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Sci Rep. 2018 Feb 22;8(1):3477. doi: 10.1038/s41598-018-21932-7.

Aberrant methylated key genes of methyl group metabolism within the molecular etiology of urothelial carcinogenesis.

Author information

1
Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany.
2
Department of Urology, University Hospital, University of Zurich, Zurich, Switzerland.
3
Department of Urology, Medical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany.
4
Urologische Klinik, Universitätsspital Basel, Basel, Switzerland.
5
Institute of Surgical Pathology, University Hospital, University of Zurich, 8091, Zurich, Switzerland.
6
Department of Pathology, Medical Faculty, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany.
7
Department of Surgery, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
8
Institut National de la Santé et de la Recherché Médicale, University of Strasbourg, 67000, Strasbourg, France.
9
Department of Urology, University Hospital, Positivo University, Curitiba, Brazil.
10
Group of Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, 20014, San Sebastián, Spain.
11
IKERBASQUE, Basque Foundation for Science, 48009, Bilbao, Spain.
12
Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany. simeon.santourlidis@med.uni-duesseldorf.de.

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.

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