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.