Associations between Single-Nucleotide Polymorphisms in the PI3K-PTEN-AKT-mTOR Pathway and Increased Risk of Brain Metastasis in Patients with Non-Small Cell Lung Cancer
Associations between Single-Nucleotide Polymorphisms in the PI3K-PTEN-AKT-mTOR Pathway and Increased Risk of Brain Metastasis in Patients with Non-Small Cell Lung Cancer
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PI3K-PTEN-AKT-mTOR 通路中的单核苷酸多态性与非小细胞肺癌患者脑转移风险增加之间的关联
DOI：
10.1158/1078-0432.ccr-13-1093
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发表时间：
2013-11-15
影响因子：
11.5
通讯作者：
Liao, Zhongxing
中科院分区：
文献类型：
--
作者：
Li, Qianxia;Yang, Ju;Liao, Zhongxing
目的：非小细胞肺癌(NSCLC)经常发生脑转移，但确定哪些患者会发生脑转移是有问题的。磷脂酰肌醇3-激酶(PI3K)-AKT-mTOR信号通路在控制细胞生长、肿瘤发生和细胞侵袭中起重要作用。我们假设该通路中的基因变异可以预测非小细胞肺癌患者的脑转移。方法：我们利用317例非小细胞肺癌患者的血液样本DNA，对5个核心基因(PIK3CA、PTEN、AKT1、AKT2和FRAP1)中的16个单核苷酸多态(SNP)进行了基因分型，并用Kaplan-Meier分析估计了其累积发生率。结果：在个体SNPs分析中，AKT1：rs2498804的GT/GG、AKT1：rs2494732的CT/TT、PIK3CA：rs2699887的AG/AA等位基因与24个月后脑转移的危险性显著相关[分别为HRs，1.860，95%可信区间(CI)1.199~2.885，P=0.006；HR 1.902，95%CI 1.259~2.875，P=0.002；HR为1.933，95%CI为1.168~3.200，P=0.010]。我们进一步发现，这些SNPs对脑转移风险有累积效应，其中携带这两种不利基因的患者的风险最高(P=0.003)。结论：首次证实我们的发现，首次表明PI3K-AKT-mTOR基因变异可以预测脑转移，在前瞻性研究中将有助于对脑转移预防试验的患者进行分层。(C)2013年AACR。
Purpose: Non-small cell lung cancer (NSCLC) metastasizes fairly often to the brain, but identifying which patients will develop brain metastases is problematic. The phosphoinositide 3-kinase (PI3K)-AKT-mTOR signaling pathway is important in the control of cell growth, tumorigenesis, and cell invasion. We hypothesized that genotype variants in this pathway could predict brain metastasis in patients with NSCLC.Methods: We genotyped 16 single-nucleotide polymorphisms (SNP) in five core genes (PIK3CA, PTEN, AKT1, AKT2, and FRAP1) by using DNA from blood samples of 317 patients with NSCLC, and evaluated potential associations with the subsequent development of brain metastasis, the cumulative incidence of which was estimated with Kaplan-Meier analysis. Multivariate Cox regression analysis was used to analyze correlations between genotype variants and the occurrence of brain metastasis.Results: In analysis of individual SNPs, the GT/GG genotype of AKT1: rs2498804, CT/TT genotype of AKT1: rs2494732, and AG/AA genotype of PIK3CA: rs2699887 were associated with higher risk of brain metastasis at 24-month follow-up [respective HRs, 1.860, 95% confidence interval (CI) 1.199-2.885, P = 0.006; HR 1.902, 95% CI 1.259-2.875, P = 0.002; and HR 1.933, 95% CI 1.168-3.200, P = 0.010]. We further found that these SNPs had a cumulative effect on brain metastasis risk, with that risk being highest for patients carrying both of these unfavorable genotypes (P = 0.003).Conclusions: Confirmation of our findings, the first to indicate that genetic variations in PI3K-AKT-mTOR can predict brain metastasis, in prospective studies would facilitate stratification of patients for brain metastasis prevention trials. (C) 2013 AACR.