Elsevier

Gene

Volume 531, Issue 2, 1 December 2013, Pages 422-425
Gene

Short Communication
FoxP3 genetic variants and risk of non-small cell lung cancer in the Chinese Han population

https://doi.org/10.1016/j.gene.2013.08.066Get rights and content

Highlights

  • FoxP3 regulates regulatory T-cell development and function and could modulate susceptibility to non-small cell lung cancer.

  • FoxP3 rs3761548 was analyzed in a hospital-based case-control study of 192 NSCLC patients and 259 healthy subjects using PCR-RFLP.

  • FoxP3 AC, AA, and AA+AC genotype of rs3761548 were associated with NSCLC risk in the Chinese Han population.

Abstract

CD4+CD25+ regulatory T cell-mediated immunosuppression is one of the crucial mechanisms that tumor cells use to evade the immune system. The forkhead box P3 (FoxP3) gene regulates regulatory T-cell development and function and may modulate the susceptibility to non-small cell lung cancer (NSCLC). Because a single nucleotide polymorphism (SNP) within the FoxP3 gene (rs3761548 in the promoter region) is associated with susceptibility to Graves' disease, this study detected rs3761548 in a hospital-based case–control study. A total of 192 NSCLC patients and 259 healthy subjects were recruited for the polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) analysis of FoxP3 SNP. The data showed that the A allele of rs3761548 significantly increased NSCLC risk (P = 0.000, OR = 2.32, 95%CI = 1.736–3.102). The AC genotype, AA genotype, and the combined A variant genotype (AA + AC) were also associated with a higher risk of NSCLC (OR [95%CI] = 2.147[1.419–3.247], 4.413[2.359–8.255], and 2.563[1.746–3.761], respectively). Moreover, a significantly higher frequency of AA + AC genotype was observed in patients with stage II NSCLC (OR, 2.053; 95%CI, 1.033–4.078). In conclusion, the data from the current study demonstrated for the first time the association of the FoxP3 SNP with a risk of developing NSCLC in the Chinese Han population.

Introduction

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer death in the world. Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancer cases, and includes two predominant subtypes, adenocarcinoma and squamous cell carcinoma (SCC) (Dutt et al., 2011, Minna et al., 2002, Wistuba, 2007). The prognosis of NSCLC remains poor, with a five-year overall survival rate of about 15% (Ferlay et al., 2010). However, there are significant prognostic differences between early and late stages of NSCLC (Naruke et al., 2001), indicating that early detection of NSCLC is key survival of NSCLC patients. A major risk factor associated with NSCLC is tobacco smoking, followed by asbestos and other mineral exposures, air pollution, and personal and family histories of lung cancer. Nevertheless, it is critical to understand the contribution of genetic and environmental interactions in the development of NSCLC (Kriek et al., 1993, Li et al., 2004, Spitz et al., 2007, Vineis and Husgafvel-Pursiainen, 2005). For example, it has been shown that when exposed to similar environmental and occupational elements, only some individuals develop NSCLC, whereas other NSCLC patients have not been exposed to any risk factors. This discrepancy suggests that there is individual variation in cancer susceptibility in the general population and there are other unknown factors (such as genetics or host predisposition or immune defense system) that contribute to NSCLC pathogenesis (Amos et al., 1992). A previous meta-analysis using 41 published studies showed that the lung cancer family history was a risk factor of lung cancer (Lissowska et al., 2010).

The host immune defense has been shown to play a role in modulating human carcinogenesis. In the host immune defense system, regulatory T cells (Tregs) play a key role in sustaining self-tolerance and immune homeostasis via suppressing a wide variety of physiological and pathological immune responses against self and nonself (Nishikawa and Sakaguchi, 2010, Sakaguchi, 2004, Shevach, 2002, Takahashi and Sakaguchi, 2003). For example, the deficiency or dysfunction of CD4+CD25+ Treg cells, which are the most physiologically relevant Treg population, causes a breach in self-tolerance and produces autoimmune diseases in normal animals and in humans (such as severe allergy and inflammatory bowel disease) (Fontenot et al., 2003, Hori et al., 2003). Recently published data demonstrated that CD4+CD25+ Tregs dominantly infiltrate into tumors and hinder immune response against tumor cells (Nishikawa and Sakaguchi, 2010). This data suggests that Treg cell-mediated immunosuppression is one of the crucial tumor immune evasion mechanisms, and may contribute to the failure of tumor immunotherapy (Khattri et al., 2003, Nishikawa and Sakaguchi, 2010).

The forkhead box P3 (FoxP3) gene is primarily expressed in regulatory T cells under normal physiological conditions. The FoxP3 gene is located on the X chromosome at Xp11.23 (Bennett et al., 2001, Wang et al., 2009) to encode FoxP3 protein, which regulates T cell activation and functions as a transcriptional repressor to downregulate cytokine production in T cells (Gao et al., 2010, Hori et al., 2003, McHugh et al., 2002, Schubert et al., 2001, Takahashi et al., 2000). Normally, FoxP3 is expressed in epithelial cells from various organs (e.g., thymus and lung) (Gupta et al., 2007, Karanikas et al., 2008, Katoh et al., 2010). However, during tumorigenesis, FoxP3 is also expressed in a variety of cancers, such as lymphoma, lung, ovary, and prostate cancers (Kono et al., 2006, Wei et al., 2004). Mutations of FoxP3 cause immune dysregulation, polyendocrinopathy, and X-linked syndrome (IPEX) in human body or breast and prostate cancers (Spatz et al., 2004). In addition, FoxP3 gene polymorphisms result in the lack of functional CD4+CD25+ Tregs, and therefore induce some autoimmune diseases, including type I diabetes and inflammatory primary biliary cirrhosis (Bassuny et al., 2003, Park et al., 2005, Wildin et al., 2002). A single nucleotide polymorphism (SNP) of the FoxP3 gene (rs3761548) is associated with susceptibility of development and intractability of Graves' disease (Owen et al., 2006).

Thus, in this study, we analyzed FoxP3 gene SNP (rs3761548) for association with the risk of NSCLC in the Chinese Han population using a polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) technique.

Section snippets

Study subjects

In this study, we carried out a hospital-based case–control study by recruiting 192 NSCLC patients (141 males and 51 females, mean age of 57.42 ± 10.26 years) from The West China Hospital of Sichuan University between April 2008 and December 2011. The diagnosis of NSCLC was confirmed by histopathological examination of the resected or biopsy tissue specimens in all cases. The control population consisted of 259 healthy subjects (181 males and 78 females, mean age: 58.90 ± 12.91 years) from a routine

Results

The cohort of 192 NSCLC patients with a mean age of 57.4 year old contained slightly more men (73.4%) than women (26.6%), whereas the 259 control individuals with a mean age of 58.9 year old consisted of 69.9% men and 30.1% women. Between case and control, the age and gender were well balanced and the distribution of rs3761548 A/C allele frequencies was also in Hardy–Weinberg equilibrium (P = 0.066 and P = 0.073), indicating that the frequencies fell into the expected equilibrium and were thus

Discussion

To the best of our knowledge, the current study is the first to assess the association of genetic variants of FoxP3 gene with the risk of NSCLC. In this hospital-based, case–control study, we analyzed FoxP3 gene SNP for NSCLC susceptibility in a Chinese Han population. Our data demonstrated that FoxP3 SNP/rs3761548 was significantly associated with risk of NSCLC, suggesting that FoxP3 polymorphism might be involved in pathogenesis of NSCLC in the Chinese Han population. We demonstrated that AA,

Conclusions

In conclusion, the current study showed that FoxP3 AA and AC genotypes had an effect on the risk of NSCLC in a Chinese Han population. Additionally, the combined AA + AC genotype was significantly associated with stage II patients. The precise mechanism by which FoxP3 gene polymorphism influences the pathogenesis of NSCLC remains to be determined. Future studies are warranted to investigate whether the SNP rs3761548 affects expression levels of FoxP3 protein and determine the role of FoxP3

Conflict of interest

The authors declare no conflict of interest.

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