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首页> 外文期刊>Clinical cancer research: an official journal of the American Association for Cancer Research >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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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

机译：非小细胞肺癌患者PI3K-PTEN-AKT-mTOR途径中单核苷酸多态性与脑转移风险增加的相关性

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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.
机译：目的：非小细胞肺癌（NSCLC）经常转移到大脑，但是确定哪些患者会发生脑转移是有问题的。磷酸肌醇3-激酶（PI3K）-AKT-mTOR信号转导通路在控制细胞生长，肿瘤发生和细胞侵袭中很重要。我们假设该途径的基因型变异可以预测NSCLC患者的脑转移。方法：我们利用来自317例NSCLC患者血液样本中的DNA，在五个核心基因（PIK3CA，PTEN，AKT1，AKT2和FRAP1）中对16个单核苷酸多态性（SNP）进行了基因分型，并评估了与脑继发发展的潜在关联转移，其累积发生率通过Kaplan-Meier分析进行估算。多变量Cox回归分析用于分析基因型变异与脑转移发生之间的相关性。结果：在单个SNP的分析中，AKT1的GT / GG基因型：rs2498804，AKT1的CT / TT基因型：rs2494732和PIK3CA的AG / AA基因型：rs2699887与24个月随访的脑转移风险更高上升[各个HR，1.860，95％置信区间（CI）1.199-2.885，P = 0.006; HR 1.902，95％CI 1.259-2.875，P = 0.002; HR 1.933，95％CI 1.168-3.200，P = 0.010]。我们进一步发现，这些SNP对脑转移风险具有累积影响，对于同时携带这两种不利基因型的患者，该风险最高（P = 0.003）。结论：我们的发现得到证实，这是第一个表明PI3K-AKT-mTOR的遗传变异可以预测脑转移的研究，在前瞻性研究中将有助于对患者进行脑转移预防试验的分层。

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