Skip to main content
Top
Published in: Journal of Cancer Research and Clinical Oncology 3/2008

01-03-2008 | Original Paper

Expression of the polycomb group protein EZH2 and its relation to outcome in patients with urothelial carcinoma of the bladder

Authors: Stefan Hinz, Carsten Kempkensteffen, Frank Christoph, Michèle Hoffmann, Hans Krause, Mark Schrader, Martin Schostak, Kurt Miller, Steffen Weikert

Published in: Journal of Cancer Research and Clinical Oncology | Issue 3/2008

Login to get access

Abstract

Purpose

The polycomb group protein Enhancer of Zeste Homolg 2 (EZH2), a repressor of gene transcription, has been linked to the progression of various malignancies. This study was done to examine a potential correlation of EZH2 mRNA expression with clinicopathological parameters and outcome in patients with urothelial carcinoma (UC) of the bladder.

Methods

We determined the relative EZH2 gene expression by quantitative RT-PCR in tumor specimens from a cohort of 100 patients with UC (mean follow-up 44.2 months). EZH2 expression levels were correlated to pathological tumor features and outcome.

Results

Enhancer of Zeste Homolg 2 was expressed in 90% of the tumor samples. Expression levels increased in parallel with tumor stage (P = 0.002). High grade UC displayed significantly elevated EZH2 levels compared to low grade disease (P < 0.0001). High EZH2 expression was related to an abbreviated time to recurrence in muscle invasive carcinomas (pT ≥ 2) (P = 0.028). No such correlation was detected in the group of superficial tumors (pT ≤ 1) (P = 0.191). High EZH2 expression levels were associated with an increased risk of tumor related death in the univariate analysis (relative risk, 3.1; P = 0.029). This association became non-significant when the prognostic effect of tumor stage was considered in a multivariate model.

Conclusions

Enhancer of Zeste Homolg 2 expression is related to an aggressive tumor behavior but due to its strong association with pathological features, EZH2 levels do not provide independent prognostic information.
Literature
go back to reference Arisan S, Buyuktuncer ED, Palavan-Unsal N, Caskurlu T, Cakir OO, Ergenekon E (2005) Increased expression of EZH2, a polycomb group protein, in bladder carcinoma. Urol Int 75:252–257PubMedCrossRef Arisan S, Buyuktuncer ED, Palavan-Unsal N, Caskurlu T, Cakir OO, Ergenekon E (2005) Increased expression of EZH2, a polycomb group protein, in bladder carcinoma. Urol Int 75:252–257PubMedCrossRef
go back to reference Bachmann IM, Halvorsen OJ, Collett K, Stefansson IM, Straume O, Haukaas SA, Salvesen HB, Otte AP, Akslen LA (2006) EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol 24:268–273PubMedCrossRef Bachmann IM, Halvorsen OJ, Collett K, Stefansson IM, Straume O, Haukaas SA, Salvesen HB, Otte AP, Akslen LA (2006) EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol 24:268–273PubMedCrossRef
go back to reference Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K (2003) EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J 22:5323–5335PubMedCrossRef Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K (2003) EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J 22:5323–5335PubMedCrossRef
go back to reference Cote RJ, Datar RH (2003) Therapeutic approaches to bladder cancer: identifying targets and mechanisms. Crit Rev Oncol Hematol 46 (Suppl):S67–S83PubMedCrossRef Cote RJ, Datar RH (2003) Therapeutic approaches to bladder cancer: identifying targets and mechanisms. Crit Rev Oncol Hematol 46 (Suppl):S67–S83PubMedCrossRef
go back to reference Ding L, Erdmann C, Chinnaiyan AM, Merajver SD, Kleer CG (2006) Identification of EZH2 as a molecular marker for a precancerous state in morphologically normal breast tissues. Cancer Res 66:4095–4099PubMedCrossRef Ding L, Erdmann C, Chinnaiyan AM, Merajver SD, Kleer CG (2006) Identification of EZH2 as a molecular marker for a precancerous state in morphologically normal breast tissues. Cancer Res 66:4095–4099PubMedCrossRef
go back to reference Eble JN, Sauter G, Epstein JI, Sesterhenn IA (2004) Pathology and genetics of tumors of the urinary system and male genital organs. IARC press, Lyon Eble JN, Sauter G, Epstein JI, Sesterhenn IA (2004) Pathology and genetics of tumors of the urinary system and male genital organs. IARC press, Lyon
go back to reference Epstein JI, Amin MB, Reuter VR, Mostofi FK (1998) The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol 22:1435–1448PubMedCrossRef Epstein JI, Amin MB, Reuter VR, Mostofi FK (1998) The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol 22:1435–1448PubMedCrossRef
go back to reference Esteller M (2006) Epigenetics provides a new generation of oncogenes and tumour-suppressor genes. Br J Cancer 94:179–183PubMedCrossRef Esteller M (2006) Epigenetics provides a new generation of oncogenes and tumour-suppressor genes. Br J Cancer 94:179–183PubMedCrossRef
go back to reference Feber A, Clark J, Goodwin G, Dodson AR, Smith PH, Fletcher A, Edwards S, Flohr P, Falconer A, Roe T, Kovacs G, Dennis N, Fisher C, Wooster R, Huddart R, Foster CS, Cooper CS (2004) Amplification and overexpression of E2F3 in human bladder cancer. Oncogene 23:1627–1630PubMedCrossRef Feber A, Clark J, Goodwin G, Dodson AR, Smith PH, Fletcher A, Edwards S, Flohr P, Falconer A, Roe T, Kovacs G, Dennis N, Fisher C, Wooster R, Huddart R, Foster CS, Cooper CS (2004) Amplification and overexpression of E2F3 in human bladder cancer. Oncogene 23:1627–1630PubMedCrossRef
go back to reference Gunster MJ, Raaphorst FM, Hamer KM, den Blaauwen JL, Fieret E, Meijer CJ, Otte AP (2001) Differential expression of human Polycomb group proteins in various tissues and cell types. J Cell Biochem Suppl (Suppl 36):129–143 Gunster MJ, Raaphorst FM, Hamer KM, den Blaauwen JL, Fieret E, Meijer CJ, Otte AP (2001) Differential expression of human Polycomb group proteins in various tissues and cell types. J Cell Biochem Suppl (Suppl 36):129–143
go back to reference Karge WH III, Schaefer EJ, Ordovas JM (1998) Quantification of mRNA by polymerase chain reaction (PCR) using an internal standard and a nonradioactive detection method. Methods Mol Biol 110:43–61PubMed Karge WH III, Schaefer EJ, Ordovas JM (1998) Quantification of mRNA by polymerase chain reaction (PCR) using an internal standard and a nonradioactive detection method. Methods Mol Biol 110:43–61PubMed
go back to reference Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF, Sabel MS, Livant D, Weiss SJ, Rubin MA, Chinnaiyan AM (2003) EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA 100:11606–11611PubMedCrossRef Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF, Sabel MS, Livant D, Weiss SJ, Rubin MA, Chinnaiyan AM (2003) EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA 100:11606–11611PubMedCrossRef
go back to reference Matsukawa Y, Semba S, Kato H, Ito A, Yanagihara K, Yokozaki H (2006) Expression of the enhancer of zeste homolog 2 is correlated with poor prognosis in human gastric cancer. Cancer Sci 97:484–491PubMedCrossRef Matsukawa Y, Semba S, Kato H, Ito A, Yanagihara K, Yokozaki H (2006) Expression of the enhancer of zeste homolog 2 is correlated with poor prognosis in human gastric cancer. Cancer Sci 97:484–491PubMedCrossRef
go back to reference Olsson AY, Feber A, Edwards S, Te PR, Giddings I, Merson S, Cooper CS (2006) Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells. Oncogene 26(7):1028–1037PubMedCrossRef Olsson AY, Feber A, Edwards S, Te PR, Giddings I, Merson S, Cooper CS (2006) Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells. Oncogene 26(7):1028–1037PubMedCrossRef
go back to reference Raman JD, Mongan NP, Tickoo SK, Boorjian SA, Scherr DS, Gudas LJ (2005) Increased expression of the polycomb group gene, EZH2, in transitional cell carcinoma of the bladder. Clin Cancer Res 11:8570–8576PubMedCrossRef Raman JD, Mongan NP, Tickoo SK, Boorjian SA, Scherr DS, Gudas LJ (2005) Increased expression of the polycomb group gene, EZH2, in transitional cell carcinoma of the bladder. Clin Cancer Res 11:8570–8576PubMedCrossRef
go back to reference Schulz WA (2006) Understanding urothelial carcinoma through cancer pathways. Int J Cancer 119:1513–1518PubMedCrossRef Schulz WA (2006) Understanding urothelial carcinoma through cancer pathways. Int J Cancer 119:1513–1518PubMedCrossRef
go back to reference Slaton JW, Benedict WF, Dinney CP (2001) P53 in bladder cancer: mechanism of action, prognostic value, and target for therapy. Urology 57:852–859PubMedCrossRef Slaton JW, Benedict WF, Dinney CP (2001) P53 in bladder cancer: mechanism of action, prognostic value, and target for therapy. Urology 57:852–859PubMedCrossRef
go back to reference Sobin LH WC (2002) TNM classification of malignant tumors, 6th edn. Springer, Berlin Sobin LH WC (2002) TNM classification of malignant tumors, 6th edn. Springer, Berlin
go back to reference Tiguert R, Fradet Y (2002) New diagnostic and prognostic tools in bladder cancer. Curr Opin Urol 12:239–243PubMedCrossRef Tiguert R, Fradet Y (2002) New diagnostic and prognostic tools in bladder cancer. Curr Opin Urol 12:239–243PubMedCrossRef
go back to reference Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP, Rubin MA, Chinnaiyan AM (2002) The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419:624–629PubMedCrossRef Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP, Rubin MA, Chinnaiyan AM (2002) The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419:624–629PubMedCrossRef
go back to reference Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, de Launoit Y, Fuks F (2006) The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439:871–874PubMedCrossRef Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, de Launoit Y, Fuks F (2006) The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439:871–874PubMedCrossRef
go back to reference Weikert S, Christoph F, Kollermann J, Muller M, Schrader M, Miller K, Krause H (2005) Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas. Int J Mol Med 16:349–353PubMed Weikert S, Christoph F, Kollermann J, Muller M, Schrader M, Miller K, Krause H (2005) Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas. Int J Mol Med 16:349–353PubMed
go back to reference Zeidler M, Varambally S, Cao Q, Chinnaiyan AM, Ferguson DO, Merajver SD, Kleer CG (2005) The Polycomb group protein EZH2 impairs DNA repair in breast epithelial cells. Neoplasia 7:1011–1019PubMedCrossRef Zeidler M, Varambally S, Cao Q, Chinnaiyan AM, Ferguson DO, Merajver SD, Kleer CG (2005) The Polycomb group protein EZH2 impairs DNA repair in breast epithelial cells. Neoplasia 7:1011–1019PubMedCrossRef
Metadata
Title
Expression of the polycomb group protein EZH2 and its relation to outcome in patients with urothelial carcinoma of the bladder
Authors
Stefan Hinz
Carsten Kempkensteffen
Frank Christoph
Michèle Hoffmann
Hans Krause
Mark Schrader
Martin Schostak
Kurt Miller
Steffen Weikert
Publication date
01-03-2008
Publisher
Springer-Verlag
Published in
Journal of Cancer Research and Clinical Oncology / Issue 3/2008
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-007-0288-8

Other articles of this Issue 3/2008

Journal of Cancer Research and Clinical Oncology 3/2008 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine