Cytokines play a critical role in regulating the immune system. In the tumor microenvironment, they influence survival, proliferation, differentiation, and movement of both tumor and stromal cells, and regulate tumor interactions with the extracellular matrix. Given these biologic properties, there is reason to hypothesize that cytokine activity influences the pathogenesis of non-Hodgkin lymphoma (NHL).
We investigated the effect of genetic variation in cytokine genes on NHL prognosis and survival by evaluating genetic variation in individual SNPs as well as the combined effect of multiple deleterious genotypes. Survival information from 496 female incident NHL cases diagnosed during 1996-2000 in Connecticut were abstracted from Connecticut Tumor Registry in 2008. Survival analyses were conducted by comparing Kaplan-Meier curves and hazard ratios (HR) were computed using Cox proportional hazard models adjusting for demographic and tumor characteristics for genes that were suggested by previous studies to be associated with NHL survival.
We found that the variant IL6 genotype is significantly associated (HR = 0.42; 95%CI: 0.23-0.77) with a decreased risk of death, as well as relapse and secondary cancer occurrence, among those with NHL. We also found that risk of death, relapse, and secondary cancers varied by specific SNPs for the follicular, DLBCL, and CLL/SLL histologic types. We identified combinations of polymorphisms whose combined deleterious effect significantly alter overall NHL survival and disease-free survival.
Our study provides evidence that the identification of genetic polymorphisms in cytokine genes may help improve the prediction of NHL survival and prognosis.
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"The cytokines coded by these genes play a key role in immune-regulating. They control lymphoid cell development and differentiation, and regulate the balance between the T-helper immune responses, as well as proliferation, differentiation, and the movement and communication between tumor and stromal cells , , . Given the biologic properties, we hypothesize that the variants in cytokine genes may alter transcription and expression, and further inhibit the cellular signaling pathways, as well as the balance of immunity. "
[Show abstract][Hide abstract] ABSTRACT: Non-Hodgkin's lymphoma (NHL) has been widely reported to be associated with autoimmune and pro-inflammatory response, and genetic polymorphisms of candidate genes involved in autoimmune and pro-inflammatory response may influence the survival and prognosis of NHL patients. To evaluate the role of such genetic variations in prognosis of NHL, we conducted this study in a Chinese population.
We used the TaqMan assay to genotype six single nucleotide polymorphisms (SNPs) (TNF rs1799964T>C, LTA rs1800683G>A, IL-10 rs1800872T>G, LEP rs2167270G>A, LEPR rs1327118C>G, TNFAIP8 rs1045241C>T) for 215 NHL cases. Kaplan-Meier analysis was performed to compare progression free survival among two common genotypes. Cox proportional hazard models were used to identify independent risk factors.
We observed that LTA rs1800683G>A was significantly associated with risk of progression or relapse in NHL patients (HR = 1.63, 95%CI = 1.06-2.51; P = 0.028), particularly in Diffuse large B cell lymphoma (DLBCL) cases (HR = 1.50, 95%CI = 1.10-2.04, P = 0.01). Both univariate and multivariate Cox regression analysis showed that in DLBCL patients, Ann Arbor stage III/IV, elevated LDH level before treatment and LTA rs1800683 AA genotype carrier were independent risk factors for progression or relapse. While in NK/T cell lymphoma, Ann Arbor stage III/IV and elevated β2-MG level before treatment indicated poorer prognosis.
The polymorphism of LTA rs1800683G>A contributes to NHL prognosis in a Chinese population. Further large-scale and well-designed studies are needed to confirm these results.
PLoS ONE 06/2013; 8(6):e66411. DOI:10.1371/journal.pone.0066411 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract Context: Interleukin-6 (IL-6) is implicated in the pathophysiology of hematologic neoplasia. Objective: To review the role of IL-6 single nucleotide polymorphisms (SNPs) in hematologic neoplasia. Methods: PubMed and EMBASE search of genetic association studies. Effects were summarized using the model-free generalized odds ratio (ORG), and the mode of inheritance was estimated for significant associations. Results: Seventeen articles provided data on 20 distinct SNPs. The IL-6 receptor rs8192284 was associated with an increased risk of hematologic malignancy (combined ORG 1.42, 95%CI 1.03-1.96), including multiple myeloma (ORG 1.39, 95%CI 0.99-1.95). The IL-6 promoter rs1800795 conferred protection against young adult Hodgkin's disease (ORG 0.68, 95%CI 0.48-0.95). Significant single-study effects for four other SNPs-disease associations were estimated. The IL-6 promoter rs1800795 and rs1800797 were not associated with overall susceptibility to non-Hodgkin's lymphomas. Conclusions: There is accumulating evidence that the IL-6 promoter, receptor and signal transducer SNPs can modify disease susceptibility.