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Alterations of G1-S checkpoint in chordoma

The prognostic impact of p53 overexpression

  1. Takahiko Naka M.D.1,†,*,
  2. Carsten Boltze M.D.1,
  3. Doerthe Kuester M.D.1,
  4. Torss-Oliver Schulz M.D.1,
  5. Regine Schneider-Stock Ph.D.1,
  6. Angela Kellner Ph.D.1,
  7. Amir Samii M.D.2,
  8. Christian Herold M.D.2,
  9. Helmut Ostertag M.D.3,
  10. Albert Roessner M.D.1

Article first published online: 2 AUG 2005

DOI: 10.1002/cncr.21296

Issue

Cancer

Cancer

Volume 104, Issue 6, pages 1255–1263, 15 September 2005

Additional Information

How to Cite

Naka, T., Boltze, C., Kuester, D., Schulz, T.-O., Schneider-Stock, R., Kellner, A., Samii, A., Herold, C., Ostertag, H. and Roessner, A. (2005), Alterations of G1-S checkpoint in chordoma. Cancer, 104: 1255–1263. doi: 10.1002/cncr.21296

Author Information

  1. 1

    Department of Pathology, Faculty of Medicine, Otto-von-Guericke University Magdeburg, Magdeburg, Germany

  2. 2

    Department of Neurosurgery, Nordstadt Medical Center, Klinikum Hanover, Hanover, Germany

  3. 3

    Department of Pathology, Nordstadt Medical Center, Klinikum Hanover, Hanover, Germany

  1. †

    Fax: (011) 81 934730627

*Department of Orthopedic Surgery, Kyushu Rosai Hospital, 1-3-1 Kuzuharatakamatsu, Kokuraminami-ku, Kitakyushu, Fukuoka, 800-0296, Japan

Publication History

  1. Issue published online: 31 AUG 2005
  2. Article first published online: 2 AUG 2005
  3. Manuscript Accepted: 25 APR 2005
  4. Manuscript Revised: 30 MAR 2005
  5. Manuscript Received: 27 JAN 2005

Funded by

  • Alexander von Humboldt Foundation, Germany

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Keywords:

  • chordoma;
  • p53;
  • murine double minute 2;
  • cyclin D1;
  • retinoblastoma protein;
  • pleomorphism;
  • prognosis

Abstract

BACKGROUND

To the authors' knowledge, little is known regarding the alterations of G1-S checkpoint and their significance in chordoma, a rare bone tumor. The authors investigated the clinicopathologic relevance of cell cycle abnormalities in chordoma.

METHODS

The expression levels of p53, murine double minute 2 (MDM2), retinoblastoma protein (pRb), cyclin D1, p16INK4a, and p27Kip1 were investigated using immunohistochemical techniques; p53 mutations were studied by polymerase chain reaction (PCR)-single-strand conformation polymorphism, and mdm2 amplification was analyzed using real-time quantitative PCR. The results were compared with clinicopathologic parameters in 101 lesions.

RESULTS

Approximately 10–45% of primary tumors presented alterations of p53, MDM2, cyclin D1, and pRb proteins; most tumors lacked expression of p16INK4a and p27Kip1. Alterations of p53, MDM2, cyclin D1, and pRb proteins were found to have cooperative effects on both higher proliferative ability (MIB-1 labeling index [LI]) and increased nuclear pleomorphism, a previously described prognostic indicator for patients with chordoma. Multivariate analyses revealed that, among these alterations, p53 overexpression was the only independent factor for higher MIB-1 LI. At the genetic level, mdm2 gene amplification was detected in 15.4% of the lesions but did not correlate with MDM2 overexpression or other clinicopathologic parameters. No p53 mutations were detected in the current series. Survival analysis revealed that p53 overexpression, but no other cell cycle alterations, was associated with a reduced overall survival.

CONCLUSIONS

Accumulation of cell cycle alterations led to an increased MIB-1 LI and nuclear pleomorphism, a previously described prognostic indicator in chordoma. The authors believe that p53 overexpression in particular is associated with an unfavorable prognosis in patients with chordoma. Cancer 2005. © 2005 American Cancer Society.

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