High Expression of Mammalian Target of Rapamycin Is Associated with Better Outcome for Patients with Early Stage Lung Adenocarcinoma
High Expression of Mammalian Target of Rapamycin Is Associated with Better Outcome for Patients with Early Stage Lung Adenocarcinoma
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DOI：
10.1158/1078-0432.ccr-09-0099
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发表时间：
2009-06-15
影响因子：
11.5
通讯作者：
Rimm, David L.
中科院分区：
文献类型：
--
作者：
Anagnostou, Valsamo K.;Bepler, Gerold;Rimm, David L.
目的：哺乳动物雷帕霉素靶蛋白（mTOR）是磷脂酰肌醇3-激酶（PI 3 K）/AKT下游的关键激酶，在营养和能量存在下主要参与翻译调控。尽管mTOR在癌发生中的作用是众所周知的，但其在肺癌中的预后潜力尚未研究。在这里，我们在两个大数据集中定量评估mTOR蛋白表达，以研究mTOR表达对患者生存的影响。自动定量分析（AQUA），一种用于原位蛋白表达分析的基于荧光的方法，用于评估167名肺癌患者的训练队列中的mTOR表达，235例肺癌患者的独立队列研究结果：在训练组和验证组中，分别有56%和50%的肿瘤在细胞质中表达mTOR; mTOR表达与标准临床或病理特征无关。与低表达者相比，高mTOR表达患者的中位总生存期较长（52.7 vs 38.5个月;对数秩P = 0.06），腺癌组中更为突出（55.7 vs 38.88个月;对数秩P = 0.018）。多变量分析显示，腺癌和腺癌IA期mTOR表达肿瘤患者的死亡风险独立降低（危害比，0.48; 95%可信区间，0.24-0.98; P = 0.04，危害比，0.12; 95%可信区间，0.03-0.72; P = 0.019）。mTOR表达定义了一个具有良好结局的患者亚组，可能有助于肺腺癌患者的预后分层以及将mTOR纳入临床决策。
Purpose: Mammalian target of rapamycin (mTOR) is a key kinase downstream of phosphoinositide 3-kinase (PI3K)/AKT predominantly involved in translational control in the presence of nutrients and energy. Despite the well known role of mTOR in carcinogenesis, its prognostic potential in lung cancer has not been investigated. Here, we quantitatively assessed mTOR protein expression in two large data sets to investigate the impact of mTOR expression on patient survival.Experimental Design: Automated quantitative analysis (AQUA), a fluorescent-based method for analysis of in situ protein expression, was used to assess mTOR expression in a training cohort of 167 lung cancer patients, An independent cohort of 235 lung cancer patients (from a second institution) was used for validation.Results: Tumors expressed mTOR in the cytoplasm in 56% and 50% of the cases in training and validation cohorts, respectively; mTOR expression was not associated with standard clinical or pathologic characteristics. Patients with high mTOR expression had a longer median overall survival compared with the low expressers (52.7 versus 38.5 months; log rank P = 0.06), which was more prominent in the adenocarcinoma group (55.7 versus 38.88 months; log rank P = 0.018). Multivariate analysis revealed an independent lower risk of death for adenocarcinoma and adenocarcinoma stage IA patients with mTOR-expressing tumors (hazard ratio, 0.48; 95% confidence interval, 0.24-0.98; P = 0.04, and hazard ratio, 0.12; 95% confidence interval, 0.03-0.72; P = 0.019, respectively).Conclusions: mTOR expression defines a subgroup of patients with a favorable outcome and may be useful for prognostic stratification of lung adenocarcinoma patients as well as incorporation of mTOR into clinical decisions.