Association between Single-Nucleotide Polymorphisms in the Interleukin-6/Interleukin-6 Receptor/Janus Kinase/Signal Transducer and Activator of Transcription Pathway and the Risk of Brain Metastasis Among Patients with Non-Small Cell Lung Cancer

Abstract

Background: Brain metastasis incidence in non-small cell lung cancer (NSCLC) patients is high; however, identifying patients that are most likely to develop brain metastases is difficult. The interleukin 6 (IL6)/interleukin 6 receptor (IL6R)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway contributes to lung cancer pathogenesis. Methods: We investigated whether the genetic variants of this pathway are useful for predicting brain metastases in non-small cell lung cancer (NSCLC). Thirty-eight single nucleotide polymorphisms (SNPs) in six core genes (IL6, IL6R, JAK1, JAK2, STAT1, and STAT3) were tested for potential associations with brain metastasis. Multivariate Cox regression analysis was used to analyse correlations between genotype variants and brain metastasis. Kaplan–Meier analysis was performed to evaluate cumulative hazard of brain metastasis. Bioinformatics tools were applied to assess the functional relevance of genetic variants. Findings: The GT/TT genotype of IL6R rs4845618 and the GA/AA genotype of JAK2 rs10815144 were associated with a higher risk of brain metastasis, after correcting for clinicopathologic variables (hazard ratio [HR], 7.888, 95% confidence interval [CI], 1.973–31.536, P = 0.003; HR, 4.378; 95% CI, 1.144–16.747; P = 0.031, respectively). These two SNPs had a cumulative effect on brain metastasis risk, and patients carrying both genotypes had a higher risk of brain metastasis. These two SNPs also affected the mRNA expression of genes. Interpretation: IL6R rs4845618 and JAK2 rs10815144 were associated with the risk of brain metastasis in NSCLC patients and may potentially be used as biomarkers of brain metastasis. Funding: This work was supported by the National Natural Science Foundation of China (Grant no. 81773360). Conflict of Interest: The authors declare no competing interests. Ethical Approval: The study was approved by the Ethics Committee of Tongji Medical College (IRBID: TJ-C20121219). All patients signed an informed consent form before the interview.