Khor Li-Yan, Desilvio Michelle, Al-Saleem Tahseen, Hammond M Elizabeth, Grignon David J, Sause William, Pilepich Michael, Okunieff Paul, Sandler Howard, Pollack Alan
Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Cancer. 2005 Sep 1;104(5):962-7. doi: 10.1002/cncr.21261.
The MDM2 oncoprotein promotes p53 degradation via ubiquitin, establishing negative feedback control of p53 and consequently affecting cell cycle arrest and apoptosis. The authors evaluated the association between MDM2 expression and local failure, distant metastasis (DM), cause-specific mortality, and overall mortality in men treated in Radiation Therapy Oncology Group 8610 with radiotherapy, with or without androgen deprivation.
Of the 456 eligible and analyzable patients (parent cohort), adequate archival diagnostic tissue specimens from 108 patients were available for MDM2 analysis (MDM2 cohort). Cox proportional hazards multivariate analysis (MVA) was used to determine the relation of MDM2 to the endpoints. MDM2 overexpression was manually classified as > 5% nuclear staining. An image analysis system was also used to quantify the proportion of tumor nuclei with MDM2 staining (ACIS index) and staining intensity.
Overexpression of MDM2 by manual counts was seen in 44% (n = 47) of the patients. In the manual count analysis, there was no significant relation between MDM2 overexpression and outcome. The ACIS index, using a cutoff point defined by the median value, < or = 3% versus > 3%, was related to 5-year DM rates in univariate analyses (32.6% vs. 45.8%; P = 0.057) and MVA (P = 0.06). The intensity of MDM2 staining was not significant.
MDM2 expression quantified by image analysis was weakly associated with DM. The cohort examined was relatively small and with larger patient numbers, MDM2 overexpression may emerge as a more significant covariate.
MDM2癌蛋白通过泛素促进p53降解，建立对p53的负反馈控制，从而影响细胞周期停滞和细胞凋亡。作者评估了在放射治疗肿瘤学组8610中接受放疗（有或无雄激素剥夺）的男性患者中，MDM2表达与局部失败、远处转移（DM）、特定病因死亡率和总死亡率之间的关联。
在456例符合条件且可分析的患者（母队列）中，有108例患者的足够存档诊断组织标本可用于MDM2分析（MDM2队列）。采用Cox比例风险多变量分析（MVA）来确定MDM2与各终点之间的关系。MDM2过表达通过手动分类为核染色>5%。还使用图像分析系统来量化具有MDM2染色的肿瘤细胞核比例（ACIS指数）和染色强度。
通过手动计数，44%（n = 47）的患者出现MDM2过表达。在手动计数分析中，MDM2过表达与结局之间无显著关系。ACIS指数采用中位数定义的截断点，≤3%与>3%，在单变量分析中与5年DM率相关（32.6%对45.8%；P = 0.057），在MVA中也相关（P = 0.06）。MDM2染色强度无显著性。
通过图像分析量化的MDM2表达与DM弱相关。所检查的队列相对较小，随着患者数量增加，MDM2过表达可能成为更显著的协变量。
