Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9110, USA.
Urology. 2013 Mar;81(3):581-6. doi: 10.1016/j.urology.2012.11.030. Epub 2013 Jan 3.
To evaluate the association of the altered expression of the mammalian target of rapamycin (mTOR) pathway components with oncologic outcomes in patients with nonmetastatic clear cell renal cell carcinoma (ccRCC).
Immunohistochemistry for phosphorylated-S6, phosphorylated-mTOR, mTOR, phosphorylated-AKT, hypoxia inducible factor-1α, Raptor, phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K), and phosphorylated 4E-binding protein-1 was performed on tissue microarray constructs of patients treated for nonmetastatic kidney cancer from 1997 to 2010. The relationship between individual altered marker expression and a prognostic marker score (low, intermediate, and high, defined as ≤ 3, 4-5, >5 altered biomarkers, respectively) and oncologic outcome was assessed.
The study included 419 patients with nonmetastatic ccRCC, with a median follow-up period of 26 months (range 6-150). The tumors were nonorgan confined (pT3-T4) in 86 (20.5%) and high Fuhrman nuclear grade (3-4) in 131 (31%). A low, intermediate, and high prognostic marker score was found in 214 (51%), 152 (36%), and 53 (13%) patients, respectively. Kaplan-Meier analysis demonstrated a statistically significant correlation between the risk groups and disease recurrence and cancer-specific survival. In a multivariate Cox regression analysis controlling for tumor stage and grade, a high marker score was an independent predictor of disease recurrence (hazard ratio 3.3, 95% confidence interval 1.33-8.39, P = .01), and a combination of a high and an intermediate score was an independent predictor of survival (hazard ratio 4.8, 95% confidence interval 1.27-4.78, P = .008).
The cumulative number of aberrantly expressed biomarkers correlated with aggressive tumor biology and inferior oncologic outcomes in patients with ccRCC. Our data support prospective pathway-based exploration of the mTOR signaling cascade to augment current clinicopathologic predictors of oncologic outcomes in patients with ccRCC.
评估哺乳动物雷帕霉素靶蛋白（mTOR）通路成分表达改变与非转移性透明细胞肾细胞癌（ccRCC）患者肿瘤学结局的相关性。
对 1997 年至 2010 年间接受非转移性肾癌治疗的患者的组织微阵列标本进行磷酸化 S6、磷酸化 mTOR、mTOR、磷酸化 AKT、缺氧诱导因子 1α、Raptor、磷酸酶和张力蛋白同源物（PTEN）、磷酸肌醇 3-激酶（PI3K）和磷酸化 4E 结合蛋白-1 的免疫组化染色。评估个体标记物表达改变与预后标记物评分（低、中、高，分别定义为≤3、4-5、>5 个改变的生物标志物）之间的关系，并评估其与肿瘤学结局的关系。
研究纳入 419 例非转移性 ccRCC 患者，中位随访时间为 26 个月（范围 6-150）。86 例肿瘤未局限于器官（pT3-T4），131 例肿瘤核分级高（3-4 级）。214 例患者的预后标志物评分低、中、高，分别为 214 例（51%）、152 例（36%）和 53 例（13%）。Kaplan-Meier 分析显示，风险组与疾病复发和癌症特异性生存之间存在统计学显著相关性。在多变量 Cox 回归分析中，控制肿瘤分期和分级后，高标志物评分是疾病复发的独立预测因子（风险比 3.3，95%置信区间 1.33-8.39，P =.01），高和中标志物评分的组合是生存的独立预测因子（风险比 4.8，95%置信区间 1.27-4.78，P =.008）。
异常表达的生物标志物数量与 ccRCC 患者侵袭性肿瘤生物学和不良肿瘤学结局相关。我们的数据支持对 mTOR 信号级联进行前瞻性的基于途径的探索，以增强目前预测 ccRCC 患者肿瘤学结局的临床病理预测因子。
