Impact of Interleukin-6 –174 G>C Gene Promoter Polymorphism on Neuroblastoma

Abstract

BackgroundCommon variants in DNA may predispose to onset and progression of neuroblastoma (NB). The genotype GG of single nucleotide polymorphism (SNP) rs1800795 (−174 G>C) in interleukin (IL)-6 promoter has been associated with lower survival of high-risk NB.ResultTo evaluate the impact of IL-6 SNP rs1800795 on disease risk and phenotype, we analyzed 326 Italian NB patients and 511 controls. Moreover, we performed in silico and quantitative Real Time (qRT)-PCR analyses to evaluate the influence of the SNP on gene expression in 198 lymphoblastoid cell lines (LCLs) and in 31 NB tumors, respectively. Kaplan-Meier analysis was used to verify the association between IL-6 gene expression and patient survival. We found that IL-6 SNP is not involved in susceptibility to NB development. However, our results show that a low frequency of genotype CC is significantly associated with a low overall survival, advanced stage, and high-risk phenotype. The in silico (p = 2.61×10−5) and qRT-PCR (p = 0.03) analyses showed similar trend indicating that the CC genotype is correlated with increased level of IL-6 expression. In report gene assay, we showed that the −174 C variant had a significantly increased transcriptional activity compared with G allele (p = 0.0006). Moreover, Kaplan-Meier analysis demonstrated that high levels of IL-6 are associated with poor outcome in children with NB in two independent gene expression array datasets.ConclusionsThe biological effect of SNP IL-6–174 G>C in relation to promotion of cancer progression is consistent with the observed decreased survival time. The present study suggests that SNP IL-6–174 G>C may be a useful marker for NB prognosis.

Gene of the month: Interleukin 6 (IL-6)

“…Two phenotypes for this polymorphism have been identified: the 174 G/G and 174 G/C genotypes as the high-producer phenotype; and the 174 C/C genotype as the low-producer phenotype 10 12. The 174 G/C phenotype has been reported to be associated with the diseases with inflammatory background such as juvenile chronic arthritis,10 Alzheimer disease,13 type 2 diabetes,14 atherosclerosis,15 osteoporosis,16 cardiovascular diseases,17 18 and also multiple cancers including hepatocellular,19 colorectal,20 prostate,21 ovarian22 and breast cancer23 as well as Hodgkin's lymphoma24 and neuroblastoma 25…”

Association between IL-6 Gene (−174 & -572 G/C) Polymorphisms and Endometrial Adenocarcinoma Risk

“…And IL-6 -174 CC genotype was associated with increased renal cancer risk [13] and bladder cancer risk [14]. While a case-control study from Italy reported that IL-6-174G > C polymorphism might be related to onset and progression of neuroblastoma [15] and it might be a carcinogenetic factor in the diffuse type gastric adenocarcinoma [16]. Meanwhile, as for IL-6-572C > G polymorphism, it was reported to influenced susceptibility of HBV-related hepatocellular carcinoma according to Tang S's case research [17].…”

Meta-analysis of IL-6 -174G/C polymorphism and psoriasis risk

“…Among these, the most studied SNP at position -174 (IL-6 -174G/C) can modify transcriptional regulation and cytokine levels, and has an impact on inflammatory phenotypes (Fishman et al, 1998). Previous studies have shown that IL-6 -174 G/C polymorphism is associated with the development and progression of various human diseases including systemic lupus erythematosus, neuroblastoma, coronary heart disease, HIV/AIDS, and nephritis (Sobti et al, 2010;Santos et al, 2011;Yin et al, 2012;Totaro et al, 2013;Yang et al, 2014).…”