p16INK4Aand p15INK4BGene Alteration Associated with Oxidative Stress in Renal Cell Carcinomas After the Chernobyl Accident (Pilot Study)

Our study was undertaken to better understand the role of G1/S transition abnormalities in the malignant progression of renal cell carcinomas (RCCs), exposed to long-term low doses of ionizing radiation (IR), from patients living in radiocontaminated areas of the Ukraine after the Chernobyl accident. We studied p16INK4Aand p15INK4Bgene alteration in association with oxidative stress markers, including inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2). We analyzed 88 samples collected from 22 patients with RCCs and with different exposure to IR. Homozygous deletion of the p16INK4Aand p15INK4Bgenes, as well as hypermethylation of the 5CpG island in the promoter region of the same genes, were analyzed by differential PCR and Methylation-Specific PCR respectively, in association with histopathology and immunohistochemical analysis of p16INK4Aand p15INK4Bproteins. COX2 and iNOS expression in the same tumors were likewise analyzed. Aberrant hypermethylation was observed in 7 (32) and 5 (23) cases accompanied, by immunohistochemical loss of expression for p16INK4Aand p15INK4Bgenes respectively, in both high stage and grade tumors from patients living in radiocontaminated areas, this being especially outstanding for the p16INK4Agene. An association with COX2 and less iNOS overexpression in the same tumors was observed. Our data suggest that inactivation of p16INK4Agene, but not p15INK4B, induced by increased oxidative stress generated by persistent chronic exposure to IR, could be one of the major pathways responsible for RCCs malignant progression.