Cytokines are small secreted or membrane-bound proteins that act in both an autocrine and paracrine fashion and have a central role in the development and regulation of the immune system. There is increasing interest in the role of these proteins in cancer etiology and pathogenesis.1,2 Interleukin 6 (IL-6) is a pro-inflammatory, pleiotropic cytokine produced by multiple cell types, including normal and malignant B and T lymphocytes.2 Growing laboratory and clinical evidence supports the hypothesis that IL-6 plays a role in the pathogenesis of hematologic and other malignancies.2,3 In Hodgkin lymphoma specifically, IL-6 levels are elevated in untreated and relapsed patients and in patients with a poorer prognosis.3 However, it has not been shown to date whether higher IL-6 levels before diagnosis (and thus unaffected by disease or treatment) are associated with risk of developing Hodgkin lymphoma, which would support an etiologic role for IL-6.
The article by Cozen and colleagues (page 3216) that appears in this issue of Blood addresses the association of IL-6 with the development of young-onset Hodgkin lymphoma (diagnosed under age 50 years) using a novel study design that integrates both genetic and phenotypic data. Using a twin registry, the authors recruited 88 young adult Hodgkin lymphoma patients, their twins, and unrelated age-matched controls, creating triads. Peripheral blood was collected on the same day from each member of the triad, shipped, and processed together. The unaffected twin of monozygotic twin pairs was used as a “surrogate case” whose immune characteristics reflect those of the affected twin, at least to the extent that IL-6 levels are genetically controlled but are not influenced by Hodgkin lymphoma or its treatment. Cozen et al found that unaffected monozygotic twins of the Hodgkin lymphoma cases had IL-6 levels that were approximately 70% greater compared with controls. The IL-6 gene also has a functional single nucleotide polymorphism (SNP) in the promotor region (-174G>C), such that the CC genotype is associated with lower levels of IL-6.3 In their study, affected twins were 70% less likely to have the low-risk (CC) genotype compared with controls, and there was a dose response with the number of low-risk (C) alleles. Finally, among unaffected twins and controls there was an inverse association of IL-6 levels with the number of C alleles, linking phenotype with genotype in this study population.
Taken together, these provocative results support the hypothesis that high levels of genetically determined IL-6 are associated with risk of young adult Hodgkin lymphoma. Is this a causal association? Maybe, but it is too early to make this conclusion. Replication of these findings will be needed. It must also be kept in mind that IL-6 is unlikely to be a lone player, as it is a part of a complex cytokine system with extensive redundancies and individual cytokines showing pleiotropic effects. Nevertheless, this study strongly supports the further evaluation of cytokines, both at the genotypic and phenotypic level, and cancer risk, with the ultimate goal of identifying new targets for prevention and treatment.
