Aberrations in the G1/S transition of the cell cycle have been observed in many malignancies and seem to be critical in the transformation process. Few studies have delineated the presence of G1/S regulatory defects and their clinical relevance in renal cell carcinoma (RCC). Therefore, we have examined the protein contents of cyclin D1, D3, E, and p27 in 218 RCCs, using tissue microarray and immunohistochemistry. The results from a subset of tumours were confirmed by Western blotting and immunohistochemical staining of regular tissue sections. Interestingly, low protein contents of cyclin D1 and p27 were associated with high nuclear grade, large tumour size, and poor prognosis for patients with conventional tumours. We further observed substantial differences in the pattern of G1/S regulatory defects between the different RCC subtypes. The majority of both conventional and papillary cases expressed p27; however, chromophobe tumours generally lacked p27 staining. In addition, conventional RCCs often expressed high cyclin D1 protein levels, while papillary RCCs exhibited high cyclin E. In summary, we have shown that G1/S regulatory defects are present in RCC and are associated with clinico-pathological parameters. The pattern of cell cycle regulatory defects also differed between RCC subtypes.

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Aberrations in the G1-S transition have been observed in several malignancies, suggesting that cell cycle defects are linked to the activation of oncogenes and inactivation of suppressor genes involved in the transformation process. The frequency of G1/S aberrations in human renal cell carcinoma (RCC) has not been fully clarified. We have therefore analyzed the cyclin E content, using Western blotting, in 79 RCC and 12 corresponding kidney cortex tissues as well as the fraction of p27-positive cells in 73 RCCs, using immunohistochemistry. Most of the tumors (65%) exhibited higher cyclin E levels than corresponding normal kidney cortex tissues. However, only a small fraction of the tumors (3 of 80) had excessive levels of cyclin E when cyclin E levels were compared with proliferation. Cyclin E levels higher than the median value were associated with aneuploidy (p ‫؍‬ 0. Key words: renal cell carcinoma; G1/S transition; cell cycle; cyclin; p27; proteinHuman renal cell carcinoma (RCC) is a malignant disease with a variable clinical course. Tumor stage is the best predictor of prognosis and is correlated with tumor progression. 1 Other parameters that predict prognosis are tumor grade, tumor cell proliferation and DNA ploidy. 2 During the last decade a detailed genetic characterization has allowed a classification of RCC that correlates with recognizable histopathologic features. 3 Conventional RCC, the most common tumor type, is characterized by chromosome 3p deletions. Aberrations on chromosomes 8, 9, 13 and 14 and nonrandom alterations involving 5q, 6q and 10q have also been described in this tumor type. 4 Papillary RCCs generally have trisomies of chromosomes 7 and 17 and loss of the Y chromosome, often in combination with additional trisomies of chromosomes 12, 16 and 20. 3 Chromophobe RCC is characterized by a combination of monosomies of chromosomes 1, 2, 10, 13, 17 and 21. 5 Among these RCC types, patients with conventional RCC had the poorest outcome. 6 A complex machinery consisting of cyclin-dependent kinases (CDKs) and sets of activating and inhibitory molecules controls the G1-S transition in the cell cycle. Both cyclins D and E are involved in the sequential activation of various CDKs, which, if the specific CDK inhibitors are detached from the cyclin-CDK complexes, allows phosphorylation of key substrates such as the retinoblastoma protein and release of transcription factors like E2F. This control system governs the transfer of cells from G1 to S-phase and initiation of DNA-replication, which for most cells lead to completion of the cell cycle and division into two daughter cells. Defects in the G1-S transition have been proposed to be one of a rather limited number of key events in the process leading to transformation. 7,8 Cyclin E and p27 are two important G1/S regulatory molecules that are often deregulated in malignancies, indicating an association with tumor development, progression or proliferation. 9 -13 The possibility for tumor cells to respond properly to genetic damages, such as a p53-...

RESULTSOf the tumours, 75% expressed endoglin, and in conventional RCC the expression was inversely correlated to the Tumour-NodeMetastasis (TNM) stage ( P = 0.008) and nuclear grade ( P = 0.01). There was no correlation between endoglin expression and gender, age, tumour size or cell type. Patients with conventional RCC and high endoglin expression had a more favourable prognosis than those with tumours with lower expression ( P = 0.04). A multivariate analysis of prognostic factors showed that TNM stage and nuclear grade were independent predictors of prognosis. Endoglin expression did not add further prognostic information. CONCLUSIONThese results indicate that endoglin expression is inversely related to stage and grade in RCC, and that it is associated with prognosis.

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