title: Impact of interleukin-6 -174 G>C gene promoter polymorphism on neuroblastoma.
abstract: BACKGROUND
  Common 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.
  
  
  RESULTS
  To 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy ; CEINGE - Biotecnologie Avanzate, Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Totaro
authors.forename: Flora
authors.initials: F
authors.lastname: Cimmino
authors.forename: Piero
authors.initials: P
authors.lastname: Pignataro
authors.forename: Giovanni
authors.initials: G
authors.lastname: Acierno
authors.forename: Marilena
authors.initials: M
authors.lastname: De Mariano
authors.forename: Luca
authors.initials: L
authors.lastname: Longo
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Tonini
authors.forename: Achille
authors.initials: A
authors.lastname: Iolascon
authors.forename: Mario
authors.initials: M
authors.lastname: Capasso
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000235:genetics; D016022:Case-Control Studies; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D007223:Infant; D015850:Interleukin-6 / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D008297:Male; D009447:Neuroblastoma / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor; D015850:Interleukin-6