Elsevier

Lung Cancer

Volume 50, Issue 3, December 2005, Pages 291-297
Lung Cancer

The involvement of genetic polymorphism of IL-10 promoter in non-small cell lung cancer

https://doi.org/10.1016/j.lungcan.2005.07.007Get rights and content

Summary

Study objectives

Interleukin-10 (IL-10) is mainly an anti-inflammatory cytokine produced by a number of cells including normal and neoplastic cells and has been implicated in autoimmunity, transplantation tolerance and tumorigenesis. Inter-individual variations in IL-10 production were genetically contributed to polymorphisms within IL-10 promoter region. The aim of this study was to determine whether polymorphisms in the IL-10 gene promoter were involved in predisposing an individual to non-small cell lung cancer (NSCLC).

Patients

A total of 154 patients with non-small cell lung cancer were recruited into this study, together with 205 age- and gender-matched healthy smokers acting as control subjects.

Measurements

Polymorphisms of sites within the promoter region of IL-10 gene were analyzed using polymerase chain reaction-restriction fragment length polymorphism technique on genomic DNA isolated from peripheral lymphocytes. The validity of this technique was proven by direct sequencing of polymerase chain reaction products. Statistical analyses were conducted to explore the contribution of polymorphism of IL-10 promoter to the susceptibility to NSCLC.

Results

The distribution frequencies of genotypes of IL-10-1082, -819 and -592 were significantly different between NSCLC patients and controls. Pearson χ2 analysis showed that the frequency for IL-10-1082 G allele, IL-10-819 C allele and IL-10-592 C allele was independently higher in NSCLC patient group than that in the control group. Higher odds ratios (ORs) for NSCLC were seen for individuals with G allele of IL-10-1082 [OR = 5.26, 95% CI 2.65–10.4, p < 0.0001], C allele of IL-10-819 [OR = 1.57, 95% CI 1.15–2.16, p = 0.005], C allele of IL-10-592 [OR = 1.59, 95% CI 1.15–2.19, p = 0.005].

Conclusion

The polymorphisms of IL-10 genes were significantly associated with the occurrence of NSCLC.

Introduction

Most cancers, including lung cancer, develop in a multistep fashion with specific genetic defects occurring in oncogenes and tumor suppressor genes during tumorigenesis. Such process may be influenced by environmental factors such as radiation and carcinogens as well as by intrinsic factors such as chronic inflammation or immunosuppression [1]. Epidemiological evidence suggested that pulmonary diseases with a prominent chronic inflammatory component could elevate the risk for lung cancer [2]. Interleukin-10 (IL-10) is a multifunctional cytokine with both immunosuppressive and anti-angiogenic functions and consequently has both tumor-promoting and tumor-inhibiting properties. Raised levels of serum and peri-tumoral IL-10 production have been reported in many malignancies [3], [4], [5], including lung cancer [6], which have been interpreted in support of a role for IL-10 in tumor escape from the immune response. Furthermore, increased production of immunosuppressive IL-10 by non-small cell lung cancer (NSCLC) and increased serum concentrations of IL-10 in NSCLC patients have both been shown recently to correlate with reduced survival [7], [8], [9].

IL-10 is encoded by a gene located on chromosome 1. The promoter spans a region of at least 5 kb upstream of the transcription start point and known to contain at least 27 polymorphic sites [10]. These polymorphisms include single nucleotide polymorphisms (SNPs) at -1082, -819 and -519, and at least two microsatellite repeats with several allelic forms [11]. Alterations in IL-10 expression have been linked to polymorphisms in the promoters of the IL-10 genes.. The homozygous AA allele at IL-10-1082, leading to a lower IL-10 expression [12], has been associated with several cancers, including advanced cutaneous malignant melanoma, breast cancer [13] and prostate cancer [14], while the higher producing genotype (GG) has been linked to cervical cancer [15].

As yet, the association between the IL-10 polymorphism with lung cancer susceptibility has not been reported in the literature. Therefore, in this study, we aimed to investigate the distribution of genotypes of the IL-10 in NSCLC patients and healthy controls with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to analyze the association of these polymorphisms with NSCLC susceptibility.

Section snippets

Study population

Study cases included in this research were 154 patients of non-small cell lung cancer (NSCLC), including 93 adenocarcinomas (AD), 59 squamous carcinomas (SQ), and 2 large-cell carcinomas (LC), who admitted to China Medical University Hospital, Taichung, Taiwan, between 2002 and 2004. The histological classifications of types and stages of these tumors were conducted according to the WHO classification method (WHO, 1982) and the TNM system (Mountain, 1986), respectively. Meanwhile, 205

Results

A total of 359 individuals, including 154 NSCLC patients, including 106 males and 48 females with a median age of 63, together with 205 healthy controls, consisting of 136 males and 69 females with a median age of 62, were studied in this research. The characteristics, including age and gender of all participants in this study were summarized in Table 2. No significant differences in abovementioned features were observed between patients and controls.

The results of genotype frequencies of IL-10

Discussion

This is the first report to attempt to evaluate the association between the polymorphisms of the IL-10 promoter and lung cancer risk. The study of IL-10 gene transcriptional control is of interest because of the pivotal role of IL-10 in the regulation of the immune response system. IL-10 was originally termed as cytokine synthesis inhibitory factor due to its ability to inhibit synthesis of pro-inflammatory cytokines such as TNF-α, IL-I, IL-6 and IL-12 [16], [17]. IL-10 is also an important

Acknowledgement

This study was supported by a grant from Chung Shan Medical University (CSMU 88-OM-B-017).

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    These authors contributed equally to this work.

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