Molecular Markers in Upper Urothelial Carcinoma Associated to Balkan Endemic Nephropathy. Aristolochic Acid as the Major Risk Factor of the Worldwide Disease

Ljubinka Jankovic Velickovic,Vladisav Stefanovic,Takanori Hattori

doi:10.1100/tsw.2009.162

Ljubinka Jankovic Velickovic, Vladisav Stefanovic + Show 1 more

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https://doi.org/10.1100/tsw.2009.162

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Abstract

The role of aristolochic acid in the etiology of Balkan endemic nephropathy (BEN) and associated upper urothelial carcinoma (UUC) was recently confirmed. The aim of this study was to determine the marker(s) specific for BEN-associated UUC. A total of 82 patients with UUC (38 from the BEN region and 44 control tumors) were included in the study. The Ki-67 index in BEN tumors correlated with the grade and multifocality (p < 0.05), but in regression analysis, only the grade of BEN tumor. The p53 index was significantly higher in BEN than in control tumors (p < 0.05), as well as the alteration of p53 (p < 0.05). BEN low-stage tumors, tumors without limphovascular invasion (LVI), and tumors of the renal pelvis had a higher p53 index than the control tumors (p < 0.05, 0.01, 0.05, respectively). The Ki-67 index was higher in control tumors with high-stage and solid growth than in BEN UUC (p < 0.050, 0.005). The Ki-67 correlated with the grade, growth, stage, LVI, and multifocality of UUC on the best way, but not with the group. In regression analysis, only multifocality of UUC had predictive influence on Ki-67 activity (p < 0.001). P53 correlated with the grade, growth, and group (p < 0.05). This investigation identifies the p53 pathway as the specific cell cycle marker involved in BEN-associated UUC.

Highlights

Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease prevalent in Bosnia and Herzegovina, Bulgaria, Croatia, Romania, and Serbia
The aims of this study were to evaluate the relationship between phenotypic characteristics and molecular markers, p53, p16, cyclin D1, HER-2, and proliferative Ki-67 activity in specimens of upper urothelial carcinomas (UUC) in the BEN region; to correlate expression of these molecular markers in UUC in the BEN region and control population; and to determine the marker(s) that is the specific indicator of BEN
P53 levels in a cell are low because the protein is rapidly degraded by its inhibitor, MDM2 protein. p53 may be knocked out by deletion, by mutation, or by the action of inhibitor MDM2

Summary

Introduction

Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease prevalent in Bosnia and Herzegovina, Bulgaria, Croatia, Romania, and Serbia. In addition to renal disease, an increased number of upper urothelial carcinomas (UUC) has been observed in the foci of BEN. Urothelial malignancies of the renal pelvis and ureter are significantly more frequent, up to 100 times, in endemic than in nonendemic areas. They tend to cluster in families affected with BEN, indicating an association between these diseases and, probably, a common etiologic. Jankovic Velickovic et al.: Molecular Markers in Upper Urothelial Carcinoma. Tumors develop usually later than the interstitial nephropathy. Their incidence increases with age at the time of diagnosis and with a longer survival, and is higher in females

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