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. 2018 Aug 24;97(34):e11927. doi: 10.1097/MD.0000000000011927

Functional Foxp3 polymorphisms and the susceptibility to cancer

An update meta-analysis

ZhenYun Cheng 1, Yan Guo 1, Liang Ming 1,∗
Editor: Zhao Sun1
PMCID: PMC6113014  PMID: 30142808

Abstract

Background:

Forkhead box P3 (Foxp3) plays important roles in the development and pathogensis of cancer. To investigate the association of 3 polymorphisms of Foxp3 (rs3761548, rs 3761549 and rs2280883) and cancer risk, an updated meta-analysis was performed.

Methods:

Around 11 studies including 4344 cancer patients and 4665 healthy controls were selected for this meta-analysis. There were nine studies with 3783 cases and 4096 controls for rs3761548, 4 studies with 1669 cases and 1613 controls for rs3761549 and 4 studies with 1821 cases and 1799 controls for rs2280883. Odds radios (ORs) and 95% confidence intervals (CIs) were used to evaluate the cancer risk.

Results:

Meta-analysis showed that rs3761548 was associated with an increased cancer risk in the overall population under the recessive model (AA vs CA + CC: OR = 1.45, 95%CI = 1.03–2.02, P = .03). No association was found between rs3761549, rs2280883 polymorphisms, and cancer susceptibility in the overall population. Nonetheless, in the genotyping methods subgroup analysis of rs2280883, a lower risk of cancer was found in studies using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) under the allelic model (C vs T: OR = 0.70, 95%CI = 0.52–0.95, P = .02), heterozygote model (TC vs TT: OR = 0.60, 95%CI = 0.41–0.87, P = .008) and dominant model (CC + TC vs TT: OR = 0.63, 95%CI = 0.45–0.90, P = .01). In the subgroup analysis by cancer types showed C allele or TC carriers were insusceptible to cancer under 3 genetic models (C vs T: OR = 0.78, 95%CI = 0.64–0.95, P = .01; TC vs TT: OR = 0.50, 95%CI = 0.32–0.79, P = .003; CC + TC vs TT: OR = 0.64, 95%CI = 0.51–0.82, P < .001).

Conclusion:

Our results suggest that rs3761548 polymorphism is associated with cancer risk.

Keywords: cancer, Foxp3, meta-analysis, polymorphism

1. Introduction

Cancer is a global public health problem, and the number of affected people is much more in recent years. Since the high rate of recurrence and metastasis, the prognosis of cancer is still poor. The genesis of cancers resulted from alterations of multiple environmental factors and genes.[1] There are a lot of reports that single nucleotide polymorphisms (SNPs) are associated with cancer risk. Several studies have showed that polymorphic genes play vital roles in the development and pathogensis of cancer.[2–4] However, the specific mechanism of numerous polymorphic genes remain to be unknown.

Regulatory T cells (Tregs), aid in the immune response and autotolerance, are characterized by CD4 + Foxp3 + expression.[5,6] Foxp3, as a transcription factor, is predominantly expressed on Tregs and involved in the regulation, activation and differentiation of T cells.[7] Foxp3 expression is crucial for Tregs which may cause an abnormal production of Tregs in several different mechanisms.[8,9] Besides, several studies showed that the lower or loss of Foxp3 expression may contribute to the development of cancers in humans.[10] The polymorphisms of Foxp3 were likely to change its expression level and impair the suppressive function of Tregs. Three polymorphisms of Foxp3, −3279/rs3761548 (C > A), −2383/rs3761549 (C > T) in the promotor and IVS9 + 459/rs2280883 (T > C) in the intron region, have been reported to be associated with cancer risk.[11,12]

In recent years, several studies have showed the association between these 3 functional polymorphisms and cancer risk.[11,13–15] Nonetheless, the results of these relevant studies remain to be inconsistent, possibly due to ethnicity, genotyping methods, and the sample size. Therefore, this meta-analysis was performed to evaluate the association of these 3 functional polymorphisms with the risk of cancer and heighten the effects of these SNPs.

2. Materials and methods

2.1. Publication search

A systematic literature search was performed using PubMed, Embase, and Chinese Wanfang database. Eligible studies were identified to investigate the associations between Foxp3 polymorphisms and cancer risk, using the following keywords: Foxp3 or rs3761548/rs3761549/rs2280883, polymorphisms cancer/carcinoma/tumor. This meta-analysis was performed according to the guideline of Preferred Reporting Items for Systemic Reviews and Meta-Analysis (PRISMA).[16] Additional eligible studies were manually searched from the reference of reviews and original articles.

2.2. Criteria for study selection

All the included studies for further meta-analysis were required to meet the following criteria: case–control study design; studies that investigated the association between the Foxp3 polymorphisms and cancer risk; all cases were cancer patients confirmed by histology or pathology; detailed allele and genotype frequencies of rs3761548 and/or rs3761549 and/or rs2280883 for estimating odds ratio (OR) and 95% confidence interval (CI). The reviews or case-only studies were excluded. If 2 or more studies included overlapping subjects, the study with the largest sample size was included in this meta-analysis.

2.3. Data extraction

All of the selected articles were independently reviewed by 2 authors. The discrepancies of data were discussed to reach an agreement by all the authors. The following information were extracted from each eligible study: first author, the year of publication, country of origin, ethnicity, genotyping methods, cancer types, number of cases and controls as well as the genotype frequencies in cases and controls. The ethnicities were classified as Caucasian, Chinese, and others. Genotyping methods were categorized as polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) and others. Additionally, selected studies were sorted as breast cancer and others by cancer types. The study was approved by the Ethics Committee of First Affiliated Hospital of Zhengzhou University.

2.4. Quality assessment

The quality of eligible case–control studies was assessed by 2 reviewers using Newcastle–Ottawa scale (NOS). The selected studies were judged on 3 broad perspectives, including the selection of study subjects (4 scores in total); the comparability of groups (2 scores in total); exposure factors or outcomes (3 scores in total). Low-quality studies: 0 to 4 points; high-quality studies: 5 to 9 points.

2.5. Statistical analysis

The association between Foxp3 polymorphisms and cancer risk was assessed by ORs and 95% CI. The significance of the pooled ORs was measured by the Z test with P < .05. This meta-analysis evaluated the association by using 5 different genetic models: homozygous model (aa vs AA), heterozygote model (Aa vs AA), dominant model (aa + Aa vs AA), recessive model (aa vs Aa + AA), and allelic model (a vs A; “a”: variant allele; “A”: wild-type allele). In addition, the stratified analysis was performed by ethnicity, genotyping methods, and cancer types. The statistical heterogeneity among studies was assessed by Cochran Q test and I2 test. If the P value of heterogeneity test was > .1 (P ≥ .10) or I2 was <50%, the fixed effects model was employed to estimate the pooled OR of the study. Otherwise, a random effects model was applied.[17] Funnel plot, egger's linear regression asymmetry test, and sensitivity analysis were performed to estimate the publication bias. All of the statistical tests were performed by review manager version 5.0 software (RevMan; The Cochrane Collaboration, Oxford, UK) and STATA 12.0.

3. Results

3.1. Characteristics of studies

By the combinations of the keywords, a total of 69 relevant studies were identified. As shown in Figure 1, 11 studies were included in this meta-analysis according to the inclusion criteria.[12–15,18–24] Among the eligible 11 studies, 4 were performed in Caucasians; 5 were carried out in Chinese and 2 were from other countries in Asia. In Haghighi's and Ozawa's studies, the men of cases and controls without detailed genotypes were excluded.

Figure 1.

Figure 1

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Flow diagram of the studies in this meta-analysis based on the selection criteria.

These studies included 4344 cancer patients and 4665 controls. In general, 9, 4, and 4 studies were pooled for this meta analysis of rs3761548, rs3761549, and rs2280883. In the view of genotyping methods, 6 studies were PCR-RFLP methods, the others were matrix assisted laser desorption/ionization-time of-flight mass spectrometry (MALDI-TOF), allele specific-polymerase chain reaction (AS-PCR), TaqMan assay, and direct sequencing. Besides, there were 5 studies about breast cancer, the others contained thyroid cancer, hepatocellular carcinoma, lung cancer, colorectal cancer, etc. Characteristics were summarized in Table 1. On the basis of NOS, each study received no <5 stars for methodological quality assessment.

Table 1.

Characteristics of the eligible studies in this meat-analysis.

3.1.

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3.2. Associations between Foxp3 polymorphisms and cancer risk

The genotypes and allele frequencies of eligible studies in this meta-analysis were shown in Table 2. The frequencies of minor allele for rs3761548, rs3761549 and rs2280883 varied widely from 0.20 to 0.53, 0.10 to 0.49, and 0.11 to 0.27 in cases, respectively; and 0.16 to 0.56, 0.05 to 0.49 and 0.15 to 0.35 in controls, respectively.

Table 2.

Genotype and allele frequency in the eligible studies.

3.2.

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The association of rs3761548 polymorphism and cancer risk was carried out in nine studies with 3783 cases and 4096 controls. As shown in Table 3 and Figure 2, rs3761548 was associated with an increased cancer risk in the overall population under the recessive model (AA vs CA + CC: OR = 1.45, 95%CI = 1.03–2.02, P = .03). In the ethnic subgroup analysis, an increased cancer risk associated with rs3761548 polymorphism was found in Chinese under all genetic models (A vs C: OR = 1.58, 95%CI = 1.12–2.23, P = .009; AA vs CC: OR = 2.31, 95%CI = 1.37–3.90, P = .002; CA vs CC: OR = 1.46, 95%CI = 1.08–1.99, P = .02; AA + CA vs CC: OR = 1.62, 95%CI = 1.12–2.36, P = .01; AA vs CA + CC: OR = 2.00, 95%CI = 1.34–2.99, P < .001). However, no association was found for Caucasian and others under all genetic models. When stratified analysis was performed by cancer types, no association was observed in Breast cancer. Whereas, a significantly increased risk of other cancers was found in all genetic models (A vs C: OR = 1.73, 95%CI = 1.34–2.23, P < .001; AA vs CC: OR = 2.49, 95%CI = 1.48–4.19, P < .001; CA vs CC: OR = 1.66, 95%CI = 1.36–2.04, P < .001; AA + CA vs CC: OR = 1.85, 95%CI = 1.45–2.36, P < .001; AA vs CA + CC: OR = 2.06, 95%CI = 1.29–3.30, P = .002). Negative results were obtained in genotyping method subgroup analysis.

Table 3.

Meta-analysis of Foxp3 polymorphisms and cancer risk.

3.2.

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Figure 2.

Figure 2

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Forest plot of rs3761548 polymorphism and cancer risk (Recessive model: AA vs CA + CC). The squares and horizontal lines represents the study specific OR and 95% CI. CI = confidence interval, OR = odds radio.

For rs3761549 polymorphism, there were 4 studies based on Asian with 1669 cases and 1613 controls. In the stratified analysis by cancer types, a boardline risk of cancer was found under the allelic model (C vs T: OR = 0.78, 95%CI = 0.61–1.00, P = .05). We failed to find any association in other groups and genetic models.

For rs2280883 polymorphism, our meta-analysis included 4 studies with 1821 cases and 1799 controls. No significant association was observed in the overall population. In the genotyping methods subgroup analysis, a lower risk of cancer was found in studies using PCR-RFLP under the allelic model (C vs T: OR = 0.70, 95%CI = 0.52–0.95, P = .02), heterozygote model (TC vs TT: OR = 0.60, 95%CI = 0.41–0.87, P = .008) and dominant model (CC + TC vs TT: OR = 0.63, 95%CI = 0.45–0.90, P = .01; Fig. 3). In addition, subgroup analysis by cancer types showed C allele or TC carriers were insusceptible to cancer under 3 genetic models (C vs T: OR = 0.78, 95%CI = 0.64–0.95, P = .01; TC vs TT: OR = 0.50, 95%CI = 0.32–0.79, P = .003; Fig. 4; CC + TC vs TT: OR = 0.64, 95%CI = 0.51–0.82, P < .001). No correlation was detected in other models.

Figure 3.

Figure 3

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Forest plot of the association between rs2280883 polymorphism and cancer risk in the genotyping methods subgroup (dominant model: CC + TC vs TT). The squares and horizontal lines represent the study specific OR and 95% CI. CI = confidence interval, OR = odds radio.

Figure 4.

Figure 4

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Forest plot of the association between rs2280883 polymorphism and cancer risk in the cancer types subgroup (heterozygote model: TC vs TT). The squares and horizontal lines represent the study specific OR and 95% CI. CI = confidence interval, OR = odds radio.

3.3. Heterogeneity analysis, sensitivity analysis and publication bias

Statistical heterogeneity among studies was tested by Q test and I2 in all models and subgroup analysis across rs3761548, rs3761549, and rs2280883. Random effects model was performed when P-value of heterogeneity was <.1, otherwise fixed effects model was applied.

Sensitivity analysis showed that the correlation of rs3761548 polymorphism (recessive model: AA vs CA + CC, Fig. 5) with cancer risk remained significant after removing any one study in the meta-analysis.

Figure 5.

Figure 5

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Sensitivity analysis of rs3761548 under the recessive model.

Funnel plot and Egger's test were applied to access the potential publication bias. As shown in Figure 6, the funnel plots were all symmetrical in the 3 site of Foxp3 polymorphisms. Furthermore, by Egger's test, no publication bias existed in this meta-analysis.

Figure 6.

Figure 6

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Funnel plots for publication bias. (A) rs3761548 (AA vs CA + CC); (B) rs3761549 (TT + CT vs CC); (C) rs2280883 (TC vs TT).

4. Discussion

Foxp3 gene was thought to be an immunological regulator and repress oncogenes whilst activating additional tumor supressor genes.[25,26] Foxp3 was able to regulate the key target gene activation and supression and alter histione modification by binding to the promotors.[27,28] Recent years, many researchers have reported the associations between rs3761548, rs3761549, rs2280883 polymorphisms and susceptibility to cancer.[19,29] However, the results from these studies are controversy. Consequently, we performed this meta-analysis to systematically analyze the associations of Foxp3 polymorphisms and cancer risk using all the eligible studies.

Lopes et al[22] showed a high expression of Foxp3 protein in the tumor microenvironment and suggested that Foxp3 transcript factor could be a promising marker of susceptibility and prognosis in human breast cancer pathogenesis. Furthermore, Foxp3 expression in differentiated thyroid cancer (DTC) patients with AA/AC genotype of rs3761548 was increased compared with DTC patients with CC genotype.[23] In the previous meta-analysis of Jiang et al.,[29] no association was found between the rs3761548 polymorphism and cancer risk in any genetic models. However, in our updated meta-analysis, we found that rs3761548 was associated with an increased cancer risk in the overall population under the recessive model (P = .03). At the same time, a significantly increased risk of cancers except breast cancer was found in all genetic models. This difference may result from 5 new articles included in our study. In addition, rs3761548 was located in the promoter of Foxp3. Studies indicated that Foxp3 bound to conserved noncoding sequence 2 (CNS2) in a Runx1 and Cbf-β-dependent manner to ensure the stability of Tregs and CNS2 interacted specifically with Foxp3 promoter in Tregs to promote stable Foxp3 expression.[30,31]

Due to the location in intron 9 near a conserved transcription region of Foxp3, rs2280883 could cause splicing downstream, resulting in the less functional gene. Therefore, for rs2280883 polymorphism of our study, no significant association was observed in the overall population under any genetic models. However, an association was found in the genotyping methods and cancer types subgroup analysis. Additionally, a significantly increased risk of other cancers was found in rs3761548 polymorphism. The results suggested that Foxp3 polymorphisms may have a varying effect on carcinogenesis within different organs. Since studies on thyroid cancer, lung cancer, colorectal cancer and other cancer are rare, further large studies are necessary to substantiate our results.

Some limitations of this meta-analysis should be considered. Firstly, some relatively small number studies and subjects were included, which may reduce the statistical power of our analysis. Secondly, several detailed information, such as gender, age, smoking status and environment factors, was not considered. Thirdly, the results were achieved according to individual unadjusted Ors. Finally, some degree of heterogeneity, which might impact the results, existed in this study.

In conclusion, the present study suggests that rs3761548 polymorphism contributes to an increased risk of cancer in the overall population. In the other cancer types and genotyping methods subgroups, rs2280883 polymorphism was associated with a lower risk of cancer. However, there was no association between rs3761549 polymorphism and cancer susceptibility. Nevertheless, a future study with larger ethnic groups and sample size is required to validate the associations.

Acknowledgments

All authors gave a great assistance in contributing and revising the manuscript. We also thank the anonymous reviewers for assistance in editing the manuscript.

Author contributions

Data curation: Yan Guo.

Visualization: Liang Ming.

Writing – original draft: Yan Guo.

Writing – review & editing: Zhenyun Cheng.

Footnotes

Abbreviations: AS-PCR = allele specific-polymerase chain reaction, CI = confidence interval, CNS2 = conserved noncoding sequence 2, DTC = differentiated thyroid cancer, Foxp3 = Forkhead box P3, MALDI-TOF = matrix assisted laser desorption/ionization-time-of-flight mass spectrometry, NOS = Newcastle–Ottawa Scale, OR = odds radio, PCR-RFLP = polymerase chain reaction-restriction fragment length polymorphism, PRISMA = Preferred Reporting Items for Systemic Reviews and Meta-Analysis, SNP = single nucleotide polymorphism, Treg = regulatory T cell.

The authors have no conflicts of interest to disclose.

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