Abstract
Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy worldwide. Interleukin-2 (IL-2) plays a key role in the proliferation of T cells and natural killer cells. It has been reported that polymorphisms in the IL-2 gene are associated with various cancers. The aim of this study was to examine the effect of polymorphisms in the IL-2 gene on the development of NHL in the Chinese population. IL-2-330T/G and +114T/G polymorphisms were detected by polymerase chain reaction–restriction fragment length polymorphism in 438 NHL cases and 482 age-matched healthy controls. Data were analyzed using the Chi-square test. Results showed that individuals with −330TG genotype or −330GG genotype had significantly increased susceptibility to NHL (Odds ratio [OR]=1.40, 95% confidence interval [CI]: 1.05–1.85, p=0.020 and OR=2.04, 95%CI: 1.28–3.24, p=0.002). Meanwhile, the +114T/G polymorphism did not show any correlation with NHL. When analyzing the haplotypes of these two polymorphisms, the prevalence of −330G/+114T haplotype was significantly higher in NHL cases than in controls (OR=1.45, 95%CI: 1.12–1.88, p=0.005). These data indicate that IL-2 gene polymorphisms may be new risk factors for NHL.
Introduction
Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy worldwide and has shown a pronounced increase in incidence in the past 10 years (Muller et al., 2005). It represents 4% of all cancers and is the fifth most commonly diagnosed cancer in the United States (Muller et al., 2005). Its rates are over 10/100,000 in the United States, Australia, and Western Europe, while <5/100,000 in Southern and Eastern Asia (Boyle and Levin, 2008).
Interleukin 2 (IL-2) secreted by Th1 cells plays a central role in the activation of T cell-mediated immune responses. It can augment natural killer (NK) cell cytolytic activity (Lenardo, 1991; Sakaguchi et al., 2008). Also, IL-2 contributes to the development of regulatory T cells and regulates the expansion and apoptosis among activated T cells (Lenardo, 1991; D'Souza and Lefrancois, 2003). As for its relation to cancer, IL-2 has been reported to play an essential role in antitumor immunity (Zhang et al., 2010). Clinical studies have shown that the transfection of the IL-2 gene into tumor cells can enhance both specific and nonspecific antitumor immune responses (Okamoto et al., 2003; Terao et al., 2005). Recent research has demonstrated that IL-2 can induce an autologous graft-versus-lymphoma effect through activation of NK cells and cytotoxic T cells (Katsanis et al., 1991) and may be used as an immunotherapy for NHL (Poiré et al., 2010).
Two polymorphisms, −330T/G and +114T/G, have been identified in the IL-2 gene. The −330T/G polymorphism lies in the promoter region of the IL-2 gene and is implicated in the increased susceptibility to a range of inflammatory diseases and cancers, including gastric atrophy from Helicobacter pylori infection, rheumatoid arthritis, gastric cancer, and myelogenous leukemia (Amirzargar et al., 2005; Pawlik et al., 2005; Togawa et al., 2005; Shin et al., 2008; Wu et al., 2009). However, no studies to date have examined the association between IL-2 polymorphisms and NHL. Clarification of the relationship between IL-2 polymorphisms and NHL may indicate a role of IL-2 function in the etiology of NHL and provide clues to guide the treatment of this disease. To clarify this relationship, we have analyzed IL-2-330T/G and +114T/G polymorphisms in 438 cases of NHL and 482 controls.
Materials and Methods
Study subjects
This study included 438 patients with confirmed NHL and 482 healthy controls. The diagnosis of lymphoma was confirmed by histopathology and, in most cases, by supplementary immunohistochemistry analyses. Cases were categorized according to the Revised European–American Lymphoma Classification (Harris et al., 1994). An additional assessment was performed at a later date to classify the samples according to the World Health Organization Classification (WHO, 2001). All patients and controls were consecutively recruited from Changhai Hospital and Shanghai East Hospital between February 2006 and May 2011. Subjects participating in the study were genetically unrelated Han Chinese. Written informed consent was obtained from all the subjects, and the study was performed with the approval of the Ethics Committees of Changhai Hospital and Shanghai East Hospital.
DNA extraction and genotyping
Genomic DNA was extracted from 5 mL frozen whole blood using the DNA Extraction Kit (Fastagen, China) according to the manufacturer's protocol. The IL-2-330T/G and +114T/G genotypes were determined using a polymerase chain reaction (PCR)–restriction fragment length polymorphism assay and DNA sequencing analysis. The PCR primers were designed as previously described (Matesanz et al., 2001). The PCR primers for the −330 T/G and +114 T/G polymorphisms were 5′-ATTCACATGTTCAGTGTAGTTCT-3′ (forward) and 5′-GTGATAGCTCTAATTCATGC- 3′ (reverse); and 5′ -ATGTACAGGATGCAACTCCT-3′ (forward) and 5′-TGGTGAGTTTGGGATTCTTG-3′ (reverse), respectively. The PCRs were performed in a total volume of 25 μL containing 100 ng genomic DNA, 20 pM of each primer, 0.2 mM dNTPs, 20 mM Tris-HCl (pH 8.8), 10 mM KCl, 10 mM (NH4)2SO4, 2 mM MgSO4, 0.1%Triton X-100, and 1 unit of Taq polymerase (New England BioLabs). The PCR cycle conditions consisted of an initial denaturation step at 94°C for 5 min, followed by 35 cycles of 30 s at 94°C ; 45 s at 61°C for −330 T/G and 63°C for +114T/G; 45 s at 72°C ; and a final elongation at 72°C for 8 min. The PCR products were digested for 3 h at 37°C with the appropriate restriction enzymes (New England BioLabs). The restriction enzymes for the −330T/G and +114 T/G genotypes were BfaI and MwoI, respectively. The digested PCR products were resolved on 8% acrylamide gels and stained with ethidium bromide for visualization under UV light. To confirm the genotyping results of the IL-2-330T/G and +114T/G polymorphisms, 18% of PCR-amplified DNA samples were examined by DNA sequencing. Results between PCR and DNA sequencing analysis were 100% concordant.
Statistical analysis
Genotype and allele frequencies of IL-2 polymorphisms were compared between NHL cases and controls using the Chi-square test and odds ratios (OR), and 95% confidence intervals (CIs) were calculated to assess the relative risk conferred by a particular allele and genotype. Demographic and clinical data between groups were compared by Chi-square test and Student's t-test. Haplotypes of the two SNPs were conducted and analyzed using the SHEsis software, from the Web site http://analysis.bio-x.cn/ (Bio-X Inc., Shanghai, China). Statistical significance was assumed at p<0.05. The SPSS statistical software package version 13.0 was used for all of the statistical analyses.
Results
The frequency distributions of select characteristics of the cases and controls are presented in Table 1. The mean ages of the patient group and the control group were 56 years and 55 years, respectively. No significant differences were observed between the NHL cases and controls in regard to age (p=0.110) and gender (p=0.461).
Table 1.
Characteristics of the Subjects
| Characteristics | Patients (n=438) | Controls (n=482) | p-Value |
|---|---|---|---|
| Mean age±SD | 56.6±8.1 | 55.5±7.9 | 0.851 |
| Age (years) no. (%) | |||
| ≤60 | 307 (70.1) | 314 (65.1) | 0.110 |
| >60 | 131 (29.9) | 168 (34.9) | |
| Sex no. (%) | |||
| Male | 255 (58.2) | 269 (55.8) | 0.461 |
| Female | 183 (41.8) | 213 (44.2) | |
| Tumor size | |||
| ≤5cm | 360 (82.2) | ||
| >5cm | 78 (17.8) | ||
| Immunohistological subtype no. (%) | |||
| B-cell subtype | 268 (61.2) | ||
| Diffuse large B-cell lymphoma | 175 (40.0) | ||
| Small lymphocytic B-cell lymphoma | 65 (14.8) | ||
| Follicular lymphoma | 10 (2.3) | ||
| Other B-cell lymphoma | 18 (4.1) | ||
| T-cell subtype | 170 (38.8) | ||
| Peripheral T-cell lymphoma | 112 (25.6) | ||
| Angioimmunoblastic T-cell lymphoma | 21 (4.8) | ||
| Extranodal T/NK cell lymphoma | 9 (2.1) | ||
| Other T-cell lymphoma | 28 (6.3) | ||
| Ann Arbor stage n. (%) | |||
| Stage I, II | 131 (29.9) | ||
| Stage III, IV | 307 (70.1) | ||
| Bone marrow involvement n. (%) | |||
| No | 328 (74.9) | ||
| Yes | 110 (25.1) | ||
| B symptoms no. (%) | |||
| With | 197 (45.0) | ||
| Without | 241 (55.0) | ||
| Lymphoma origin no. (%) | |||
| Lymph node | 246 (56.2) | ||
| Extranodal origin | 192 (43.8) | ||
| Types of treatment no. (%) | |||
| Chemotherapy | 395 (90.1) | ||
| Chemotherapy and radiation | 31 (7.1) | ||
| Chemotherapy and anti-CD20 mAb | 9 (2.1) | ||
| Autologous stem cell transplantation | 3 (0.7) | ||
NK, natural killer.
The genotype and allele frequencies of the IL-2-330T/G and +114T/G polymorphisms in NHL cases and controls are summarized in Table 2. The genotype distributions of these two polymorphisms among the controls were in agreement with the Hardy–Weinberg equilibrium (p>0.05). The T versus G allele frequencies of IL-2-330 polymorphism were 59.1% versus 40.9% among the cases and 66.0% versus 34.0% among the controls (p=0.002). Prevalence of the IL-2-330TG and GG genotype were significantly higher in patients than in controls (OR=1.40, 95% CI: 1.05–1.85, p=0.020; and OR=2.04, 95%CI: 1.28–3.24, p=0.002). As for the +114T/G polymorphism, the prevalence of T and G allele were 54.3% and 45.7% in patients and 53.5% and 46.5% in controls (p=0.727). The IL-2 +114TG and GG genotype did not show any significant difference between the patients and the controls (OR=0.99, 95%CI: 0.73–1.34, p=0.939 and OR=0.93, 95%CI: 0.64–1.35, p=0.714). When analyzing the haplotypes of these two polymorphisms, 4 haplotypes were observed (Table 2). The −330G/+114T haplotype had significantly higher numbers in NHL cases compared with healthy controls (OR=1.45, 95%CI: 1.12–1.88, p=0.005). These data suggest that both IL-2-330T/G polymorphism and −330G/+114T haplotype are associated with an increased susceptibility to NHL in the Chinese population.
Table 2.
Genotype and Allele Frequencies of the Interleukin-2 Polymorphisms Among Non-Hodgkin Lymphoma Patients and Controls
| Polymorphism | NHL Cases n=438 (%) | Controls n=482 (%) | OR (95%CI) | p-Value |
|---|---|---|---|---|
| −330 T/G | ||||
| Genotype | ||||
| TT | 136 (31.1) | 193 (40.0) | Referent | |
| TG | 246 (56.2) | 250 (51.9) | 1.40 (1.05–1.85) | 0.020a |
| GG | 56 (12.7) | 39 (8.1) | 2.04 (1.28–3.24) | 0.002a |
| Allele | ||||
| T | 518 (59.1) | 636 (66.0) | Referent | |
| G | 358 (40.9) | 328 (34.0) | 1.34 (1.11–1.62) | 0.002a |
| +114 T/G | ||||
| Genotype | ||||
| TT | 128 (29.2) | 138 (28.6) | Referent | |
| TG | 220 (50.3) | 240 (49.8) | 0.99 (0.73–1.34) | 0.939 |
| GG | 90 (20.5) | 104 (21.6) | 0.93 (0.64–1.35) | 0.714 |
| Allele | ||||
| T | 476 (54.3) | 516 (53.5) | Referent | |
| G | 400 (45.7) | 448 (46.5) | 0.97 (0.81–1.16) | 0.727 |
| Haplotypes | ||||
| −330/+114 | ||||
| TT | 277 (31.6) | 345 (35.8) | Referent | |
| TG | 241 (27.5) | 291 (30.2) | 1.03 (0.82–1.30) | 0.794 |
| GT | 199 (22.7) | 171 (17.7) | 1.45 (1.12–1.88) | 0.005a |
| GG | 159 (18.2) | 157 (16.3) | 1.26 (0.96–1.66) | 0.093 |
p-Values in bold are statistically significant (<0.05).
NHL, Non-Hodgkin lymphoma; OR, odds radio; CI, confidence interval.
We further evaluated the association of IL-2-330T/G and +114T/G polymorphisms with different clinical parameters in the 438 NHL patients (Table 3). Neither −330T/G polymorphism nor +114T/G polymorphism demonstrated significantly different genotype and allele distributions in regard to Ann Arbor stage (I+II vs. III+IV; p>0.05), tumor size (≤5 cm vs. >5 cm; p>0.05), cell subtype (B cell vs. T cell) (p>0.05), or bone marrow involvement (p>0.05). Similarly, when analyzing the correlation of the two-polymorphism haplotypes with these clinical-pathological factors, we did not find any statistically significant association (p>0.05). These results indicate that the two polymorphisms are not correlated with these clinical-pathological factors in NHL patients.
Table 3.
Association of Interleukin-2 Polymorphisms with Different Clinical Parameters in Non-Hodgkin Lymphoma
| Polymorphism | Tumor size (%) ≤5 cm/>5 cm (360)/(78) | OR 95%CI | p-Value | Ann Arbor stage (%) I+II/III+IV (131)/(307) | OR 95%CI | p-Value |
|---|---|---|---|---|---|---|
| −330 T/G | ||||||
| TT | 116 (32.2) 20 (25.6) | Referent | 38 (29.0) 98 (31.9) | Referent | ||
| TG | 199 (55.3) 47 (60.3) | 0.73 (0.41–1.29) | 0.279 | 77 (58.8) 169 (55.0) | 1.18 (0.74–1.86) | 0.493 |
| GG | 45 (12.5) 11 (14.1) | 0.71 (0.31–1.59) | 0.398 | 16 (12.2) 40 (13.1) | 1.03 (0.52–2.06) | 0.930 |
| T | 431 (59.9) 87 (55.8) | Referent | 153 (58.4) 365 (59.4) | Referent | ||
| G | 289 (40.1) 69 (44.2) | 0.85 (0.60–1.20) | 0.346 | 109 (41.6) 249 (40.6) | 1.04 (0.78–1.40) | 0.772 |
| +114 T/G | ||||||
| TT | 106 (29.4) 22 (28.2) | Referent | 42 (32.1) 86 (28.0) | Referent | ||
| TG | 182 (50.6) 38 (48.7) | 0.99 (0.56–1.77) | 0.984 | 65 (49.6) 155 (50.5) | 0.86 (0.54–1.37) | 0.524 |
| GG | 72 (20.0) 18 (23.1) | 0.83 (0.42–1.66) | 0.597 | 24 (18.3) 66 (21.5) | 0.74 (0.41–1.35) | 0.331 |
| T | 394 (54.7) 82 (52.6) | Referent | 149 (56.9) 327 (53.3) | Referent | ||
| G | 326 (45.3) 74 (47.4) | 0.92 (0.65–1.30) | 0.624 | 113 (43.1) 287 (46.7) | 0.86 (0.65–1.16) | 0.326 |
| Haplotypes | ||||||
| −330/+114 | ||||||
| TT | 236 (32.8) 41 (26.3) | Referent | 84 (32.1) 193 (31.4) | Referent | ||
| TG | 195 (27.1) 46 (29.5) | 0.74 (0.46–1.17) | 0.193 | 69 (26.3) 172 (28.0) | 0.92 (0.63–1.35) | 0.673 |
| GT | 158 (21.9) 41 (26.3) | 0.67 (0.42–1.08) | 0.098 | 65 (24.8) 134 (21.8) | 1.12 (0.75–1.65) | 0.587 |
| GG | 131 (18.2) 28 (17.9) | 0.81 (0.48–1.38) | 0.439 | 44 (16.8) 115 (18.8) | 0.88 (0.57–1.35) | 0.558 |
| Polymorphism | Subtype (%) B cell/T cell (268)/(170) | OR 95%CI | p-value | Bone marrow involvement (%) No/Yes (328)/(110) | OR 95%CI | p- value |
|---|---|---|---|---|---|---|
| −330 T/G | ||||||
| TT | 116 (32.2) 20 (25.6) | Referent | 38 (29.0) 98 (31.9) | Referent | ||
| TG | 199 (55.3) 47 (60.3) | 0.73 (0.41–1.29) | 0.279 | 77 (58.8) 169 (55.0) | 1.18 (0.74–1.86) | 0.493 |
| GG | 45 (12.5) 11 (14.1) | 0.71 (0.31–1.59) | 0.398 | 16 (12.2) 40 (13.1) | 1.03 (0.52–2.06) | 0.930 |
| T | 431 (59.9) 87 (55.8) | Referent | 153 (58.4) 365 (59.4) | Referent | ||
| G | 289 (40.1) 69 (44.2) | 0.85 (0.60–1.20) | 0.346 | 109 (41.6) 249 (40.6) | 1.04 (0.78–1.40) | 0.772 |
| +114 T/G | ||||||
| TT | 106 (29.4) 22 (28.2) | Referent | 42 (32.1) 86 (28.0) | Referent | ||
| TG | 182 (50.6) 38 (48.7) | 0.99 (0.56–1.77) | 0.984 | 65 (49.6) 155 (50.5) | 0.86 (0.54–1.37) | 0.524 |
| GG | 72 (20.0) 18 (23.1) | 0.83 (0.42–1.66) | 0.597 | 24 (18.3) 66 (21.5) | 0.74 (0.41–1.35) | 0.331 |
| T | 394 (54.7) 82 (52.6) | Referent | 149 (56.9) 327 (53.3) | Referent | ||
| G | 326 (45.3) 74 (47.4) | 0.92 (0.65–1.30) | 0.624 | 113 (43.1) 287 (46.7) | 0.86 (0.65–1.16) | 0.326 |
| Haplotypes | ||||||
| −330/+114 | ||||||
| TT | 236 (32.8) 41 (26.3) | Referent | 84 (32.1) 193 (31.4) | Referent | ||
| TG | 195 (27.1) 46 (29.5) | 0.74 (0.46–1.17) | 0.193 | 69 (26.3) 172 (28.0) | 0.92 (0.63–1.35) | 0.673 |
| GT | 158 (21.9) 41 (26.3) | 0.67 (0.42–1.08) | 0.098 | 65 (24.8) 134 (21.8) | 1.12 (0.75–1.65) | 0.587 |
| GG | 131 (18.2) 28 (17.9) | 0.81 (0.48–1.38) | 0.439 | 44 (16.8) 115 (18.8) | 0.88 (0.57–1.35) | 0.558 |
Discussion
Lymphomas are comprised of a series of heterogeneous malignant diseases that originate from lymphoid tissue; there is a great deal of variability in clinical-biological behavior exhibited by lymphomas (Pennanen et al., 2008). The prognosis of this tumor is diverse and is dependent upon the immunohistological subtype, clinical staging, programs of treatment, and prognostic markers utilized. Studies have shown that IL-2 may serve as a prognostic indicator in certain types of solid carcinomas, including lymphoma (Cooper et al., 2001a). In the current study, we investigated the role of the IL-2-330T/G and +114T/G polymorphisms in susceptibility to NHL in the Chinese population and found for the first time that the IL-2-330T/G polymorphism and the −330G/+114T haplotype are risk factors for this disease.
Human genetic polymorphisms can play critical roles in various diseases (Wang et al., 2011; Liu et al., 2011; Ma et al., 2011). Due to the importance of IL-2, polymorphisms in this gene have been extensively researched and two polymorphisms have been identified; one located in the promoter region at nucleotide −330 (John et al., 1998) and another in the first exon at position +114 (Matesanz et al., 2000). According to the HapMap Project and Environmental Genome Project, the frequency of the IL-2-330G allele is about 0.34 in Asian populations, which is consistent with our findings (G=34%). The −330T/G polymorphism has been shown to alter the level of IL-2 and is associated with diseases and cancers, including gastric atrophy from Helicobacter pylori infection, rheumatoid arthritis, gastric cancer, and myelogenous leukemia (Amirzargar et al., 2005; Pawlik et al., 2005; Togawa et al., 2005; Shin et al., 2008; Wu et al., 2009). Our data have shown that this polymorphism also affects the development of NHL. The other polymorphism, +114T/G, lies in the first exon of the IL-2 gene. It is silent and does not produce any amino acid change. Wei et al. (2010) have reported that the distribution of the IL-2 +114G allele is 46.7 in the western Chinese population, while our study has shown that this G allele is 46.5 in eastern Chinese. These data suggest that the distribution of this polymorphism is very similar in different Chinese populations. Since study has shown that some SNPs may be correlated with bone marrow involvement in NHL (Muller, et al., 2005), we compared the two IL-2 polymorphisms in NHL patients with or without bone marrow involvement (Table 3). However, we did not find any association between IL-2 polymorphisms and NHL bone marrow involvement (Table 3). In addition, the two major cell subtypes of NHL, B-cell subtype and T-cell subtype, may have very different clinical characteristics. We therefore performed the stratification analysis of the IL-2 polymorphisms between B-cell subtype group and T-cell subtype group (Table 3). Data did not show any significant difference between these groups. These results indicate that the IL-2 polymorphisms may affect the whole NHL group rather than a specific subtype of this disease.
The mechanism in which the IL-2-330T/G polymorphism affects NHL remains unclear. IL-2 is involved in the differentiation of B cells into plasmocytes, which could translate in B lymphoma. More importantly, IL-2 promotes NK cell expansion (Meropol et al., 1998) and enhances intrinsic NK cell cytotoxicity (Eisenbeis et al., 2004). NK cells are large granular lymphocytes that comprise 10% to 15% of peripheral blood lymphocytes (Cooper et al., 2001b) and mediate antibody-dependent cellular cytotoxicity (ADCC) via expression of an activating receptor for the Fc portion of IgG antibodies (Cooper et al., 2001a). Since ADCC plays critical roles against NHL, IL-2, one of the modulators of ADCC, may affect NHL and is considered as a possible therapy for this disease. It is reported that the G allele of the −330 polymorphism is correlated with reduced IL-2 production in vivo (Hoffmann et al., 2001; Matesanz et al., 2004). It is possible that the decreased IL-2 level can downregulate the antitumor response through ADCC in NHL patients and, therefore, increase the susceptibility to this disease.
There are some limitations to this study. For example, our patient sample size was relatively small. Our data might be of limited value and therefore, an additional study of more cases is needed. Since our study focused on the Chinese population, it would be important to conduct a similar study in other ethnic populations. In addition, the current research studied two polymorphisms. It would be interesting to identify more polymorphisms in the IL-2 gene and study their correlations with NHL.
In conclusion, this study investigated the allele and genotype frequencies of IL-2 gene polymorphisms and identified the relationship between IL-2 polymorphisms and susceptibility to NHL. The −330T/G polymorphism and −330G/+114T haplotype can act as potential risk markers for NHL and may assist in the design of therapeutic programs for this disease.
Acknowledgments
This research was funded by the Project of Modern Chinese Medicine, Shanghai Committee of Science and Technology, China (Grant No. 09dz1972400).
Disclosure Statement
No competing financial interests exist.
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