancer Diagnosis & Prognosis May-June; 3(3): 291-296 DOI: 10.21873/cdp.10214
Received 05 December 2022 | Revised 13 July 2024 | Accepted 22 February 2023
Corresponding author
Alexandros Georgiou, First Department of Pathology, School of Medicine National and Kapodistrian University of Athens, 75 Mikras Asias Street, Athens 115 27, Greece. Tel: +30 6943218393, email: alexandrosge11@gmail.com

Abstract

Background/Aim: The purpose of this article was to review the association between the ETS-related gene (ERG) and the phosphatase and tensin homolog (PTEN) genes with pathologic parameters of prostate cancer, emphasizing on Gleason score. Materials and Methods: We performed a PubMed-based search of the literature emphasizing on articles that use pathological techniques, and especially on those that report the use immunohistochemical staining and FISH to investigate the association between ERG and PTEN mutations with the histopathologic parameters of prostate cancer. Results: ERG expression is frequently marked in patients with prostate cancer, usually due to the occurrence of the TMPRSS2:ERG gene fusion. Although some studies reported a potential link between the expression of ERG and Gleason score, there is no strong evidence supporting this finding. On the contrary, there is more solid evidence correlating loss of PTEN expression with worse prognosis and higher Gleason scores. Few studies correlate the over-expression of ERG gene with the loss of PTEN expression. Finally, PTEN and ERG have been studied as potential therapeutic targets, and several promising results have been reported. Conclusion: Although, at some degree, ERG expression seems to be associated with the morphological features of prostate cancer, different studies reported controversial results. However, expression of PTEN is more clearly associated with the pathology and clinical course of the disease. More research is required to elucidate the role of these molecules in the molecular pathology of prostate cancer, as well as their potential use as therapeutic targets.
Keywords: prostate cancer, Gleason score, ERG, PTEN, molecular pathology, precision medicine, review

Prostate cancer represents one of the most common forms of malignancy, with an estimated 1,4 million new diagnosed cases in 2020. The incidence of prostate cancer varies geographically, with a higher number of cases being reported in developed compared to developing countries; an observation residing in various modifiable and unmodifiable risk factors (1,2). Despite being such a prominent health issue, the exact mechanism underlying the molecular pathology of prostate cancer has not been elucidated. Recent advances in the field of molecular biology and the wide use of sequencing techniques in medical research have transformed our understanding of this disease, showing the way for the era of precision medicine (3-5). The ETS-related gene (ERG) and the phosphatase and tensin homolog (PTEN) gene are two of the most widely studied molecular elements that have been correlated with the pathogenesis of prostate cancer. The purpose of this study is to investigate the association between ERG/PTEN expression and different pathologic parameters, with an emphasis on Gleason score, an important histopathological prognosticator of the disease.

Implications of ERG in the Molecular Pathology of Prostate Cancer

ERG is located at chromosome 21q22.2 and it is a member of the erythroblast transformation – specific (ETS) family of transcriptions factors, a group of highly conserved molecules with an important role in multiple cellular processes, including embryonic development, proliferation, and differentiation (6). It was originally introduced by Reddy et al., in 1987, who determined its sequence in colon cancer cell-lines, as a member of the ETS oncogene family (7).

Under normal circumstances, ERG is not expressed in the epithelial cells of the prostate. However, increased expression is frequently present in patients with prostate cancer (8). The over-expression of ERG is highly attributed to the TMPRSS2: ERG gene fusion, a recurrent chromosomal rearrangement that represents the most common molecular alteration in prostate cancer, occurring approximately in one half of the cases (9,10). TMRSS2:ERG fusion can occur due to genomic translocations or to interstitial deletions of the intergenic region between the two genes (8,11). This genomic event results to the fusion of the ERG proto-oncogene with the androgen – driven promoter of the TMPRSS2, setting the transcription of the former under hormonal control and resulting to its over-expression in cancerous cells (9,11). The exact molecular mechanisms underlying the pathogenic role of TMPRSS2:ERG fusion in prostate cancer are yet to be fully uncovered, but there is evidence suggesting its association with the clinical course of the disease (12,13).

Correlation of ERG Expression With the Gleason Score

Since the discovery of the TMPRSS2:ERG chromosomal rearrangement, there has been a lot of discussion regarding the association of ERG expression with specific histopathologic features of prostate cancer and with the prognosis of the disease. However, the results from studies worldwide are controversial. For example, Fine et al., investigated the association of TMPRSS2: ERG fusion with the Gleason score, using a cohort of patients with prostate cancer who underwent radical prostatectomy prior to any neoadjuvant therapeutic intervention. By applying FISH analysis, they assessed for any genetic aberration in the TMPRSS2 and the ERG gene. They showed that genomic rearrangements in TMPRSS2-ERG genes were associated with a lower Gleason score, whereas copy number increase was correlated with a higher Gleason score (14).

In a different study by Peterson et al., the expression of ERG protein, as an indicator of the presence of TMPRSS2: ERG gene fusion, was assessed by immunohistochemistry, in a cohort of 1,180 male patients (15). The results were statistically analyzed to examine the correlation between ERG expression and the clinical outcome of the disease. In the same inquiry, the authors conducted a meta-analysis of 47 studies so as to further investigate the association between the rearrangement status and patient prognosis. This study indicated that, 49% of the cohort population demonstrated over-expression of ERG. However, although these patients were most likely to demonstrate a higher tumor stage, no important correlation was found between the ERG expression and the Gleason score or the clinical outcomes of the disease. These results were further supported by a simultaneously conducted meta-analysis, which showed that the presence of TMPRSS2: ERG fusion was associated with a higher risk for increased tumor stage at the time of diagnosis, but it was not correlated with the final outcome (15). Absence of any statistically significant correlation between ERG expression and the Gleason score was further documented in other studies that were performed on tissue samples retrieved from prostatectomy specimens or needle biopsies (16-18).

Implications of PTEN in the Molecular Pathology of Prostate Cancer

PTEN gene is located in chromosome 10 and encodes an enzymatically active molecule that acts as a phosphatase and impedes the activity of PI3K/Akt pathway. PTEN has been shown to represent the most frequently inactivated tumour suppressor gene in primary prostate cancer, and its loss has been associated with disease progression in both hormone naive and castration-resistant prostate cancer (19). Gray et al. observed in 1995 that the region q23-24 was often absent from chromosome 10 in patients with prostate cancer (20). The genetic localisation of PTEN gene was firstly described by two independent groups in 1997. They detected mutations of this tumour suppressor gene in samples originating from patients with different types of malignancies, including prostate cancer (21,22). Various methods including immunohistochemistry, in situ and array comparative genomic hybridization have been used to highlight the loss of PTEN function in prostate cancer. Genomic deletion is the most commonly found PTEN alteration, while point mutations are rarer. Loss of PTEN expression in pathology specimens, as evidenced using immunohistochemistry staining, has been correlated with low PTEN molecular expression. Immunohistochemical staining showed the presence of PTEN protein in the nucleus and the cytoplasm of the basal and luminal prostatic cells, while loss of this staining pattern is frequently found in prostate cancer. Higher rates of PTEN loss have been associated with disease severity and progression along with poorer clinical outcomes (23).

Correlation of Loss of PTEN Expression With the Gleason Score

Without any doubt, Gleason score represents one of the most useful histopathologic variables for defining prostate cancer course and prognosis (24). Many studies indicated the association between Gleason score and PTEN expression. Yoshimoto et al., by applying tissue micro-arrays (TMAs) in 142 radical prostatectomy specimens, reported deletions of PTEN that occurred more frequently in specimens with a modified Gleason pattern of 4 and 5, compared to those of Gleason pattern 3. The authors documented, in the discussion part of their article, that deletion of PTEN in prostate biopsies could potentially represent more aggressive tumors, questioning whether patients with these alterations should be set under surveillance (25). Likewise, Lotan et al., studied PTEN expression by immunohistochemistry in specimens from 376 patients and reported that loss of PTEN was highly correlated with the pathologic stage and the Gleason score of the disease. PTEN deletion was found in 45% of patients with a Gleason score of 8-10 and 39% of patients with a Gleason score of 7, while only 20% of patients with a Gleason score of 5-6 showed loss of expression of PTEN protein. Regarding the pathologic stage of the disease, PTEN loss was more frequently reported in patients with pT3bN0 over pT3aN0 and pT2N0. Moreover, lymph node and distant metastases were associated with loss of PTEN, while PTEN deletion was an infrequent event in patients in patients with high grade prostatic intraepithelial neoplasia (HGPIN) (26). Strong evidence for the association of PTEN with the Gleason score arrives from a meta-analysis performed by Wang et al. in 2015, which included 7 studies, published from 1999 to 2004. Only studies involving patients with localized and operable prostate cancer were included. This study demonstrated that loss of PTEN expression was associated with a higher Gleason score, increased probability for capsular penetration and worse overall outcome (27).

In a different study, loss of PTEN expression, as evidenced by immunohistochemistry and FISH, was found as a potential indicator in a subgroup of prostate cancer patients with Gleason score 6 in needle biopsy specimens, who were later found to have progressed to 7 or higher Gleason scores, in their radical prostatectomy specimens. The study compared 71 patients with different Gleason scores in biopsy with 103 patients with the same Gleason scores in and prostatectomy specimens and concluded that PTEN loss could predict pathologic upgrading in a statistically significant manner. This study once again outlines the potential role of molecular markers in identifying patients with more aggressive prostatic tumors (28).

Similarly, Picanço-Albuquerque et al. reported that loss of PTEN in patients with a Gleason Grade 7 prostate cancer could predict unfavourable pathological parameters, such as positive surgical margins and higher Gleason score (29). Cuzick et al., noted that loss of PTEN, documented with immunohistochemistry staining, in patients with localised prostate cancer and low Gleason scores, could add prognostic value and predict prostate cancer associated death, along with already documented parameters, such as the Gleason score, Ki-67 expression and extent of the disease. PTEN immunohistochemistry pattern was available for 675 men from 6 different cancer registries in Great Britain and was found to predict prostate cancer death reliably but only in low-risk patients (30).

Relationship Between ERG Expression and PTEN Loss

There is a lot of discussion regarding the molecular interconnection between ERG and PTEN, as two of the most important molecular elements underlying the pathogenesis and the progression of prostate cancer. Deletion of PTEN has been found to be two to five times more frequent in patients with ERG rearrangements in comparison with patients with intact ERG (19). Moreover, it has been reported that over-expression of ERG potentially cooperates with loss of PTEN expression in promoting progression of HGPIN to invasive prostatic adenocarcinoma (31). In a Brazilian cohort of 116 patients with prostate cancer, immunohistochemical staining for ERG and PTEN was examined and correlated with various parameters. All different combinations of ERG and PTEN expression patterns were observed. Only 32% of patients who did not express ERG also showed loss of expression of PTEN, while PTEN deletion was evidenced in 46% of patients with preserved ERG expression. However, this difference was not statistically significant. Positive expression of both ERG and PTEN was associated with lower Gleason scores, lower grading, and lower prostate weight. Although this study included only a small group of patients, it underlined the importance of molecular profiling and personalized treatment approach in prostate cancer (32). Similarly, Bismar et al. performed immunohistochemical staining for both ERG and PTEN in 463 prostate cancer samples and correlated their expression with different pathological features, including Gleason score. In their study, 21.8% of patients with loss of PTEN expression were ERG positive, while only 16.1% of them were ERG negative. This difference was statistically significant. According to the results of their study, Gleason score was positively and negatively associated with ERG and PTEN expression, respectively. Patients with combined loss of PTEN and ERG showed the worst prognosis, and not these with ERG rearrangements and PTEN deletion as it was reported in other studies, including that by Morais et al. described before (33).

Brady et al. studied 132 patients with prostate cancer and divided them in 3 groups. Group 1 consisted of patients with biochemical recurrence, Group 2 included patients without biochemical recurrence and Group 3 consisted of patients who progressed shortly after surgery. Immunohistochemical staining for ERG and PTEN was performed and the combination of their expression was studied in all three patient groups. Most patients with PTEN deletion (74.2%) were also ERG negative, while 47% of patients without PTEN loss were ERG negative. Immediate progression after prostatectomy was more frequently observed in patients without ERG expression, while loss of PTEN expression was also correlated with rapid disease progression but not in statistically significant manner. Although the combination of negative expression of ERG and PTEN tended to be associated with immediate disease progression, this trend was not statistically significant (34). Shah et al. reported heterogeneity regarding ERG and PTEN expression on core needle biopsies from patients with prostate cancer. In their study, aberrant expression of ERG was significantly correlated with loss of PTEN expression. Moreover, the association between ERG over-expression and PTEN loss with different Gleason scores was investigated. Researchers noted that despite the absence of a strong connection between PTEN and higher Gleason scores, a significant correlation of ERG with Gleason score was not documented. In their conclusion the authors emphasized the importance of recognizing ERG and PTEN heterogeneity. Finally, ERG and PTEN expression was studied in combination in a systematic review and meta-analysis, which correlated these parameters with disease recurrence. A total of 17 eligible studies involving 6744 patients with prostate cancer were included in the final qualitative and quantitative synthesis. The authors observed significant correlation between the loss of PTEN expression and poorer biochemical recurrence free (BRF) and shorter recurrence-free survival (RFS) rates, but failed to document a suchlike trend for ERG over-expression. BRF and RFS were also conversely related with Gleason score (35).

ERG and PTEN as Therapeutic Targets

Shao et al. targeted the TMPRSS2/ERG fusion gene with liposomal nanovectors and studied the efficacy of this strategy in docetaxel therapy response. The authors reported increased docetaxel effectiveness in patients with advanced disease. Moreover, they concluded that this approach could potentially be used as a monotherapy (36). Tanaka et al. investigated the efficacy of PTEN gene therapy in enhancing response to chemotherapy. Using human prostate cancer cell lines and recombinant PTEN adenoviruses, they showed that this therapeutic strategy increased doxorubicin chemotherapy efficacy (37). PTEN pathway targeting was also reported by Qi et al. In their study, they demonstrated that intermittent P13K blockage could represent a solution to immune checkpoint therapy (ICT) resistance (38). In a review article, Turnham et al., summarized all the reported therapeutic strategies for targeting the PTEN gene and restoring its function (39). Lahdensuo et al. proposed that patients with ERG-negative prostate cancer with loss of PTEN could benefit from adjuvant therapies (40). Finally, Rescigno et al. studied the response of patients with prostate cancer and abnormal ERG and PTEN expression to docetaxel therapy. They concluded that in patients with loss of PTEN and castration-resistant prostate cancer, docetaxel chemotherapy was more effective than hormonal treatment, while no correlation was found between ERG expression and docetaxel response (41).

Conclusion

Although some articles report a correlation between ERG protein and Gleason score, there is no strong evidence supporting this finding. Furthermore, a meta-analysis of 47 studies failed to show any association between these two parameters (15). On the contrary, loss of PTEN expression has been clearly connected with worse prognosis and higher Gleason scores. A meta-analysis demonstrated a statistically significant correlation of these two parameters (27). Few studies relate over-expression of ERG gene with loss of PTEN expression. Regarding the combined expression of ERG and PTEN, all studies correlated negative PTEN expressions with higher Gleason scores, while both positive and negative ERG expression were reported in different studies. Some articles report the combined negative PTEN and ERG expression is associated with the highest Gleason score, while others conclude the over-expression of ERG combined with the deletion of PTEN is the least favorable combination. Finally, PTEN and ERG have been studied as potential therapeutic target and several promising results have been reported. An important limitation of this review is that not all articles studied exclusively the expression of PTEN and ERG in pathologic specimens using immunohistochemistry. Thus, some studies were based in molecular biology assays or were in vitro experiments. Additional studies on the association between PTEN and ERG immunohistochemical expression and pathologic parameters, such as the Gleason score, are of outmost importance.

Conflicts of Interest

The Authors have no conflicts of interest to declare in relation to this study.

Authors’ Contributions

All Authors contributed to the conception and design of the manuscript. The authors T. Spinos and A. Georgiou have equally participated in the writing process of the text. Dr. Andreas C. Lazaris and Dr. Georgia Eleni Thomopoulou supervised the writing of this review.

Acknowledgements

The Authors would like to acknowledge the contribution of the SB BioAnalytica SA, for covering the full expenses for the processing and the publication of this article.

References

1 Sung H Ferlay J Siegel RL Laversanne M Soerjomataram I Jemal A & Bray F Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71(3) 209 - 249 2021. PMID: 33538338. DOI: 10.3322/caac.21660
2 Pernar CH Ebot EM Wilson KM & Mucci LA The epidemiology of prostate cancer. Cold Spring Harb Perspect Med. 8(12) a030361 2018. PMID: 29311132. DOI: 10.1101/cshperspect.a030361
3 Hughes C Murphy A Martin C Sheils O & O’Leary J Molecular pathology of prostate cancer. J Clin Pathol. 58(7) 673 - 684 2005. PMID: 15976331. DOI: 10.1136/jcp.2002.003954
4 Vlajnic T & Bubendorf L Molecular pathology of prostate cancer: a practical approach. Pathology. 53(1) 36 - 43 2021. PMID: 33234230. DOI: 10.1016/j.pathol.2020.10.003
5 Assadi M Jokar N Ghasemi M Nabipour I Gholamrezanezhad A & Ahmadzadehfar H Precision medicine approach in prostate cancer. Curr Pharm Des. 26(31) 3783 - 3798 2020. PMID: 32067601. DOI: 10.2174/1381612826666200218104921
6 ERG ETS transcription factor ERG [Homo sapiens (human)] - Gene - NCBI. Available at: https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=2078.
7 Reddy ES Rao VN & Papas TS The erg gene: a human gene related to the ets oncogene. Proc Natl Acad Sci USA. 84(17) 6131 - 6135 1987. PMID: 3476934. DOI: 10.1073/pnas.84.17.6131
8 Adamo P & Ladomery MR The oncogene ERG: a key factor in prostate cancer. Oncogene. 35(4) 403 - 414 2016. PMID: 25915839. DOI: 10.1038/onc.2015.109
9 Tomlins SA Rhodes DR Perner S Dhanasekaran SM Mehra R Sun XW Varambally S Cao X Tchinda J Kuefer R Lee C Montie JE Shah RB Pienta KJ Rubin MA & Chinnaiyan AM Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 310(5748) 644 - 648 2005. PMID: 16254181. DOI: 10.1126/science.1117679
10 Tu JJ Rohan S Kao J Kitabayashi N Mathew S & Chen YT Gene fusions between TMPRSS2 and ETS family genes in prostate cancer: frequency and transcript variant analysis by RT-PCR and FISH on paraffin-embedded tissues. Mod Pathol. 20(9) 921 - 928 2007. PMID: 17632455. DOI: 10.1038/modpathol.3800903
11 Wang Z Wang Y Zhang J Hu Q Zhi F Zhang S Mao D Zhang Y & Liang H Significance of the TMPRSS2:ERG gene fusion in prostate cancer. Mol Med Rep. 16(4) 5450 - 5458 2017. PMID: 28849022. DOI: 10.3892/mmr.2017.7281
12 Hägglöf C Hammarsten P Strömvall K Egevad L Josefsson A Stattin P Granfors T & Bergh A TMPRSS2-ERG expression predicts prostate cancer survival and associates with stromal biomarkers. PLoS One. 9(2) e86824 2014. PMID: 24505269. DOI: 10.1371/journal.pone.0086824
13 St John J Powell K Conley-Lacomb MK & Chinni SR TMPRSS2-ERG fusion gene expression in prostate tumor cells and its clinical and biological significance in prostate cancer progression. J Cancer Sci Ther. 4(4) 94 - 101 2012. PMID: 23264855. DOI: 10.4172/1948-5956.1000119
14 Fine SW Gopalan A Leversha MA Al-Ahmadie HA Tickoo SK Zhou Q Satagopan JM Scardino PT Gerald WL & Reuter VE TMPRSS2-ERG gene fusion is associated with low Gleason scores and not with high-grade morphological features. Mod Pathol. 23(10) 1325 - 1333 2010. PMID: 20562851. DOI: 10.1038/modpathol.2010.120
15 Pettersson A Graff RE Bauer SR Pitt MJ Lis RT Stack EC Martin NE Kunz L Penney KL Ligon AH Suppan C Flavin R Sesso HD Rider JR Sweeney C Stampfer MJ Fiorentino M Kantoff PW Sanda MG Giovannucci EL Ding EL Loda M & Mucci LA The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: a cohort study and meta-analysis. Cancer Epidemiol Biomarkers Prev. 21(9) 1497 - 1509 2012. PMID: 22736790. DOI: 10.1158/1055-9965.EPI-12-0042
16 Birol IE Bahadir B Ozdamar SO Kaymaz E & Girgin R Immunohistochemical expression of the ERG gene in prostatic adenocarcinoma and its relationship with clinicopathological parameters. Malays J Pathol. 43(3) 381 - 388 2021. PMID: 34958059.
Pubmed |
17 Gülhan Ö & Mahi B The role of AMACR, CD10, TMPRSS2-ERG, and p27 protein expression among different gleason grades of prostatic adenocarcinoma on needle biopsy. Clin Med Insights Oncol. 14 1179554920947322 2020. PMID: 35185351. DOI: 10.1177/1179554920947322
18 Mosquera JM Mehra R Regan MM Perner S Genega EM Bueti G Shah RB Gaston S Tomlins SA Wei JT Kearney MC Johnson LA Tang JM Chinnaiyan AM Rubin MA & Sanda MG Prevalence of TMPRSS2-ERG fusion prostate cancer among men undergoing prostate biopsy in the United States. Clin Cancer Res. 15(14) 4706 - 4711 2009. PMID: 19584163. DOI: 10.1158/1078-0432.CCR-08-2927
19 Jamaspishvili T Berman DM Ross AE Scher HI De Marzo AM Squire JA & Lotan TL Clinical implications of PTEN loss in prostate cancer. Nat Rev Urol. 15(4) 222 - 234 2018. PMID: 29460925. DOI: 10.1038/nrurol.2018.9
20 Gray IC Phillips SM Lee SJ Neoptolemos JP Weissenbach J & Spurr NK Loss of the chromosomal region 10q23-25 in prostate cancer. Cancer Res. 55(21) 4800 - 4803 1995. PMID: 7585509.
Pubmed |
21 Li J Yen C Liaw D Podsypanina K Bose S Wang SI Puc J Miliaresis C Rodgers L McCombie R Bigner SH Giovanella BC Ittmann M Tycko B Hibshoosh H Wigler MH & Parsons R PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 275(5308) 1943 - 1947 1997. PMID: 9072974. DOI: 10.1126/science.275.5308.1943
22 Steck PA Pershouse MA Jasser SA Yung WK Lin H Ligon AH Langford LA Baumgard ML Hattier T Davis T Frye C Hu R Swedlund B Teng DH & Tavtigian SV Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 15(4) 356 - 362 1997. PMID: 9090379. DOI: 10.1038/ng0497-356
23 Wise HM Hermida MA & Leslie NR Prostate cancer, PI3K, PTEN and prognosis. Clin Sci (Lond). 131(3) 197 - 210 2017. PMID: 28057891. DOI: 10.1042/CS20160026
24 Lavery HJ & Droller MJ Do Gleason patterns 3 and 4 prostate cancer represent separate disease states. J Urol. 188(5) 1667 - 1675 2012. PMID: 22998919. DOI: 10.1016/j.juro.2012.07.055
25 Yoshimoto M Ding K Sweet JM Ludkovski O Trottier G Song KS Joshua AM Fleshner NE Squire JA & Evans AJ PTEN losses exhibit heterogeneity in multifocal prostatic adenocarcinoma and are associated with higher Gleason grade. Mod Pathol. 26(3) 435 - 447 2013. PMID: 23018874. DOI: 10.1038/modpathol.2012.162
26 Lotan TL Gurel B Sutcliffe S Esopi D Liu W Xu J Hicks JL Park BH Humphreys E Partin AW Han M Netto GJ Isaacs WB & De Marzo AM PTEN protein loss by immunostaining: analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients. Clin Cancer Res. 17(20) 6563 - 6573 2011. PMID: 21878536. DOI: 10.1158/1078-0432.CCR-11-1244
27 Wang Y & Dai B PTEN genomic deletion defines favorable prognostic biomarkers in localized prostate cancer: a systematic review and meta-analysis. Int J Clin Exp Med. 8(4) 5430 - 5437 2015. PMID: 26131120.
Pubmed |
28 Lotan TL Carvalho FL Peskoe SB Hicks JL Good J Fedor H Humphreys E Han M Platz EA Squire JA De Marzo AM & Berman DM PTEN loss is associated with upgrading of prostate cancer from biopsy to radical prostatectomy. Mod Pathol. 28(1) 128 - 137 2015. PMID: 24993522. DOI: 10.1038/modpathol.2014.85
29 Picanço-Albuquerque CG Vidotto T Pereira CS Saggioro FP Jamaspishvili T Koti M Berman DM Squire JA & Reis RB PTEN loss in Gleason grade 7 prostate tumors exhibits intratumoral heterogeneity and is associated with unfavorable pathological features. Applied Cancer Res. 39 1 2019. DOI: 10.1186/s41241-018-0071-y
30 Cuzick J Yang ZH Fisher G Tikishvili E Stone S Lanchbury JS Camacho N Merson S Brewer D Cooper CS Clark J Berney DM Møller H Scardino P Sangale Z & Transatlantic Prostate Group Prognostic value of PTEN loss in men with conservatively managed localised prostate cancer. Br J Cancer. 108(12) 2582 - 2589 2013. PMID: 23695019. DOI: 10.1038/bjc.2013.248
31 Carver BS Tran J Gopalan A Chen Z Shaikh S Carracedo A Alimonti A Nardella C Varmeh S Scardino PT Cordon-Cardo C Gerald W & Pandolfi PP Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat Genet. 41(5) 619 - 624 2009. PMID: 19396168. DOI: 10.1038/ng.370
32 Morais CE Gurgel DC Teixeira AC Mattos TVA Silva AVAD & Tavora F Prevalence of ERG expression and PTEN loss in a Brazilian prostate cancer cohort. Braz J Med Biol Res. 52(12) e8483 2019. PMID: 31826177. DOI: 10.1590/1414-431X20198483
33 Bismar TA Hegazy S Feng Z Yu D Donnelly B Palanisamy N & Trock BJ Clinical utility of assessing PTEN and ERG protein expression in prostate cancer patients: a proposed method for risk stratification. J Cancer Res Clin Oncol. 144(11) 2117 - 2125 2018. PMID: 30101374. DOI: 10.1007/s00432-018-2730-5
34 Brady L Carlsson J Baird AM Casey O Vlajnic T Murchan P Cormican D Costigan D Gray S Sheils O O’Neill A Watson RW Andren O & Finn S Correlation of integrated ERG/PTEN assessment with biochemical recurrence in prostate cancer. Cancer Treat Res Commun. 29 100451 2021. PMID: 34507017. DOI: 10.1016/j.ctarc.2021.100451
35 Liu R Zhou J Xia S & Li T The impact of PTEN deletion and ERG rearrangement on recurrence after treatment for prostate cancer: a systematic review and meta-analysis. Clin Transl Oncol. 22(5) 694 - 702 2020. PMID: 31359337. DOI: 10.1007/s12094-019-02170-3
36 Shao L Kahraman N Yan G Wang J Ozpolat B & Ittmann M Targeting the TMPRSS2/ERG fusion mRNA using liposomal nanovectors enhances docetaxel treatment in prostate cancer. Prostate. 80(1) 65 - 73 2020. PMID: 31614005. DOI: 10.1002/pros.23918
37 Tanaka M Rosser CJ & Grossman HB PTEN gene therapy induces growth inhibition and increases efficacy of chemotherapy in prostate cancer. Cancer Detect Prev. 29(2) 170 - 174 2005. PMID: 15829377. DOI: 10.1016/j.cdp.2004.07.006
38 Qi Z Xu Z Zhang L Zou Y Li J Yan W Li C Liu N & Wu H Overcoming resistance to immune checkpoint therapy in PTEN-null prostate cancer by intermittent anti-PI3Kα/β/δ treatment. Nat Commun. 13(1) 182 2022. PMID: 35013322. DOI: 10.1038/s41467-021-27833-0
39 Turnham DJ Bullock N Dass MS Staffurth JN & Pearson HB The PTEN conundrum: How to target PTEN-deficient prostate cancer. Cells. 9(11) 2342 2020. PMID: 33105713. DOI: 10.3390/cells9112342
40 Lahdensuo K Erickson A Saarinen I Seikkula H Lundin J Lundin M Nordling S Bützow A Vasarainen H Boström PJ Taimen P Rannikko A & Mirtti T Loss of PTEN expression in ERG-negative prostate cancer predicts secondary therapies and leads to shorter disease-specific survival time after radical prostatectomy. Mod Pathol. 29(12) 1565 - 1574 2016. PMID: 27562498. DOI: 10.1038/modpathol.2016.154
41 Rescigno P Lorente D Dolling D Ferraldeschi R Rodrigues DN Riisnaes R Miranda S Bianchini D Zafeiriou Z Sideris S Ferreira A Figueiredo I Sumanasuriya S Mateo J Perez-Lopez R Sharp A Tunariu N & de Bono JS Docetaxel treatment in PTEN- and ERG-aberrant metastatic prostate cancers. Eur Urol Oncol. 1(1) 71 - 77 2018. PMID: 29911685. DOI: 10.1016/j.euo.2018.02.006