Polymorphisms in immune function genes and non-Hodgkin lymphoma survival.
ABSTRACT 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.
Full-textDOI: · Available from: Xuesong Han, Feb 19, 2015
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Article: Polymorphisms in immune function genes and non-Hodgkin lymphoma survival.
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ABSTRACT: Background Survival in follicular lymphoma (FL) is highly variable, even within prognostic groups defined by tumor grade and the Follicular Lymphoma International Prognostic Index. Studies suggest that germline single nucleotide polymorphisms (SNPs) may hold prognostic information but further investigation is needed.Methods We explored the association between SNPs and FL outcome using two approaches: 1) Two independent genome-wide association studies (GWAS) of ~300.000 SNPs followed by a meta-analysis encompassing 586 FL patients diagnosed in Denmark/Sweden 1999¿2002 and in the United States 2001¿2006; and 2) Investigation of 22 candidate-gene variants previously associated with FL outcome in the Danish/Swedish cohort (N¿=¿373). We estimated time to lymphoma-specific death (approach 1 and 2) and lymphoma progression (approach 2) with hazard ratios (HR) and 95% confidence intervals (CI) in a multivariable Cox regression model.ResultsIn the GWAS meta-analysis, using a random effects model, no variants were associated with lymphoma-specific death at a genome-wide significant level (p¿<¿5.0 x10¿8). The strongest association was observed for tightly linked SNPs on 17q24 near the ABCA10 and ABCA6 genes (rs10491178 HRrandom¿=¿3.17, 95% CI 2.09-4.79, prandom¿=¿5.24 x10¿8). The ABCA10 and ABCA6 genes belong to a family of genes encoding for ABC transporter proteins, implicated in multidrug resistance. In line with a previous study, rs2466571 in CD46 (HR¿=¿0.73, 95% CI 0.58-0.91, p¿=¿0.006) showed nominal association with lymphoma progression, as did two highly linked SNPs in IL8 (rs4073 HR¿=¿0.78, 95% CI 0.62-0.97, p¿=¿0.02; rs2227307 HR¿=¿0.75, 95% CI 0.60-0.94, p¿=¿0.01) previously associated with overall survival.Conclusions The results suggest a possible role for multidrug resistance in FL survival and add to the evidence that genetic variation in CD46 and IL8 may have prognostic implications in FL. Our findings need further confirmation in other independent populations or in a larger multicenter GWAS.BMC Medical Genetics 10/2014; 15(1):113. DOI:10.1186/s12881-014-0113-6 · 2.45 Impact Factor
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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.Biomarkers 09/2013; DOI:10.3109/1354750X.2013.840799 · 2.52 Impact Factor
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ABSTRACT: We investigated the role of common genetic variation in immune-related genes on breast cancer disease-free survival (DFS) in Korean women. 107 breast cancer patients of the Seoul Breast Cancer Study (SEBCS) were selected for this study. A total of 2,432 tag single nucleotide polymorphisms (SNPs) in 283 immune-related genes were genotyped with the GoldenGate Oligonucleotide pool assay (OPA). A multivariate Cox-proportional hazard model and polygenic risk score model were used to estimate the effects of SNPs on breast cancer prognosis. Harrell's C index was calculated to estimate the predictive accuracy of polygenic risk score model. Subsequently, an extended gene set enrichment analysis (GSEA-SNP) was conducted to approximate the biological pathway. In addition, to confirm our results with current evidence, previous studies were systematically reviewed. Sixty-two SNPs were statistically significant at p-value less than 0.05. The most significant SNPs were rs1952438 in SOCS4 gene (hazard ratio (HR) = 11.99, 95% CI = 3.62-39.72, P = 4.84E-05), rs2289278 in TSLP gene (HR = 4.25, 95% CI = 2.10-8.62, P = 5.99E-05) and rs2074724 in HGF gene (HR = 4.63, 95% CI = 2.18-9.87, P = 7.04E-05). In the polygenic risk score model, the HR of women in the 3rd tertile was 6.78 (95% CI = 1.48-31.06) compared to patients in the 1st tertile of polygenic risk score. Harrell's C index was 0.813 with total patients and 0.924 in 4-fold cross validation. In the pathway analysis, 18 pathways were significantly associated with breast cancer prognosis (P<0.1). The IL-6R, IL-8, IL-10RB, IL-12A, and IL-12B was associated with the prognosis of cancer in data of both our study and a previous study. Therefore, our results suggest that genetic polymorphisms in immune-related genes have relevance to breast cancer prognosis among Korean women.PLoS ONE 07/2014; 9(7):e103593. DOI:10.1371/journal.pone.0103593 · 3.53 Impact Factor