Abstract
Purpose: The aim of this study was to assess the impact of cyclin D1 overexpression (considered separately or jointly with previously assessed p53 and pRb statuses) on survival in a group of 111 surgically treated non-small cell lung cancer patients (NSCLC). Methods: Cyclin D1 accumulation was assessed immunohistochemically, with the use of monoclonal antibody (DCS-6, DakoCytomation) and the alkaline phosphatase–anti-alkaline phosphatase (APAAP) technique. Results: Overexpression of cyclin D1 was found in 55 samples (49%), whereas the altered phenotypes cyclin D1+/p53+ or cyclin D1+/pRb− were found in 23 (22%) and 9 samples (9%), respectively. Statistical analysis was performed for different cut-off values and the only significant differences were found if samples with some expression of each protein were considered positive. There was no relationship between cyclin D1 overexpression and major clinicopathological factors, including p53 expression; however, there was a direct correlation between cyclin D1 and pRb protein expression (p=0.007). Cyclin D1 accumulation did not influence patients’ survival. Of all possible cyclin D1/p53, cyclin D1/pRb and cyclin D1/p53/pRb phenotypes, patients with cyclin D1−/p53+ phenotype had shortened overall survival compared to other patients (p=0.027, HR=1.8). In the multivariate analysis, the only variable associated with shortened overall and disease-free survival was the stage of disease (p<0.001). Conclusions: These results suggest the lack of prognostic value of cyclin D1 overexpression in NSCLC patients.
Similar content being viewed by others
References
Akervall JA, Michalides RJ, Mineta H, Balm A, Borg A, Dictor MR, Jin Y, Loftus B, Mertens F, Wennerberg JP (1997) Amplification of cyclin D1 in squamous cell carcinoma of the head and neck and the prognostic value of chromosomal abnormalities and cyclin D1 overexpression. Cancer 79:380–389
Anton RC, Coffey DM, Gondo MM, Stephenson MA, Brown RW, Cagle PT (2000) The expression of cyclins D1 and E in predicting short-term survival in squamous cell carcinoma of the lung. Mod Pathol 13:1167–1172
Betticher DC, Heighway J, Hasleton PS, Altermatt HJ, Ryder WD, Cerny T, Thatcher N (1996) Prognostic significance of CCND1 (cyclin D1) overexpression in primary resected non-small-cell lung cancer. Br J Cancer 73:294–300
Brambilla E, Moro D, Gazzeri S, Brambilla C (1999) Alterations of expression of Rb, p16(INK4A) and cyclin D1 in non-small cell lung carcinoma and their clinical significance. J Pathol 188:351–60
Caputi M, De Luca L, Papaccio G, D’Aponte A, Cavallotti I, Scala P, Scarano F, Manna M, Gualdiero L, De Luca B (1997) Prognostic role of cyclin D1 in non small cell lung cancer: an immunohistochemical analysis. Eur J Histochem 41:133–138
De Vita VTJ, Hellman S, Rosenberg SA (1997) Cancer: principles and practices of oncology, 5th edn. Lippincott, Philadelphia
Dworakowska D, Gozdz S, Jassem E, Badzio A, Kobierska G, Urbaniak A, Skokowski J, Damps I, Jassem J (2002) Prognostic relevance of proliferating cell nuclear antigen and p53 expression in non-small cell lung cancer. Lung Cancer 35:35–41
Dworakowska D, Jassem E, Jassem J, Wiedorn KH, Boltze C, Karoliński A, Dworakowski R, Skokowski J, Jaśkiewicz K, Bosse A, Częstochowska E (2004) Prognostic relevance of altered pRb and p53 protein expression in surgically treated non-small cell lung cancer patients. Oncology 67:60–66
Gugger M, Kappeler A, Vonlanthen S, Altermatt HJ, Ris HB, Lardinois D, Borner MM, Heighway J, Betticher DC (2001) Alterations of cell cycle regulators are less frequent in advanced non-small cell lung cancer than in resectable tumours. Lung Cancer 33:229–239
Ikehara M, Oshita F, Ito H, Ohgane N, Suzuki R, Saito H, Yamada K, Noda K, Mitsuda A, Kameda Y (2003) Expression of cyclin D1 but not of cyclin E is an indicator of poor prognosis in small adenocarcinomas of the lung. Oncol Rep 10:137–139
Sobin LH, Wittekind CH (1997) TNM classification of malignant tumors, 5th edn. Wiley-Liss, New York
Jin M, Inoue S, Umemura T, Moriya J, Arakawa M, Nagashima K, Kato H (2001) Cyclin D1, p16 and retinoblastoma gene product expression as a predictor for prognosis in non-small cell lung cancer at stages I and II. Lung Cancer 34:207–218
Keum JS, Kong G, Yang SC, Shin DH, Park SS, Lee JH, Lee JD (1999) Cyclin D1 overexpression is an indicator of poor prognosis in resectable non-small cell lung cancer. Br J Cancer 81:127–132
Keyomarsi K, Pardee AB (1993) Redundant cyclin overexpression and gene amplification in breast cancer cells. Proc Natl Acad Sci USA 90:1112–1116
Kwa HB, Michalides RJ, Dijkman JH, Mooi WJ (1996) The prognostic value of NCAM, p53 and cyclin D1 in resected non-small cell lung cancer. Lung Cancer 14:207–217
Lukas J, Muller H, Bartkova J, Spitkovsky D, Kjerulff AA, Jansen-Durr P, Strauss M, Bartek J (1994) DNA tumor virus oncoproteins and retinoblastoma gene mutations share the ability to relieve the cell’s requirement for cyclin D1 function in G1. J Cell Biol 125:625–638
Marchetti A, Doglioni C, Barbareschi M, Buttitta F, Pellegrini S, Gaeta P, La Rocca R, Merlo G, Chella A, Angeletti CA, Dalla Palma P, Bevilacqua G (1998) Cyclin D1 and retinoblastoma susceptibility gene alterations in non-small cell lung cancer. Int J Cancer 75:187–192
Mate JL, Ariza A, Aracil C, Lopez D, Isamat M, Perez-Piteira J, Navas-Palacios JJ (1996) Cyclin D1 overexpression in non-small cell lung carcinoma: correlation with Ki67 labelling index and poor cytoplasmic differentiation. J Pathol 180:395–9
Matsushime H, Roussel MF, Ashmun RA, Sherr CJ (1991) Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell 65:701–713
Mishina T, Dosaka-Akita H, Kinoshita I, Hommura F, Morikawa T, Katoh H, Kawakami Y (1999) Cyclin D1 expression in non-small-cell lung cancers: its association with altered p53 expression, cell proliferation and clinical outcome. Br J Cancer 80:1289–1295
Muller H, Lukas J, Schneider A, Warthoe P, Bartek J, Eilers M, Strauss M (1994) Cyclin D1 expression is regulated by the retinoblastoma protein. Proc Natl Acad Sci USA 91:2945–2949
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
Nguyen VN, Mirejovsky P, Mirejovsky T, Melinova L, Mandys V (2000) Expression of cyclin D1, Ki-67 and PCNA in non-small cell lung cancer: prognostic significance and comparison with p53 and bcl-2. Acta Histochem 102:323–338
Nishida N, Fukuda Y, Komeda T, Kita R, Sando T, Furukawa M, Amenomori M, Shibagaki I, Nakao K, Ikenaga M (1994) Amplification and overexpression of the cyclin D1 gene in aggressive human hepatocellular carcinoma. Cancer Res 54:3107–3110
Nishio M, Koshikawa T, Yatabe Y, Kuroishi T, Suyama M, Nagatake M, Sugiura T, Ariyoshi Y, Mitsudomi T, Takahashi T (1997) Prognostic significance of cyclin D1 and retinoblastoma expression in combination with p53 abnormalities in primary, resected non-small cell lung cancers. Clin Cancer Res 3:1051–1058
Saitoh G, Sugio K, Ishida T, Sugimachi K (2001) Prognostic significance of p21waf1, cyclin D1 and retinoblastoma expression detected by immunohistochemistry in non-small cell lung cancer. Oncol Rep 8:737–743
Serrano M, Hannon GJ, Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366:704–707
Spitkovsky D, Steiner P, Gopalkrishnan RV, Eilers M, Jansen-Durr P (1995) The role of p53 in coordinated regulation of cyclin D1 and p21 gene expression by the adenovirus E1A and E1B oncogenes. Oncogene 10:2421–2425
Volm M, Koomagi R (2000) Relevance of proliferative and pro-apoptotic factors in non-small-cell lung cancer for patient survival. Br J Cancer 82:1747–1754
World Health Organization (1981) Histological typing of lung tumors. International classification of tumors, 2nd edn. World Health Organization, Geneva
Zukerberg LR, Yang WI, Arnold A, Harris NL (1995) Cyclin D1 expression in non-Hodgkin’s lymphomas. Detection by immunohistochemistry. Am J Clin Pathol 103:756–60
Acknowledgements
This project was supported by the Batory Foundation in Poland. The authors would like to thank the staff of the Department of Pathology, Katharinenhospital, Stuttgart, especially Mrs. Brigitte Öchsle for her excellent laboratory assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Dworakowska, D., Jassem, E., Jassem, J. et al. Prognostic value of cyclin D1 overexpression in correlation with pRb and p53 status in non-small cell lung cancer (NSCLC). J Cancer Res Clin Oncol 131, 479–485 (2005). https://doi.org/10.1007/s00432-004-0661-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-004-0661-9