|Year : 2014 | Volume
| Issue : 7 | Page : 135-139
Association between interleukin-4 polymorphisms and environment and nonsmall cell lung cancer in Chinese population
Jianzhong Gu1, Yingying Shen1, Yongjun Zhang2
1 The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou 310035, China
2 Department of Integration of Traditional Chinese and Western Medicine, Zhejiang Cancer Hospital, Hangzhou 310022, China
|Date of Web Publication||29-Nov-2014|
Department of Integration of Traditional Chinese and Western Medicine, Zhejiang Cancer Hospital, 38 Banshan Road, Hangzhou 310022
Source of Support: None, Conflict of Interest: None
Aim: The aim was to evaluate the influence of interleukin (IL)-4-590 C/T gene polymorphism in the susceptibility to nonsmall cell lung cancer (NSCLC), whether the environment also affects genetic polymorphisms.
Materials and Methods: A case-control study was conducted with 500 NSCLC patients and 500 healthy controls, matched on age and gender. The single nucleotide polymorphisms distributed in IL-4 gene were selected for genotyping. The association between genotype and NSCLC risk was evaluated by computing the odds ratio and 95% confidence interval with multivariate unconditional logistic regression analyses.
Results: The allele frequencies were not associated with NSCLC regardless of histological type or gender. The genotype distributions were similar between cases and controls, between adenocarcinoma patients and controls, and between male squamous-cell carcinoma (SCC) patients and male controls. However, genotype (C/C + C/T) frequencies polymorphism of rs2243250 were different between female SCC patients and female controls.
Conclusions: These results suggest that environmental agents might have the potential for interacting with human genetic polymorphisms in NSCLC. IL-4-590 C/T polymorphism (C/C + C/T frequencies) may be a potential susceptibility marker for female SCC patients in China.
Keywords: Chinese population, interleukin-4, nonsmall cell lung cancer, polymorphism
|How to cite this article:|
Gu J, Shen Y, Zhang Y. Association between interleukin-4 polymorphisms and environment and nonsmall cell lung cancer in Chinese population. J Can Res Ther 2014;10, Suppl S3:135-9
|How to cite this URL:|
Gu J, Shen Y, Zhang Y. Association between interleukin-4 polymorphisms and environment and nonsmall cell lung cancer in Chinese population. J Can Res Ther [serial online] 2014 [cited 2019 Aug 22];10:135-9. Available from: http://www.cancerjournal.net/text.asp?2014/10/7/135/145839
| > Introduction|| |
Worldwide, lung cancer is remained the leading cause of cancer death, due to its high mortality and morbidity.  Nonsmall cell lung cancer (NSCLC) corresponds to 80-85% of lung cancer cases, and despite development of antitumor therapy, NSCLC patient prognosis remains unsatisfactory, with a 5-year overall survival of <15%.  In China, the incidence and mortality associated with lung cancer are estimated to be 0.7 and 0.6 million cases. 
Recent studies have provided evidence that gene polymorphisms may influence the susceptibility to NSCLC. , Interleukin-4 (IL-4) is a major role in some carcinomas (oral,  gastric,  renal,  lung  ), which plays an important role in regulating the immune response of B-cells, T-cells, and macrophages against infections and malignant cells. , The human IL-4 gene is located within the cytokine gene cluster on chromosome 5q31 1, , where an important polymorphism − 590C/T polymorphism (rs2243250) in the promoter region has been identified.  In lung cancer, IL-4 rs2243250 single nucleotide polymorphisms (SNPs) have been associated with a reduced risk of NSCLC among Portuguese.  In this study, the possible association of the IL-4-590 C/T gene polymorphism with risk for NSCLC in Chinese patients in comparison with healthy control subjects was investigated.
| > Materials and methods|| |
The study is a population-based case-control study of 500 cases and 500 unrelated healthy controls. They were recruited from The Zhejiang Cancer Hospital between March 2011 and April 2012. Participants have no history of previous primary cancer other than lung cancer. The controls were independent lung-related diseases to avoid probable interferences from overlapping genes. All the controls were matched with patients in terms of gender and age. Current smoker or former smoker or nonsmoker was included. All cases and controls were Chinese Han origin and lived in Zhejiang Province, China. All subjects provided their informed consent approved by the Ethic Committee of Zhejiang Cancer Hospital.
Single nucleotide polymorphisms selection and genotyping
Interleukin-4 rs2243250 was selected according to a previous study.  DNA was extracted from whole blood by AxyPrep Blood Genomic DNA Miniprep Kit (Axygen Biosciences, Union City, CA, USA). DNA was subjected to genotyping of IL-4 SNPs with the SEQUENOM MassARRAY matrix-assisted laser desorption ionization-time of flight mass spectrometry platform (Sequenom, San Diego, CA, USA). Primers for polymerase chain reaction and single-base extension were designed using Assay Designer's software version 3.0 (Sequenom) and synthesized by Sangon Biotech (Shanghai, China).
The SPSS statistical software package version 13.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Hardy-Weinberg equilibrium (HWE) was carried out for all SNPs, cases and controls were compared using the Chi-square test and a P < 0.001 was considered as statistically different. The Chi-square test was used to assess frequencies of the selected allele and genotype between the cases and controls. The association between SNPs and NSCLC risk was analyzed by computing the odds ratio and 95% confidence interval from multivariate unconditional logistic regression analysis. All P values were two-sided, and P < 0.05 was considered as statistically significant.
| > Results|| |
A total of 500 patients (350 males and 150 females) and 500 healthy controls (259 males and 240 females, and gender information for one control subject was missed) were of Chinese Han origin. 280 male and 21 female patients are smokers or former smokers, 359 male and 14 female controls are smokers or former smokers. 1000 subjects (331 with adenocarcinoma (ADC), 169 with squamous-cell carcinomas (SCC), and 500 healthy controls) were successfully genotyped for polymorphisms of IL-4 rs2243250. The studied population was in HWE with the P values of 0.77629.
The allele frequency of IL-4 rs2243250 was 79.9% (T) and 20.1% (C) in NSCLC patients, 79.5% (T) and 20.5% (C) in ADC patients, 80.8% (T) and 19.2% (C) in SCC patients, and 80.9% (T) and 19.1% (C) in controls. No statistical differences in allele frequencies of the SNPs were found between the case and control subjects (P > 0.05). We then stratified by analysis of gender. The distributions differences of allele frequencies were not statistically significant between male patients and male controls, and female patients and female controls [Table 1], [Table 2] and [Table 3].
|Table 1: Allele frequency of IL-4 SNPs in NSCLC patients and healthy controls |
Click here to view
Genotype frequencies of IL-4 rs2243250 were 4.4% (C/C), 64.2% (T/T) and 31.4% (C/T) in NSCLC patients, 5.1% (C/C), 64.0% (T/T) and 30.8% (C/T) in ADC patients, 3.0% (C/C), 64.5% (T/T) and 32.5% (C/T) in SCC patients, 3.0% (C/C) 64.8% (T/T), and 32.2% (C/T) in the controls. The difference between controls and patients with NSCLC, ADC, or SCC were not statistically significant. We then stratified by analysis of gender. However, the frequencies of C/C + C/T in female SCC patients and female controls (0.0% vs. 36.2%) were statistically significantly different (P = 0.0346). This suggests the C allele of rs2243250 polymorphism in the IL-4 gene may be a risk factor for SCC development in Chinese females [Table 4], [Table 5] and [Table 6].
| > Discussion|| |
In this study, we analyzed whether the SNPs (rs2243250 in IL-4) are associated with NSCLC risk. The results show that, the allele frequencies were not associated with NSCLC regardless of histological type or gender. The genotype distributions were similar between cases and controls, between ADC patients and controls, and between male SCC patients and male controls. But, genotype (C/C + C/T) frequencies polymorphism of rs2243250 were different between female SCC patients and female controls. However, there were just only 8 female SCC patients in the study. More cases are needed to explore the relationship between this polymorphism and the risk of female SCC patients. Our results are not in agreement with those of the study by Gomes et al.  These differences may primarily be attributed to the distinct genetic background and the different living environments of the Chinese population compared with other populations. , Together with earlier studies, ,,, our date suggested that environmental agents might have the potential for interacting with human genetic polymorphisms in NSCLC.
Lung cancer is a complex disease resulted from environmental factors, genetic factors, and their interactions. , Geographic differences, ethnic background, tobacco, air pollution, radiation, occupational exposures, dietary, physical activity, and reproductive history have been identified as independent or contributing risk factors for lung cancer. ,
Gene polymorphisms also play critical roles in NSCLC. IL-4 is an important mediator of the Th1/Th2 balance and apoptosis potential and involved in the process of inflammation-mediated carcinogenesis in human organs. But, the role of IL-4 in cancer is paradoxical. , IL-4 induces the most effective immune response among several cytokines in both prophylactic and therapeutic models.  Besides immune cells, IL-4 also acts on endothelial cells, inhibiting tumor-induced vascularization and starving tumor cells.  IL-4 can modulate the activation of cancer-associated fibroblasts (that are important promoters of tumor growth and progression),  so that they do not support the growth of angiogenesis needed for tumor growth.  All these indicate IL-4 has strong potential as a tumor therapy agent. However, contrary evidence indeed exists, which shows IL-4 is a tumor-promoting molecule. IL-4 was usually up-regulated in patients with different types of cancers, such as renal cell cancer, prostate cancer, colon cancer, breast cancer, and other types of tumors. ,, IL-4 knockout mice are more resistant to tumor challenge than IL-4 competent mice. , Even worse, IL-4 promotes tumor metastasis.  The polymorphisms in its gene have been extensively studied due to the importance of IL-4.
| > Conclusions|| |
Our data suggested that environmental agents may play an important role in genetic polymorphism development and IL-4 polymorphism (C/C + C/T frequencies) may be a potential susceptibility marker for female SCC patients in China. However, more research is required to test our results.
| > References|| |
Edwards BK, Noone AM, Mariotto AB, Simard EP, Boscoe FP, Henley SJ, et al
. Annual Report to the Nation on the status of cancer, 1975-2010, featuring prevalence of comorbidity and impact on survival among persons with lung, colorectal, breast, or prostate cancer. Cancer 2014;120:1290-314.
Sculier JP, Chansky K, Crowley JJ, Van Meerbeeck J, Goldstraw P, International Staging Committee and Participating Institutions. The impact of additional prognostic factors on survival and their relationship with the anatomical extent of disease expressed by the 6 th
Edition of the TNM Classification of Malignant Tumors and the proposals for the 7 th
Edition. J Thorac Oncol 2008;3:457-66.
Zeng H, Zheng R, Zhang S, He J, Chen W. Lung cancer incidence and mortality in China, 2008. Thorac Cancer 2013;4:53-8.
Zhang Y, Hua S, Zhang A, Kong X, Jiang C, Deng D, et al.
Association between polymorphisms in COMT, PLCH1, and CYP17A1, and non-small-cell lung cancer risk in Chinese nonsmokers. Clin Lung Cancer 2013;14:45-9.
Li Z, Bao S, Xu X, Bao Y, Zhang Y. Polymorphisms of CHRNA5-CHRNA3-CHRNB4 gene cluster and NSCLC risk in Chinese population. Transl Oncol 2012;5:448-52.
Gaur P, Mittal M, Mohanti B, Das S. Functional variants of IL4 and IL6 genes and risk of tobacco-related oral carcinoma in high-risk Asian Indians. Oral Dis 2011;17:720-6.
Lai KC, Chen WC, Jeng LB, Li SY, Chou MC, Tsai FJ. Association of genetic polymorphisms of MK, IL-4, p16, p21, p53 genes and human gastric cancer in Taiwan. Eur J Surg Oncol 2005;31:1135-40.
Cozar JM, Romero JM, Aptsiauri N, Vazquez F, Vilchez JR, Tallada M, et al.
High incidence of CTLA-4 AA (CT60) polymorphism in renal cell cancer. Hum Immunol 2007;68:698-704.
Gomes M, Coelho A, Araújo A, Teixeira AL, Catarino R, Medeiros R. Influence of functional genetic polymorphism (-590C/T) in non-small cell lung cancer (NSCLC) development: The paradoxal role of IL-4. Gene 2012;504:111-5.
Li-Weber M, Krammer PH. Regulation of IL4 gene expression by T cells and therapeutic perspectives. Nat Rev Immunol 2003;3:534-43.
Rosenwasser LJ, Klemm DJ, Dresback JK, Inamura H, Mascali JJ, Klinnert M, et al.
Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy. Clin Exp Allergy 1995;25 Suppl 2:74-8.
Kelso A. Cytokines: Principles and prospects. Immunol Cell Biol 1998;76:300-17.
Zhang Y, Gu C, Shi H, Zhang A, Kong X, Bao W, et al.
Association between C3orf21, TP63 polymorphisms and environment and NSCLC in never-smoking Chinese population. Gene 2012;497:93-7.
Walter R, Gottlieb DJ, O'Connor GT. Environmental and genetic risk factors and gene-environment interactions in the pathogenesis of chronic obstructive lung disease. Environ Health Perspect 2000;108 Suppl 4:733-42.
Kuehl KS, Loffredo CA. Genetic and environmental influences on malformations of the cardiac outflow tract. Expert Rev Cardiovasc Ther 2005;3:1125-30.
Hoover RN. Cancer - nature, nurture, or both. N Engl J Med 2000;343:135-6.
Zhang R, Chu M, Zhao Y, Wu C, Guo H, Shi Y, et al.
A genome-wide gene-environment interaction analysis for tobacco smoke and lung cancer susceptibility. Carcinogenesis 2014;35:1528-35.
Kiyohara C, Yoshimasu K, Shirakawa T, Hopkin JM. Genetic polymorphisms and environmental risk of lung cancer: A review. Rev Environ Health 2004;19:15-38.
Voets AM, Oberije C, Struijk RB, Reymen B, De Ruyck K, Thierens H, et al.
No association between TGF-ß1 polymorphisms and radiation-induced lung toxicity in a European cohort of lung cancer patients. Radiother Oncol 2012;105:296-8.
Li Z, Chen L, Qin Z. Paradoxical roles of IL-4 in tumor immunity. Cell Mol Immunol 2009;6:415-22.
Yannopoulos A, Nikiteas N, Chatzitheofylaktou A, Tsigris C. The (-590 C/T) polymorphism in the interleukin-4 gene is associated with increased risk for early stages of corolectal adenocarcinoma. In Vivo
Okada H, Villa L, Attanucci J, Erff M, Fellows WK, Lotze MT, et al.
Cytokine gene therapy of gliomas: Effective induction of therapeutic immunity to intracranial tumors by peripheral immunization with interleukin-4 transduced glioma cells. Gene Ther 2001;8:1157-66.
Lee IY, Kim J, Ko EM, Jeoung EJ, Kwon YG, Choe J. Interleukin-4 inhibits the vascular endothelial growth factor-and basic fibroblast growth factor-induced angiogenesis in vitro
. Mol Cells 2002;14:115-21.
Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer 2006;6:392-401.
Olver S, Apte S, Baz A, Kienzle N. The duplicitous effects of interleukin 4 on tumour immunity: How can the same cytokine improve or impair control of tumour growth? Tissue Antigens 2007;69:293-8.
Zhenzhen L, Xianghua L, Qingwei W, Zhan G, Ning S. Three common polymorphisms in the IL-4 gene and cancer risk: A meta-analysis involving 5,392 cases and 6,930 controls. Tumour Biol 2013;34:2215-24.
Zhang J, Xie D, Zhou H, Fan R, Zhang L, Li C, et al.
The-590C/T polymorphism in the IL-4 gene and the risk of cancer: A meta-analysis. Tumour Biol 2013;34:2261-8.
Shurin MR, Lu L, Kalinski P, Stewart-Akers AM, Lotze MT. Th1/Th2 balance in cancer, transplantation and pregnancy. Springer Semin Immunopathol 1999;21:339-59.
Stremmel C, Greenfield EA, Howard E, Freeman GJ, Kuchroo VK. B7-2 expressed on EL4 lymphoma suppresses antitumor immunity by an interleukin 4-dependent mechanism. J Exp Med 1999;189:919-30.
Kemp RA, Ronchese F. Tumor-specific Tc1, but not Tc2, cells deliver protective antitumor immunity. J Immunol 2001;167:6497-502.
Kobayashi M, Kobayashi H, Pollard RB, Suzuki F. A pathogenic role of Th2 cells and their cytokine products on the pulmonary metastasis of murine B16 melanoma. J Immunol 1998;160:5869-73.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]