Abstract
Urothelial carcinoma (UC), the most common cancer of the urinary bladder causes severe morbidity and mortality, e.g. about 40.000 deaths in the EU annually, and incurs considerable costs for the health system due to the need for prolonged treatments and long-term monitoring. Extensive aberrant DNA methylation is described to prevail in urothelial carcinoma and is thought to contribute to genetic instability, altered gene expression and tumor progression. However, it is unknown how this epigenetic alteration arises during carcinogenesis. Intact methyl group metabolism is required to ensure maintenance of cell-type specific methylomes and thereby genetic integrity and proper cellular function. Here, using two independent techniques for detecting DNA methylation, we observed DNA hypermethylation of the 5′-regulatory regions of the key methyl group metabolism genes ODC1, AHCY and MTHFR in early urothelial carcinoma. These hypermethylation events are associated with genome-wide DNA hypomethylation which is commonly associated with genetic instability. We therefore infer that hypermethylation of methyl group metabolism genes acts in a feed-forward cycle to promote additional DNA methylation changes and suggest a new hypothesis on the molecular etiology of urothelial carcinoma.
Highlights
Urothelial carcinoma (UC), the most common cancer of the urinary bladder causes severe morbidity and mortality, e.g. about 40.000 deaths in the EU annually, and incurs considerable costs for the health system due to the need for prolonged treatments and long-term monitoring
There is evidence that tumor adjacent uroepithelium, it might pathologically be reviewed to consist of healthy uroepithelial cells, is already in a premalignant state which is characterized by genetic, e.g. TP53 mutant cells[4], and widespread epigenetic alterations, e.g. hypermethylated genes which are present in bladder cancer cells[19]
Genome-wide DNA methylation data sets were generated from pathologically classified UC, tumor-adjacent normal-appearing and healthy urothelial tissue samples by Methylated DNA Immunoprecipitation (MeDIP) and promoter array analyses
Summary
Urothelial carcinoma (UC), the most common cancer of the urinary bladder causes severe morbidity and mortality, e.g. about 40.000 deaths in the EU annually, and incurs considerable costs for the health system due to the need for prolonged treatments and long-term monitoring. Extensive aberrant DNA methylation is described to prevail in urothelial carcinoma and is thought to contribute to genetic instability, altered gene expression and tumor progression. It is unknown how this epigenetic alteration arises during carcinogenesis. It is thought that a “field defect” underlies both high relapse rates and multifocality According to this hypothesis, urothelial cells in regions adjacent to the tumors are already primed to undergo transformation because their genetic integrity has been already disturbed by environmental mutagens[4]. It may contribute to carcinogenesis in various ways, including induction of genomic instability[10] and aberrant transcription patterns[11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
