Expression of cyclins A and D and p21(waf1/cip1) proteins in renal cell cancer and their relation to clinicopathological variables and patient survival

Abstract

SummaryWe have studied 118 renal cell carcinomas to analyse the expressions of cyclins A and D1 and p21 (waf1/cip1) , and their relationship to clinical and histopathological parameters as well as to clinical outcome. Cyclins A and D1 and cyclin-dependent kinase inhibitor p21 (waf1/cip1) were not expressed in normal renal tissue. Staining signals of cyclin D1 and p21 (waf1/cip1) were always nuclear but cyclin A was also expressed in the cytoplasm of the tumour cells. The mean (range) fractions of cyclin A, cyclin D1 and p21 (waf1/cip1) -positive tumour cells were 2.2% (range 0-20%), 23.3% (range 0-90%) and 6.8% (range 0-70%) respectively. The expression of cyclin A was related to venous invasion, high nuclear grade, high mitotic rate, high Ki-67 and high PCNA expressions (P ≤ 0.006 for all). The expression of cyclin D1 was linked with age over 65 years, low nuclear grade and high p53 expression (P ≤ 0.05 for all). An inverse correlation was present between p21 (waf1/cip1) and cyclin D1 (P = 0.011). Cyclin A predicted survival in the entire study group (P = 0.0014), in T1-4/N0-2/M0 (P = 0.0007) and in T1-2/N0/M0 tumours (P = 0.0007). Cyclin A was also a powerful predictor of disease-free survival in T1-4/N0/M0 (P = 0.0027) tumours (P = 0.0007). Cyclin D1 and p21 (waf1/cip1) were not significantly related to survival or disease-free survival in any of the groups. In the entire material the independent prognostic factors were the presence of distant metastases (relative risk (RR) 5.16, P < 0.001), T category (RR 2.68, P < 0.001), Ki-67 expression (RR 1.02, P = 0.026) and cyclin A expression (RR 1.12, P = 0.001). The independent predictors in T1-4/N0/M0 tumours were T-category (RR 2.67, P = 0.001) and cyclin A (RR 1.21, P < 0.001), and in T1-2/N0/M0 tumours the only significant predictor was cyclin A (RR 1.19, P = 0.0002). In renal cell carcinoma, cyclin A is a powerful and independent prognostic factor in all clinical stages of the disease, whereas cyclin D1 and p21 (waf1/cip1) have no prognostic value.

Gene array of VHL mutation and hypoxia shows novel hypoxia-induced genes and that cyclin D1 is a VHL target gene

“…Nevertheless, the renal cell lines stand out as consistently maintaining CCND1 expression under hypoxia in contrast to all other types examined here and reported in the literature. Our findings are in agreement with clinical data that approximately 75% of RCCs expressed a higher level of CCND1 protein than the normal kidney cortex (Lin et al, 1998;Aaltomaa et al, 1999;Hedberg et al, 1999;Stassar et al, 2001).…”

Low expression of p27Kip1 is associated with tumor size and poor prognosis in patients with renal cell carcinoma

“…In patients with RCC, there have been some reports suggesting that low cyclin D1 expression, high cyclin A expression, and high Ki-67 expression indicate a poor clinical outcome. 3,29,30 Renshaw et al 5 reported that there was a positive correlation between cyclin A and Ki-67, but neither of these proliferative markers was correlated with tumor grade or stage in 33 patients with RCC. In contrast, other investigators have reported that increased cyclin A is a powerful and independent, unfavorable prognostic marker and that increased cyclin D1 is a favorable prognostic marker in patients with RCC.…”

“…In each complete section, 1000 tumor cells were counted manually, and the percentage of positive cells was calculated. We referred to previously reported 3 and well-prespecified criteria regarding the immunohistochemical expression of p27 in various types of tumors and, accordingly, divided the tumors into a group that had p27 expression with a labeling index (LI) Ն 50% (high p27 expression) and a group that had p27 expression with an LI Ͻ 50% (low p27 expression). In addition, the tumors were divided into two groups with regard to the other cell cycle-related proteins: high expression (Ն 1%) and low expression (Յ 1%) for cyclin A, 3 high expression (Ն 10%) and low expression (Ͻ 10%) for cyclin D1, 4 and high expression (Ն 1%) and low expression (Ͻ 1%) for MIB-1.…”

“…In addition, the tumors were divided into two groups with regard to the other cell cycle-related proteins: high expression (Ն 1%) and low expression (Յ 1%) for cyclin A, 3 high expression (Ն 10%) and low expression (Ͻ 10%) for cyclin D1, 4 and high expression (Ն 1%) and low expression (Ͻ 1%) for MIB-1. 3 …”

“…Correlation between the expression of cyclins and tumor progression has been reported in many kinds of malignant tumors, including RCC. [2][3][4][5] Conversely, p27 Kip1 (p27), a member of the Cip/Kip family proteins, regulates the CDKs and is a major negative regulator of the G1-to-S transition in the cell cycle. The role of p27 as a diagnostic or prognostic marker has been reviewed in human malignancies 6 but has not been reported in RCC.…”