We have demonstrated that the -174 IL-6 (G>C) SNP is an independent prognostic marker for clinical outcome in high risk neuroblastoma patients ( and ). In contrast to the -174 IL-6 (G>C) SNP located in the IL-6 promoter, the D358A IL-6R receptor SNP failed to demonstrate any association between high risk neuroblastoma and disease progression or survival ().
In the Caucasian population, the published distribution of G/G, G/C and C/C polymorphisms at the -174 IL-6 (G>C) SNP promoter region is 37.1%, 45.6% and 17.3%, respectively 26–29
. Individuals who harbor the homozygous G/G polymorphism produce IL-6 concentrations of [5.35 ± 3.01 pg/L] compared with those carrying G/C [3.96 ± 2.71 pg/ml] or C/C [3.52 ± 2.4 pg/ml] (G/G versus C/C, P-value < 0.05) 29
and other studies support a similar association between the G allele and elevated serum IL-6 levels in healthy volunteers 23, 24
. Data from several studies have demonstrated that the -174 IL-6 (G>C) SNP results in a functional alteration which affects gene transcription and subsequent serum levels of IL-6 cytokine 23, 24, 26–28, 32–35
. These data support the use of the -174 IL-6 (G>C) SNP genotype as a surrogate marker of cumulative IL-6 exposure. In our population of high risk neuroblastoma patients, 57.3% were carriers of the G/G polymorphism (), and the IL-6 promoter polymorphism identified two subsets of high risk neuroblastoma patients (). In the first subset, individuals carrying one or more C alleles had a 3-year overall survival of 56% ± 8%, while those who are homozygous for the G allele had a lower overall survival, 45% ± 7% at 3-years (). As shown recently by Egler et al 14
, patients with elevated IL-6 have significantly decreased EFS. The consequent elevated production of IL-6 in individuals with G/G SNP in the IL6 promoter region may be a plausible explanation for these data, suggesting that IL-6 may be a factor involved in neuroblastoma disease progression. Although elevated IL-6 level may be the consequence of advanced disease, our data suggest that the genetic makeup of the individual could also play a role in neuroblastoma disease progression. The correlation between IL-6 level, advanced disease and poor outcome may be part of a neuroblastoma-stimulated proliferation loop, similar to the one seen in multiple myeloma. Interestingly, stable physiological differences in the soluble IL-6 receptor due to the D358A sIL-6R polymorphism (e.g., A/A = 23.8 ng/ml, A/C = 29.7 ng/ml, C/C = 39.7 ng/[ml]26
), did not impact clinical outcomes within the same patient population suggesting that elevated sIL6-R levels are not compensatory during limited bioavailability of IL-6 ().
Neuroblastoma is a biologically heterogeneous tumor, with a spectrum of clinical presentations and responsiveness to therapy. Despite the ability to identify high-risk disease by numerous adverse prognostic biomarkers for neuroblastoma, the overall survival of high risk patients remains poor 1
. The identification of yet another biomarker of inferior outcome in high-risk neuroblastoma in itself adds little. However, there is growing evidence that suggests that IL-6 may plays a role in neuroblastoma growth and dissemination. Retinoic acid has been shown to down modulate the expression of IL-6 receptor α chain 36, 37
, inhibit secretion of IL-6 by stromal cells 37
, and disrupt the IL-6 autocrine signaling pathway 38, 39
. In CCG3891, it was demonstrated that the addition of cis-retinoic acid during the post-transplant consolidation phase of therapy was beneficial with improved EFS in high risk neuroblastoma patients 40
. It is felt the primary benefit of cis-retinoic acid is inducing terminal differentiation in neuroblastoma cells; however, the role of cis-retinoic acid may also function by down regulating IL-6 signaling events, a hypothesis worthy of further investigation. Additionally, IL-6 can now be targeted therapeutically anti-IL-6 monoclonal antibodies which are commercially available (e.g., CNTO 328, Tocilizumab®).
Additional retrospective and prospective studies are underway to expand on our current data and to elucidate the functional consequences of the -174 IL-6 (G>C) promoter polymorphism within the entire neuroblastoma patient population. Data from this study adds to the growing literature of the association between the -174 IL-6 (G>C) SNP and clinical outcomes of various cancers. 11, 12, 20, 21