Alterations of G1-S checkpoint in chordoma: the prognostic impact of p53 overexpression.
BACKGROUND
To the authors' knowledge, little is known regarding the alterations of G(1)-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, p16(INK4a), and p27(Kip1) 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 p16(INK4a) and p27(Kip1). 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.
Naka
Takahiko
T
Department of Pathology, Faculty of Medicine, Otto-von-Guericke University Magdeburg, Germany. takahicom@hotmail.com
Boltze
Carsten
C
Kuester
Doerthe
D
Schulz
Torss-Oliver
TO
Schneider-Stock
Regine
R
Kellner
Angela
A
Samii
Amir
A
Herold
Christian
C
Ostertag
Helmut
H
Roessner
Albert
A
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001859:Bone Neoplasms / Q000737:chemistry / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D002648:Child; D002817:Chordoma / Q000737:chemistry / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D019938:Cyclin D1 / Q000032:analysis; D016193:G1 Phase; D006801:Humans; D008875:Middle Aged; D009687:Nuclear Proteins / Q000032:analysis; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000032:analysis; D051736:Proto-Oncogene Proteins c-mdm2; D016160:Retinoblastoma Protein / Q000032:analysis; D016196:S Phase; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*
D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2