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 found in human cancers and also has been identified in clear cell renal carcinoma (RCC). Their role in RCC progression, however, is still unclear. By contrast, the prognostic significance of ploidy and S-phase fraction (SPF) have been studied extensively in RCC. To better characterize the biologic role 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 in 296 specimens, selected by multiple sampling of 33 consecutive operable RCCs. The expression of p53 and bcl-2 proteins was studied by immunohistochemistry, 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 stage tumor (P = 0.03). Intratumor heterogeneity also was detected for p53 and 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 normal DNA content (P < 0.0001) and low SPF (P = 0.035). CONCLUSIONS Within each RCC, p53 and bcl-2 expression is markedly heterogeneous. Our results depicted a scenario in which bcl-2 protein, expressed by normal renal parenchyma, is still present in euploid cell clones of RCC but disappears during the progression of renal neoplasm toward a more aggressive phenotype characterized by overexpression of p53 protein, aneuploidy, and high SPF
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