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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Purpose:Non-small cell lung cancer (NSCLC) metastasizes fairly often to the brain, but identifying which patients will develop brain metastases (BM) is problematic. The phosphatidylinositol-3 kinase (PI3K)-AKT-mammalian target of rapamycin (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 BM in patients with NSCLC. Experimental Design:We genotyped 16 single nucleotide polymorphisms (SNPs) in 5 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 BM, 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 BM. 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 BM at 24 months' follow-up (respective hazard ratios [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 BM 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 BM, in prospective studies would facilitate stratification of patients for BM prevention trials. |
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