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Study Type - Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Epigenetic alterations play an essential role during carcinogenesis. While DNA methylation has been extensively studied in bladder cancer, the relevance of histone modifications remains to be clarified. Earlier studies suggested that global histone modification levels are predictive for patients' outcome in various tumour entities (e.g. prostate, lung, breast and kidney cancer). The possibility to determine global histone modification levels easily and inexpensively using immunohistochemistry increases a potential routine use in the future. Our aim was therefore to investigate the global levels of histone H3K4 and H4K20 mono-, di- and trimethylation. For this purpose we prepared tissue microarrays with non-muscle-invasive bladder cancer (NMIBC), muscle-invasive bladder cancer (MIBC), bladder cancer metastases (METS) and normal urothelium (NU) tissue to compare global H3K4 and H4K20 methylation in these tissues, as well to assess the prognostic value of histone modifications. We show that global histone modification levels (H3K4me1, H3K4me3, H4K20me1, H4K20me2, H4K20me3) are lower in bladder cancer than in NU tissue. Furthermore, there was a decrease of histone modification levels (H3K4me1, H4K20me1, H4K20me2, H4K20me3) from NU over NMIBC and MIBCto METS. Histone modifications are correlated to advanced pathological stage in NMIBC and MIBC. Furthermore, H4K20me3 appeared to be a significant and independent prognostic predictor of bladder cancer-specific survival in patients with MIBC undergoing radical cystectomy. Our findings therefore provide a rationale for further investigation of histone modifications and their manipulation in bladder cancer. OBJECTIVE • To determine the role of global histone methylation as a prognostic parameter in patients with bladder cancer. PATIENTS AND METHODS • We used a tissue microarray with samples from patients with non-muscle-invasive bladder cancer (NMIBC; n= 161), muscle-invasive bladder cancer (MIBC, n= 127), normal urothelium (NU; n= 31) and bladder cancer metastases (METS; n= 31) to determine global histone methylation (me) levels at histone H3 lysine 4 (H3K4) and H4K20. RESULTS • Global histone modification levels (H3K4me1, H3K4me3, H4K20me1, H4K20me2, and H4K20me3) were lower in bladder cancersamples than in NU tissue • Global levels of H3K4me1, H4K20me1, H4K20me2 and H4K20me3 were decreasing from NU over NMIBC and MIBC to METS. • H4K20me1 levels were increased in patients with NMIBC with advanced pTstage and less differentiated bladder cancer. • In patients with MIBC, pTstage was negatively correlated with H3K4me1, H4K20me1 and H4K20me2 levels. • H4K20me3 levels were significantly correlated in a univariate and multivariate model with bladder cancer-specific mortality after radical cystectomy in patients with MIBC. CONCLUSION • Global histone methylation levels may help to identify patients with bladder cancerwith poor prognosis after radical cystectomy. [ABSTRACT FROM AUTHOR]