Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Oct;81(4):696–701. doi: 10.1038/sj.bjc.6690750

Predictive value of expression of p16INK4A, retinoblastoma and p53 proteins for the prognosis of non-small-cell lung cancers

F Hommura 1, H Dosaka-Akita 1, I Kinoshita 1, T Mishina 1, H Hiroumi 1, S Ogura 1, H Katoh 2, Y Kawakami 1
PMCID: PMC2362891  PMID: 10574258

Abstract

The predictive value of expression of p16INK4A, retinoblastoma (Rb) and p53 proteins for prognosis was evaluated in 76 patients with non-small-cell lung cancers (NSCLCs) that were potentially curatively resected between 1990 and 1995, using the results of immunostaining analyses of these proteins as reported in our previous study (Kinoshita et al, 1996). Of these NSCLCs, 22 (29%) lacked p16 protein expression and eight (11%) Rb protein, while 30 (39%) showed positive (altered) p53 protein expression. Survival of patients with p16-negative tumours was not significantly different from that of patients with p16-positive tumours (5-year survival rates 67% and 72% respectively, P = 0.8), nor was survival of patients with Rb-negative tumours significantly different from that of patients with Rb-positive tumours (5-year survival rates 42% and 69% respectively, P = 0.9). Moreover, survival of patients with p16/Rb-negative (either p16- or Rb-negative) tumours was not significantly different from that of patients with p16/Rb-positive (both p16- and Rb-positive) tumours (5-year survival rates 67% and 68% respectively, P = 0.7). In contrast, survival of patients with p53-positive (altered) tumours tended to be shorter than that of patients with p53-negative (unaltered) tumours (5-year survival rates 56% and 78% respectively, P = 0.06). In univariate analysis of potential prognostic factors, p16, Rb and p16/Rb proteins were not significant prognostic factors in the present cohort of potentially curatively resected NSCLCs. Altered p53 protein status tended to be a negative prognostic factor (P = 0.06 by the univariate analysis). These results indicate that loss of p16 protein alone, or in combination with loss of Rb protein, does not predict the clinical outcome of patients with resected NSCLCs. © 1999 Cancer Research Campaign

Keywords: cell cycle regulator, G1 checkpoint, clinical outcome

Full Text

The Full Text of this article is available as a PDF (231.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Betticher D. C., White G. R., Vonlanthen S., Liu X., Kappeler A., Altermatt H. J., Thatcher N., Heighway J. G1 control gene status is frequently altered in resectable non-small cell lung cancer. Int J Cancer. 1997 Oct 21;74(5):556–562. doi: 10.1002/(sici)1097-0215(19971021)74:5<556::aid-ijc14>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]
  2. Cairns P., Mao L., Merlo A., Lee D. J., Schwab D., Eby Y., Tokino K., van der Riet P., Blaugrund J. E., Sidransky D. Rates of p16 (MTS1) mutations in primary tumors with 9p loss. Science. 1994 Jul 15;265(5170):415–417. doi: 10.1126/science.8023167. [DOI] [PubMed] [Google Scholar]
  3. Dosaka-Akita H., Hu S. X., Fujino M., Harada M., Kinoshita I., Xu H. J., Kuzumaki N., Kawakami Y., Benedict W. F. Altered retinoblastoma protein expression in nonsmall cell lung cancer: its synergistic effects with altered ras and p53 protein status on prognosis. Cancer. 1997 Apr 1;79(7):1329–1337. [PubMed] [Google Scholar]
  4. Dosaka-Akita H., Shindoh M., Fujino M., Kinoshita I., Akie K., Katoh M., Kawakami Y. Abnormal p53 expression in human lung cancer is associated with histologic subtypes and patient smoking history. Am J Clin Pathol. 1994 Nov;102(5):660–664. doi: 10.1093/ajcp/102.5.660. [DOI] [PubMed] [Google Scholar]
  5. Fujino M., Dosaka-Akita H., Harada M., Hiroumi H., Kinoshita I., Akie K., Kawakami Y. Prognostic significance of p53 and ras p21 expression in nonsmall cell lung cancer. Cancer. 1995 Dec 15;76(12):2457–2463. doi: 10.1002/1097-0142(19951215)76:12<2457::aid-cncr2820761209>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  6. GEHAN E. A. A GENERALIZED WILCOXON TEST FOR COMPARING ARBITRARILY SINGLY-CENSORED SAMPLES. Biometrika. 1965 Jun;52:203–223. [PubMed] [Google Scholar]
  7. Geradts J., Kratzke R. A., Niehans G. A., Lincoln C. E. Immunohistochemical detection of the cyclin-dependent kinase inhibitor 2/multiple tumor suppressor gene 1 (CDKN2/MTS1) product p16INK4A in archival human solid tumors: correlation with retinoblastoma protein expression. Cancer Res. 1995 Dec 15;55(24):6006–6011. [PubMed] [Google Scholar]
  8. Hannon G. J., Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature. 1994 Sep 15;371(6494):257–261. doi: 10.1038/371257a0. [DOI] [PubMed] [Google Scholar]
  9. Hayashi N., Sugimoto Y., Tsuchiya E., Ogawa M., Nakamura Y. Somatic mutations of the MTS (multiple tumor suppressor) 1/CDK4l (cyclin-dependent kinase-4 inhibitor) gene in human primary non-small cell lung carcinomas. Biochem Biophys Res Commun. 1994 Aug 15;202(3):1426–1430. doi: 10.1006/bbrc.1994.2090. [DOI] [PubMed] [Google Scholar]
  10. Horio Y., Takahashi T., Kuroishi T., Hibi K., Suyama M., Niimi T., Shimokata K., Yamakawa K., Nakamura Y., Ueda R. Prognostic significance of p53 mutations and 3p deletions in primary resected non-small cell lung cancer. Cancer Res. 1993 Jan 1;53(1):1–4. [PubMed] [Google Scholar]
  11. Kelley M. J., Nakagawa K., Steinberg S. M., Mulshine J. L., Kamb A., Johnson B. E. Differential inactivation of CDKN2 and Rb protein in non-small-cell and small-cell lung cancer cell lines. J Natl Cancer Inst. 1995 May 17;87(10):756–761. doi: 10.1093/jnci/87.10.756. [DOI] [PubMed] [Google Scholar]
  12. Kinoshita I., Dosaka-Akita H., Mishina T., Akie K., Nishi M., Hiroumi H., Hommura F., Kawakami Y. Altered p16INK4 and retinoblastoma protein status in non-small cell lung cancer: potential synergistic effect with altered p53 protein on proliferative activity. Cancer Res. 1996 Dec 15;56(24):5557–5562. [PubMed] [Google Scholar]
  13. Kratzke R. A., Greatens T. M., Rubins J. B., Maddaus M. A., Niewoehner D. E., Niehans G. A., Geradts J. Rb and p16INK4a expression in resected non-small cell lung tumors. Cancer Res. 1996 Aug 1;56(15):3415–3420. [PubMed] [Google Scholar]
  14. Lukas J., Parry D., Aagaard L., Mann D. J., Bartkova J., Strauss M., Peters G., Bartek J. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature. 1995 Jun 8;375(6531):503–506. doi: 10.1038/375503a0. [DOI] [PubMed] [Google Scholar]
  15. Mitsudomi T., Oyama T., Kusano T., Osaki T., Nakanishi R., Shirakusa T. Mutations of the p53 gene as a predictor of poor prognosis in patients with non-small-cell lung cancer. J Natl Cancer Inst. 1993 Dec 15;85(24):2018–2023. doi: 10.1093/jnci/85.24.2018. [DOI] [PubMed] [Google Scholar]
  16. Nakagawa K., Conrad N. K., Williams J. P., Johnson B. E., Kelley M. J. Mechanism of inactivation of CDKN2 and MTS2 in non-small cell lung cancer and association with advanced stage. Oncogene. 1995 Nov 2;11(9):1843–1851. [PubMed] [Google Scholar]
  17. Nishio M., Koshikawa T., Kuroishi T., Suyama M., Uchida K., Takagi Y., Washimi O., Sugiura T., Ariyoshi Y., Takahashi T. Prognostic significance of abnormal p53 accumulation in primary, resected non-small-cell lung cancers. J Clin Oncol. 1996 Feb;14(2):497–502. doi: 10.1200/JCO.1996.14.2.497. [DOI] [PubMed] [Google Scholar]
  18. Nishio M., Koshikawa T., Yatabe Y., Kuroishi T., Suyama M., Nagatake M., Sugiura T., Ariyoshi Y., Mitsudomi T., Takahashi T. Prognostic significance of cyclin D1 and retinoblastoma expression in combination with p53 abnormalities in primary, resected non-small cell lung cancers. Clin Cancer Res. 1997 Jul;3(7):1051–1058. [PubMed] [Google Scholar]
  19. Okamoto A., Demetrick D. J., Spillare E. A., Hagiwara K., Hussain S. P., Bennett W. P., Forrester K., Gerwin B., Serrano M., Beach D. H. Mutations and altered expression of p16INK4 in human cancer. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11045–11049. doi: 10.1073/pnas.91.23.11045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Okamoto A., Hussain S. P., Hagiwara K., Spillare E. A., Rusin M. R., Demetrick D. J., Serrano M., Hannon G. J., Shiseki M., Zariwala M. Mutations in the p16INK4/MTS1/CDKN2, p15INK4B/MTS2, and p18 genes in primary and metastatic lung cancer. Cancer Res. 1995 Apr 1;55(7):1448–1451. [PubMed] [Google Scholar]
  21. Otterson G. A., Khleif S. N., Chen W., Coxon A. B., Kaye F. J. CDKN2 gene silencing in lung cancer by DNA hypermethylation and kinetics of p16INK4 protein induction by 5-aza 2'deoxycytidine. Oncogene. 1995 Sep 21;11(6):1211–1216. [PubMed] [Google Scholar]
  22. Otterson G. A., Kratzke R. A., Coxon A., Kim Y. W., Kaye F. J. Absence of p16INK4 protein is restricted to the subset of lung cancer lines that retains wildtype RB. Oncogene. 1994 Nov;9(11):3375–3378. [PubMed] [Google Scholar]
  23. Quinlan D. C., Davidson A. G., Summers C. L., Warden H. E., Doshi H. M. Accumulation of p53 protein correlates with a poor prognosis in human lung cancer. Cancer Res. 1992 Sep 1;52(17):4828–4831. [PubMed] [Google Scholar]
  24. Serrano M., Hannon G. J., Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993 Dec 16;366(6456):704–707. doi: 10.1038/366704a0. [DOI] [PubMed] [Google Scholar]
  25. Shapiro G. I., Edwards C. D., Kobzik L., Godleski J., Richards W., Sugarbaker D. J., Rollins B. J. Reciprocal Rb inactivation and p16INK4 expression in primary lung cancers and cell lines. Cancer Res. 1995 Feb 1;55(3):505–509. [PubMed] [Google Scholar]
  26. Taga S., Osaki T., Ohgami A., Imoto H., Yoshimatsu T., Yoshino I., Yano K., Nakanishi R., Ichiyoshi Y., Yasumoto K. Prognostic value of the immunohistochemical detection of p16INK4 expression in nonsmall cell lung carcinoma. Cancer. 1997 Aug 1;80(3):389–395. doi: 10.1002/(sici)1097-0142(19970801)80:3<389::aid-cncr6>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
  27. Tam S. W., Shay J. W., Pagano M. Differential expression and cell cycle regulation of the cyclin-dependent kinase 4 inhibitor p16Ink4. Cancer Res. 1994 Nov 15;54(22):5816–5820. [PubMed] [Google Scholar]
  28. Xu H. J., Cagle P. T., Hu S. X., Li J., Benedict W. F. Altered retinoblastoma and p53 protein status in non-small cell carcinoma of the lung: potential synergistic effects on prognosis. Clin Cancer Res. 1996 Jul;2(7):1169–1176. [PubMed] [Google Scholar]
  29. Xu H. J., Hu S. X., Benedict W. F. Lack of nuclear RB protein staining in G0/middle G1 cells: correlation to changes in total RB protein level. Oncogene. 1991 Jul;6(7):1139–1146. [PubMed] [Google Scholar]
  30. Xu H. J., Hu S. X., Cagle P. T., Moore G. E., Benedict W. F. Absence of retinoblastoma protein expression in primary non-small cell lung carcinomas. Cancer Res. 1991 May 15;51(10):2735–2739. [PubMed] [Google Scholar]
  31. Xu H. J., Quinlan D. C., Davidson A. G., Hu S. X., Summers C. L., Li J., Benedict W. F. Altered retinoblastoma protein expression and prognosis in early-stage non-small-cell lung carcinoma. J Natl Cancer Inst. 1994 May 4;86(9):695–699. doi: 10.1093/jnci/86.9.695. [DOI] [PubMed] [Google Scholar]
  32. Yatabe Y., Masuda A., Koshikawa T., Nakamura S., Kuroishi T., Osada H., Takahashi T., Mitsudomi T., Takahashi T. p27KIP1 in human lung cancers: differential changes in small cell and non-small cell carcinomas. Cancer Res. 1998 Mar 1;58(5):1042–1047. [PubMed] [Google Scholar]
  33. Zhang X., Xu H. J., Murakami Y., Sachse R., Yashima K., Hirohashi S., Hu S. X., Benedict W. F., Sekiya T. Deletions of chromosome 13q, mutations in Retinoblastoma 1, and retinoblastoma protein state in human hepatocellular carcinoma. Cancer Res. 1994 Aug 1;54(15):4177–4182. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES