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BMC Cancer
Published in: BMC Cancer 1/2010

Open Access 01-12-2010 | Research article

Enhancer of zeste homolog 2 (EZH2) expression is an independent prognostic factor in renal cell carcinoma

Authors: Nina Wagener, Stephan Macher-Goeppinger, Maria Pritsch, Johannes Hüsing, Karin Hoppe-Seyler, Peter Schirmacher, Jesco Pfitzenmaier, Axel Haferkamp, Felix Hoppe-Seyler, Markus Hohenfellner

Published in: BMC Cancer | Issue 1/2010

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Abstract

Background

The enhancer of zeste homolog 2 (EZH2) gene exerts oncogene-like activities and its (over)expression has been linked to several human malignancies. Here, we studied a possible association between EZH2 expression and prognosis in patients with renal cell carcinoma (RCC).

Methods

EZH2 protein expression in RCC specimens was analyzed by immunohistochemistry using a tissue microarray (TMA) containing RCC tumor tissue and corresponding normal tissue samples of 520 patients. For immunohistochemical assessment of EZH2 expression, nuclear staining quantity was evaluated using a semiquantitative score. The effect of EZH2 expression on cancer specific survival (CSS) was assessed by univariate and multivariate Cox regression analyses.

Results

During follow-up, 147 patients (28%) had died of their disease, median follow-up of patients still alive was 6.0 years (range 0-16.1 years). EZH2 nuclear staining was present in tumor cores of 411 (79%) patients. A multivariate Cox regression analysis revealed that high nuclear EZH2 expression was an independent predictor of poor CSS (> 25-50% vs. 0%: HR 2.72, p = 0.025) in patients suffering from non-metastatic RCC. Apart from high nuclear EZH2 expression, tumor stage and Fuhrman's grading emerged as significant prognostic markers. In metastatic disease, nuclear EZH2 expression and histopathological subtype were independent predictive parameters of poor CSS (EZH2: 1-5%: HR 2.63, p = 0.043, >5-25%: HR 3.35, p = 0.013, >25%-50%: HR 4.92, p = 0.003, all compared to 0%: HR 0.36, p = 0.025, respectively).

Conclusions

This study defines EZH2 as a powerful independent unfavourable prognostic marker of CSS in patients with metastatic and non-metastatic RCC.
Appendix
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Literature
1.
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 2009, 59 (4): 225-249. 10.3322/caac.20006.CrossRefPubMed
2.
Baldewijns MM, van Vlodrop IJ, Schouten LJ, Soetekouw PM, de Bruine AP, van Engeland M: Genetics and epigenetics of renal cell cancer. Biochim Biophys Acta. 2008, 1785 (2): 133-155.PubMed
3.
Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y: Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002, 298 (5595): 1039-1043. 10.1126/science.1076997.CrossRefPubMed
4.
Czermin B, Melfi R, McCabe D, Seitz V, Imhof A, Pirrotta V: Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell. 2002, 111 (2): 185-196. 10.1016/S0092-8674(02)00975-3.CrossRefPubMed
5.
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: The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006, 439 (7078): 871-874. 10.1038/nature04431.CrossRefPubMed
6.
Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K: EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. Embo J. 2003, 22 (20): 5323-5335. 10.1093/emboj/cdg542.CrossRefPubMedPubMedCentral
7.
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: EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA. 2003, 100 (20): 11606-11611. 10.1073/pnas.1933744100.CrossRefPubMedPubMedCentral
8.
Croonquist PA, Van Ness B: The polycomb group protein enhancer of zeste homolog 2 (EZH 2) is an oncogene that influences myeloma cell growth and the mutant ras phenotype. Oncogene. 2005, 24 (41): 6269-6280. 10.1038/sj.onc.1208771.CrossRefPubMed
9.
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: The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002, 419 (6907): 624-629. 10.1038/nature01075.CrossRefPubMed
10.
Tang X, Milyavsky M, Shats I, Erez N, Goldfinger N, Rotter V: Activated p53 suppresses the histone methyltransferase EZH2 gene. Oncogene. 2004, 23 (34): 5759-5769. 10.1038/sj.onc.1207706.CrossRefPubMed
11.
Berezovska OP, Glinskii AB, Yang Z, Li XM, Hoffman RM, Glinsky GV: Essential role for activation of the Polycomb group (PcG) protein chromatin silencing pathway in metastatic prostate cancer. Cell Cycle. 2006, 5 (16): 1886-1901.CrossRefPubMed
12.
Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, Karuturi RK, Tan PB, Liu ET, Yu Q: Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 2007, 21 (9): 1050-1063. 10.1101/gad.1524107.CrossRefPubMedPubMedCentral
13.
Wagener N, Holland D, Bulkescher J, Crnkovic-Mertens I, Hoppe-Seyler K, Zentgraf H, Pritsch M, Buse S, Pfitzenmaier J, Haferkamp A, Hohenfellner M, Hoppe-Seyler F: The enhancer of zeste homolog 2 gene contributes to cell proliferation and apoptosis resistance in renal cell carcinoma cells. Int J Cancer. 2008, 123 (7): 1545-1550. 10.1002/ijc.23683.CrossRefPubMed
14.
Holland D, Hoppe-Seyler K, Schuller B, Lohrey C, Maroldt J, Durst M, Hoppe-Seyler F: Activation of the enhancer of zeste homologue 2 gene by the human papillomavirus E7 oncoprotein. Cancer Res. 2008, 68 (23): 9964-9972. 10.1158/0008-5472.CAN-08-1134.CrossRefPubMed
15.
Ding L, Erdmann C, Chinnaiyan AM, Merajver SD, Kleer CG: Identification of EZH2 as a molecular marker for a precancerous state in morphologically normal breast tissues. Cancer Res. 2006, 66 (8): 4095-4099. 10.1158/0008-5472.CAN-05-4300.CrossRefPubMed
16.
Ding L, Kleer CG: Enhancer of zeste 2 as a marker of preneoplastic progression in the breast. Cancer Res. 2006, 66 (19): 9352-9355. 10.1158/0008-5472.CAN-06-2384.CrossRefPubMed
17.
Bachmann IM, Halvorsen OJ, Collett K, Stefansson IM, Straume O, Haukaas SA, Salvesen HB, Otte AP, Akslen LA: 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. 2006, 24 (2): 268-273. 10.1200/JCO.2005.01.5180.CrossRefPubMed
18.
Motzer RJ, Bacik J, Schwartz LH, Reuter V, Russo P, Marion S, Mazumdar M: Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol. 2004, 22 (3): 454-463. 10.1200/JCO.2004.06.132.CrossRefPubMed
19.
Macher-Goeppinger S, Aulmann S, Wagener N, Funke B, Tagscherer KE, Haferkamp A, Hohenfellner M, Kim S, Autschbach F, Schirmacher P, Roth W: Decoy receptor 3 is a prognostic factor in renal cell cancer. Neoplasia. 2008, 10 (10): 1049-1056.CrossRefPubMedPubMedCentral
20.
Dukers DF, van Galen JC, Giroth C, Jansen P, Sewalt RG, Otte AP, Kluin-Nelemans HC, Meijer CJ, Raaphorst FM: Unique polycomb gene expression pattern in Hodgkin's lymphoma and Hodgkin's lymphoma-derived cell lines. Am J Pathol. 2004, 164 (3): 873-881.CrossRefPubMedPubMedCentral
21.
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM: REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat. 2006, 100 (2): 229-235. 10.1007/s10549-006-9242-8.CrossRefPubMed
22.
Goenen M, Heller G: Concordance probability and discriminatory power in proportional hazards regression. Biometrika. 2005, 92 (4): 965-970. 10.1093/biomet/92.4.965.CrossRef
23.
Cohen HT, McGovern FJ: Renal-cell carcinoma. N Engl J Med. 2005, 353 (23): 2477-2490. 10.1056/NEJMra043172.CrossRefPubMed
24.
Chow WH, Devesa SS, Warren JL, Fraumeni JF: Rising incidence of renal cell cancer in the United States. Jama. 1999, 281 (17): 1628-1631. 10.1001/jama.281.17.1628.CrossRefPubMed
25.
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007, 356 (2): 125-134. 10.1056/NEJMoa060655.CrossRefPubMed
26.
Fisher RI, Rosenberg SA, Fyfe G: Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am. 2000, 6 (Suppl 1): 55-57.
27.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007, 356 (2): 115-124. 10.1056/NEJMoa065044.CrossRefPubMed
28.
Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N: Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007, 370 (9605): 2103-2111. 10.1016/S0140-6736(07)61904-7.CrossRefPubMed
29.
Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A: Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008, 372 (9637): 449-456. 10.1016/S0140-6736(08)61039-9.CrossRefPubMed
30.
Eichelberg C, Junker K, Ljungberg B, Moch H: Diagnostic and Prognostic Molecular Markers for Renal Cell Carcinoma: A Critical Appraisal of the Current State of Research and Clinical Applicability. Eur Urol. 2009, 55 (4): 851-863. 10.1016/j.eururo.2009.01.003.CrossRefPubMed
31.
McShane LM, Altman DG, Sauerbrei W: Identification of clinically useful cancer prognostic factors: what are we missing?. J Natl Cancer Inst. 2005, 97 (14): 1023-1025. 10.1093/jnci/dji193.CrossRefPubMed
32.
Zisman A, Pantuck AJ, Wieder J, Chao DH, Dorey F, Said JW, deKernion JB, Figlin RA, Belldegrun AS: Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol. 2002, 20 (23): 4559-4566. 10.1200/JCO.2002.05.111.CrossRefPubMed
33.
Kim HL, Seligson D, Liu X, Janzen N, Bui MH, Yu H, Shi T, Belldegrun AS, Horvath S, Figlin RA: Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma. J Urol. 2005, 173 (5): 1496-1501. 10.1097/01.ju.0000154351.37249.f0.CrossRefPubMed
34.
Kim HL, Seligson D, Liu X, Janzen N, Bui MH, Yu H, Shi T, Figlin RA, Horvath S, Belldegrun AS: Using protein expressions to predict survival in clear cell renal carcinoma. Clin Cancer Res. 2004, 10 (16): 5464-5471. 10.1158/1078-0432.CCR-04-0488.CrossRefPubMed
35.
Hinz S, Weikert S, Magheli A, Hoffmann M, Engers R, Miller K, Kempkensteffen C: Expression profile of the Polycomb group protein Enhancer of zeste homologue 2 and its prognostic relevance in renal cell carcinoma. J Urol. 2009, 182 (6): 2920-2925. 10.1016/j.juro.2009.08.014.CrossRefPubMed
36.
Matsukawa Y, Semba S, Kato H, Ito A, Yanagihara K, Yokozaki H: Expression of the enhancer of zeste homolog 2 is correlated with poor prognosis in human gastric cancer. Cancer Sci. 2006, 97 (6): 484-491. 10.1111/j.1349-7006.2006.00203.x.CrossRefPubMed
37.
Sudo T, Utsunomiya T, Mimori K, Nagahara H, Ogawa K, Inoue H, Wakiyama S, Fujita H, Shirouzu K, Mori M: Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma. Br J Cancer. 2005, 92 (9): 1754-1758. 10.1038/sj.bjc.6602531.CrossRefPubMedPubMedCentral
38.
Pietersen AM, Horlings HM, Hauptmann M, Langerod A, Ajouaou A, Cornelissen-Steijger P, Wessels LF, Jonkers J, van de Vijver MJ, van Lohuizen M: EZH2 and BMI1 inversely correlate with prognosis and TP53 mutation in breast cancer. Breast Cancer Res. 2008, 10 (6): R109-10.1186/bcr2214.CrossRefPubMedPubMedCentral
39.
Metsuyanim S, Pode-Shakked N, Schmidt-Ott KM, Keshet G, Rechavi G, Blumental D, Dekel B: Accumulation of malignant renal stem cells is associated with epigenetic changes in normal renal progenitor genes. Stem Cells. 2008, 26 (7): 1808-1817. 10.1634/stemcells.2007-0322.CrossRefPubMed
40.
Yu J, Yu J, Rhodes DR, Tomlins SA, Cao X, Chen G, Mehra R, Wang X, Ghosh D, Shah RB, Varambally S, Pienta KJ, Chinnaiyan AM: A polycomb repression signature in metastatic prostate cancer predicts cancer outcome. Cancer Res. 2007, 67 (22): 10657-10663. 10.1158/0008-5472.CAN-07-2498.CrossRefPubMed
Metadata
Title
Enhancer of zeste homolog 2 (EZH2) expression is an independent prognostic factor in renal cell carcinoma
Authors
Nina Wagener
Stephan Macher-Goeppinger
Maria Pritsch
Johannes Hüsing
Karin Hoppe-Seyler
Peter Schirmacher
Jesco Pfitzenmaier
Axel Haferkamp
Felix Hoppe-Seyler
Markus Hohenfellner
Publication date
01-12-2010
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2010
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-10-524

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