Prognostic Significance of Cyclin D1 Expression in Renal Cell Carcinoma: a Systematic Review and Meta-analysis

Abstract

Previous studies indicated that cyclin D1 shown the potential as a tumor biomarker. However, the prognostic value of cyclin D1 in renal cell carcinoma (RCC) remains controversial. This study investigated the correlation of cyclin D1 expression with the prognostic and clinicopathological features in RCC patients. We systematically searched the database of PubMed, Embase, Cochrane, and Web of Science updated on November 26, 2017. Eighteen studies with 2282 patients satisfied the inclusion criteria. Results demonstrated that cyclin D1 overexpression in RCC showed significant favorable prognostic impact on disease-free survival (DFS) (HR 0.57, 95% CI: 0.43–0.74) and disease-specific survival (DSS) (HR 0.59, 95% CI 0.41–0.85) without significant heterogeneity. In subgroup of clear cell RCC, the prognostic effect on DFS was robust and the pooled HR was 0.39 (95% CI: 0.27–0.57). However, no association between overall survival (OS) and cyclin D1 expression was observed. Stratified analysis in DFS studies by sample size, staining patterns race and metastasis status showed similar results. Otherwise, cyclin D1 overexpression predicted a reduced prevalence of high TNM stage (T3 + T4) (OR 0.63, 95% CI: 0.40–0.99), high-grade tumor (G3 + G4) (OR 0.51, 95% CI: 0.31–0.81) and large tumor size (OR 0.35, 95% CI: 0.19–0.62). Our meta-analysis indicated that cyclin D1 overexpression could predict the favorable prognosis in patients with RCC.

This is a preview of subscription content, log in to check access.

Fig. 1:
Fig. 2:
Fig. 3:

References

  1. 1.

    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90. https://doi.org/10.3322/caac.20107

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    MacLennan S, Imamura M, Lapitan MC, Omar MI, Lam TB, Hilvano-Cabungcal AM, Royle P, Stewart F, MacLennan G, MacLennan SJ, Canfield SE, McClinton S, Griffiths TR, Ljungberg B, N’Dow J (2012) Systematic review of oncological outcomes following surgical management of localised renal cancer. Eur Urol 61(5):972–993. https://doi.org/10.1016/j.eururo.2012.02.039

    Article  PubMed  Google Scholar 

  3. 3.

    Ljungberg B, Mehle C, Stenling R, Roos G (1996) Heterogeneity in renal cell carcinoma and its impact no prognosis--a flow cytometric study. Br J Cancer 74(1):123–127

    CAS  Article  Google Scholar 

  4. 4.

    Diehl JA (2002) Cycling to cancer with cyclin D1. Cancer Biol Ther 1(3):226–231

  5. 5.

    Shan J, Zhao W, Gu W (2009) Suppression of cancer cell growth by promoting cyclin D1 degradation. Mol Cell 36(3):469–476. https://doi.org/10.1016/j.molcel.2009.10.018

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Palmqvist R, Stenling R, Oberg A, Landberg G (1998) Expression of cyclin D1 and retinoblastoma protein in colorectal cancer. Eur J Cancer (Oxford, England : 1990) 34(10):1575–1581

  7. 7.

    Aaltomaa S, Lipponen P, Ala-Opas M, Eskelinen M, Syrjanen K, Kosma VM (1999) 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(12):2001–2007. https://doi.org/10.1038/sj.bjc.6690634

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Hedberg Y, Ljungberg B, Roos G, Landberg G (2003) Expression of cyclin D1, D3, E, and p27 in human renal cell carcinoma analysed by tissue microarray. Br J Cancer 88(9):1417–1423. https://doi.org/10.1038/sj.bjc.6600922

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Xu XL, Chen SZ, Chen W, Zheng WH, Xia XH, Yang HJ, Li B, Mao WM (2013) The impact of cyclin D1 overexpression on the prognosis of ER-positive breast cancers: a meta-analysis. Breast Cancer Res Treat 139(2):329–339. https://doi.org/10.1007/s10549-013-2563-5

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Li Y, Wei J, Xu C, Zhao Z, You T (2014) Prognostic significance of cyclin D1 expression in colorectal cancer: a meta-analysis of observational studies. PLoS One 9(4):e94508. https://doi.org/10.1371/journal.pone.0094508

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Ren B, Li W, Yang Y, Wu S (2014) The impact of cyclin D1 overexpression on the prognosis of bladder cancer: a meta-analysis. World J Surg Oncol 12:55. https://doi.org/10.1186/1477-7819-12-55

  12. 12.

    Zhang LQ, Jiang F, Xu L, Wang J, Bai JL, Yin R, Wu YQ, Meng LJ (2012) The role of cyclin D1 expression and patient's survival in non-small-cell lung cancer: a systematic review with meta-analysis. Clin Lung Cancer 13(3):188–195. https://doi.org/10.1016/j.cllc.2011.10.003

  13. 13.

    Tobin NP, Sims AH, Lundgren KL, Lehn S, Landberg G (2011) Cyclin D1, Id1 and EMT in breast cancer. BMC Cancer 11:417. https://doi.org/10.1186/1471-2407-11-417

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Ishii Y, Pirkmaier A, Alvarez JV, Frank DA, Keselman I, Logothetis D, Mandeli J, O’Connell MJ, Waxman S, Germain D (2006) Cyclin D1 overexpression and response to bortezomib treatment in a breast cancer model. J Natl Cancer Inst 98(17):1238–1247. https://doi.org/10.1093/jnci/djj334

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62(10):1006–1012. https://doi.org/10.1016/j.jclinepi.2009.06.005

    Article  PubMed  Google Scholar 

  16. 16.

    Furukawa J, Miyake H, Fujisawa M (2016) GLI2 expression levels in radical nephrectomy specimens as a predictor of disease progression in patients with metastatic clear cell renal cell carcinoma following treatment with sunitinib. Mol Clin Oncol 5(3):186–192. https://doi.org/10.3892/mco.2016.950

  17. 17.

    Haddad AQ, Luo JH, Krabbe LM, Darwish O, Gayed B, Youssef R, Kapur P, Rakheja D, Lotan Y, Sagalowsky A, Margulis V (2017) Prognostic value of tissue-based biomarker signature in clear cell renal cell carcinoma. BJU Int 119(5):741–747. https://doi.org/10.1111/bju.13776

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Chaves Portela S, Santos-Arrontes D, Fernandez-Acenero MJ, Garcia Gonzalez J, Paniagua P (2011) Stage pT3a of renal clear cell carcinoma: do tumors with sinus fat involvement behave the same as those with perinephric fat involvement? Rom J Morphol Embryol = Revue Roumaine de Morphologie et EMBRYOLOGIE 52(2):569–574

  19. 19.

    Lima MS, Pereira RA, Costa RS, Tucci S, Dantas M, Muglia VF, Ravinal RC, Barros-Silva GE (2014) The prognostic value of cyclin D1 in renal cell carcinoma. Int Urol Nephrol 46(5):905–913. https://doi.org/10.1007/s11255-013-0602-0

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Biswas S, Charlesworth PJ, Turner GD, Leek R, Thamboo PT, Campo L, Turley H, Dildey P, Protheroe A, Cranston D, Gatter KC, Pezzella F, Harris AL (2012) CD31 angiogenesis and combined expression of HIF-1alpha and HIF-2alpha are prognostic in primary clear-cell renal cell carcinoma (CC-RCC), but HIFalpha transcriptional products are not: implications for antiangiogenic trials and HIFalpha biomarker studies in primary CC-RCC. Carcinogenesis 33(9):1717–1725. https://doi.org/10.1093/carcin/bgs222

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Phuoc NB, Ehara H, Gotoh T, Nakano M, Yokoi S, Deguchi T, Hirose Y (2007) Immunohistochemical analysis with multiple antibodies in search of prognostic markers for clear cell renal cell carcinoma. Urology 69(5):843–848. https://doi.org/10.1016/j.urology.2007.01.069

    Article  PubMed  Google Scholar 

  22. 22.

    Allory Y, Matsuoka Y, Bazille C, Christensen EI, Ronco P, Debiec H (2005) The L1 cell adhesion molecule is induced in renal cancer cells and correlates with metastasis in clear cell carcinomas. Clin Cancer Res : an Official Journal of the American Association for Cancer Research 11(3):1190–1197

  23. 23.

    Stubbs C, Bardoli AD, Afshar M, Pirrie S, Miscoria M, Wheeley I, Porfiri E (2017) A study of angiogenesis markers in patients with renal cell carcinoma undergoing therapy with Sunitinib. Anticancer Research 37(1):253–259. https://doi.org/10.21873/anticanres.11315

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Kusuda Y, Miyake H, Behnsawy HM, Fukuhara T, Inoue TA, Fujisawa M (2013) Prognostic prediction in patients with metastatic renal cell carcinoma treated with sorafenib based on expression levels of potential molecular markers in radical nephrectomy specimens. Urol Oncol 31(1):42–50. https://doi.org/10.1016/j.urolonc.2010.09.008

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Bodnar L, Stec R, Cierniak S, Synowiec A, Wcislo G, Jesiotr M, Koktysz R, Kozlowski W, Szczylik C (2015) Clinical usefulness of PI3K/Akt/mTOR genotyping in companion with other clinical variables in metastatic renal cell carcinoma patients treated with everolimus in the second and subsequent lines. Ann Oncol : OFFICIAL journal of the European Society for Medical Oncology 26(7):1385–1389. https://doi.org/10.1093/annonc/mdv166

  26. 26.

    Su T, Han Y, Yu Y, Tan X, Li X, Hou J, Du Y, Shen J, Wang G, Ma L, Jiang S, Zhang H, Cao G (2013) A GWAS-identified susceptibility locus on chromosome 11q13.3 and its putative molecular target for prediction of postoperative prognosis of human renal cell carcinoma. Oncol Lett 6(2):421–426. https://doi.org/10.3892/ol.2013.1422

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Dahinden C, Ingold B, Wild P, Boysen G, Luu VD, Montani M, Kristiansen G, Sulser T, Buhlmann P, Moch H, Schraml P (2010) Mining tissue microarray data to uncover combinations of biomarker expression patterns that improve intermediate staging and grading of clear cell renal cell cancer. Clin Cancer Res : an Official Journal of the American Association for Cancer Research 16(1):88–98. https://doi.org/10.1158/1078-0432.ccr-09-0260

  28. 28.

    Wang F, Guo CH, Sun W, Dong Y, Yang Z (2012) Expressions of E-cadherin, β-catenin and Cyclin D1 in renal clear cell carcinoma. Chinese Journal of Cancer Prevention and Treatment 19(22):1716–1718+1729

    CAS  Google Scholar 

  29. 29.

    Migita T, Oda Y, Naito S, Tsuneyoshi M (2002) Low expression of p27(Kip1) is associated with tumor size and poor prognosis in patients with renal cell carcinoma. Cancer 94(4):973–979

    CAS  Article  Google Scholar 

  30. 30.

    Ge JR, Ren GP, Yao HP (2007) Expression of cyclin D1 and p27kip1 in renal cell carcinoma and its significance. Zhejiang Da Xue Xue Bao Yi Xue Ban = Journal of Zhejiang University Medical sciences 36(5):483–487

  31. 31.

    Hsu RJ, Ho JY, Cha TL, Yu DS, Wu CL, Huang WP, Chu P, Chen YH, Chen JT, Yu CP (2012) WNT10A plays an oncogenic role in renal cell carcinoma by activating WNT/beta-catenin pathway. PLoS One 7(10):e47649. https://doi.org/10.1371/journal.pone.0047649

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Wells G (2004) The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analysis. Cancer. 2002 Feb 15;94(4):973-9. http://www.ohrica/programs/clinical_epidemiologyoxford.htm

  33. 33.

    Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA 283(15):2008–2012

    CAS  Article  Google Scholar 

  34. 34.

    Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR (2007) Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 8:16. https://doi.org/10.1186/1745-6215-8-16

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Strauss M, Lukas J, Bartek J (1995) Unrestricted cell cycling and cancer. Nat Med 1(12):1245–1246

    CAS  Article  Google Scholar 

  36. 36.

    Jirawatnotai S, Hu Y, Michowski W, Elias JE, Becks L, Bienvenu F, Zagozdzon A, Goswami T, Wang YE, Clark AB, Kunkel TA, van Harn T, Xia B, Correll M, Quackenbush J, Livingston DM, Gygi SP, Sicinski P (2011) A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. Nature 474(7350):230–234. https://doi.org/10.1038/nature10155

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Han EK, Sgambato A, Jiang W, Zhang YJ, Santella RM, Doki Y, Cacace AM, Schieren I, Weinstein IB (1995) Stable overexpression of cyclin D1 in a human mammary epithelial cell line prolongs the S-phase and inhibits growth. Oncogene 10(5):953–961

    CAS  PubMed  Google Scholar 

  38. 38.

    Parry D, Bates S, Mann DJ, Peters G (1995) Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product. EMBO J 14(3):503–511

    CAS  Article  Google Scholar 

  39. 39.

    Atadja P, Wong H, Veillete C, Riabowol K (1995) Overexpression of cyclin D1 blocks proliferation of normal diploid fibroblasts. Exp Cell Res 217(2):205–216. https://doi.org/10.1006/excr.1995.1080

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Freeman RS, Estus S, Johnson EM Jr (1994) Analysis of cell cycle-related gene expression in postmitotic neurons: selective induction of Cyclin D1 during programmed cell death. Neuron 12(2):343–355. https://doi.org/10.1016/0896-6273(94)90276-3

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4(7):844–847

    CAS  Article  Google Scholar 

  42. 42.

    Simon RM, Paik S, Hayes DF (2009) Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 101(21):1446–1452. https://doi.org/10.1093/jnci/djp335

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Dr. Lubomir Bodnar for providing the original data. This work was supported by grants of Science Foundation of Shandong Province (No.ZR2015HM046) and a grant of National Natural Science Foundation of China (81672522).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Yueqing Tang or Yidong Fan.

Ethics declarations

This research does not involve Human Participants and/or Animals.

This article does not contain any studies with human participants performed by any of the authors. No informed consent is needed.

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 654 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, Z., Liu, J., Zhang, X. et al. Prognostic Significance of Cyclin D1 Expression in Renal Cell Carcinoma: a Systematic Review and Meta-analysis. Pathol. Oncol. Res. 26, 1401–1409 (2020). https://doi.org/10.1007/s12253-019-00776-0

Download citation

Keywords

  • Cyclin D1
  • Renal cell carcinoma
  • Prognosis
  • Meta-analysis