Journal of Cancer Research and Clinical Oncology

, Volume 144, Issue 11, pp 2117–2125 | Cite as

Clinical utility of assessing PTEN and ERG protein expression in prostate cancer patients: a proposed method for risk stratification

  • Tarek A. BismarEmail author
  • Samar Hegazy
  • Zhaoyong Feng
  • Darryl Yu
  • Bryan Donnelly
  • Nallasivam Palanisamy
  • Bruce J. Trock
Original Article – Cancer Research



To assess the prognostic value of ERG and PTEN protein expression as two of the most common genetic aberration in men with prostate cancer managed non-surgically by androgen deprivation therapy (ADT).

Materials and methods

463 tumor samples were assessed by double immunohistochemistry stains for ERG and PTEN and data correlated with clinical pathological features including, Gleason score, patients’ outcome and ADT.


ERG expression and PTEN protein loss were present in 28.2% and 38% of total patients respectively. There was a significant interplay between ERG and PTEN expression with 21.8% PTEN negative tumors being ERG positive (p < 0.001). Both ERG and PTEN showed significant association with lethal disease in all patients and those treated with prior ADT representing castrate-resistant disease. However, only PTEN remained significant in multivariable proportional hazards regression analysis, when including Gleason score and patients’ age. Depending on patient’s subgroup, intact positive PTEN intensity showed better cancer-specific survival with HR ranging from 0.25 to 0.4 compared to tumors with loss of PTEN expression. Assessing combined marker status, patients with decreased PTEN intensity without ERG positivity showed the worst clinical outcome compared to those with no PTEN loss and no ERG expression, where they had best clinical outcome. Patients with ERG expression with or without PTEN loss showed intermediate risk in relation to lethal disease.


This study confirms a significant prognostic role for assessing ERG and PTEN in men with prostate cancer. It supports a role for utilizing combined ERG/PTEN status clinically and prospectively for stratifying PCa patients into different prognostic groups.


ERG protein expression PTEN expression Immunohistochemistry Gleason score Androgen deprivation therapy Cancer-specific mortality 



The study was supported in part by the Prostate Cancer Foundation Young Investigator Award (T.A.B). This work was also supported by Prostate cancer Canada and is proudly funded by the Movember Foundation-Grant #B2013-01.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

The study was approved by the U Calgary Cumming School of Medicine ethics review board and in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.


  1. Abou-Ouf H, Zhao L, Bismar TA (2016) ERG expression in prostate cancer: biological relevance and clinical implication. J Cancer Res Clin Oncol 142(8):1781–1793. CrossRefPubMedGoogle Scholar
  2. Ahearn TU, Pettersson A, Ebot EM, Gerke T, Graff RE, Morais CL, Hicks JL, Wilson KM, Rider JR, Sesso HD, Fiorentino M, Flavin R, Finn S, Giovannucci EL, Loda M, Stampfer MJ, De Marzo AM, Mucci LA, Lotan TL (2016) A prospective investigation of PTEN loss and ERG expression in lethal prostate cancer. J Natl Cancer Inst. CrossRefPubMedGoogle Scholar
  3. Bismar TA, Yoshimoto M, Vollmer RT, Duan Q, Firszt M, Corcos J, Squire JA (2011) PTEN genomic deletion is an early event associated with ERG gene rearrangements in prostate cancer. BJU Int 107 (3):477–485. CrossRefPubMedGoogle Scholar
  4. Bismar TA, Dolph M, Teng LH, Liu S, Donnelly B (2012) ERG protein expression reflects hormonal treatment response and is associated with Gleason score and prostate cancer specific mortality. Eur J Cancer 48(4):538–546. CrossRefPubMedGoogle Scholar
  5. Dal Pra A, Lalonde E, Sykes J, Warde F, Ishkanian A, Meng A, Maloff C, Srigley J, Joshua AM, Petrovics G, van der Kwast T, Evans A, Milosevic M, Saad F, Collins C, Squire J, Lam W, Bismar TA, Boutros PC, Bristow RG (2013) TMPRSS2-ERG status is not prognostic following prostate cancer radiotherapy: implications for fusion status and DSB repair. Clin Cancer Research 19(18):5202–5209. CrossRefGoogle Scholar
  6. Demichelis F, Fall K, Perner S, Andren O, Schmidt F, Setlur SR, Hoshida Y, Mosquera JM, Pawitan Y, Lee C, Adami HO, Mucci LA, Kantoff PW, Andersson SO, Chinnaiyan AM, Johansson JE, Rubin MA (2007) TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene 26(31):4596–4599. CrossRefGoogle Scholar
  7. Facher EA, Law JC (1998) PTEN and prostate cancer. J Med Genet 35(9):790CrossRefGoogle Scholar
  8. Fine JP, Gray RJ (1999) A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 94:496CrossRefGoogle Scholar
  9. Guedes LB, Tosoian JJ, Hicks J, Ross AE, Lotan TL (2017) PTEN loss in Gleason score 3 + 4 = 7 prostate biopsies is associated with nonorgan confined disease at radical prostatectomy. J Urol 197(4):1054–1059. CrossRefPubMedGoogle Scholar
  10. Hoogland AM, Jenster G, van Weerden WM, Trapman J, van der Kwast T, Roobol MJ, Schroder FH, Wildhagen MF, van Leenders GJ (2012) ERG immunohistochemistry is not predictive for PSA recurrence, local recurrence or overall survival after radical prostatectomy for prostate cancer. Mod Pathol 25(3):471–479. CrossRefPubMedGoogle Scholar
  11. Huang KC, Alshalalfa M, Hegazy SA, Dolph M, Donnelly B, Bismar TA (2014a) The prognostic significance of combined ERG and androgen receptor expression in patients with prostate cancer managed by androgen deprivation therapy. Cancer Biol Ther 15(9):1120–1128. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Huang KC, Dolph M, Donnelly B, Bismar TA (2014b) ERG expression is associated with increased risk of biochemical relapse following radical prostatectomy in early onset prostate cancer. Clin Transl Oncol 16(11):973–979. CrossRefPubMedGoogle Scholar
  13. Huang KC, Begin LR, Palanisamy N, Donnelly B, Bismar TA (2016) SPINK1 expression in relation to PTEN and ERG in matched primary and lymph node metastatic prostate cancer: implications for biomarker development. Urol Oncol 34(5):235 e231–210. CrossRefGoogle Scholar
  14. Hyun T, Yam A, Pece S, Xie X, Zhang J, Miki T, Gutkind JS, Li W (2000) Loss of PTEN expression leading to high Akt activation in human multiple myelomas. Blood 96(10):3560–3568PubMedGoogle Scholar
  15. Johansson JE, Andren O, Andersson SO, Dickman PW, Holmberg L, Magnuson A, Adami HO (2004) Natural history of early, localized prostate cancer. Jama 291(22):2713–2719CrossRefGoogle Scholar
  16. Lee SL, Yu D, Wang C, Saba R, Liu S, Trpkov K, Donnelly B, Bismar TA (2015) ERG expression in prostate needle biopsy: potential diagnostic and prognostic implications. Appl Immunohistochem Mol Morphol 23(7):499–505. CrossRefPubMedGoogle Scholar
  17. Liu S, Yoshimoto M, Trpkov K, Duan Q, Firszt M, Corcos J, Squire JA, Bismar TA (2011) Detection of ERG gene rearrangements and PTEN deletions in unsuspected prostate cancer of the transition zone. Cancer Biol Ther 11(6):562–566CrossRefGoogle Scholar
  18. Lotan TL, Carvalho FL, Peskoe SB, Hicks JL, Good J, Fedor HL, Humphreys E, Han M, Platz EA, Squire JA, De Marzo AM, Berman DM (2015) PTEN loss is associated with upgrading of prostate cancer from biopsy to radical prostatectomy. Mod Pathol 28(1):128–137. CrossRefPubMedGoogle Scholar
  19. Matsui S, Simon R, Qu P, Shaughnessy JD Jr, Barlogie B, Crowley J (2012) Developing and validating continuous genomic signatures in randomized clinical trials for predictive medicine. Clin Cancer Res 18(21):6065–6073. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Reid AH, Attard G, Ambroisine L, Fisher G, Kovacs G, Brewer D, Clark J, Flohr P, Edwards S, Berney DM, Foster CS, Fletcher A, Gerald WL, Moller H, Reuter VE, Scardino PT, Cuzick J, de Bono JS, Cooper CS (2010) Molecular characterisation of ERG, ETV1 and PTEN gene loci identifies patients at low and high risk of death from prostate cancer. Br J Cancer 102(4):678–684. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Teng LH, Wang C, Begin LR, Dolph M, Yilmaz A, Trpkov K, Donnelly B, Bismar TA (2013a) ERG protein expression and gene rearrangements are present at lower rates in metastatic and locally advanced castration-resistant prostate cancer compared to localized disease. Urology 82(2):394–399. CrossRefPubMedGoogle Scholar
  22. Teng LH, Wang C, Dolph M, Donnelly B, Bismar TA (2013b) ERG protein expression is of limited prognostic value in men with localized prostate cancer. ISRN Urol 2013:786545. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Tomlins SA, Palanisamy N, Siddiqui J, Chinnaiyan AM, Kunju LP (2012) Antibody-based detection of ERG rearrangements in prostate core biopsies, including diagnostically challenging cases: ERG staining in prostate core biopsies. Arch Pathol Lab Med 136(8):935–946. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Yoshimoto M, Joshua AM, Cunha IW, Coudry RA, Fonseca FP, Ludkovski O, Zielenska M, Soares FA, Squire JA (2008) Absence of TMPRSS2:ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome. Mod Pathol 21:1451CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineUniversity of Calgary-Cumming School of MedicineCalgaryCanada
  2. 2.Brady Urological InstituteJohn Hopkins School of MedicineBaltimoreUSA
  3. 3.Departments of Oncology, Biochemistry and Molecular BiologyUniversity of Calgary-Cumming School of MedicineCalgaryCanada
  4. 4.Arnie Charbonneau Cancer Institute, Tom Baker Cancer CenterCalgaryCanada
  5. 5.Department of UrologyUniversity of CalgaryCalgaryCanada
  6. 6.Prostate Cancer CenterCalgaryCanada
  7. 7.Department of UrologyVattikuti Urology Institute, Henry Ford Health SystemDetroitUSA
  8. 8.Department of Pathology, College of MedicineUniversity of SaskatchewanSaskatoonCanada
  9. 9.Rokyview General HospitalCalgary Laboratory ServicesCalgaryCanada

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