Combined loss of TFF3 and PTEN is associated with lethal outcome and overall survival in men with prostate cancer
Trefoil Factor 3 (TFF3) has been implicated in Prostate Cancer (PCa) progression. However, its prognostic value and association with other biomarkers have not been fully explored. We assessed the combined value of TFF3 and PTEN in two cohorts: one is managed surgically for localized PCa and the second is managed non-surgically by androgen deprivation therapy for advanced disease.
228 radical prostatectomies (RP) and 318 transurethral resection of prostate (TURP) samples were assessed by immunohistochemistry (IHC) for TFF3 and by IHC and fluorescent in situ hybridization (FISH) for PTEN. Results of biomarkers expression were correlated with various pathological and clinical outcome parameters including biochemical recurrence (BCR) in the RP cohort and cancer-specific mortality (PCSM) and overall survival (OS) in the TURP cohort.
TFF3 expression was detected in 131/226 (57.9%) RP samples and 148/318 (46.5%) of TURP cases. In general, TFF3 positivity was less frequently observed with advanced Gleason Groups. TFF3 expression was also assessed in relation to PTEN expression. Only 15–16% of TFF3-expressed cases were present in association with complete loss of PTEN expression in the TURP and localized cohorts, respectively. Loss of TFF3 expression was not related to BCR after RP, but was prognostic in the non-surgical cohort and associated with decrease OS and PCSM (HR 2.31, CI: 1.67–3.18, p < 0.0001) and (HR 3.99, CI: 2.43–6.56; p < 0.0001), respectively. Adjusting for Gleason score, combined loss of TFF3/PTEN was most associated with OS (HR 2.33, CI: 1.49–3.62; p < 0.0001) and PCSM (HR = 3.44, CI: 1.75–6.78, p < 0.0001).
The study documents for the first time significant association for combined status of TFF3 expression and PTEN loss in OS and PCSM in patients not managed by surgical intervention. Prospective assessment of PTEN and TFF3 may provide further insight into molecularly subtyping PCa and aid in stratifying patients at risk for lethal disease.
KeywordsTFF3 PTEN Protein expression Immunohistochemistry Gleason score Androgen deprivation therapy Cancer specific mortality Biochemical recurrence
The study was supported in part by the Prostate Cancer Foundation Young Investigator Award (T.A.B). This work is also supported by Prostate cancer Canada and is proudly funded by the Movember Foundation-Grant#B2013-01 and Funds from Ride for Dads (TAB). The authors would like to thank Mrs. Ruby Reyes for technical support in this manuscript.
Compliance with ethical standards
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.
Conflict of interest
The authors declare no conflict of interest.
- 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 Res 19:5202–5209. https://doi.org/10.1158/1078-0432.ccr-13-1049 CrossRefGoogle Scholar
- 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 26:4596–4599. https://doi.org/10.1038/sj.onc.1210237 CrossRefGoogle Scholar
- 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 25:471–479. https://doi.org/10.1038/modpathol.2011.176 CrossRefGoogle Scholar
- 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 15:1120–1128. https://doi.org/10.4161/cbt.29689 CrossRefGoogle Scholar
- 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(235):e231–210. https://doi.org/10.1016/j.urolonc.2015.11.015 Google Scholar
- Lee SH, Poulogiannis G, Pyne S, Jia S, Zou L, Signoretti S, Loda M, Cantley LC, Roberts TM (2010) A constitutively activated form of the p110beta isoform of PI3-kinase induces prostatic intraepithelial neoplasia in mice. Proc Natl Acad Sci USA 107:11002–11007. https://doi.org/10.1073/pnas.1005642107 CrossRefGoogle Scholar
- 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 102:678–684. https://doi.org/10.1038/sj.bjc.6605554 CrossRefGoogle Scholar
- Rickman DS, Chen YB, Banerjee S, Pan Y, Yu J, Vuong T, Perner S, Lafargue CJ, Mertz KD, Setlur SR, Sircar K, Chinnaiyan AM, Bismar TA, Rubin MA, Demichelis F (2010) ERG cooperates with androgen receptor in regulating trefoil factor 3 in prostate cancer disease progression. Neoplasia 12:1031–1040CrossRefGoogle Scholar
- Sircar K, Yoshimoto M, Monzon FA, Koumakpayi IH, Katz RL, Khanna A, Alvarez K, Chen G, Darnel AD, Aprikian AG, Saad F, Bismar TA, Squire JA (2009) PTEN genomic deletion is associated with p-Akt and AR signalling in poorer outcome, hormone refractory prostate cancer. J Pathol 218:505–513. https://doi.org/10.1002/path.2559 CrossRefGoogle Scholar
- 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 82:394–399. https://doi.org/10.1016/j.urology.2013.03.029 CrossRefGoogle Scholar
- 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 136:935–946. https://doi.org/10.5858/arpa.2011-0424-oa CrossRefGoogle Scholar