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. 2015 Jan 15;8(1):311–321.

Association of three common BARD1 variants with cancer susceptibility: a system review and meta-analysis

Xiangfan Liu 1,*, Xiao Zhang 2,*, Ying Chen 3, Xiyi Yang 3, Yi Xing 3, Lijun Ma 3
PMCID: PMC4358457  PMID: 25785002

Abstract

BARD1 has been shown to play tumor suppressive roles in human cancer. We performed this meta-analysis and firstly evaluated the association between three common BARD1 polymorphisms (Arg378Ser, Val507Met and Pro24Ser) and cancer susceptibility. We performed this meta-analysis following PRISMA guidelines. A comprehensive search of PubMed, EMBASE, Cochrane Library, OVID and Web of Science databases was done from database inception to August 2014. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were combined to measure the association between BARD1 polymorphisms and cancer risk. On the basis of 10 studies about BARD1 polymorphisms and cancer, we found that BARD1 Val507Met (G/A) polymorphism was associated with decreased cancer susceptibility (allelic model: OR = 0.76, 95% CI: 0.66-0.87, P < 0.00001; dominant model: OR = 0.77, 95% CI: 0.65-0.91, P < 0.00001; recessive model: OR = 0.64, 95% CI: 0.55-0.74, P < 0.00001; homozygote comparison: OR = 0.58, 95% CI: 0.49-0.70, P < 0.00001; heterozygote comparison: OR = 0.85, 95% CI: 0.74-0.99 , P = 0.0008). BARD1 Pro24Ser (C/T) polymorphism was also associated decreased cancer risk in allelic model (OR = 0.72, 95% CI: 0.60-0.88, P = 0.0009), dominant model (OR = 0.70, 95% CI: 0.56-0.87, P = 0.004), recessive model (OR = 0.70, 95% CI: 0.56-0.87 , P = 0.004), homozygote comparison (OR = 0.55, 95% CI: 0.39-0.78, P = 0.0007) and heterozygote comparison (OR = 0.75, 95% CI: 0.62-0.91, P = 0.004). And in our sensitivity analysis, when deleting the study performed by Capasso in 2009, we found that BARD1 Arg378Ser polymorphism was associated with decreased cancer risk in allelic model (OR = 0.81, 95% CI: 0.67-0.97, P = 0.02), dominant model (OR = 0.72, 95% CI: 0.56-0.91, P = 0.007) and heterozygote comparison (OR = 0.72, 95% CI: 0.57-0.91, 0 = 0.006). In conclusion, BARD1 Arg378Ser, Val507Met and Pro24Ser may be associated with decreased cancer risk. More studies with larger samples and gene-environment interactions are needed to confirm our findings.

Keywords: BARD1, polymorphism, cancer risk, meta-analysis

Introduction

BRCA1-associated RING domain protein-1 (BARD1) is firstly identified through a yeast two-hybrid screen using a BRCA1 RING domain as bait. The BARD1 gene has been localized to the distal end of chromosome 2q and shares homology with two highly conserved domains of BRCA1 [1]. BRCA1 and BARD1 interact via their respective amino terminal RING finger domains, and both proteins have BRCT domains at their C-terminal [2]. The interaction between BRCA1 and BARD1 is mediated via their RING-finger motifs [3]. Functional studies have demonstrated that disruption of the endogenous BRCA1–BARD1 complex decreases homology-directed repair, which is important to the tumor-suppressor activity of BRCA1 [4].

Since BARD1 stabilizes BRCA1 by binding with it and participates with BRCA1 in mediating tumor suppressor functions, BARD1 is also regarded as a kind of tumor suppressor [5]. BARD1 has been implicated in multiple crucial cellular processes including DNA repair [6], RNA processing [7], apoptosis [8], cell cycle regulation [9] and transcription [10]. The tumor suppressor functions of BARD1 may be affected by functional single nucleotide polymorphisms (SNPs) [11]. Some BARD1 polymorphism like Arg378Ser (rs2229571), Val507Met (rs2070094), and Pro24Ser (rs1048108) were reported to be associated with cancer susceptibility recently.

As BARD1 plays important roles in some types of cancer in which these mutations occur [12], the aim of this meta-analysis was to assess whether combined evidence showed the association between three BARD1 polymorphisms (Arg378Ser, Val507Met and Pro24Ser) and cancer risk.

Materials and methods

Literature search

The PRISMA statement (Checklist S1) was followed in our meta-analysis. A comprehensive search of EMBASE, PubMed, Web of Science, OVID, Cochrane Library and China National Knowledge Infrastructure (CNKI) was performed from database inception to August 10, 2014 without language restriction. The search strategy was “BRCA1-associated RING domain protein-1 or BARD1 or BARD-1” and “polymorphism or variant or mutation or genotype”. We also read the review articles and reference lists of retrieved articles manually to complete our research. The database search was performed by X. Zhang and X. Liu respectively and the disagreements were resolved through consensus by all of the authors.

Selection criteria

Studies were included in the meta-analysis if the following inclusion criteria were satisfied:1) case-control studies focused on association between the BARD1 polymorphisms (Arg378Ser, Val507Met, Pro24Ser) and cancer risk; 2) more than 30 patients were enrolled in each study; 3) studies provided sufficient data to estimate the odds ratio (OR) and 95% confidence intervals (CI) according to BARD1 polymorphisms; 4) when study patients overlapped with patients in other included studies, we selected the study firstly published. The two researchers (X. Liu and X. Zhang) read the titles and abstracts and excluded the uncorrelated studies, respectively; then the full-texts were examined by our review team. The studies would be included due to the inclusion criteria.

Data abstraction

Two reviewers (X. Zhang and X. Liu) independently extracted the following information: authors, year of publication, country, tumor type, number of cases and controls analyzed, mean value of age, source of controls (hospital-based controls or population-based controls), genotyping method. If insufficient data (missing data, inconsistencies, or any other uncertainties) were reported in articles, we tried our best to ask the first and corresponding authors for necessary information by telephone or E-mail.

Statistical analysis

Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were combined to measure the association between BARD1 polymorphisms and cancer susceptibility. The pooled ORs were calculated for the allelic model (mutation [M] allele versus [vs] wild [W] allele), dominant model (WM + MM vs WW), recessive model (MM vs WM + WW), homozygote comparison (MM vs WW) and heterozygote comparison (WM vs WW),respectively. And P values < 0.05 indicated statistical significance. Statistical heterogeneity among the studies was evaluated using the Q test and I2 test. When heterogeneity among the studies was observed, the pooled OR was calculated by random-effects models. Sensitivity analyses were performed to identify the potential influence of the individual data set to the pooled ORs. Subgroup analyses were performed with respect to ethnicity, tumor type and source of controls. These analyses were performed by Review Manager Version 5.1 software (http://ims.cochrane.org/revman). The Begg’s and Egger’s test was performed by R (http://cran.r-project.org/bin/windows/base).

Results

Characteristics of identified studies

Following an initial search, 131 studies were searched in PubMed, 158 studies were searched in EMBASE, 375 studies were searched in OVID, 156 studies were searched in Web of Science, 0 were searched in Cochrane Library. 288 published studies were identified after duplicates were removed. 213 studies were excluded by reading titles and abstracts. Next, full-text of the remaining 75 studies were downloaded and the unrelated studies were excluded. We tried our best to communicate with the first and corresponding author to get the complete data in some articles. Some authors were kind to provide the data for us. Eventually, ten studies were included in our meta-analysis [13-22]. The selection process was showed in Figure 1. These ten studies were published between 2003 and 2013. There were eight studies evaluating BARD1 Arg378Ser polymorphism, eight studies evaluating Val507Met polymorphism and eight studies evaluating Pro24Ser polymorphism and cancer susceptibility, respectively. Studies were carried out in China, France, Japan, Finland, Canada and USA. The control of two studies was hospital-based [15,19] and population-based control was in the other eight studies [13,14,16-18,20-22]. Seven studies assessed breast cancer [13-17,19,22], two studies assessed neuroblastoma [18,21] and one studies assessed cervical cancer [20]. The main characteristics of all the included studies is shown in Table S1.

Figure 1.

Figure 1

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Flow diagram summarizing the selection of eligible studies.

Meta-analysis

A significant association between BARD1 Val507Met (G/A) polymorphism and cancer susceptibility was found in allelic model (OR = 0.76, 95% CI: 0.66-0.87, P < 0.00001), dominant model (OR = 0.77, 95% CI: 0.65-0.91, P < 0.00001), recessive model (OR = 0.64, 95% CI: 0.55-0.74, P < 0.00001), homozygote comparison (OR = 0.58, 95% CI: 0.49-0.70, P < 0.00001), heterozygote comparison (OR = 0.85, 95% CI: 0.74-0.99, P = 0.0008) (Figure 2). BARD1 Pro24Ser (C/T) polymorphism was also associated decreased cancer risk in allelic model (OR = 0.72, 95% CI: 0.60-0.88, P = 0.0009), dominant model (OR = 0.70, 95% CI: 0.56-0.87, P = 0.004), recessive model (OR = 0.70, 95% CI: 0.56-0.87, P = 0.004), homozygote comparison (OR = 0.55, 95% CI: 0.39-0.78, P = 0.0007) and heterozygote comparison (OR = 0.75, 95% CI: 0.62-0.91, P = 0.004) (Figure 3). No significant association was found between Arg378Ser polymorphism and cancer risk under five genetic models (allelic model: OR = 0.88, 95% CI: 0.69-1.12, P = 0.30; dominant model: OR = 0.81, 95% CI: 0.59-1.11, P = 0.20; recessive model: OR = 0.94, 95% CI: 0.65-1.37, P = 0.75; homozygote comparison: OR = 0.83, 95% CI: 0.50-1.40, P = 0.49; heterozygote comparison: OR = 0.80, 95% CI: 0.61-1.06, P = 0.13) (Figure 4).

Figure 2.

Figure 2

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Forest plot of BARD1 Val507Met polymorphism and cancer risk in five genetic models. A. Forest plot of BARD1 Val507Met polymorphism and cancer risk in allelic model; B. Forest plot of BARD1 Val507Met polymorphism and cancer risk in dominant model; C. Forest plot of BARD1 Val507Met polymorphism and cancer risk in recessive model; D. Forest plot of BARD1 Val507Met polymorphism and cancer risk in homozygote comparison; E. Forest plot of BARD1 Val507Met polymorphism and cancer risk in heterozygote comparison.

Figure 3.

Figure 3

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Forest plot of BARD1 Pro24Ser polymorphism and cancer risk in five genetic models. A. Forest plot of BARD1 Pro24Ser polymorphism and cancer risk in allelic model; B. Forest plot of BARD1 Pro24Ser polymorphism and cancer risk in dominant model; C. Forest plot of BARD1 Pro24Ser polymorphism and cancer risk in recessive model; D. Forest plot of BARD1 Pro24Ser polymorphism and cancer risk in homozygote comparison; E. Forest plot of BARD1 Pro24Ser polymorphism and cancer risk in heterozygote comparison.

Figure 4.

Figure 4

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Forest plot of BARD1 Arg378Ser polymorphism and cancer risk in five genetic models. A. Forest plot of BARD1 Arg378Ser polymorphism and cancer risk in allelic model; B. Forest plot of BARD1 Arg378Ser polymorphism and cancer risk in dominant model; C. Forest plot of BARD1 Arg378Ser polymorphism and cancer risk in recessive model; D. Forest plot of BARD1 Arg378Ser polymorphism and cancer risk in homozygote comparison; E. Forest plot of BARD1 Arg378Ser polymorphism and cancer risk in heterozygote comparison.

Subgroup analysis

In our subgroup analysis, we evaluated BARD1 Arg378Ser, Val507Met and Pro24Ser polymorphisms with respect to ethnicity, tumor type and source of control in five different genotypes. We found that BARD1 Arg378Ser polymorphism was associated with decreased cancer risk in breast cancer (allelic model: OR = 0.81, 95% CI: 0.73-0.90, P < 0.0001; dominant model: OR = 0.73, 95% CI: 0.61-0.87, P = 0.0005; heterozygote comparison: OR = 0.75, 95% CI: 0.58-0.97, P = 0.03) and in Asians (allelic model: OR = 0.85, 95% CI: 0.73-0.98, P = 0.03; dominant model: OR = 0.77, 95% CI: 0.63-0.95, P = 0.02; heterozygote comparison: OR = 0.77, 95% CI: 0.61-0.98, P = 0.03) (Table S2). BARD1 Val507Met polymorphism (allelic model: OR = 0.87, 95% CI: 0.80-0.94, P = 0.0007; dominant model: OR = 0.90, 95% CI: 0.80-1.01, P = 0.01; recessive model: OR = 0.69, 95% CI: 0.59-0.82, P < 0.0001; homozygote comparison: OR = 0.66, 95% CI: 0.55-0.80, P < 0.0001) (Table S3) and Pro24Ser (allelic model: OR = 0.70, 95% CI: 0.52-0.95, P = 0.02; dominant model: OR = 0.70, 95% CI: 0.52-0.96, P = 0.03; recessive model: OR = 0.57, 95% CI: 0.35-0.94, P = 0.03; homozygote comparison: OR = 0.50, 95% CI: 0.29-0.87, P = 0.01) was also associated with decreased breast cancer risk (Table S4).

Sensitivity analysis

Sensitivity analysis was performed by omitting one study at a time and calculating the pooled ORs again. When the study performed by Capasso in 2009 was deleted, BARD1 Arg378Ser polymorphism was associated with decreased cancer risk in allelic model (OR = 0.81, 95% CI: 0.67-0.97, P = 0.02), dominant model (OR = 0.72, 95% CI: 0.56-0.91, P = 0.007) and heterozygote comparison (OR = 0.72, 95% CI: 0.57-0.91, 0 = 0.006) (Figure 5).

Figure 5.

Figure 5

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Forest plot of BARD1 Arg378Ser polymorphism and cancer risk in sensitivity analysis. A. Forest plot of BARD1 Arg378Ser polymorphism and cancer risk in allelic model when study performed by Capasso in 2009 was omitted; B. Forest plot of BARD1 Arg378Ser polymorphism and cancer risk in dominant model when study performed by Capasso in 2009 was omitted; C. Forest plot of BARD1 Arg378Ser polymorphism and cancer risk in recessive model when study performed by Capasso in 2009 was omitted; D. Forest plot of BARD1 Arg378Ser polymorphism and cancer risk in homozygote comparison when study performed by Capasso in 2009 was omitted; E. Forest plot of BARD1 Arg378Ser polymorphism and cancer risk in heterozygote comparison when study performed by Capasso in 2009 was omitted.

Publication bias

Both Begg’s funnel plot and Egger’s test were carried out to evaluate the publication bias of the studies. The result was displayed in Table 1. Begg’s funnel plot and Egger’s test didn’t suggest any evidence of publication bias.

Table 1.

Begg’s funnel plot and Egger’s test of publication bias on the relationships between BARD1 polymorphisms and cancer susceptibility in five genetic models

BARD1 polymorphism Genetic model Begg’s funnel plot Egger’s test
Z test for plot asymmetry P value Kendall’s tau P value
Arg378Ser allelic model -0.2797 0.7797 0 1
dominant model 0.1585 0.8741 0 1
recessive model -0.3596 0.174 -0.1429 0.7726
homozygote comparison -0.6312 0.5279 -0.0476 1
heterozygote comparison 0.2421 0.8087 -0.1429 0.7195
Val507Met allelic model -0.6832 0.4945 -0.2143 0.5484
dominant model -0.6896 0.4905 -0.2857 0.3988
recessive model -0.841 0.4003 -0.3571 0.2751
homozygote comparison -0.6139 0.5393 -0.0714 0.9049
heterozygote comparison -0.9299 0.3524 -0.5 0.1087
Pro24Ser allelic model -0.9753 0.3294 -0.2857 0.3988
dominant model -1.5398 0.1236 -0.2857 0.3988
recessive model 0.0157 0.9874 0.1429 0.7195
homozygote comparison -0.5005 0.6167 0 1
heterozygote comparison -1.0237 0.306 -0.1429 0.7195
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Discussion

In our meta-analysis, we firstly evaluated whether three common BARD1 polymorphisms (Arg378Ser, Val507Met and Pro24Ser) was associated with cancer susceptibility. And we found that BARD1 Val507Met (G/A) polymorphism was associated with decreased cancer susceptibility (allelic model: OR = 0.76, 95% CI: 0.66-0.87, P < 0.00001; dominant model: OR = 0.77, 95% CI: 0.65-0.91, P < 0.00001; recessive model: OR = 0.64, 95% CI: 0.55-0.74, P < 0.00001; homozygote comparison: OR = 0.58, 95% CI: 0.49-0.70, P < 0.00001; heterozygote comparison: OR = 0.85, 95% CI: 0.74-0.99 , P = 0.0008). BARD1 Pro24Ser (C/T) polymorphism was also associated decreased cancer risk in allelic model (OR = 0.72, 95% CI: 0.60-0.88, P = 0.0009), dominant model (OR = 0.70, 95% CI: 0.56-0.87, P = 0.004), recessive model (OR = 0.70, 95% CI: 0.56-0.87, P = 0.004), homozygote comparison (OR = 0.55, 95% CI: 0.39-0.78, P = 0.0007) and heterozygote comparison (OR = 0.75, 95% CI: 0.62-0.91, P = 0.004). And in our sensitivity analysis, when deleting the study performed by Capasso in 2009, we found that BARD1 Arg378Ser polymorphism was associated with decreased cancer risk in allelic model (OR = 0.81, 95% CI: 0.67-0.97, P = 0.02), dominant model (OR = 0.72, 95% CI: 0.56-0.91, P = 0.007) and heterozygote comparison (OR = 0.72, 95% CI: 0.57-0.91, 0 = 0.006).

BARD1 interacts with BRCA1 via their RING finger domains [23]. This important interaction is required for BRCA1 stability, nuclear localization and the E3 ubiquitin ligase activity of the BRCA1-BARD1 complex which has a crucial function in cell cycle check point control [24]. Some mutations in BARD1 will disrupt the ubiquitin ligase activity of the BRCA1-BARD1 heterodimer and lead to ER-α upregulation, causing even more BARD1 isoform expression [25]. Some mutations in BARD1 will promote the tumor-suppressive role of BARD1 compared to the wild type genotypes [13]. Mutations in BARD1 are apparently likely to have an influence on susceptibility to cancer, as they are often found, along with their products, in patients with breast [26], uterine [27], or endometrial cancers [28]. The Arg378Ser, Val507Met and Pro24Ser polymorphisms in BARD1 are located directly on BRCA1 binding domain [13,14,29,30], so the associated residue changes probably affect the E3 ligase activity of the BRCA1-BARD1 interaction. These mutations may have a protective function compared to the wild type genotype.

We performed subgroup analysis with respect to tumor type, ethnicity and the source of control. Breast cancer is the leading cause of cancer death in women [31]. BRCA1 and BRCA2 are identified as two highly penetrant breast cancer susceptibility genes [32]. The mutations in BARD1 might have an impact on the interaction between BARD1 and BRCA1/2 and have an impact on the breast cancer susceptibility [33]. We found that these three polymorphisms were all associated decreased susceptibility of breast cancer. So we speculated that these three polymorphisms might play a tumor suppressive role compared to the wild type genotype.

In our sensitivity analysis, the study performed by Capasso 2009 evaluating the association between BARD1 Arg378Ser polymorphism and neuroblastoma susceptibility was omitted by us. When deleting this study, we found BARD1 Arg378Ser polymorphism was significantly associated with decreased cancer risk in allelic model (OR = 0.81, 95% CI: 0.67-0.97, P = 0.02), dominant model (OR = 0.72, 95% CI: 0.56-0.91, P = 0.007) and heterozygote comparison (OR = 0.72, 95% CI: 0.57-0.91, 0 = 0.006). Moreover, the study performed by Capasso 2009 evaluating the association between BARD1 Arg378Ser polymorphism and neuroblastoma susceptibility reported the completely opposite result compared to the study performed Capasso 2013. We read these two papers carefully and didn’t find the interpretation about this phenomenon by the author.

Although the association between BARD1 polymorphisms and cancer susceptibility was found in our meta-analysis, the limitations should be acknowledged. Firstly, studies included in our meta-analysis were not sufficient, which leads to the relative insufficiency of studies in subgroup analyses. If more studies are included in our meta-analysis especially studies evaluating BARD1 polymorphism and breast cancer susceptibility, more representative conclusions will get. Secondly, some genome-wide association studies reported that these BARD1 polymorphisms were investigated. However, when we communicated with the authors, they informed us that the specific data couldn’t be found and provide for us. It’s a shame that these studies are not able to be included in our metaanalysis.

Despite these limitations, our meta-analysis concluded that BARD1 Val507Met and Pro24Ser polymorphisms were both associated with decreased cancer susceptibility. Moreover, Arg378Ser might also be associated with decreased cancer susceptibility. Since BARD1 has a tumor-suppressive function and has been implicated in multiple crucial cellular processes including DNA repair, RNA processing, apoptosis, cell cycle regulation and transcription. With more studies in the future emerging, some effective tumor prevention methods may be generated according to these BARD1 polymorphisms which play a tumor suppressive role compared to the wild type genotype.

Acknowledgements

This study was supported by Natural science foundation of China (Grant No.: 81201913).

Disclosure of conflict of interest

None.

Supporting Information

ijcem0008-0311-f6.pdf (319.5KB, pdf)

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