Abstract
Polymorphisms in the IL-2 gene are associated with various diseases and cancers including non-Hodgkin lymphoma (NHL). The aim of the study is to assess the impact of IL-2 genetic polymorphisms [− 330 T/G (rs2069762) and + 114 T/G (rs2069763)] on the susceptibility and prognosis of NHL. Sixty patients with NHL as well as 60 age and sex matched healthy control subjects are included in this study. IL-2 genotypes were determined by Polymerase Chain Reaction-Restriction Fragment length Polymorphism assay (PCR–RFLP). Our study revealed that both IL-2 rs2069762 and rs2069763 gene polymorphisms are associated with increased risk of developing NHL; OR = 3.609 (95% CI = 1.527–8.417) and 4.142 (95% CI = 1.637–10.538) respectively. Moreover, the simultaneous presence of both polymorphisms is associated with about 6 fold increased risk of developing NHL. Also, IL-2 rs2069762 and rs2069763 gene polymorphisms increase the risk of unfavorable prognosis with OR = 17.300 (95% CI = 3.392–87.725) and 10.424(95% CI = 1.870–58.413) respectively. These findings suggest that IL-2 (rs2069762) and (rs2069763) gene polymorphisms could be involved in the development of NHL.
Keywords: Non-hodgkin lymphoma, IL-2 (rs2069762), IL-2 (rs2069763), Genetic polymorphisms, PCR–RFLP
Introduction
Non-Hodgkin lymphomas (NHL) are a heterogeneous group of malignancies that arise from mature lymphocytes. Epidemiological studies have identified numerous environmental and genetic risk factors for developing NHL [1]. Polymorphisms in immunoregulatory genes have been found to be associated with increased risk of NHL [2]. Some of these polymorphisms have a prognostic significance as well [3]. Interleukin-2 (IL-2) is a potent immunoregulatory cytokine that is secreted by T helper-1 cells in response to stimulation by antigens [4]. Human IL-2 gene is located on chromosome 4q26. Two single nucleotide polymorphisms (SNPs) have been identified in IL-2 gene. One of them lies in the promoter region (− 330 T/G, rs2069762) [5] and the other is present at position 114 from the initiation codon in the first exon (+ 114 T/G, rs2069763) [6]. These SNPs were implicated in increased susceptibility to cancers, such as bladder cancer [4], nasopharyngeal carcinoma [7], gastric cancer [8], hepatocellular carcinoma [9], basal cell carcinoma [10] and breast cancer [11]. The aim of this study is to investigate the relation between IL-2 (rs2069762) and (rs2069763) gene polymorphisms and the risk of development of NHL as well as their prognostic significance in a cohort of Egyptian patients.
Materials and Methods
Study Population
The present study included 60 patients with NHL and 60 age and sex-matched healthy control subjects. Patients were invited to participate in the study during their visits to Kasr Al-Ainy Center of Clinical Oncology and Nuclear Medicine (NEMROCK), Kasr Al-Ainy school of Medicine, Cairo University, after taking their informed consents. The study was approved by the Institutional Review board (IRB) of Kasr Al-Ainy School of Medicine, Cairo University (IRB number I-171007). Diagnosis of NHL was based on lymph node biopsy. Histopathological and immunohistochemical studies were done for proper classification according to the world health organization (WHO) classification [12]. Bone marrow biopsy was done for staging. Patients were categorized for the extent of the disease according to the Ann Arbor classification [13]. Based on disease outcome after chemotherapy, patients were classified into 4 groups; complete remission (CR), partial remission (PR), stable disease (SD), and relapsed/progressive disease [14]. CR is considered as favorable outcome, while PR, SD and relapsed/progressive disease are considered as unfavorable outcome. High serum LDH level was defined as ≥ 245 U/L and high β2 microglobulin level as ≥ 4.0 mg/L [15].
Methods
Genomic DNA was extracted from whole blood using Gene JET Whole blood Genomic DNA purification kit (Thermo scientific, Massachusetts, USA). Detection of IL-2 (rs2069762) and (rs2069763) gene polymorphisms was performed by Polymerase Chain Reaction-Restriction Fragment length Polymorphism (PCR- RFLP) assay as described before [16]. Primers were provided by Biosearch Technologies, Inc. (California, USA). The PCRs were performed in a total volume of 25 µL containing 100 ng genomic DNA, 25 pM of each primer and 12.5 µL PCR master mix (Fermentas, Lithuania).
For IL-2 (rs2069762); the following primers are used:
Forward primer: 5′-ATTCACATGTTCAGTGTAGTTCT -3′ and.
Reverse primer: 5′-GTGATAGCTCTAATTCATGC -3′.
For IL-2 (rs2069763); the following primers are used:
Forward primer: 5′-ATGTACAGGATGCAACTCCT -3′ and.
Reverse primer: 5′-TGGTGAGTTTGGGATTCTTG -3′
The PCR conditions consisted of an initial denaturation step at 94 °C for 5 min followed by 35 cycles of denaturation at 94 °C for 30 s, annealing at 61 °C for rs2069762 polymorphism; and 63 °C for rs2069763 polymorphism; for 45 s and extension at 72 °C for 45 s and final extension at 72 °C for 8 min. The presence of the PCR amplicon (150 bp for rs2069762 and 262 bp for rs2069763) was examined on 2% agarose gel electrophoresis. The PCR products were digested overnight at 37 °C with the appropriate restriction enzyme (BfaI for rs2069762 and MwoI for rs2069763) (Thermo scientific, Massachusetts, USA). The digested PCR products were visualized on ethidium bromide stained 3% agarose gel electrophoresis.
For IL-2 rs2069762, the subjects were considered as; wild type (TT genotype) if only one band (150 bp) is detected, homozygous (GG genotype) if 2 bands (26 bp and 124 bp) are detected and heterozygous (TG genotype) if 3 bands (26 bp, 124 bp and 150 bp) are detected.
For IL-2 rs2069763, the subjects were considered as; wild type (TT genotype) if only one band (262 bp) is detected, homozygous (GG genotype) if 2 bands (111 bp) and (151 bp) are detected and heterozygous (TG genotype) if 3 bands (111 bp), (151 bp) and (262 bp) are detected.
Statistical Analysis
Data was analyzed using SPSS win statistical package version 13 (SPSS Inc., Chicago, Illinois, USA). Numerical data were expressed as mean and standard deviation and compared by student’s t test. Qualitative data were expressed as frequency and percentage and compared by Chi-square test. Odds ratio (OR) with its 95% confidence interval (CI) were used for risk estimation. A multiple regression analysis was done to study the relation between disease outcome as a dependent factor and clinical/laboratory and genetic variables as independent factors. Overall survival (OS) was estimated using Kaplan–Meier method. OS was calculated from the date of diagnosis to the date of death or the last follow up. Association between various genotypes and patients’ OS was estimated by Cox regression analysis. A p-value < 0.05 was considered significant.
Results
The study included 60 NHL patients aged 47.1 ± 12.5 years. They were 32 males and 28 females. Sixty age and sex matched healthy subjects were included as a control group (p = 0.334 and 0.855 respectively).
Clinical and laboratory characteristics of NHL patients are shown in Table 1.
Table 1.
Clinical and laboratory characteristics of NHL patients (N = 60)
| Item | NHL patients n (%) |
|---|---|
| LN pathology (type of lymphoma) | |
| B-NHL | |
| DLBCL | 34 (56.7) |
| Follicular Lymphoma | 9 (15.0) |
| Large B-cell lymphoma of post follicular origin | 4 (6.7) |
| Mantle cell lymphoma | 3 (5.0) |
| MALT Lymphoma | 1 (1.7) |
| Marginal zone Lymphoma | 1 (1.7) |
| Small Lymphocytic Lymphoma | 1 (1.7) |
| T-cell rich/Histocytes rich large B-cell lymphoma | 1 (1.7) |
| T-NHL | |
| Anaplastic large T-cell lymphoma | 2 (3.3) |
| T-lymphoblastic lymphoma | 1 (1.7) |
| Other T-cell Lymphomas | 3 (5.0) |
| Laboratory characteristics (Mean ± SD) | |
| Hemoglobin (g/dL) | 9.7 ± 2.0 |
| Total leucocyte count (× 103/µL) | 13.9 ± 16.2 |
| Lymphocytes % | 43.0 ± 11.6 |
| Platelets (× 103/µL) | 211.9 ± 91.9 |
| Serum LDH (U/L) | 501.2 ± 405.8 |
| β2 microglobulin (mg/dL) | 4.6 ± 2.4 |
| BM involvement | |
| Yes | 41 (68.3) |
| No | 19 (31.7) |
| Ann Arbor staging | |
| IA | 9 (15.0) |
| IB | 5 (8.3) |
| IIA | 4 (6.7) |
| IIB | 3 (5.0) |
| IIIA | 7 (11.7) |
| IIIB | 10 (16.7) |
| IVA | 11 (18.3) |
| IVB | 11 (18.3) |
| Disease outcome | |
| Complete remission | 10 (16.7) |
| Partial remission | 17 (28.3) |
| Stable disease | 16 (26.7) |
| Relapsed/ Progressive Disease | 17 (28.3) |
Genotype and allele frequency of IL-2 polymorphisms (rs2069762) and (rs2069763) among NHL patients and control groups are shown in Table 2.
Table 2.
Genotype and allele frequency of IL-2 polymorphisms (rs2069762 and rs2069763) among NHL patients (N = 60) and control groups (N = 60)
| Polymorphism | NHL n (%) |
Controls n (%) |
OR (95% CI) | p value |
|---|---|---|---|---|
| IL-2 (rs2069762) | ||||
| Wild (TT) | 10 (17) | 25 (42) | Reference | |
| Heterozygous (TG) | 30 (50) | 27 (45) | 2.77(1.13–6.82) | 0.031 |
| Homozygous (GG) | 20 (33) | 8 (13) | 6.25 (2.08–18.77) | < 0.001 |
| Variant (TG/GG) | 50 (83) | 35 (58) | 3.61 (1.53–8.42) | 0.003 |
| Allele | ||||
| Wild (T) | 50 (42) | 77 (64) | ||
| Variant (G) | 70 (58) | 43 (36) | 2.51 (1.49–4.21) | < 0.001 |
| IL-2 (rs2069763) | ||||
| Wild (TT) | 7 (12) | 21 (35) | Reference | |
| Heterozygous (TG) | 28 (46) | 25 (42) | 3.36 (1.22–9.24) | 0.019 |
| Homozygous (GG) | 25 (42) | 14 (23) | 5.36 (1.82–15.73) | 0.003 |
| Variant (TG/GG) | 53 (88) | 39 (65) | 4.14 (1.64–10.54) | 0.003 |
| Allele | ||||
| Wild (T) | 43 (36) | 67 (56) | ||
| Variant (G) | 77 (64) | 53 (44) | 2.51 (1.49 -4.21) | < 0.001 |
The two studied polymorphisms of IL-2 genes were significantly associated with risk of NHL. The variant genotypes (TG/GG) of IL-2 (rs2069762) polymorphism conferred more than 3 fold increased risk of development of NHL (p = 0.003, OR = 3.61, 95%CI = 1.53–8.42). Again, the variant genotypes (TG/GG) of IL-2 (rs2069763) polymorphism were associated with about 4 fold increased susceptibility of development of NHL (p = 0.003, OR = 4.14, 95%CI = 1.64–10.54).
When we analyzed the presence of these 2 gene polymorphisms in NHL patients, we found that 75% of NHL patients carry the two gene polymorphisms (rs2069762) and (rs2069763), while 22% carries single gene polymorphism (either rs2069762 or rs2069763). The presence of both gene polymorphisms was associated with about 6 fold increased risk of NHL than single gene polymorphism (p < 0.001, OR = 5.94, 95% CI = 2.57–13.47) (Table 3).
Table 3.
Association between the presence of both IL-2 gene polymorphisms (rs2069762 and rs2069763) and risk of NHL
| Polymorphism | NHL n (%) |
Controls n (%) |
OR (95% CI) | p-value |
|---|---|---|---|---|
| Both gene polymorphisms | 45 (75) | 20 (33) | 5.94 (2.57–13.47) | < 0.001 |
| Single gene polymorphism | 13 (22) | 34 (57) |
We evaluated the association between IL-2 polymorphisms and different clinical and laboratory variables. We found that the variant genotypes were associated with variables that may indicate poor prognosis like lower hemoglobin level, higher total leucocyte count, higher lymphocytes percentage, lower platelets count, higher β2 microglobulin level, higher LDH level, bone marrow involvement and late disease stages as compared to the wild genotypes (Table 4).
Table 4.
Relation between IL-2 gene polymorphisms and clinical-laboratory variables among NHL patients (N = 60)
| Item | IL-2 rs2069762 | IL-2 rs2069763 | ||||
|---|---|---|---|---|---|---|
| Wild TT n = 10 |
Variant (TG, GG) n = 50 |
p | Wild TT n = 7 |
Variant (TG, GG) n = 53 |
p | |
| Hemoglobin (g/dL) | 12.1 ± 1.6 | 9.2 ± 1.7 | < 0.001 | 12.2 ± 2.0 | 9.4 ± 1.8 | < 0.001 |
| TLC (× 103/µL) | 7.8 ± 5.3 | 15.1 ± 17.4 | 0.197 | 6.5 ± 2.5 | 14.8 ± 17.0 | 0.002 |
| Lymphocytes % | 32.2 ± 8.3 | 45.1 ± 11.0 | < 0.001 | 27.7 ± 7.6 | 45.0 ± 10.5 | < 0.001 |
| Platelet (× 103/µL) | 277.1 ± 116.4 | 198.9 ± 81.5 | 0.013 | 389.6 ± 74.6 | 188.5 ± 64.3 | < 0.001 |
| β2 microglobulin (mg/dL) | 2.2 ± 0.6 | 4.6 ± 5.0 | < 0.001 | 2.1 ± 0.6 | 4.5 ± 4.9 | < 0.001 |
| LDH (U/L) | 213.2 ± 59.0 | 558.8 ± 421.1 | 0.013 | 227.4 ± 97.1 | 537.3 ± 417.5 | < 0.001 |
| B.M involvement n(%) | 0 (0%) | 19 (38%) | 0.018 | 0 (0%) | 19 (36%) | 0.055 |
| Ann Arbor staging n(%) | ||||||
| Stage I &II | 10 | 11 | < 0.001 | 7 | 14 | < 0.001 |
| Stage III & IV | 0 | 39 | 0 | 39 | ||
Data are expressed as mean ± SD unless stated otherwise
Univariate analysis studying the impact of IL-2 polymorphisms on outcome of NHL patients following chemotherapy revealed that, the variant genotypes (TG/GG) of IL-2 (rs2069762) and (rs2069763) gene polymorphisms were associated with poor disease outcome. Moreover, patients who carry both IL-2 gene polymorphisms were more susceptible to unfavorable disease outcome following treatment than those having a single gene polymorphism (p < 0.001, OR = 18.41, 95% CI = 3.14–110.24) (Table 5). In addition, univariate analysis revealed that late disease stage (p = 0.001), high LDH (p < 0.001) and high β2 microglobulin levels (p = 0.023) were significantly associated with unfavorable prognosis. In multivariate analysis, only IL-2 (rs2069762) and (rs2069763) polymorphisms retain their poor prognostic effect (p = 0.011 and 0.046 respectively).
Table 5.
Relation between IL-2 gene polymorphisms and disease outcome among NHL patients (N = 60)
| Polymorphism | Favorable outcome n (%) |
Unfavorable outcome n (%) |
OR (95% CI) | p value |
|---|---|---|---|---|
| IL-2 (rs2069762) | ||||
| Wild (TT) | 6 (10) | 4 (6.7) | 17.30 (3.39–87.73) | < 0.001 |
| Variant (TG/GG) | 4 (6.7) | 46 (76.7) | ||
| IL-2 (rs2069763) | ||||
| Wild (TT) | 4 (6.7) | 3 (5) | 10.42 (1.87–58.41) | 0.002 |
| Variant (TG/GG) | 6 (10) | 47 (78.3) | ||
| Both gene polymorphisms | 2 (3.3) | 43 (71.7) | 18.41 (3.14–110.24) | < 0.001 |
| Single gene polymorphism | 6 (10) | 7 (11.7) | ||
The median OS of the patients was 24 months. The estimated OS at 1 year was 95%. No significant association was found between IL-2 (rs2069762) and (rs2069763) genotypes and OS among the studied patients (p = 0.545 and 0.605 respectively).
Discussion
Genetic polymorphisms in cytokine genes have been found to be associated with increased risk of NHL [17]. SNPs particularly those within the promoter regions of the genes are associated with differential levels of gene transcription and thus may upregulate or downregulate the production of cytokines that play an important role in lymphomagenesis and its prognosis [18].
In the present study, we investigated the relation between two SNPs in IL-2 gene and the risk of NHL. We found that the variant genotypes of IL-2 (rs2069762) polymorphism are significantly more frequent among NHL patients compared to controls. The variant allele (G) is associated with increased risk (2.5 fold) of development of NHL. Positive association between IL-2 (rs2069762) polymorphism and cancer risk was observed in a meta-analysis including 15 published case control studies [19]. In the study of Song and colleagues that is included in this meta-analysis, significantly higher prevalence of the variant genotypes of IL-2 (rs2069762) polymorphism was detected in NHL patients relative to controls with subsequent increased risk (1.34 fold) of development of NHL [16]. In a previous study including Egyptian patients with B-NHL, the variant genotypes (TG & GG) were found to be associated with almost 3 fold increased risk of B-NHL with a 4 fold increased risk of the indolent subtypes [20]. A similar association between this polymorphism and risk of cutaneous T-cell lymphoma was observed in another study [21].
Regarding IL-2 (rs2069763) gene polymorphism, we found that the variant allele (G) is associated with elevated risk (2.26 fold) of NHL development. In contrast to our results, no correlation between IL-2 (rs2069763) polymorphism and cancer risk was detected in a meta-analysis including 6 published case control studies [19] including one study with NHL cases [16]. However, in this study, haplotype analysis of IL-2 (rs2069762) and (rs2069763) polymorphisms revealed that the − 330G/ + 114 T haplotype is associated with an increased susceptibility (1.45 fold) to NHL [16].
In our study, we found that the presence of both IL-2 (rs2069762) and (rs2069763) gene polymorphisms is associated with more increased risk of NHL (6 folds) than single gene polymorphism.
Significant association was found between IL-2 variant genotypes and clinical-laboratory variables that may carry poor prognosis like anemia, leucocytosis, lymphocytosis, lower platelet counts, high LDH, high β2 microglobulin, bone marrow infiltration and late disease stage. However this is in contrast with what was reported by Song and colleagues who found no significant association between IL-2 genotypes and clinical-pathological variables [16]. Regarding disease outcome, a deleterious effect of the variant genotypes of IL-2 gene polymorphisms; (rs2069762) and (rs2069763) on clinical outcome of NHL patients following chemotherapy was detected in both univariate and multivariate analyses including other clinical/laboratory prognostic variables. Patients who carry both IL-2 gene polymorphisms are even more susceptible to poor clinical outcome than those with single gene polymorphism. However, no significant association was found between various genotypes and patients’ overall survival. Polymorphisms in cytokines genes have been found to be associated with prognosis and overall NHL survival [22, 23]. The variant genotype of IL-2 (rs2069762) polymorphism was found to have a deleterious effect on follicular lymphoma survival in both univariate and multivariate analyses that included polymorphisms in another 3 cytokine genes (IL-8, IL-12B and IL-1RN) [3].
In conclusion, IL-2 gene polymorphisms (individually and, more importantly, in combination) could be involved in the pathogenesis and development of NHL, and may have an impact on prognosis and disease outcome following chemotherapy. This study is limited by the relatively small sample size. Future larger studies with detailed treatment data and longer follow up are warranted to validate the result of this study and make a firm conclusion.
Author contributions
Study design and supervision of the work were performed by S.M.M., M.M.M. Medical practice and sample collection were performed by H.M.Z., E.T.M. Genotyping was done by M.M.M., E.T.M. Data analysis, procession and interpretation of the results were performed by S.M.M., M.M.M., E.T.M. The manuscript was written by S.M.M., M.M.M. All authors approved the final manuscript.
Compliance with Ethical Standards
Conflict of interest
None to declare.
Ethical Approval
The study protocol was approved by the Institutional Review board of Kasr Al-Ainy School of Medicine, Cairo University.
Informed Consent
Informed consent was provided prior to patient enrolment.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Nieters A, Conde L, Slager SL, Brooks-Wilson A, Morton L, Skibola DR, et al. PRRC2A and BCL2L11 gene variants influence risk of non-hodgkin lymphoma: results from the Interlymph consortium. Blood. 2012;120(23):4645–4648. doi: 10.1182/blood-2012-05-427989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Skibola CF, Curry JD, Nieters A. Genetic susceptibility to lymphoma. Haematologica. 2007;92:960–969. doi: 10.3324/haematol.11011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Cerhan JR, Wang S, Maurer MJ, Ansell SM, Geyer SM, Cozen W, et al. Prognostic significance of host immune gene polymorphisms in follicular lymphoma survival. Blood. 2007;109(12):5439–5446. doi: 10.1182/blood-2006-11-058040. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Shen Y, Liu Y, Liu S, Zhang A. The association between-330T/G polymorphism of interleukin 2 gene and bladder cancer. DNA Cell Biol. 2012;31(6):983–987. doi: 10.1089/dna.2011.1476. [DOI] [PubMed] [Google Scholar]
- 5.Togawa S, Joh T, Itoh M, Katsuda N, Ito H, Matsuo K, et al. Interleukin-2 gene polymorphisms associated with increased risk of gastric atrophy from Helicobacter pylori infection. Helicobacter. 2005;10(3):172–178. doi: 10.1111/j.1523-5378.2005.00308.x. [DOI] [PubMed] [Google Scholar]
- 6.Matesanz F, Delgado C, Fresno M, Alcina A. Allelic selection of human IL-2 gene. Eur J Immunol. 2000;30(12):3516–3521. doi: 10.1002/1521-4141(2000012)30:12<3516::AID-IMMU3516>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]
- 7.Wei YS, Lan Y, Zhang L, Wang JC. Association of the interleukin-2 polymorphisms with interleukin-2 serum levels and risk of nasopharyngeal carcinoma. DNA Cell Biol. 2010;29(7):363–368. doi: 10.1089/dna.2010.1019. [DOI] [PubMed] [Google Scholar]
- 8.Shin WG, Jang JS, Kim HS, Kim SJ, Kim KH, Jang MK, et al. Polymorphisms of interleukin-1 and interleukin-2 genes in patients with gastric cancer in Korea. J Gastroenterol Hepatol. 2008;23(10):1567–1573. doi: 10.1111/j.1440-1746.2008.05479.x. [DOI] [PubMed] [Google Scholar]
- 9.Peng Q, Li H, Lao X, Deng Y, Chen Z, Qin X, et al. Association of IL-2 polymorphisms and IL-2 serum levels with susceptibility to HBV-related hepatocellular carcinoma in a Chinese Zhuang population. Infect Genet Evol. 2014;27:375–381. doi: 10.1016/j.meegid.2014.08.021. [DOI] [PubMed] [Google Scholar]
- 10.Sobjanek M, Zabłotna M, Bień E, Gleń J, Sokołowska-Wojdyło M, Ruckemann-Dziurdzińska K, et al. Clinical significance of IL-2 and IL-10 gene polymorphisms and serum levels in patients with basal-cell carcinoma. Biomark Med. 2016;10(2):185–195. doi: 10.2217/bmm.15.113. [DOI] [PubMed] [Google Scholar]
- 11.Hu XB, Ouyang LZ, Tang LL. Interleukin-2 gene polymorphisms and prognosis of breast cancer. Genet Test Mol Biomark. 2013;17(6):453–457. doi: 10.1089/gtmb.2012.0494. [DOI] [PubMed] [Google Scholar]
- 12.Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–2390. doi: 10.1182/blood-2016-01-643569. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Armitage JO. Staging non-hodgkin lymphoma. CA Cancer J Clin. 2005;55(6):368–376. doi: 10.3322/canjclin.55.6.368. [DOI] [PubMed] [Google Scholar]
- 14.Oken MM, Costello WG, Johnson GJ, Lenhard RE, Ezdinli EZ, Orlow E, et al. The influence of histologic subtype on toxicity and response to chemotherapy in non-hodgkin's lymphoma. An eastern cooperative oncology group study utilizing the BCVP regimen. Cancer. 1983;5(9):1581–1586. doi: 10.1002/1097-0142(19830501)51:9<1581::AID-CNCR2820510905>3.0.CO;2-L. [DOI] [PubMed] [Google Scholar]
- 15.Zhuang H, Shen J, Zheng Z, Luo X, Gao R, Zhuang X. MicroRNA-146a rs2910164 polymorphism and the risk of diffuse large B cell lymphoma in the Chinese Han population. Med Oncol. 2014;31(12):306. doi: 10.1007/s12032-014-0306-z. [DOI] [PubMed] [Google Scholar]
- 16.Song H, Chen L, Cha Z, Bai J. Interleukin 2 gene polymorphisms are associated with non-hodgkin lymphoma. DNA Cell Biol. 2012;31(7):1279–1284. doi: 10.1089/dna.2011.1603. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Ye X, Zhao K, Wu C, Hu P, Fu H. Associations between genetic variants in immunoregulatory genes and risk of non-hodgkin lymphoma in a Chinese population. Oncotarget. 2017;8(6):10450–10457. doi: 10.18632/oncotarget.14426. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Howell WM, Rose-Zerilli MJ. Cytokine gene polymorphisms, cancer susceptibility, and prognosis. J Nutr. 2007;137(1 Suppl):194S–199S. doi: 10.1093/jn/137.1.194S. [DOI] [PubMed] [Google Scholar]
- 19.Zhang M, Tan X, Huang J, Xie L, Wang H, Shi J, et al. Association between two interleukin-2 gene polymorphisms and cancer susceptibility: a meta-analysis. Onco Targets Ther. 2016;9:2181–2192. doi: 10.2147/OTT.S94761. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Abdel Rahman HA, Khorshied MM, Reda Khorshid OM, Mourad HM. Association of Interleukin-2-330T/G and interleukin-10-1082A/G genetic polymorphisms with B-cell non-hodgkin lymphoma in a cohort of egyptians. Turk J Haematol. 2018;35(2):99–108. doi: 10.4274/tjh.2017.0106. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Nedoszytko B, Olszewska B, Roszkiewicz J, Glen J, Zabłotna M, Ługowska-Umer H, et al. The role of polymorphism of interleukin-2, −10, −13 and TNF-α genes in cutaneous T-cell lymphoma pathogenesis. Postepy Dermatol Alergol. 2016;33(6):429–434. doi: 10.5114/ada.2016.63881. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Lech-Maranda E, Baseggio L, Bienvenu J, Charlot C, Berger F, Rigal D, et al. Interleukin-10 gene promoter polymorphisms influence the clinical outcome of diffuse large B-cell lymphoma. Blood. 2004;103(9):3529–3534. doi: 10.1182/blood-2003-06-1850. [DOI] [PubMed] [Google Scholar]
- 23.Juszczynski P, Kalinka E, Bienvenu J, Woszczek G, Borowiec M, Robak T, et al. Human leukocyte antigens class II and tumor necrosis factor genetic polymorphisms are independent predictors of non-hodgkin lymphoma outcome. Blood. 2002;100(8):3037–3040. doi: 10.1182/blood-2002-02-0654. [DOI] [PubMed] [Google Scholar]