Genes and Immunity (2006) 00, 1–4& 2006 Nature Publishing Group All rights reserved 1466-4879/06 $30.00 SHORT COMMUNICATIONThe interleukin-10 gene promoter polymorphismÀ1087AG does not correlate with clinical outcome in non-Hodgkin’s lymphoma D Kube1, T-D Hua1, M Klo¨ss2, B Kulle3,4, J Brockmo¨ller5, L Wojnowski5,6, M Lo¨ffler2, M Pfreundschuh7and L Tru¨mper11Department of Internal Medicine Hematology and Oncology, Georg-August Universita¨t Go¨ttingen, Mainz, Germany; 2University ofLeipzig, Mainz, Germany; 3Institute of Epidemiology, Mainz, Germany; 4Section of Statistics, Institute of Basic Medical Science,University of Oslo, Oslo, Norway; 5Department of Pharmacology and Toxicology, Mainz, Germany; 6University Mainz, Institute ofPharmacology, Mainz, Germany and 7Department of Internal Medicine I, Saarland University, Homburg/Saar for the DSHNHL(German High Grade NHL Study Group), Mainz, Germany The Interleukin 10 (IL-10) gene is highly polymorphic, and the IL-10À (rs1800896) gene variation is the only so far studied intensively in association with certain diseases. Conflicting data have been published about an association of IL-10À variation with lower rates of complete remission and lower overall survival (OS) in patients with diffuse large B-cell lymphoma.
To further investigate this in malignant lymphoma, we established the IL-10 genotypes in patients from the NHL-B1/ B2 studiesfrom the German High-Grade Non-Hodgkin’s Lymphoma Study Group. In our study, allele frequencies of lymphoma patientsare comparable as in healthy controls. No increase of IL-10 alleles was found. In addition we did not find any difference in OS or event-free survival between patients with IL-10 and the other genotypes. Comparable results were obtained for the IL-10 loci at À3538 (A/T), À1354 (A/G), À824 (C/T) and À597 (A/C) (rs1800890, rs1800893, rs1800871 and rs1800872).
Genes and Immunity (2006) 0, 000–000. doi:10.1038/sj.gene.6364364 With conventional chemotherapy, long-term remission Interleukin 10 (IL-10) is an important immunoregula- can be achieved in approximately 50% of patients with tory cytokine in man and is part of a balanced network of disseminated ‘aggressive’ lymphoma. The disease in- immunoregulatory factors, where it also stimulates cidence is increasing, but aetiologic factors contributing proliferation of certain B-cell malignancies or suppresses to this phenomenon remain still largely unknown.
the immune response against lymphomas.1 IL-10 is Although it is a curable disease, many patients do not produced by a number of cells including normal and achieve complete remission (CR), or they relapse after neoplastic B cells, stimulated monocytes/macrophages conventional chemotherapy. Tumour- and host-related and subsets of T cells. IL-10 has been implicated in parameters are likely to reflect some underlying biologic certain infectious diseases, autoimmunity, transplanta- mechanisms and differences in the response to therapy tion tolerance and tumorigenesis.2–15 Polymorphisms in may be related to genetic factors of the host.
the IL-10 50-flanking region genetically affect inter- One suggestion is that deregulated components of the individual differences in IL-10 production.16–21 Increased immune system may be linked to the incidence and IL-10 plasma levels and poor outcome of some lympho- clinical course of lymphomas. Cytokines are major ma entities have been shown, suggesting an role for IL-10 mediators of inflammation and deregulated expression of defined subsets of cytokines was found to be Recently Lech-Maranda and co-workers reported that associated with lymphoid malignancies. Therefore, at- homozygocity for À1087A (rs1800896 A/G) of the IL-10 tempts to clarify the mechanisms involved in immune promoter is associated with lower rates of complete UNCORRECTED PROOF
deregulation in lymphoma should contribute to a remission and lower overall survival (OS) in patients better understanding of the clinical course of these with diffuse large B-cell lymphoma (DLBCL), whereas Berglund and co-workers showed an absence of such anassociation.22,23 In a recent epidemiological multicenterstudy, evidence was provided that for carriers of the IL- Correspondence: D Kube, Georg-August Universita¨t Go¨ttingen, 10À3538A allele (rs1800890 A/T) the risk of NHL is Department of Internal Medicine Hematology and Oncology, doubled, but this was not verified by a follow-up To further investigate IL-10 promoter gene variations Received 8 August 2006; revised 30 October 2006; accepted 31October 2006 in malignant lymphoma, we established the IL-10À1087 Interleukin-10, polymorphism, non-Hodgkin’s lymphoma genotype, in comparison to IL-10À3538, IL-10À1354, IL- All patients included in this study received anthracy- 10À824 and IL-10À597 genotypes (rs 1800893, 1800871 and cline-containing regimens, consisting of CHOP/CHOEP 1800872, respectively) in patients from the NHL-B1/ B2 (cyclophosphamide, adriamycin, vincristine, etoposide, studies from the German High-Grade Non-Hodgkin’s prednisone).26,27 Complete remission (CR) was defined as Lymphoma Study Group (DSHNHL) and compared it the disappearance of all disease manifestations for at with OS and event-free survival (EFS).26,27 We used for least 2 months after the final restaging. EFS was this analysis a homogeneous, equally treated cohort of determined from the onset of treatment until either patients with non-Hodgkin’s Lymphoma (NHL). Pa- disease progression, initiation of salvage therapy; or tients were eligible if they had previously untreated, additional (off-protocol) treatment, relapse, death or in biopsy-confirmed, aggressive NHL according to the case of no event OS was determined from the onset of Revised European-American Lymphoma Classification treatment until the last follow-up evaluation or death (translated into the World Health Organization (WHO) from any cause. Within 5 years the OS was 60.2% (95% classification). Patients were excluded if the diagnosis of confidence interval: 54.8:65.5) for all and 61.8% (95% aggressive lymphoma was not confirmed (i.e., no confidence interval: 55.3:68.3) for the DLBCL subgroup.
pathology review was available) or if the diagnosis had The EFS was respectively 49.4% (95% confidence inter- to be changed into indolent lymphoma or no lymphoma val: 44.1:54.8) and 49.7 (95% confidence interval: at all by a panel of expert hematopathologists who 43.0:56.4). Further clinical characteristics of the patients conducted a blinded central pathology review. The enrolled in the study are described in detail in patients had mandatory baseline examinations that Pfreundschuh et al.26,27 and Wojnowski et al.28 included clinical examination, laboratory tests, chest We also assessed the allele frequencies in 193 ethni- radiograph, abdominal sonography, computed tomogra- cally matched healthy controls. The frequency of IL-10– phy of chest and abdomen, and a bone marrow biopsy.
alleles and corresponding genotypes were not significant different between patients and controls(0.285 vs 0.271% for À1087AA; P ¼ 0.516). The same Genotype frequency of the IL10 promoter gene variation was found when only DLBCL-patients were analysed at À1087 in 409 NHL patients (including 256 patients with DLBCL) (0.285 vs 0.305%; P ¼ 0.344) (see also Table 1). The frequency of IL-10À1354, IL-10À824 and IL-10 IL-10À597 alleles and corresponding genotypes were not significantdifferent between patients and controls (P ¼ 0.273, 0.855 or 0.543, respectively) (Table 2). Analysing the IL-10À3538gene variation significant differences between healthy controls and lymphoma patients can be visualized: genotype and allele based analysis showed P-values of 0.008 and 0.015, respectively, suggesting a risk for aggressive NHL for carriers of the A-allele as described by Rothman et al.24 Using Fishers exact test the odds ratiois 1.62 (confidence interval: 1.12;2.38). However perform- Abbreviations: DLBCL, diffuse large B-cell lymphoma; IL-10, ing multivariate testing (Bonferoni, FDR-method) these interleukin 10; NHL, non-Hodgkin’s lymphoma.
differences at IL-10À3538 were not longer significant. For Analysis of the IL-10 gene variation was performed as described in the DLBCL subgroup no significant differences for the Mo¨rmann et al. or using an TaqMan-assay for the IL-10À1087 gene analysed IL-10 loci were found. Overall our data did not snp.cfm?both_snp_id ¼ IL10-03.21,26,27 Sixty-seven percent of the show differences in allele frequencies between lympho- patients were older than 60 years (median 64; range 23–75), whereas in the DLBCL subgroup (n ¼ 256) 69% were older than 60 years Thus, in our study allele frequencies of lymphoma patients are comparable as in healthy controls. No Genotype frequency of the IL10 promoter gene variations at À3538, À1354, À824 and À597 in NHL and control subjects UNCORRECTED PROOF
Abbreviations: IL-10, interleukin 10; NHL, non-Hodgkin’s lymphoma.
Analysis of the IL-10 gene variation was performed as described in Mo¨rmann et al.21 pCAT: P-value using the Freidlin test (genotype basedassociation); Chi allele: P-value of the respective allele-based comparison; PCHI: P-values when comparing one genotype against the otherstogether; 11 represents the minor genotype, 12 the respective heterozygous genotype and 22 the major genotype; N – number of individuals.
Genes and Immunity
Interleukin-10, polymorphism, non-Hodgkin’s lymphomaD Kube et al OS for the 409 patients with NHL in comparison to the IL-10 –1087 genotype. Inset presents the same data for the DLBCL group increase of IL-10–1087G alleles was found. In addition, we producer haplotype.16,18–21 The mechanism behind this did not find any difference in OS (all P ¼ 0.704, DLBC is still unkown, probably because of the close proximity P ¼ 0.892) or EFS (all P ¼ 0.822, DLBC 0.86) between of À1087AG to the IL-10.G microsatellite. The IL-10.R patients with IL-10–1087AA genotype and the other microsatellite in close proximity of À3538AT may also genotypes, calculated in different ways as presented by affect IL-10 expression levels. First reports on structural Lech-Maranda et al. or Berglund et al. (Figure 1). No changes of the chromatin within the IL10 gene in significant differences in the clinical presentation were differentiated Th1 and Th2 cells or macrophages empha- detected between the genotype groups compared when size the surprising diversity of mechanisms used to sex, the factors of international prognostic index (IPI) regulate cytokine gene expression at the chromatin level (age460, LDH4N, ECOG41, stage III/IV, extranodal and might be opening the chance to understand the involvement 41) or the IPI score were taken into mechanism of interindividual differences in IL-10 ex- consideration. There were no differences according to pression.29–34 DNase I-hypersensitive sites on a con- the complete remission rate between the genotype served 40-kb region between the IL-19 and IL-10 genes in groups. No associations were found between the prog- different murine T-cell populations revealed three nostic variables, EFS, or OS intervals and alleles/ enhancer elements, which function in T cells in vitro.35 genotypes for the other analysed gene loci (OS: À3538 The role of inherited factors in the extend of IL-10 deregulation in malignant disorders is still controversy.
P ¼ 0.294; EFS: À3538 P ¼ 0.521; À1354 P ¼ 0.695; À824 The data obtained so far indicate that additional, probably larger studies are required, also in order to In our study, 67.0% of all patients were older than 60 confirm initial results. This will significantly contribute years with a range between 23 and 75 years (69.5% 460 to the understanding of the role of IL-10 in lymphoma years within the DLBCL-group). IPI low low intermedi- development. Some studies revealed that the IL-10 ate, CS III/IV, extranodal sites, bulky disease and B promoter region was associated with a poor prognosis symptoms were comparable in our cohort to those of aggressive NHL. However, as in our study in the described by Lech-Maranda et al., percentage of LDH4N majority of single SNP analysis this effect is not. This was lower in our group. In addition after adjusting the may suggest that additional not yet identified gene analysis for the prognostic factors from the IPI no variations within the chromosomal region 1q31/32 significant differences between the genotype groups around the IL-10 gene are important for our under- standing of the role of inherited factors in lymphomas. In At this stage the precise role of IL-10 promoter gene addition it is relevant to analyse the relation of respective UNCORRECTED PROOF
variations, both individually or as part of defined gene variations in this chromosomal area to intergenic proximal or distal haplotypes in determining IL-10 RNAs and their role in regulating the expression of IL-10 expression is still a subject awaiting answers. The IL-10 family members 35. Follow-up analysis will need to gene is highly polymorphic, and the IL-10À1087 gene analyse additional gene variations across 1q31/32 and variation is the most intensively studied variation in this other immunological important cytokines as suggested cytokine gene promoter. Furthermore in most studies published so far the SNPs –1087, À824 and –597 or theso-called proximal haplotypes GCC/ATA/ACC werefound to be related to the IL-10 production capacity invitro, where GCC was described as an IL-10 high Genes and Immunity
Interleukin-10, polymorphism, non-Hodgkin’s lymphoma 19 Eskdale J, Gallagher G, Verweij C et al. Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci The authors are gratefull to the Deutsche Forschnugsge- meinschaft (Graduiertenkolleg 1034), the BMBF (NGFN- 20 Crawley E, Kay R, Sillibourne J et al. Polymorphic haplotypes 1) and the Deutsche Krebshilfe/BMBF (NHL-B) for of the IL-10 50 flanking region determine variable IL-10 transcription and are associated with particular phenotypesof juvenile rheumatoid arthritis. Arthr Rheum 1999; 42: 1101–1108.
21 Mormann M, Rieth H, Hua TD et al. Mosaics of gene variations in the Interleukin-10 gene promoter affect inter-leukin-10 production depending on the stimulation used.
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24 Rothman N, Skibola CF, Wang SS et al. Genetic variation in 4 Blay JY, Burdin N, Rousset F et al. Serum interleukin-10 in non- TNF and IL10 and risk of non-Hodgkin lymphoma: a report Hodgkin’s lymphoma: a prognostic factor. Blood 1993; 82: from the InterLymph Consortium. Lancet Oncol 2006; 7: 27–38.
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Genes and Immunity


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