Naka Takahiko, Boltze Carsten, Kuester Doerthe, Schulz Torss-Oliver, Schneider-Stock Regine, Kellner Angela, Samii Amir, Herold Christian, Ostertag Helmut, Roessner Albert
Department of Pathology, Faculty of Medicine, Otto-von-Guericke University Magdeburg, Germany.
Cancer. 2005 Sep 15;104(6):1255-63. doi: 10.1002/cncr.21296.
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.
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.
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.
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.
据作者所知，关于G(1)-S 检查点的改变及其在脊索瘤（一种罕见的骨肿瘤）中的意义，人们了解甚少。作者研究了脊索瘤中细胞周期异常的临床病理相关性。
采用免疫组织化学技术检测p53、鼠双微体2（MDM2）、视网膜母细胞瘤蛋白（pRb）、细胞周期蛋白D1、p16(INK4a)和p27(Kip1)的表达水平；通过聚合酶链反应（PCR）-单链构象多态性研究p53突变，并使用实时定量PCR分析mdm2扩增情况。将结果与101个病变的临床病理参数进行比较。
约10%-45%的原发性肿瘤存在p53、MDM2、细胞周期蛋白D1和pRb蛋白的改变；大多数肿瘤缺乏p16(INK4a)和p27(Kip1)的表达。发现p53、MDM2、细胞周期蛋白D1和pRb蛋白的改变对较高的增殖能力（MIB-1标记指数[LI]）和增加的核多形性均有协同作用，核多形性是先前描述的脊索瘤患者的预后指标。多变量分析显示，在这些改变中，p53过表达是较高MIB-1 LI的唯一独立因素。在基因水平上，15.4%的病变中检测到mdm2基因扩增，但与MDM2过表达或其他临床病理参数无关。在本系列中未检测到p53突变。生存分析显示，p53过表达而非其他细胞周期改变与总生存率降低相关。
细胞周期改变的积累导致MIB-1 LI增加和核多形性增加，核多形性是先前描述的脊索瘤预后指标。作者认为，特别是p53过表达与脊索瘤患者的不良预后相关。
