Summary
We 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.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Aaltomaa, S., Lipponen, P., Vesalainen, S., Eskelinen, M. & Syrjänen, K. (1997). Value of Ki-67 expression in renal cell carcinomas. Eur Urol 32: 350–355.
Aaltomaa, S., Eskelinen, M. & Lipponen, P. (1999a). Expression of cyclin A and D proteins in prostate cancer and their relation to clinicopathological variables and patient survival. Prostate 30: 175–182.
Aaltomaa, S., Lipponen, P., Eskelinen, M., Ala-Opas, M. & Kosma, V-M (1999b). The prognostic value and expression of p21(waf/cip1) protein in prostate cancer. Prostate 39: 8–15.
Backe, J., Gassel, A. M., Hauber, K., Krebs, S., Bartek, J., Caffier, H., Kreibe, H. H., Muller-Hermelink, H. K. & Dietl, J. (1997). p53 protein in endometrial cancer is related to proliferative activity and prognosis but not to expression of p21 protein. Int J Gynecol Pathol 16: 361–368.
Barbareschi, M., Pelosio, P., Caffo, O., Buttitta, F., Pellegrini, S., Barbazza, R., Dalla Parma, P., Bevilacqua, G. & Marchetti, A. (1997). Cyclin D1-gene amplification and expression in breast carcinoma: relation with clinicopathologic characteristics and with retinoblastoma gene product, p53 and p21/waf1 immunohistochemical expression. Int J Cancer 74: 171–174.
Barbieri, F., Cagnoli, M., Ragni, N., Pedulla, F., Foglia, G. & Alama, A. (1997). Expression of cyclin D1 correlates with malignancy in human ovarian tumors. Br J Cancer 75: 1263–1268.
Byrne, R. L., Horne, C. H., Robinson, M. C., Autzen, P., Apakama, I., Bishop, R. I., Neal, D. E. & Hamdy, F. C. (1997). The expression of waf-1, p53 and bcl-2 in prostatic adenocarcinoma. Br J Urol 79: 190–195.
Donnellan, R. & Chetty, R. (1998). Cyclin D1 and human neoplasia. J Clin Pathol Mol Pathol 51: 1–7.
El Deiry, W. S., Tokino, T. & Waldman, T. (1995). Topological control of p21(waf1/cip1) expression in normal and neoplastic tissues. Cancer Res 55: 2910–2919.
Giberti, C., Oneto, F., Martorana, G., Rovida, S. & Carmignani, G. (1997). Radical nephrectomy for renal cell carcinoma: long-term results and prognostic factors on a series of 328 cases. Eur Urol 31: 40–48.
Gillet, C. E., Smith, P., Gregory, W. M., Richards, M. A., Millis, R. R., Peters, G. & Barnes, D. M. (1996). Cyclin D1 and prognosis in breast cancer. Int J Cancer 69: 92–99.
Haapasalo, H., Pesonen, E. & Collan, Y. (1989). Volume corrected mitotic index (M/V-INDEX): the standard of mitotic activity in neoplasms. Path Res Prac 185: 551–554.
Hofmockel, G., Bassukas, I. D., Wittmann, A. & Dämmrich, J. (1997). Is the expression of multidrug resistance gene product a prognostic indicator for the clinical outcome of patients with renal cell cancer? Br J Urol 80: 11–17.
Ishikawa, T., Furihata, M., Ohtsuki, Y., Murakami, H., Inoue, A. & Ogoshi, S. (1998). Cyclin D1 overexpression related to retinoblastoma protein expression as a prognostic marker in human oesophageal squamous cell carcinoma. Br J Cancer 77: 92–97.
Kato, J. Y. (1997). Control of G1 progression by D-types cyclins: key event for cell proliferation. Leukemia 3: 347–351.
Kawasaki, T., Tomita, Y., Bilim, V., Takeda, M., Takahashi, K. & Kumanishi, T. (1998). Abrogation of apoptosis induced by DNA-damaging agents in human bladder-cancer cell lines with p21/waf1/cip1 and/or p53 gene alterations. Int J Cancer 68: 501–505.
Koga, H., Naito, S., Hasegawa, S., Watanabe, T. & Kumazawa, J. (1997). A flow cytometric analysis of the expression of adhesion molecules on human renal cell carcinoma cells with different metastatic potentials. Eur Urol 31: 86–91.
Lee, C. C., Yamamoto, S., Morimura, K., Wanibuchi, H., Nishisaka, N., Ikemoto, S., Nakatani, T., Wada, S., Kishimoto, T. & Fukushima, S. (1997). Significance of cyclin D1 overexpression in transitional cell carcinomas of the urinary bladder and its correlation with histopathologic features. Cancer 15: 780–789.
Lipponen, P., Aaltomaa, S., Eskelinen, M., Ala-Opas, M. & Kosma, V-M (1998). Expression of p21 (waf1/cip1) protein in transitional cell bladder tumours and its prognostic value. Eur Urol 34: 237–243.
Lipponen, P., Eskelinen, M., Hietala, K. & Syrjänen, K. (1994). Expression of proliferating cell nuclear antigen (PC10), p53 protein and c-erbB-2 in renal adenocarcinoma. Int J Cancer 57: 275–280.
Maeda, K., Chung, Y., Kang, S., Ogawa, M., Nishiguchi, Y., Ikehara, T., Nakata, B., Okuno, M. & Sowa, M. (1998). Cyclin D1 overexpression and prognosis in colorectal adenocarcinoma. Oncology 55: 145–151.
Marshall, R. D., Lester, S., Corless, C., Richie, J. P., Chandra, R., Propert, K. J. & Dutta, A. (1996). Expression of cell cycle-regulated proteins in prostate cancer. Cancer Res 56: 4159–4163.
Michalides, R. J., van Veelen, N. M., Kristel, P. M., Hart, A. A., Loftus, B. M., Hilgers, F. J. & Balm, J. A. (1997). Over-expression of cyclin D1 indicates poor prognosis in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 123: 497–502.
Naitoh, H., Shibata, J., Kawaguchi, A., Kodama, M. & Hattori, T. (1995). Overexpression and localization of cyclin D1 mRNA and antigen in esophageal cancer. Am J Pathol 146: 1161–1169.
Naka, T., Toyota, N., Kaneko, T. & Kaibara, N. (1998). Protein expression of p53, p21WAF1, and Rb as prognostic indicators in patients with surgically treated hepatocellular carcinoma. Anticancer Res 18: 555–564.
Nakamura, M., Katano, M., Fujimoto, K. & Morisaki, T. (1997). A new prognostic strategy for gastric carcinoma: mRNA expression of tumor growth-related factors in endoscopic biopsy specimens. Ann Surg 226: 35–42.
Papandopoulos, I., Rudolph, P. & Weichert-Jacobsen, K. (1997). Value of p53 expression, cellular proliferation and DNA content as prognostic indicators in renal cell carcinoma. Eur Urol 32: 110–117.
Papandreou, C. N., Bogenrieder, T., Loganzo, F., Albino, A. P. & Nanus, D. M. (1997). Expression and sequence analysis of the p21 (waf1/cip1) gene in renal cancers. Urology 49: 481–486.
Paul, R., Ewing, C. M., Robinson, J. C., Marshall, F. F., Johnson, K. R., Wheelock, M. J. & lsaacs, W. B. (1998). Catherin-6, a cell adhesion molecule specifically expressed in the proximal renal tubule and renal cell carcinoma. Cancer Res 57: 2741–2748.
Pignataro, L., Pruneri, G., Carboni, N., Capaccio, P., Cesana, B. M., Neri, A. & Butler, M. R. (1998). Clinical relevance of cyclin D1 protein expression in laryngeal squamous cell carcinomas. J Clin Oncol 16: 3069–3077.
Shiina, H., Igawa, M., Urakami, S., Ishibe, T. & Kawanishi, M. (1997). Clinical significance of immunohistochemically detectable p53 protein in renal cell carcinoma. Eur Urol 31: 73–80.
Shin, K. Y., Kong, G., Kim, W. S., Lee, T. Y., Woo, Y. N. & Lee, J. D. (1997). Over-expression of cyclin D1 correlates with early recurrence in superficial bladder cancer. Br J Cancer 75: 1788–1792.
Strauss, M., Lukas, J. & Bartek, J. (1995). Unrestricted cell cycling and cancer. Recent data suggest that de-regulation of the restriction point in the cell cycle G1 phase appears to be required for the development of neoplasia. Nat Med 1: 1245–1246.
Sweeney, J. P., Thornhill, J. A., Grainger, R., Mcdermott, T. E. D. & Butler, M. R. (1996). Incidentally detected renal cell carcinoma: pathological features, survival trends and implications for treatment. Br J Urol 78: 351–353.
Syrjänen, K. & Hjelt, L. (1978). Grading of human renal adenocarcinoma. Scand J Urol Nephrol 12: 49–52.
Volm, M., Koomagi, R. & Rittgen, W. (1998). Clinical implication of cyclins, cyclin-dependent kinases, RB and E2F1 in squamous-cell lung carcinoma. Int J Cancer 79: 294–299.
Waga, S., Hannon, G. J., Beach, D. & Stillman, B. (1994). The p21 inhibitor of cyclin dependent kinases controls DNA replication by interaction with PCNA. Nature 369: 574–578.
Yasui, W., Akama, Y., Yokozaki, H., Semba, S., Kudo, Y., Shimamoto, F. & Tahara, E. (1997). Expression of p21 waf1/cip1 in colorectal adenomas and adenocarcinomas and its correlation with p53 protein expression stage. Pathol Int 47: 470–477.
Zhang, H., Hannon, G. J. & Beach, D. (1994). p21-containing cyclin kinases exist in both active and inactive states. Genes Dev 8: 1750–1758.
Zeng, Y-X & El-Deiry, W. S. (1996). Regulation of p21 (waf1/cip1) expression by p53-independent pathways. Oncogene 12: 1557–1564.
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Aaltomaa, S., Lipponen, P., Ala-Opas, M. et al. Expression of cyclins A and D and p21(waf1/cip1) proteins in renal cell cancer and their relation to clinicopathological variables and patient survival. Br J Cancer 80, 2001–2007 (1999). https://doi.org/10.1038/sj.bjc.6690634
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.bjc.6690634
Keywords
This article is cited by
-
How metformin affects various malignancies by means of microRNAs: a brief review
Cancer Cell International (2021)
-
Prognostic Significance of Cyclin D1 Expression in Renal Cell Carcinoma: a Systematic Review and Meta-analysis
Pathology & Oncology Research (2020)
-
Cyclin A2 as a potential differential marker of splenic diffuse red pulp small B-cell lymphoma: a report of the first case
Annals of Hematology (2017)
-
The prognostic value of cyclin D1 in renal cell carcinoma
International Urology and Nephrology (2014)
-
Cyclin A2, a novel regulator of EMT
Cellular and Molecular Life Sciences (2014)
