Abstract
BackgroundThe 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).MethodsEZH2 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.ResultsDuring 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).ConclusionsThis study defines EZH2 as a powerful independent unfavourable prognostic marker of CSS in patients with metastatic and non-metastatic RCC.
Highlights
The enhancer of zeste homolog 2 (EZH2) gene exerts oncogene-like activities and itsexpression has been linked to several human malignancies
We recently found that inhibition of endogenous EZH2 expression in renal cell carcinoma (RCC) cell lines by RNA interference (RNAi) was linked to reduced proliferation and increased apoptosis in RCC [13] and cervical carcinoma cells [14]
The following clinical and pathological features were studied for their prognostic relevance on long term survival of RCC patients: Age (≥65 years vs. 25-50%, >50% vs. 0%)
Summary
The enhancer of zeste homolog 2 (EZH2) gene exerts oncogene-like activities and its (over)expression has been linked to several human malignancies. We studied a possible association between EZH2 expression and prognosis in patients with renal cell carcinoma (RCC). Renal cell carcinoma (RCC) is estimated to account for more than 57000 new cases and 13000 cancer-related deaths in the United States in 2009, making it the second most lethal of all urological cancers [1]. Inhibition of EZH2 expression by antisense constructs or RNA interference (RNAi) resulted in growth inhibition of cancer cells [9,10], and induced anoikis in circulating prostate carcinoma precursor cells [11] or apoptotic cell death in breast cancer cells [12]. We recently found that inhibition of endogenous EZH2 expression in RCC cell lines by RNAi was linked to reduced proliferation and increased apoptosis in RCC [13] and cervical carcinoma cells [14]
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