Prognostic value of p53, c-ErbB2 and tunel data in upper urothelial carcinoma associated with Balkan nephropathy

Abstract

A characteristic tumor suppressor protein 53 (p53) mutational profile of genotoxic action of aristolochic acid was identified in the upper urothelial carcinoma (UUTT) associated with Balkan nephropathy (BEN). In the present study, we examined the prognostic value of tissue-based molecular markers in overall-survival (OS) risk after surgical treatment of UUTT, adjusted for gender, age and urological characteristics in 32 patients with BEN. Immunohistochemical examination of p53, the proliferation cell nuclear antigen (PCNA), the human epidermal growth factor receptor 2 (c-ErbB2; also known as HER-2/neu) proto-oncogene and the in situ terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay for apoptosis detection were used to examine serial tumor sections. The median OS-time was 60 months for UUTT operation; the mortality rate (18.7%) was related to (new) disease (re)occurrence or invasion in 12-216 months. High-grade (p=0.029), TUNEL>0.36%+ cells (p=0.010), and c-ErbB2+ cells (p=0.014) can define the risk of tumor invasion. Patients with Balkan nephropathy that develop UUTT at a stage greater than pT1 (with apoptosis TUNEL+ cells >0.36% and p53+ cells greater than 10%) were at high risk of poor-OS after the tumor surgery (h(x)=6.35; p=0.045). The obtained data present evidence for p53, cErbB2 and apoptosis deregulation, as a result of environmental toxin action. This is the first report of molecular biomarker linkage with OS for BEN-associated UUTT.