A DNA adductome analysis revealed a reduction in the global level of C5-hydroxymethyl-2'-deoxycytidine in the non-tumoral upper urinary tract mucosa of urothelial carcinoma patients.
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引用次数: 3
Abstract
Background: DNA adducts, covalent modifications to DNA due to exposure to specific carcinogens, cause the mispairing of DNA bases, which ultimately results in DNA mutations. DNA methylation in the promoter region, another type of DNA base modification, alters the DNA transcription process, and has been implicated in carcinogenesis in humans due to the down-regulation of tumor suppressor genes. Difficulties are associated with demonstrating the existence of DNA adducts or chemically modified bases in the human urological system. Apart from aristolochic acid-DNA adducts, which cause urothelial carcinoma and endemic nephropathy in a particular geographical area (Balkan), limited information is currently available on DNA adduct profiles in renal cell carcinoma and upper urinary tract urothelial carcinoma, including renal pelvic cancer and ureteral cancer.
Method: To elucidate the significance of DNA adducts in carcinogenesis in the urothelial system, we investigated 53 DNA adducts in the non-tumoral renal parenchyma and non-tumoral renal pelvis of patients with renal cell carcinoma, upper urinary tract urothelial carcinoma, and other diseases using liquid chromatography coupled with tandem mass spectrometry. A comparative analysis of tissue types, the status of malignancy, and clinical characteristics, including lifestyle factors, was performed.
Results: C5-Methyl-2'-deoxycytidine, C5-hydroxymethyl-2'-deoxycytidine (5hmdC), C5-formyl-2'-deoxycytidine, 2'-deoxyinosine, C8-oxo-2'-deoxyadenosine, and C8-oxo-2'-deoxyguanosine (8-OHdG) were detected in the renal parenchyma and renal pelvis. 8-OHdG was more frequently detected in the renal pelvis than in the renal cortex and medulla (p = 0.048 and p = 0.038, respectively). 5hmdC levels were significantly lower in the renal pelvis of urothelial carcinoma patients (n = 10) than in the urothelium of patients without urothelial carcinoma (n = 15) (p = 0.010). Regarding 5hmdC levels in the renal cortex and medulla, Spearman's rank correlation test revealed a negative correlation between age and 5hmdC levels (r = - 0.46, p = 0.018 and r = - 0.45, p = 0.042, respectively).
Conclusions: The present results revealed a reduction of 5hmdC levels in the non-tumoral urinary tract mucosa of patients with upper urinary tract urothelial carcinoma. Therefore, the urothelial cell epithelia of patients with upper urinary tract cancer, even in non-cancerous areas, may be predisposed to urothelial cancer.
期刊介绍：
Genes and Environment is an open access, peer-reviewed journal that aims to accelerate communications among global scientists working in the field of genes and environment. The journal publishes articles across a broad range of topics including environmental mutagenesis and carcinogenesis, environmental genomics and epigenetics, molecular epidemiology, genetic toxicology and regulatory sciences.
Topics published in the journal include, but are not limited to, mutagenesis and anti-mutagenesis in bacteria; genotoxicity in mammalian somatic cells; genotoxicity in germ cells; replication and repair; DNA damage; metabolic activation and inactivation; water and air pollution; ROS, NO and photoactivation; pharmaceuticals and anticancer agents; radiation; endocrine disrupters; indirect mutagenesis; threshold; new techniques for environmental mutagenesis studies; DNA methylation (enzymatic); structure activity relationship; chemoprevention of cancer; regulatory science. Genetic toxicology including risk evaluation for human health, validation studies on testing methods and subjects of guidelines for regulation of chemicals are also within its scope.
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