Association Between Single-Nucleotide Polymorphisms In The IL6/IL6R/JAK/STAT Pathway And The Risk Of Brain Metastasis Among Patients With Non-Small Cell Lung Cancer

Objective: 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.We investigated whether the genetic variants of this pathway are useful for predicting brain metastases in NSCLC patients.Methods: Eleven single nucleotide polymorphisms(SNPs)in five core genes(IL6,IL6 R,JAK2,STAT1,and STAT3)were tested for potential associations with brain metastasis using DNA from the blood samples of 167 NSCLC patients.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.Results: The GT/TT genotype of IL6 R rs4845618 and the GA/AA genotype of JAK2rs10815144 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(P=0.003).These two SNPs also affected the m RNA expression of genes.Conclusion: Genetic variations in the IL6/IL6R/JAK/STAT pathway were associated with the risk of brain metastasis in NSCLC patients and may potentially be used as biomarkers of brain metastasis.