Nuclear DNA content-derived parameters correlated with heterogeneous expression of p53 and bcl-2 proteins in clear cell renal carcinomas

BACKGROUND, p53 and bcl-2 are two key genes involved in cell cycle and cell death regulation. Altered expression or mutation of these genes has been f ound in human cancers and also has been identified in clear cell renal carc inoma (RCC). Their role in RCC progression, however, is still unclear. By c ontrast, the prognostic significance of ploidy and S-phase fraction (SPF) h ave been studied extensively in RCC. To better characterize the biologic ro le of p53 and bcl-2 oncoproteins in RCC, we offer a multisample correlative analysis of the expression of these two proteins with ploidy and SPF. METHODS, Ploidy and SPF along with p53 and bcl-2 expression were analyzed i n 296 specimens, selected by multiple sampling of 33 consecutive operable R CCs. The expression of p53 and bcl-2 proteins was studied by immunohistoche mistry, and SPF and tumor ploidy were studied by flow cytometry. RESULTS. In our study, 4 of 32 (12.5%) were found to be diploid, and 28 of 32 (87.5%) cases showed an abnormal DNA content. Among the aneuploid tumors , 14 of 28 (50%) were multiploid. Heterogeneous DNA content was detected in 21 of 32 (65.6%) tumors and was correlated with the more advanced Robson s tage tumor (P = 0.03). Intratumor heterogeneity also was detected for p53 a nd bcl-2 protein expression. Expression of p53 protein correlated with the lack of bcl-2 protein expression (P = 0.0032), aneuploidy (P < 0.0001), and high SPF (P = 0.0006), whereas bcl-2 expression was associated with a norm al DNA content (P < 0.0001) and low SPF (P = 0.035). CONCLUSIONS. Within each RCC, p53 and bcl-2 expression is markedly heteroge neous. Our results depicted a scenario in which bcl-2 protein, expressed by normal renal parenchyma, is still present in euploid cell clones of RCC bu t disappears during the progression of renal neoplasm toward a more aggress ive phenotype characterized by overexpression of p53 protein, aneuploidy, a nd high SPF. (C) 2000 American Cancer Society.