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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 8  |  Page : 208-212

TOX high mobility group box family member 3 rs3803662 and breast cancer risk: A meta-analysis


Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China

Date of Web Publication26-Mar-2018

Correspondence Address:
Yuanting Gu
No. 1, East Jianshe Road, Zhengzhou 450052, Henan
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.167611

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 > Abstract 


Aims: Some studies suggested that TOX high mobility group box family member 3 (TOX3) rs3803662 polymorphism was associated with the risk of breast cancer. However, the results were controversy. Therefore, in order to derive a more comprehensive estimation of the association between TOX3 rs3803662 polymorphism and breast cancer risk, we conducted a meta-analysis to investigate this relationship.
Materials and Methods: An electronic literature search was conducted using the following database: PubMed, EMBASE, and China National Knowledge Infrastructure till to March 31, 2015. The strength of the associations between the TOX3 rs3803662 polymorphism and breast cancer risk in per alle model was measured by odds ratios (ORs) and 95% confidence intervals (CIs).
Results: A statistically significant association between TOX3 rs3803662 polymorphism and breast cancer risk was fond. The data showed that TOX3 rs3803662 polymorphism could increase the risk of breast cancer (OR = 1.20; 95% CI: 1.16–1.25; P < 0.00001). In the subgroup analysis of race, Caucasians, Asians, and Hispanics also showed increased breast cancer risk (OR = 1.21; 95% CI: 1.17–1.25; P < 0.00001; OR = 1.20; 95% CI: 1.08–1.33; P = 0.0004; OR = 1.32; 95% CI: 1.12–1.57; P = 0.001). However, African-Americans with TOX3 rs3803662 polymorphism showed decreased breast cancer risk (OR = 0.95; 95% CI: 0.86–1.04; P = 0.28), although the result was not significant. When considered estrogen receptor (ER) status, we found that ER + subjects and ER subjects all had increased breast cancer risk, if they carried this polymorphism (OR = 1.27; 95% CI: 1.19–1.35; P < 0.00001; OR = 1.12; 95%CI: 1.08–1.17; P < 0.00001). Similarly, both progesterone receptor–positive (PR +) subjects and PR subjects all showed increased breast cancer risk, if they carried this polymorphism (OR = 1.32; 95% CI: 1.17–1.49; P < 0.00001; OR = 1.15; 95% CI: 1.09–1.23; P < 0.00001).
Conclusions: This meta-analysis suggested that TOX3 rs3803662 polymorphism was associated with increased breast cancer risk.

Keywords: Association, breast cancer, meta-analysis, TOX high mobility group box family member 3


How to cite this article:
Li L, Guo G, Wang F, Lv P, Zhu M, Gu Y, Han M, Pei X. TOX high mobility group box family member 3 rs3803662 and breast cancer risk: A meta-analysis. J Can Res Ther 2018;14, Suppl S1:208-12

How to cite this URL:
Li L, Guo G, Wang F, Lv P, Zhu M, Gu Y, Han M, Pei X. TOX high mobility group box family member 3 rs3803662 and breast cancer risk: A meta-analysis. J Can Res Ther [serial online] 2018 [cited 2019 Jun 20];14:208-12. Available from: http://www.cancerjournal.net/text.asp?2018/14/8/208/167611




 > Introduction Top


Breast cancer is the second most common cancer in the USA among women, accounting for approximately 40,000 deaths in 2013.[1] The risk factors contributing to breast cancer initiation and progression include both environmental and genetic components, which interact in a complex and poorly understood fashion.

TOX high mobility group box family member 3 (TOX3) is also called trinucleotide repeat containing 9. It is a member of the high mobility group family of nonhistone chromatin proteins. The gene of TOX3 is located at chromosome 16q12.[2] TOX3 could regulate Ca2+-dependent neuronal transcription through interaction with the cAMP-response-element-binding protein.[3] In normal human tissues, TOX3 is largely expressed in the central nervous system, in the ileum, and within the brain in the frontal and occipital lobe. TOX3 overexpression induces transcription involving isolated estrogen-responsive elements and estrogen-responsive promoters, and protects neuronal cells from cell death caused by endoplasmic reticulum stress or BAX overexpression through the induction of anti-apoptotic transcripts and repression of pro-apoptotic transcripts.[4] TOX3 is also found to express in estrogen receptor–positive (ER +) mammary epithelial cells, including progenitor cells.[5] Two different roles for TOX3 were also suggested: One was the initiation of breast cancer, potentially related to expression of TOX3 in mammary epithelial cell progenitors, and another role was the progression of cancer.

Some studies suggested that TOX3 rs3803662 polymorphism was associated with the risk of breast cancer. However, other studies have shown that TOX3 rs3803662 polymorphism was unlikely to play a crucial role in breast cancer development.[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20] The reason for this discrepancy may be due to different sample size and race. Therefore, in order to derive a more comprehensive estimation of the association between TOX3 rs3803662 polymorphism and breast cancer risk, we conducted a meta-analysis to investigate this relationship.


 > Materials and Methods Top


Publication search

An electronic literature search was conducted using the following database: PubMed, EMBASE, and China National Knowledge Infrastructure till to March 31, 2015. The Medical Subject Heading terms “TOX3,” “mutation,” “breast cancer” and the individual corresponding free terms were employed as the searching words. In addition, the citations in the retrieved articles were reviewed to search for relevant studies.

Inclusion and exclusion criteria

All selected studies complied with the following two criteria: (1) Case–control study on the TOX3 rs3803662 polymorphism and breast cancer risk; (2) sufficient published data for estimating the odds ratio (OR) with 95% confidence interval (CI). Studies were excluded if one of the following existed: (1) Not relevant to TOX3 or breast cancer, (2) not designed as case–control studies, (3) genotype frequencies or number not offered, (4) animal studies, (5) editorials, reviews and abstracts, and (6) overlapping studies.

Data extraction

Two investigators independently assessed the extracted data from the included study, and reached final common results. Any disagreement was resolved by discussing with the third expert. The following information was extracted from all obtained publications:First author's name, publication year, race, ER status, progesterone receptor (PR) status, alcohol consumption, and the included subject number.

Quality assessment

The included studies were assessed independently by the two reviewers using the Newcastle–Ottawa Scale (NOS). The NOS employs a star rating system to assess quality from three broad perspectives of the study: (1) Selection of the study groups, (2) comparability of the groups, and (3) identification of the exposure (for case–control studies) or outcome of interest (for cohort studies). Scores ranged from 0 to 9 stars.

Statistical analysis

The strength of the associations between the TOX3 rs3803662 polymorphism and breast cancer risk in per alle model was measured by ORs and 95% CIs. The random-effects model was used. The statistical significance of summary OR was determined with Z-test. Between study heterogeneity was assessed by Chi-square test, and was quantified using the I2 statistic (ranging from 0% to 100%), which was defined as the percentage of the observed between-study variability that is due to heterogeneity rather than chance. To evaluate the ethnic-specific, ER-specific, and PR-specific effects, subgroup analyses were performed. To access the stability of the meta-analysis, a one-way sensitivity analysis was carried out. Publication bias was assessed by visual inspection of funnel plots, in which the standard error of log (OR) of each study was plotted against its log (OR). The Egger's test was used to assess publication bias statistically. All statistical tests were performed by using RevMan version 5.1 software (Nordic Cochrane Center, Copenhagen, Denmark) and STATA version 11.0 software (Stata Corporation, College Station, TX, USA). A P < 0.05 was considered significant. All the P values were two-sided.


 > Results Top


Study characteristics

A total of 56 relevant studies were identified [Figure 1]. After carefully review, 15 eligible case–control studies on the relationship between the TOX3 rs3803662 polymorphism and breast cancer risk were included in this meta-analysis. [Table 1] presents the main characteristics of these studies. Six studies involved Caucasian populations, whereas five studies involved Asians. Two studies included African-Americans and Hispanics, respectively. The quality of these studies was high.
Figure 1: Flow of study identification, inclusion, and exclusion

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Table 1: Characteristics of the included studies in this meta-analysis

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Quantitative data synthesis

As shown in [Figure 2], a statistically significant association between the TOX3 rs3803662 polymorphism and breast cancer risk was fond. The data showed that TOX3 rs3803662 polymorphism could increase the risk of breast cancer (OR = 1.20; 95% CI: 1.16–1.25; P < 0.00001). In the subgroup analysis of race, Caucasians, Asians, and Hispanics also showed increased breast cancer risk (OR = 1.21; 95% CI: 1.17–1.25; P < 0.00001; OR = 1.20; 95% CI: 1.08–1.33; P= 0.0004; OR = 1.32; 95% CI: 1.12–1.57; P= 0.001). However, African-Americans with TOX3 rs3803662 polymorphism showed decreased breast cancer risk (OR = 0.95; 95% CI: 0.86–1.04; P= 0.28), although the result was not significant. When considered ER status, we found that ER + subjects and ER subjects all had increased breast cancer risk, if they carried this polymorphism (OR = 1.27; 95% CI: 1.19–1.35; P < 0.00001; OR = 1.12; 95% CI: 1.08–1.17; P < 0.00001). Similarly, both PR + subjects and PR subjects all showed increased breast cancer risk, if they carried this polymorphism (OR = 1.32; 95% CI: 1.17–1.49; P < 0.00001; OR = 1.15; 95% CI: 1.09–1.23; P < 0.00001).
Figure 2: Effect of TOX high mobility group box family member 3 rs3803662 polymorphism on risk of breast cancer

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A single study involved in the meta-analysis was deleted each time to reflect the influence of the individual data set to the pooled ORs, and the corresponding pooled ORs were not materially altered (data not shown). The publication bias of the included studies was assessed by the funnel plot and Egger's test. The funnel plot showed no evidence for asymmetry [Figure 3]. Egger's linear regression test showed no significant publication bias was observed (P = 0.65).
Figure 3: Funnel plot to assess publication bias

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 > Discussion Top


This meta-analysis of 15 case–control studies evaluated the association between the TOX3 rs3803662 polymorphism and breast cancer risk. The result indicated that TOX3 rs3803662 polymorphism might be a risk factor for developing breast cancer. Our result suggested that individuals who carried the rs3803662 polymorphism may have a 20% increased breast cancer risk. In the subgroup analysis by ethnicity, both significant associations were found in Asians, Caucasians, and Hispanics. This result suggested that Asians, Caucasians, and Hispanics who carried rs3803662 polymorphism might have an increased breast cancer risk. In the subgroup analysis by ER- and PR-status, we found TOX3 rs3803662 polymorphism showed increased breast cancer risk. This result indicated that the role of TOX3 rs3803662 polymorphism was not selective by ER- and PR-status.

TOX3 has been associated with disease susceptibility, but its function is undetermined. Shan et al. found that TOX3 was often amplified and overexpressed in breast cancer, particularly in advanced breast cancer.[21] They also suggested that TOX3-mediated suppression of BRCA1 expression might result in the disruption of normal DNA damage response resulting in the accumulation of DNA damage. Seksenyan et al. suggested that knockdown of TOX3 in a luminal B breast cancer cell line that highly expresses TOX3 is associated with slower growth.[5] Barrdahl et al. found that rs3803662 was significantly associated with increased breast cancer death hazard.[22]

Our study had some advantages. First, the methodological issues for meta-analysis, such as a one-way sensitivity analysis were well-investigated. Second, this meta-analysis included almost all the studies, thus the statistical power was enough. Third, funnel plots and Egger's tests did not find potential publication bias. All together, these results suggested that results of this meta-analysis were reliable.

However, this meta-analysis had some limitations. First, subgroup analyses were not performed by the factors such as alcohol and smoking because insufficient data could be extracted from the primary articles. Second, because small negative studies are less likely to published, the possibility of publication bias cannot be ruled out completely, even though the Egger's test and funnel plots did not provide any evidence of publication bias in this meta-analysis. Third, a lack of original data from the eligible studies the limited evaluation of the effects of the gene-gene and gene-environment interactions during breast cancer development. Finally, there was only one single-nucleotide polymorphism (SNP) in the focus of this meta-analysis. However, since breast cancer is a complex disease it seems rather unlikely that only one SNP can influence the risk of breast cancer. Thus, SNP-SNP interactions should also be investigated in future studies.


 > Conclusion Top


This meta-analysis suggested that TOX3 rs3803662 polymorphism was associated with increased breast cancer risk.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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