Association of Genetic Polymorphisms and Serum Levels of IL-6 and IL-8 with the Prognosis in Children with Neuroblastoma

SIMPLE SUMMARY: Neuroblastoma (NB) presents diverse biological and clinical characteristics, from spontaneous regression to highly malignant and aggressive unfavorable tumors that condition the therapeutic failure of conventional treatments. The tumorigenesis of NB can be the result of different genetic variants, which can influence the clinical outcome, and the survival of patients who have metastatic tumors is low. The role of cytokines such as interleukin (IL)-6 has been described in the NB microenvironment promoting tumor progression and metastasis. Single nucleotide polymorphism (SNP)-174 G > C in IL-6 and -251 T > A and +781 C > T in IL-8 regulate the expression of these cytokines, and could be associated with the clinical outcome in patients with NB. Our objective was to evaluate the association of the genetic polymorphisms of IL-6 and IL-8, as well as the serum levels of these cytokines in patients with NB, as this will allow the genetic bases of NB to be characterized and understood, in order to predict the outcome of the disease and develop new therapeutic strategies. ABSTRACT: There is evidence that high circulating levels of IL-6 and IL-8 are markers of a poor prognosis in various types of cancer, including NB. The participation of these cytokines in the tumor microenvironment has been described to promote progression and metastasis. Our objective was to evaluate the prognostic role of genetic polymorphisms and serum levels of IL-6 and IL-8 in a cohort of Mexican pediatric patients with NB. The detection of the SNPs rs1800795 IL-6 and rs4073 and rs2227306 IL-8 was carried out by PCR-RFLP and the levels of cytokines were determined by the ELISA method. We found elevated circulating levels of IL-8 and IL-6 in NB patients compared to the control group. The genotype frequencies of the rs1800795 IL-6 and rs4073 IL-8 variants were different between the patients with NB and the control group. Likewise, the survival analysis showed that the GG genotypes of rs1800795 IL-6 (p = 0.014) and AA genotypes of rs4073 IL-8 (p = 0.002), as well as high levels of IL-6 (p = 0.009) and IL-8 (p = 0.046), were associated with lower overall survival. We confirmed the impact on an adverse prognosis in a multivariate model. This study suggests that the SNPs rs1800795 IL-6 and rs4073 IL-8 and their serum levels could be promising biomarkers of a poor prognosis, associated with overall survival, metastasis, and a high risk in Mexican children with NB.