Effect of Interleukin-10 Gene Polymorphisms on Clinical Outcome of Patients with Aggressive Non-Hodgkin's Lymphoma: An Exploratory Study

Abstract

Purpose: Current chemotherapy can achieve high response rates in aggressive non-Hodgkin's lymphoma (NHL), but the factors that influence regression and survival remain unknown. The present exploratory study tested the hypothesis whether interleukin-10 (IL-10) polymorphisms predict clinical outcome, leukocytopenia, or infectivity during therapy. IL-10 was chosen because immune alterations are a major risk factor for NHL, and IL-10 is a cytokine involved in inflammatory processes associated with clinical outcome. Experimental Design: Five hundred patients with aggressive NHL treated with CHOP/CHOEP were analyzed for IL-10 gene polymorphisms, including distal loci -7400InDel, -6752AT (rs6676671), and -6208CG (rs10494879) in comparison with proximal loci -3538AT (rs1800890), -1087AG (rs1800896), and -597AC (rs1800872) according to the incidence and outcome of the lymphoma. Results: No differences in allele frequencies or haplotypes were found comparing a cohort of patients with aggressive NHL/diffuse large B-cell lymphoma with a healthy control group. Patients with aggressive NHL characterized by IL-10 -7400DelDel had shorter overall survival periods compared with the other genotypes (P = 0.004). The 3-year rate is 43.4% for IL-10 -7400DelDel and 73.4% for IL-10 -7400InIn and IL-10 -7400InDel together. A significant increased risk for event-free survival is found for carriers of the genotype IL-10 -6752TT-6208CC-3538AA (P = 0.047). Multivariate analysis of IL-10 -7400 gene variation in relation to overall survival adjusted to international prognostic index revealed a relative risk of 1.9 for carriers of IL-10 -7400Del-Del (P = 0.037). No associations were found analyzing diffuse large B-cell lymphoma patients separately. Conclusion: Our results indicate that IL-10 gene variations could be associated to the clinical course of aggressive NHL, which points out the importance of host factors and respective genetic elements for treatment response.

Circulating Levels of TNF Receptor II Are Prognostic for Patients with Peripheral T-cell Non–Hodgkin Lymphoma

“…We have recently observed an increased risk for patients suffering from aNHLs that carry the gene variation IL-10-7400Del/Del leading to a significantly shorter OS (44). However, the number of patients with peripheral T-NHLs in this cohort was too small (n ¼ 45) to allow valid conclusions related to this lymphoma subgroup.…”

Distal and proximal interleukin (IL)-10 promoter polymorphisms associated with risk of cutaneous melanoma development: a case–control study

“…17 Allele frequencies, genotypes and haplotypes were defined and compared with corresponding healthy controls. In Table 2 genotypic data are summarized for the IL-10 gene variations.…”

“…17 The four major haplotypes, IATAA, IATAC, ITAGC and DTAGC, are present for the respective IL-10 gene variations, IL-10 À7400InDel , IL-10 À6752AT , IL-10 À3538AT , IL-10 À1087AG and IL-10 À597AC . Further analysis of haplotypes revealed that the ITAGC haplotype of the IL-10 gene was an independent predictor for a reduced risk to develop cutaneous melanoma, if corrected for the phenotypic risk factors skin type and number of nevi in our study population (adjusted P ¼ 0.02).…”

“…16 Polymorphisms in the IL-10 5 0 -flanking region genetically affect inter-individual differences in IL-10 production. 17 Variable associations between the capability of IL-10 production and IL-10 microsatellite alleles, single-nucleotide polymorphisms (SNP) or SNP haplotypes in a 7-kbp IL-10 5 0 -flanking region have been reported. 17 In most studies the major proximal IL-10 promoter haplotypes GCC, ACC and ATA formed by the SNPs IL-10 À1087AG , IL-10 À824CT and IL-10 À597AC were found to be related to the in vitro capability of IL-10 production.…”

“…17 Variable associations between the capability of IL-10 production and IL-10 microsatellite alleles, single-nucleotide polymorphisms (SNP) or SNP haplotypes in a 7-kbp IL-10 5 0 -flanking region have been reported. 17 In most studies the major proximal IL-10 promoter haplotypes GCC, ACC and ATA formed by the SNPs IL-10 À1087AG , IL-10 À824CT and IL-10 À597AC were found to be related to the in vitro capability of IL-10 production. GCC/GCC genotypes can be defined as 'high producer', GCC/ACC and GCC/ATA as 'medium producer', and ACC/ACC, ACC/ATA and ATA/ATA as 'low producer'.…”