Authors' Affiliations: Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei Province, China; and Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2013 Nov 15;19(22):6252-60. doi: 10.1158/1078-0432.CCR-13-1093. Epub 2013 Sep 27.
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.
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.
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).
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.
非小细胞肺癌（NSCLC）经常转移到大脑，但确定哪些患者会发生脑转移是一个问题。磷酸肌醇 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着重要作用。我们假设该通路中的基因型变异可以预测 NSCLC 患者的脑转移。
我们通过使用来自 317 名 NSCLC 患者的血液样本中的 DNA，对五个核心基因（PIK3CA、PTEN、AKT1、AKT2 和 FRAP1）中的 16 个单核苷酸多态性（SNP）进行了基因分型，并评估了与随后发生脑转移的潜在关联，使用 Kaplan-Meier 分析估计了累积发生率。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。
在对个体 SNP 的分析中，AKT1：rs2498804 的 GT/GG 基因型、AKT1：rs2494732 的 CT/TT 基因型和 PIK3CA：rs2699887 的 AG/AA 基因型与 24 个月随访时发生脑转移的风险较高相关[各自的 HR 分别为 1.860（95%置信区间[CI]：1.199-2.885），P = 0.006；HR 为 1.902（95%CI：1.259-2.875），P = 0.002；HR 为 1.933（95%CI：1.168-3.200），P = 0.010]。我们还发现这些 SNP 对脑转移风险有累积效应，同时携带这两种不利基因型的患者风险最高（P = 0.003）。
如果在前瞻性研究中证实我们的发现，即 PI3K-AKT-mTOR 的遗传变异可以预测脑转移，这将有助于为脑转移预防试验对患者进行分层。
