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Open Access Research

Poorly differentiated synovial sarcoma is associated with high expression of enhancer of zeste homologue 2 (EZH2)

Yi-Che Changchien1, Péter Tátrai2, Gergő Papp1, Johanna Sápi3, László Fónyad1, Miklós Szendrői4, Zsuzsanna Pápai5 and Zoltán Sápi1*

Author Affiliations

1 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, H-1085, Hungary

2 Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary

3 Department of Control Engineering and Information Technology, Budapest University of Technology and Economics, Budapest, Hungary

4 Department of Orthopedics, Semmelweis University, Budapest, Hungary

5 Military Hospital-State Health Centre Department of Oncology, Budapest, Hungary

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Journal of Translational Medicine 2012, 10:216  doi:10.1186/1479-5876-10-216

Published: 30 October 2012

Abstract

Background

Enhancer of zeste homologue 2 (EZH2) is a polycomb group (PcG) family protein. Acting as a histone methyltransferase it plays crucial roles in maintaining epigenetic stem cell signature, while its deregulation leads to tumor development. EZH2 overexpression is commonly associated with poor prognosis in a variety of tumor types including carcinomas, lymphomas and soft tissue sarcomas. However, although the synovial sarcoma fusion proteins SYT-SSX1/2/4 are known to interact with PcG members, the diagnostic and prognostic significance of EZH2 expression in synovial sarcoma has not yet been investigated. Also, literature data are equivocal on the correlation between EZH2 expression and the abundance of trimethylated histone 3 lysine 27 (H3K27me3) motifs in tumors.

Methods

Immunohistochemical stains of EZH2, H3K27me3, and Ki-67 were performed on tissue microarrays containing cores from 6 poorly differentiated, 39 monophasic and 10 biphasic synovial sarcomas, and evaluated by pre-established scoring criteria. Results of the three immunostainings were compared, and differences were sought between the histological subtypes as well as patient groups defined by gender, age, tumor location, the presence of distant metastasis, and the type of fusion gene. The relationship between EZH2 expression and survival was plotted on a Kaplan-Meier curve.

Results

High expression of EZH2 mRNA and protein was specifically detected in the poorly differentiated subtype. EZH2 scores were found to correlate with those of Ki-67 and H3K27me3. Cases with high EZH2 score were characterized by larger tumor size (≥ 5cm), distant metastasis, and poor prognosis. Even in the monophasic and biphasic subtypes, higher expression of EZH2 was associated with higher proliferation rate, larger tumor size, and the risk of developing distant metastasis. In these histological groups, EZH2 was superior to Ki-67 in predicting metastatic disease.

Conclusions

High expression of EZH2 helps to distinguish poorly differentiated synovial sarcoma from the monophasic and biphasic subtypes, and it is associated with unfavorable clinical outcome. Importantly, high EZH2 expression is predictive of developing distant metastasis even in the better-differentiated subtypes. EZH2 overexpression in synovial sarcoma is correlated with high H3K27 trimethylation. Thus, along with other epigenetic regulators, EZH2 may be a future therapeutic target.

Keywords:
Synovial sarcoma; EZH2; Polycomb group; Histone methyltransferase; H3K27me3