Skip to main content

Advertisement

Log in

P53 immunoexpression as a prognostic marker for human astrocytomas: a meta-analysis and review of the literature

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

An Erratum to this article was published on 18 June 2010

Abstract

During the past few decades, researchers have been looking for parameters with an impact on the prognosis of patients with astrocytic tumors. p53 is one of the most widely investigated molecules in human gliomas. We aimed to comprehensively review the evidence for the prognostic usefulness of p53 immunohistochemical expression in paraffin-embedded tissue specimens from diffusely infiltrating astrocytomas. We conducted a systematic review of the PubMed database through December 2007 to identify cohort studies that evaluated p53 immunohistochemical expression as a prognostic marker for human astrocytomas. Estimates of significance were extracted from association tests and hazard ratios with 95% CI from actuarial curves and Cox regression analyses. A meta-analysis was performed on the studies that applied Cox models and had adjusted the hazard ratio of p53 expression with tumor grade and patients’ age. We reviewed 44 publications (including 3,627 patients), 14 of which included the estimates (HR and 95% CI) derived from Cox regression. Descriptive analysis showed that most of the published articles did not contain information on important variables such as sex and age (missing from 25% and 11% of studies, respectively), previous treatment, tissue-retrieval and follow-up period (56%). The quantitative synthesis showed that p53 expression is not a significant prognostic factor (combined HR = 1.034, P = 0.531). There was no significant between-study heterogeneity and publication bias. A second meta-analysis performed only on glioblastomas showed that the overall risk of mortality in these tumors was −0.123 (−0.346 to 0.100) and was not statistically significant. After almost 20 years of research, published evidence does not substantiate the usefulness of p53 immunohistochemical expression as a prognostic marker in patients with astrocytic neoplasms.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumors of the central nervous system. Acta Neuropathol (Berl) 114(2):97–109

    Article  Google Scholar 

  2. Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C, Chin L, DePinho RA, Cavenee WK (2007) Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 21(21):2683–2710

    Article  CAS  PubMed  Google Scholar 

  3. Vogelstein B, Lane D, Levine A (2000) Surfing the p53 network. Nature 408:107–110

    Article  Google Scholar 

  4. Ishii N, deTribolet N (1998) Are p53 mutations and p53 overexpression prognostic factors for astrocytic tumors? Crit Rev Neurosurg 8:269–274

    Article  PubMed  Google Scholar 

  5. Nieder C, Petersen S, Petersen C, Thames HD (2000) The challenge of p53 as prognostic and predictive factor in gliomas. Cancer Treat Rev 26(1):67–73

    Article  CAS  PubMed  Google Scholar 

  6. Kyritsis AP, Bondy ML, Hess KR, Cunningham JE, Zhu D, Amos CJ, Yung WK, Levin VA, Bruner JM (1995) Prognostic significance of p53 immunoreactivity in patients with glioma. Clin Cancer Res 1(12):1617–1622

    CAS  PubMed  Google Scholar 

  7. al-Sarraj S, Bridges LR (1995) p53 immunoreactivity in astrocytomas and its relationship to survival. Br J Neurosurg 9(2):143–149

    Article  CAS  PubMed  Google Scholar 

  8. Burton EC, Lamborn KR, Forsyth P, Scott J, O’Campo J, Uyehara-Lock J, Prados M, Berger M, Passe S, Uhm J, O’Neill BP, Jenkins RB, Aldape KD (2002) Aberrant p53, mdm2, and proliferation differ in glioblastomas from long-term compared with typical survivors. Clin Cancer Res 8(1):180–187

    CAS  PubMed  Google Scholar 

  9. Cunningham JM, Kimmel DW, Scheithauer BW, O’Fallon JR, Novotny PJ, Jenkins RB (1997) Analysis of proliferation markers and p53 expression in gliomas of astrocytic origin: relationships and prognostic value. J Neurosurg 86(1):121–130

    Article  CAS  PubMed  Google Scholar 

  10. Grunnet ML, O’Neill A, Gilbert M, Hellman R (2000) Correlation of tumor p53 and PCNA with response and survival of glioblastoma in patients treated with an ECOG protocol of pre-irradiation chemotherapy. Clin Neuropathol 19(5):230–234

    CAS  PubMed  Google Scholar 

  11. Perry A, Jenkins RB, O’Fallon JR, Schaefer PL, Kimmel DW, Mahoney MR, Scheithauer BW, Smith SM, Hill EM, Sebo TJ, Levitt R, Krook J, Tschetter LK, Morton RF, Buckner JC (1999) Clinicopathologic study of 85 similarly treated patients with anaplastic astrocytic tumors. An analysis of DNA content (ploidy), cellular proliferation, and p53 expression. Cancer 86(4):672–683

    Google Scholar 

  12. Reavey-Cantwell JF, Haroun RI, Zahurak M, Clatterbuck RE, Parker RJ, Mehta R, Fruehauf JP, Brem H (2001) The prognostic value of tumor markers in patients with glioblastoma multiforme: analysis of 32 patients and review of the literature. J Neurooncol 55(3):195–204

    Article  CAS  PubMed  Google Scholar 

  13. Iuzzolino P, Ghimenton C, Nicolato A, Giorgiutti F, Fina P, Doglioni C, Barbareschi M (1994) p53 protein in low-grade astrocytomas: a study with long-term follow-up. Br J Cancer 69(3):586–591

    CAS  PubMed  Google Scholar 

  14. Sarkar C, Ralte AM, Sharma MC, Mehta VS (2002) Recurrent astrocytic tumors—a study of p53 immunoreactivity and malignant progression. Br J Neurosurg 16(4):335–342

    Article  CAS  PubMed  Google Scholar 

  15. Tortosa A, Viñolas N, Villà S, Verger E, Gil JM, Brell M, Caral L, Pujol T, Acebes JJ, Ribalta T, Ferrer I, Graus F (2003) Prognostic implication of clinical, radiologic, and pathologic features in patients with anaplastic gliomas. Cancer 97(4):1063–1071

    Article  PubMed  Google Scholar 

  16. Pakmar MKB, Torri V, Stewart L (1998) Extracting summary statistics to perform meta-analysis of the published literature for survival endpoints. Stat Med 17:2815–2834

    Article  Google Scholar 

  17. Drach LM, Kammermeier M, Neirich U, Jacobi G, Kornhuber B, Lorenz R, Schlote W (1996) Accumulation of nuclear p53 protein and prognosis of astrocytomas in childhood and adolescence. Clin Neuropathol 15(2):67–73

    CAS  PubMed  Google Scholar 

  18. Jaros E, Perry RH, Adam L, Kelly PJ, Crawford PJ, Kalbag RM, Mendelow AD, Sengupta RP, Pearson AD (1992) Prognostic implications of p53 protein, epidermal growth factor receptor, and Ki-67 labelling in brain tumors. Br J Cancer 66(2):373–385

    CAS  PubMed  Google Scholar 

  19. Kleinschmidt-DeMasters BK, Meltesen L, McGavran L, Lillehei KO (2006) Characterization of glioblastomas in young adults. Brain Pathol 16(4):273–286

    Article  CAS  PubMed  Google Scholar 

  20. Layfield LJ, Willmore C, Tripp S, Jones C, Jensen RL (2006) Epidermal growth factor receptor gene amplification and protein expression in glioblastoma multiforme: prognostic significance and relationship to other prognostic factors. Appl Immunohistochem Mol Morphol 14(1):91–96

    Article  CAS  PubMed  Google Scholar 

  21. Muhammad AK, Yoshimine T, Maruno M, Tokiyoshi K, Takemoto O, Ninomiya H, Hayakawa T (1997) Chromosome 17 allelic loss in astrocytic tumors and its clinico-pathologic implications. Clin Neuropathol 16(4):220–226

    CAS  PubMed  Google Scholar 

  22. Vital A, Loiseau H, Kantor G, Daucourt V, Chene G, Cohadon F, Rougier A, Rivel J, Vital C (1998) p53 protein expression in grade II astrocytomas: immunohistochemical study of 100 cases with long-term follow-up. Pathol Res Pract 194(12):831–836

    CAS  PubMed  Google Scholar 

  23. Martins DC, Malheiros SM, Santiago LH, Stávale JN (2006) Gemistocytes in astrocytomas: are they a significant prognostic factor? J Neurooncol 80(1):49–55

    Article  CAS  PubMed  Google Scholar 

  24. Saito T, Hama S, Kajiwara Y, Sugiyama K, Yamasaki F, Arifin MT, Arita K, Kurisu K (2006) Prognosis of cerebellar glioblastomas: correlation between prognosis and immunoreactivity for epidermal growth factor receptor compared with supratentorial glioblastomas. Anticancer Res 26(2B):1351–1357

    Google Scholar 

  25. Avninder S, Sharma MC, Deb P, Mehta VS, Karak AK, Mahapatra AK, Sarkar C (2006) Gemistocytic astrocytomas: histomorphology, proliferative potential and genetic alterations—a study of 32 cases. J Neurooncol 78(2):123–127. Epub 2006 Apr 14

    Google Scholar 

  26. Haapasalo JA, Nordfors KM, Hilvo M, Rantala IJ, Soini Y, Parkkila AK, Pastoreková S, Pastorek J, Parkkila SM, Haapasalo HK (2006) Expression of carbonic anhydrase IX in astrocytic tumors predicts poor prognosis. Clin Cancer Res 12(2):473–477

    Google Scholar 

  27. Ganigi PM, Santosh V, Anandh B, Chandramouli BA, Sastry Kolluri VR (2005) Expression of p53, EGFR, pRb and bcl-2 proteins in pediatric glioblastoma multiforme: a study of 54 patients. Pediatr Neurosurg 41(6):292–299

    Article  CAS  PubMed  Google Scholar 

  28. Pardo FS, Hsu DW, Zeheb R, Efird JT, Okunieff PG, Malkin DM (2004) Mutant, wild type, or overall p53 expression: freedom from clinical progression in tumors of astrocytic lineage. Br J Cancer 91(9):1678–1686

    CAS  PubMed  Google Scholar 

  29. Ribeiro Mde C, Coutinho LM, Hilbig A (2004) The role of apoptosis, cell proliferation index, bcl-2, and p53 in glioblastoma prognosis. Arq Neuropsiquiatr 62(2A):262–270. Epub 2004 Jun 23

    Google Scholar 

  30. Kirla RM, Haapasalo HK, Kalimo H, Salminen EK (2003) Low expression of p27 indicates a poor prognosis in patients with high-grade astrocytomas. Cancer 97(3):644–648

    Article  PubMed  Google Scholar 

  31. Stark AM, Hugo HH, Witzel P, Mihajlovic Z, Mehdorn HM (2003) Age-related expression of p53, Mdm2, EGFR and Msh2 in glioblastoma multiforme. Zentralbl Neurochir 64(1):30–36

    Article  CAS  PubMed  Google Scholar 

  32. Korshunov A, Golanov A, Sycheva R (2002) Immunohistochemical markers for prognosis of cerebral glioblastomas. J Neurooncol 58(3):217–236

    Article  PubMed  Google Scholar 

  33. Korshunov A, Golanov A, Sycheva R (2002) Immunohistochemical markers for prognosis of anaplastic astrocytomas. J Neurooncol 58(3):203–215

    Article  PubMed  Google Scholar 

  34. Birner P, Piribauer M, Fischer I, Gatterbauer B, Marosi C, Ungersböck K, Rössler K, Budka H, Hainfellner JA (2002) Prognostic relevance of p53 protein expression in glioblastoma. Oncol Rep 9(4):703–707

    CAS  PubMed  Google Scholar 

  35. Peraud A, Kreth FW, Wiestler OD, Kleihues P, Reulen HJ (2002) Prognostic impact of TP53 mutations and P53 protein overexpression in supratentorial WHO grade II astrocytomas and oligoastrocytomas. Clin Cancer Res 8(5):1117–1124

    CAS  PubMed  Google Scholar 

  36. Hara A, Saegusa M, Mikami T, Okayasu I (2001) Loss of DCC expression in astrocytomas: relation to p53 abnormalities, cell kinetics, and survival. J Clin Pathol 54(11):860–865

    Google Scholar 

  37. Simmons ML, Lamborn KR, Takahashi M, Chen P, Israel MA, Berger MS, Godfrey T, Nigro J, Prados M, Chang S, Barker FG 2nd, Aldape K (2001) Analysis of complex relationships between age, p53, epidermal growth factor receptor, and survival in glioblastoma patients. Cancer Res 61(3):1122–1128

    Google Scholar 

  38. Haapasalo H, Sallinen S, Sallinen P, Helén P, Jääskeläinen J, Salmi TT, Paetau A, Paljärvi L, Visakorpi T, Kalimo H (1999) Clinicopathological correlation of cell proliferation, apoptosis and p53 in cerebellar pilocytic astrocytomas. Neuropathol Appl Neurobiol 25(2):134–142

    Article  CAS  PubMed  Google Scholar 

  39. Shinoda J, Sakai N, Nakatani K, Funakoshi T (1998) Prognostic factors in supratentorial WHO grade II astrocytoma in adults. Br J Neurosurg 12(4):318–324

    Article  CAS  PubMed  Google Scholar 

  40. Bouvier-Labit C, Chinot O, Ochi C, Gambarelli D, Dufour H, Figarella-Branger D (1998) Prognostic significance of Ki67, p53 and epidermal growth factor receptor immunostaining in human glioblastomas. Neuropathol Appl Neurobiol 24(5):381–388

    Article  CAS  PubMed  Google Scholar 

  41. Hwang SL, Hong YR, Chai CY, Lin HJ, Howng SL (1998) Prognostic evaluation in supratentorial astrocytic tumors using p53, epidermal growth factor receptor, c-erbB-2 immunostaining. Kaohsiung J Med Sci 14(10):607–615

    CAS  PubMed  Google Scholar 

  42. Hilton DA, Love S, Barber R, Ellison D, Sandeman DR (1998) Accumulation of p53 and Ki-67 expression do not predict survival in patients with fibrillary astrocytomas or the response of these tumors to radiotherapy. Neurosurgery 42(4):724–729

    Article  CAS  PubMed  Google Scholar 

  43. Baxendine-Jones J, Campbell I, Ellison D (1997) p53 status has no prognostic significance in glioblastomas treated with radiotherapy. Clin Neuropathol 16(6):332–336

    CAS  PubMed  Google Scholar 

  44. Rainov NG, Dobberstein KU, Bahn H, Holzhausen HJ, Lautenschläger C, Heidecke V, Burkert W (1997) Prognostic factors in malignant glioma: influence of the overexpression of oncogene and tumor-suppressor gene products on survival. J Neurooncol 35(1):13–28

    Article  CAS  PubMed  Google Scholar 

  45. Nakamura M, Konishi N, Tsunoda S, Hiasa Y, Tsuzuki T, Inui T, Sakaki T (1997) Retinoblastoma protein expression and MIB-1 correlate with survival of patients with malignant astrocytoma. Cancer 80(2):242–249

    Article  CAS  PubMed  Google Scholar 

  46. Korkolopoulou P, Christodoulou P, Kouzelis K, Hadjiyannakis M, Priftis A, Stamoulis G, Seretis A, Thomas-Tsagli E (1997) MDM2 and p53 expression in gliomas: a multivariate survival analysis including proliferation markers and epidermal growth factor receptor. Br J Cancer 75(9):1269–1278

    CAS  PubMed  Google Scholar 

  47. Ellison DW, Steart PV, Bateman AC, Pickering RM, Palmer JD, Weller RO (1995) Prognostic indicators in a range of astrocytic tumors: an immunohistochemical study with Ki-67 and p53 antibodies. J Neurol Neurosurg Psychiatry 59(4):413–419

    Article  CAS  PubMed  Google Scholar 

  48. Danks RA, Chopra G, Gonzales MF, Orian JM, Kaye AH (1995) Aberrant p53 expression does not correlate with the prognosis in anaplastic astrocytoma. Neurosurgery 37(2):246–254

    Article  CAS  PubMed  Google Scholar 

  49. Montine TJ, Bruner JM, Vandersteenhoven JJ, Dodge RK, Burger PC (1994) Prognostic significance of p53 immunoreactivity in adult patients with supratentorial fibrillary astrocytic neoplasms. Diagn Mol Pathol 3(4):240–245

    Article  CAS  PubMed  Google Scholar 

  50. Soini Y, Niemelä A, Kamel D, Herva R, Bloigu R, Pääkkö P, Vähäkangas K (1994) p53 immunohistochemical positivity as a prognostic marker in intracranial tumors. Acta Pathol Microbiol Scand 102(10):786–792

    CAS  Google Scholar 

  51. Hainaut P, Hollstein M (2000) p53 and human cancer: the first ten thousand mutations. Adv Cancer Res 77:81–137

    Article  CAS  PubMed  Google Scholar 

  52. Greenblatt MS, Bennett WP, Hollstein M et al (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54:4855–4878

    CAS  PubMed  Google Scholar 

  53. Cordon-Cardo C, Dalbagni G, Saez GT et al (1994) p53 mutations in human bladder cancer: genotypic versus phenotypic patterns. Int J Cancer 56:347–353

    Article  CAS  PubMed  Google Scholar 

  54. Li M, Brooks CL, Kon N, Gu W (2004) A dynamic role of HAUSP in the p53-Mdm2 pathway. Mol Cell 13:879–886

    Article  CAS  PubMed  Google Scholar 

  55. Kelsey KT, Hirao T, Schned A et al (2004) A population-based study of immunohistochemical detection of p53 alteration in bladder cancer. Br J Cancer 90:1572–1576

    Article  CAS  PubMed  Google Scholar 

  56. Wynford-Thomas D (1992) Editorial: P53 in tumor pathology: can we trust immunohistochemistry? J Pathol 166:329–330

    Article  CAS  PubMed  Google Scholar 

  57. Steels E, Paesmans M, Berghmans T, Branle F, Lemaitre F, Mascaux C, Meert AP, Vallot F, Lafitte JJ, Sculier JP (2001) Role of p53 as a prognostic factor for survival in lung cancer: a systematic review of the literature with a meta-analysis. Eur Respir J 18(4):705–719

    Article  CAS  PubMed  Google Scholar 

  58. Bast RC Jr, Ravdin P, Hayes DF et al (2001) American Society of Clinical Oncology Tumor Markers Expert Panel. 2000 Update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 19:1865–1878

    PubMed  Google Scholar 

  59. Altman DG, Lausen B, Sauerbrei W et al (1994) Dangers of using “optimal” cutpoints in the evaluation of prognostic factors. J Natl Cancer Inst 86:829–835

    Article  CAS  PubMed  Google Scholar 

  60. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics. REporting recommendations for tumor MARKer prognostic studies (REMARK). Nat Clin Pract Urol 2(8):416–422

    Google Scholar 

  61. Stewart L, Parmar MKB (1993) Meta-analysis of the literature or individual patient data; is there a difference? Lancet 341:418–422

    Article  CAS  PubMed  Google Scholar 

  62. Riley RD, Burchill SA, Abrams KR et al (2003) A systematic review and evaluation of the use of tumor markers in paediatric oncology: Ewing’s sarcoma and neuroblastoma. Health Technol Assess 7:1–162

    CAS  PubMed  Google Scholar 

  63. Malats N, Bustos A, Nascimento CM, Fernandez F, Rivas M, Puente D, Kogevinas M, Real FX (2005) P53 as a prognostic marker for bladder cancer: a meta-analysis and review. Lancet Oncol 6(9):678–686

    Article  CAS  PubMed  Google Scholar 

  64. Cordon-Cardo C (2004) p53 and Rb: simple interesting correlates or tumor markers of clinical predictive nature? J Clin Oncol 22:1–3

    Article  Google Scholar 

  65. Laupacis A, Wells G, Richardson WS, for the Evidence-Based Medicine Working Group et al (1994) Users’ guides to the medical literature V: how to use an article about prognosis. J Am Med Assoc 272:234–237

    Article  CAS  Google Scholar 

Download references

Acknowledgment

This work was partly funded by a scholarship of Propondis Foundation to Georgia Levidou.

Conflict of Interest

We declare that there are no conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Georgia Levidou.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s11060-010-0270-1

Rights and permissions

Reprints and permissions

About this article

Cite this article

Levidou, G., El-Habr, E., Saetta, A.A. et al. P53 immunoexpression as a prognostic marker for human astrocytomas: a meta-analysis and review of the literature. J Neurooncol 100, 363–371 (2010). https://doi.org/10.1007/s11060-010-0204-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-010-0204-y

Keywords

Navigation