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

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.

Screening DNA Damage in the Rat Kidney and Liver by Untargeted DNA Adductomics

“…However, the levels of these oxidative adducts were not significantly different between medulla-RCC and non-RCC patients or between pelvis-UTUC and pelvis-non-UTUC groups. 26 In the same study, investigators reported a reduction in the global level of 5-hydroxymethyl-2′-deoxycytidine in the nontumoral urinary tract mucosa of urothelial carcinoma patients, which may impact epigenetic events in renal cancer development.…”

LC-MS based urine untargeted metabolomic analyses to identify and subdivide urothelial cancer

“…Wang et al reported that deoxyinosine could be the biomarker to differentiate bladder cancer and kidney cancer patients from healthy people (24). Additionally, the deoxyinosine analog, C5hydroxymethyl-2′-deoxycytidine (5hmdC), is considerably decreased in the renal pelvis of UC patients (25).…”

Aristolochic acid I induces proximal tubule injury through ROS/HMGB1/mt DNA mediated activation of TLRs

“…The incidence of AA‐induced nephropathy (AAN) is not limited to any specific geographic region and cases occur regularly throughout the world, despite warnings from many health agencies. Kidney injury and fibrosis are predictable features of AAN, such that it is now used as a kidney injury/fibrosis model in vitro and in vivo studies 11–13 . Although studies have provided considerable insights into mechanisms of AA‐induced nephropathy, the pathophysiology of AAN remains incompletely understood 14–19 …”

“…Kidney injury and fibrosis are predictable features of AAN, such that it is now used as a kidney injury/fibrosis model in vitro and in vivo studies. 11 , 12 , 13 Although studies have provided considerable insights into mechanisms of AA‐induced nephropathy, the pathophysiology of AAN remains incompletely understood. 14 , 15 , 16 , 17 , 18 , 19 …”

“…Kidney injury and fibrosis are predictable features of AAN, such that it is now used as a kidney injury/ fibrosis model in vitro and in vivo studies. [11][12][13] Although studies have provided considerable insights into mechanisms of AA-induced nephropathy, the pathophysiology of AAN remains incompletely understood. [14][15][16][17][18][19] The toll-like receptors (TLRs) are pattern recognition receptors (PRRs) that have a unique and essential function in innate immunity.…”