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What's known on the subject? and What does the study add?Epigenetic alterations are important during carcinogenesis, and earlier studies suggested that global histone modification levels are predictive for patients' outcome in various tumor entities.We demonstrate that H3K27me1 and H3K27me3 are markers of progression-free survival in patients with renal cell carcinoma.To evaluate if histone H3 lysine 27 (H3K27) methylation plays a role in renal cell carcinoma (RCC) tissue and whether its expression is a predictor of cancer recurrence in RCC.A tissue microarray (TMA) with 193 RCC specimens (comprising 142 clear-cell, 31 papillary, 10 chromophobe and 10 sarcomatoid RCC), 10 oncocytoma tissue specimens and a TMA with 30 benign renal tissue samples were stained with antibodies against H3K27-monomethyl (H3K27me1), H3K27-dimethyl (H3K27me2) and H3K27-trimethyl (H3K27me3).Sections were scored according to staining intensity and the proportion of epithelial cells showing nuclear staining.H3K27 methylation levels were correlated with established clinical-pathological variables (tumour-node-metastasis [TNM] stage, Fuhrman grade) and progression-free/cancer-specific survival.H3K27me1/-me2/-me3 staining was significantly more intense in papillary RCC then in clear-cell RCC.H3K27me3 levels were higher in oncocytoma than in RCC.H3K27me1/-me2/-me3 methylation levels were inversely correlated with Fuhrman grading and pT-stage.Global H3K27me1/-me2/-me3 methylation levels were always higher in benign renal tissue than in RCC with tumour relapse (H3K27me1 P < 0.001, H3K27me2 P= 0.032, H3K27me3 P= 0.004).Progression-free survival was shorter in patients with lower levels of H3K27me1 and H3K27me3 in the univariate analysis. The newly created H3K27me score (combining the staining levels of the single modifications) was a significant and independent predictor of RCC progression-free survival.The present study on H3K27-methylation supports the hypothesis that global histone modifications are potential markers of cancer prognosis in RCC. One reason could be that decreased H3K27 indicates transcriptional activation and therefore predicts cancer activation.