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

Abstract

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)-AKTmTOR 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 ¼ 0.006; HR 1.902, 95% CI 1.259-2.875, P ¼ 0.002; and HR 1.933, 95% CI 1.168-3.200, P ¼ 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 ¼ 0.003).Conclusions: Confirmation of our findings, the first to indicate that genetic variations in PI3K-AKTmTOR can predict brain metastasis, in prospective studies would facilitate stratification of patients for brain metastasis prevention trials.

Association of mTOR Polymorphisms with Cancer Risk and Clinical Outcomes: A Meta-Analysis

“…The remaining 18 articles were reviewed and, 8 of them were removed due to lack of sufficient data or examing other mTOR polymorphisms but not rs2295080, rs2536 (T>C) and rs11121704 [26]–[33]. Finally, 10 studies were met the inclusion criteria [12]–[20], [35], and 6 studies evaluated the influence on cancer risks [12]–[13], [15]–[18] and 3 assessed the clinical outcomes [19], [20], [35], such as death, metastasis, resistance to chemotherapy, and toxicity, and one examined both [14]. The flow of study identification, inclusion, exclusion was shown in Fig.…”

“…The genotypes in the controls in all studies were in Hardy-Weinberg equilibrium. For estimating the influence of mTOR polymorphisms (rs2295080 and rs11121704) on clinical outcomes in cancer patients, 4 eligible studies included 1594 cancer patients, were identified: 2 were conducted in USA [19], [20] and two were in China [14], [35]. Two studies in USA evaluating evaluated more than one clinical outcome parameter, and these parameters were separately analyzed as separate observations.…”

The Thr300Ala variant of ATG16L1 is associated with decreased risk of brain metastasis in patients with non-small cell lung cancer

“…We previously reported that genetic variations in the phosphoinositide 3-kinase-AKT pathway are associated with an increased risk of BM in patients with NSCLC. 16 Additional investigations on candidate genes that are crucial for metastasis may uncover missing links in the heritability of BM. Autophagy is an important adaptive prosurvival mechanism that mediates cancer cell survival during metastasis.…”

SNPs in PI3K-PTEN-mTOR and Brain Metastases in NSCLC—Response

“…Furthermore, the association remained significant after the Bonferroni correction for AKT1: rs2494732 (i.e., <0.05/16 ¼ 0.003) in our study. Otherwise, AKT1:rs2498804 and rs2494732 were in strong linkage disequilibrium (D ¼ 0.95), and we believe that AKT1: rs2498804 is not a false-positive gene (1). In addition, we are pleased to find that the association of AKT1:rs2498804 was confirmed in your independent cohorts.…”