|Year : 2021 | Volume
| Issue : 5 | Page : 1225-1233
Associations of rs1799794 and rs1799796 polymorphisms with risk of breast cancer: A meta-analysis
Heng Niu, Jingyu Yang, Xin Chen
Department of Breast and Thyroid Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan Province, China
|Date of Submission||28-Jan-2021|
|Date of Decision||03-Sep-2021|
|Date of Acceptance||17-Sep-2021|
|Date of Web Publication||27-Nov-2021|
Department of Breast and Thyroid Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, Xishan District, Kunming 650032, Yunnan Province
Source of Support: None, Conflict of Interest: None
Background: The aim of this meta-analysis was to investigate the rs1799794 and rs1799796 polymorphisms of X-ray repair cross-complementing group 3 (XRCC3) in relation to breast cancer susceptibility.
Materials and Methods: PubMed, Embase, the Cochrane Library, Web of Science, and Scopus were searched for eligible studies published until June 24, 2019. All analyses were carried out using Stata 14.0 software. Subgroup analyses were performed according to cancer types, ethnicity, source of controls, and method.
Results: Our meta-analysis included articles reporting 13 studies of SNP rs1799794 and seven articles reporting 10 studies of SNP rs1799796. Overall, significant associations were observed between the XRCC3 rs1799794 polymorphism and breast cancer risk in the dominant model and heterozygote model (GG + AG vs. AA: odds ratio [OR] =1.06, 95% confidence interval [CI]: 1.00–1.11, P = 0.037, I2 = 47%; AG vs. AA: OR = 1.08, 95% CI: 1.02–1.13, P = 0.006, I2 = 42.3%) and between the XRCC3 rs1799796 polymorphism and breast cancer risk in the homozygote model (GG vs. AA: OR = 0.91, 95% CI: 0.84–0.99, P = 0.021, I2 = 33.3%).
Conclusions: The results of this meta-analysis suggest that the variant G allele of the XRCC3 rs1799794 polymorphism is a low-penetrant risk factor for developing breast cancer, whereas the variant G allele of the XRCC3 rs1799796 polymorphism has a protective effect against breast cancer development.
Keywords: Breast cancer, meta-analysis, polymorphism, rs1799794, rs1799796
|How to cite this article:|
Niu H, Yang J, Chen X. Associations of rs1799794 and rs1799796 polymorphisms with risk of breast cancer: A meta-analysis. J Can Res Ther 2021;17:1225-33
| > Introduction|| |
Breast cancer represents the majority of all female-related cancers and has a high morbidity and mortality rate. The occurrence of cancer, including breast cancer, is closely related to genetic and environmental factors. Genetic factors include changes in gene sequence and gene expression levels, genetic modification, and DNA double-strand breaks (DSB) and the ability to repair DSB. Some single nucleotide polymorphisms in the sequences of genes involved in the nonhomologous end-joining (NHEJ) pathway are involved in the occurrence of breast cancer. In addition, studies have shown that homologous recombination (HR) and NHEJ pathways participate in these repair processes. The BRCA1 and BRCA2 genes, which are involved in the HR process, are considered to be susceptibility genes for breast cancer because of their germline mutations and the fact that insufficient HR has been detected in a significant proportion of BRCA1/2 wild-type breast cancer patients. The X-ray repair cross-complementing group 3 (XRCC3), an important component of HR, plays an important part in maintaining the chromosomal integrity of mammalian cells; it is thus a candidate gene for identifying breast cancer susceptibility.
Studies have examined the relationship between breast cancer susceptibility and two XRCC3 gene polymorphisms: rs1799794 in the 5'-untranslated region and rs1799796 on intron 5. These studies include case–control studies and meta-analyses.,,,,,,,, However, the three meta-studies on rs1799794 and rs1799796 and breast cancer susceptibility reported inconsistent results.,, Owing to the inconclusive results of previous meta-analyses and the lack of systematic reviews on this relationship, we conducted a systematic review and meta-analysis to assess the associations of rs1799794 and rs1799796 of XRCC3 with breast cancer risk in diverse inheritance models.
| > Methods|| |
PubMed, Embase, the Cochrane Library, Web of Science, and Scopus Research were comprehensively searched for research published as of June 24, 2019, using the following keywords and MeSH terms: “(X-ray repair cross complementing 3 OR rs1799794 OR 4541A/G OR XRCC3 OR rs1799796 OR IVS5-14 OR A17893G OR 17893A/G) AND (polymorphisms, genetic OR genetic polymorphisms OR genetic polymorphism OR polymorphism (genetics) OR polymorphisms (genetics) OR polymorphism, single nucleotide OR nucleotide polymorphism, single OR nucleotide polymorphisms, single OR polymorphisms, single nucleotide OR single nucleotide polymorphisms OR polymorphisms OR polymorphism OR variant OR mutation OR single nucleotide polymorphism OR SNP) AND (Carcinomas, Breast OR Carcinoma, Breast OR Breast Carcinomas OR Breast Carcinoma OR Mammary Neoplasm, Human OR Neoplasms, Human Mammary OR Neoplasm, Human Mammary OR Human Mammary Neoplasms OR Human Mammary Neoplasm OR Mammary Neoplasms, Human OR Human Mammary Carcinoma OR Mammary Carcinomas, Human OR Human Mammary Carcinomas OR Carcinomas, Human Mammary OR Carcinoma, Human Mammary OR Mammary Carcinoma, Human OR Cancer of the Breast OR Cancer of Breast OR Breast Malignant Tumors OR Breast Malignant Tumor OR Malignant Tumor of Breast OR Breast Malignant Neoplasms OR Breast Malignant Neoplasm OR Malignant Neoplasm of Breast OR Mammary Cancers OR Cancers, Mammary OR Cancer, Mammary OR Mammary Cancer OR Cancer, Breast OR Breast Cancer OR Neoplasms, Breast OR Tumors, Breast OR Tumor, Breast OR Breast Tumor OR Breast Tumors OR Neoplasm, Breast OR Breast Neoplasm).” In addition, we scanned the list of references included in the articles to make sure that no other relevant articles were left out.
We included studies where the original case–control study detected the relationship between rs1799794 or rs1799796 and breast cancer risk and provided the frequency of XRCC3 rs1799794 or rs1799796 mutant genotypes in the case and control groups. Studies reporting republished data or insufficient data were excluded.
Data extraction and quality assessment
Two independent authors performed the initial search, imported the results into EndNote, deleted duplicate records automatically or manually, screened the titles and abstracts, identified potentially eligible studies, and retrieved the full texts. The same two investigators independently determined studies for inclusion and data collection. In addition, the probability value (P value) of the Hardy–Weinberg equilibrium (HWE) was also calculated on the basis of genotypic frequencies of the rs1799794 and rs1799796 polymorphisms in the control group.
The quality of qualifying case–control studies was estimated by the same two investigators, using the Newcastle–Ottawa Scale (NOS). Articles were assessed with respect to three domains, including selection, comparability, and outcomes [Supplementary Table 1]. Scores of 0–4, 5–7, and 8–10 were considered to indicate low-quality, moderate-quality, and high-quality studies, respectively.
We estimated the relationship between the XRCC3 rs1799794 and rs1799796 polymorphisms and breast cancer risk in five genetic models using pooled odds ratio (OR) and 95% confidence interval (CI). If P was <0.05, or the 95% CI did not include 1, the result was considered statistically significant. The Cochran Q statistic with Chi-square (with PQ) and the Higgins I2 test were used to determine the heterogeneity among studies. When the results indicated significant heterogeneity (PQ < 0.05 or I2 > 50%), the data were analyzed using a random effect model; otherwise, a fixed effect model was chosen. We also performed subgroup analyses to explore the sources of heterogeneity, with stratification of studies by ethnicity (Arabian, Asian, Caucasian), method (PCR-RFLP, sequencing, TaqMan, ND), and source of control (HB, PB Nested). We assessed publication bias by funnel plots and Egger's test (P < 0.05). Statistical calculations were performed using Stata 14.0.
| > Results|| |
Literature search and study characteristics
As shown in [Figure 1], a total of 754 articles were abstracted from PubMed (n = 163), Embase (n = 162), Web of Science (n = 281), Scopus (n = 147), and the Cochrane Library (n = 1). Of these, 376 were excluded as duplicate records, 356 were excluded after reading titles and abstracts: 281 were unrelated to rs1799794 or rs1799796 and breast cancer; 54 were review or meta-analysis articles; and 21 were conference abstracts. Finally, our meta-analysis included nine articles reporting 13 studies of SNP rs1799794,,,,,,,, and seven articles reporting 10 studies of SNP rs1799796.,,,,,,
The main characteristics of the nine articles (13 studies) are shown in [Table 1]. For SNP rs1799794, two studies were conducted in Arabian populations,, two in Asian populations,, and nine in Caucasian populations.,,,,, In addition, in terms of the source of controls, six studies were hospital-based,,,,,, six were population-based,,,, and one was nested. For SNP rs1799796, seven studies were conducted in Caucasian populations,,,,, one in an Asian population, and one in an Arabian population. In addition, in terms of source of controls, four studies were hospital-based,,,, five were population-based,,,, and one was nested. Two case–control studies did not conform to the HWE,, and two were not available. We further conducted a sensitivity analysis for the integrated data. To evaluate the quality of each enrolled study, we applied the NOS. The PRISMA 2009 checklist was also used to report the results of our meta-analysis.
|Table 1: Characteristics of the individual studies included in the meta-analysis|
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X-ray repair cross-complementing group 3 rs1799794 polymorphism
Overall, significant associations were observed between the XRCC3 rs1799794 polymorphism and breast cancer risk in the GG + AG versus AA model (OR = 1.06, 95% CI: 1.00–1.11, P = 0.037) and the AG versus AA model (OR = 1.08, 95% CI: 1.02–1.13, P = 0.006) using fixed effect models (I2 = 47% or I2 = 42.3%) [Figure 2]. Hence, we then performed subgroup analysis by ethnicity. We found that the XRCC3 rs1799794 polymorphism was significantly associated with the risk of breast cancer in Caucasian populations in the AG versus AA model (OR = 1.07, 95% CI: 1.01–1.13, P = 0.021, I2 = 39.6%). We further examined the association between the XRCC3 rs1799794 polymorphism and breast cancer risk according to the source of controls. For population-based studies, we found that individuals with minor variant genotypes had higher risk of breast cancer in the GG + AG versus AA model (OR = 1.07, 95% CI: 1.01–1.13, P = 0.022, I2 = 16.6%) and the AG versus AA model (OR = 1.09, 95% CI: 1.02–1.15, P = 0.007, I2 = 20%). However, no significant association was found in hospital-based studies. When the meta-analysis was limited to studies conforming to the HWE, there was no significant association between the XRCC3 rs1799794 polymorphism and breast cancer [Table 2].
|Figure 2: Forest plot of X-ray repair cross-complementing group 3 rs1799794 polymorphism for cancer susceptibility under the 5 genetic models|
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|Table 2: Results of meta-analysis for polymorphisms in and cancer susceptibility|
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X-ray repair cross-complementing group 3 rs1799796 polymorphism
Overall, a significant association was observed between the XRCC3 rs1799796 polymorphism and breast cancer risk in the GG versus AA model (OR = 0.91, 95% CI: 0.84–0.99, P = 0.021, I2 = 33.3%) [Figure 3]. Hence, we performed subgroup analysis by ethnicity. We found that the XRCC3 rs1799796 polymorphism was significant associated with breast cancer in Caucasians under the GG versus AA model (OR = 0.91, 95% CI: 0.84–0.99, P = 0.021, I2 = 46.6%). We further examined the association between the XRCC3 rs1799794 polymorphism and breast cancer risk according to the source of controls. We found that individuals with minor variant genotypes had higher risk of breast cancer in the five models (A vs. G: OR = 0.93, 95% CI = 0.88–0.99, P = 0.022, I2 = 53.2%; GG + AG vs. AA: OR = 0.91, 95% CI = 0.84–1.00, P = 0.043, I2 = 57.7%; GG vs. AA + AG: OR = 0.90, 95% CI = 0.82–0.98, P = 0.011, I2 = 0.0%; GG vs. AA: OR = 0.86, 95% CI = 0.79–0.94, P = 0.001, I2 = 11.2%; AG vs. AA: OR = 0.93, 95% CI = 0.88–0.98, P = 0.006, I2 = 49.1%). However, no significant association was found in hospital-based studies. When the meta-analysis was limited to studies conforming to the HWE, similar significant results were also observed in the GG versus AA model (OR = 0.91, 95% CI: 0.84–0.99, P = 0.021, I2 = 46.6%) [Table 2].
|Figure 3: Forest plot of X-ray repair cross-complementing group 3 rs1799796 polymorphism for cancer susceptibility under the 5 genetic models|
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The shapes of the funnel plots [Figure 4] and [Figure 5] and the results of Egger's test for rs1799794 (allele: P =0.075; dominant: P =0.025; recessive: P =0.245; homozygote: P =0.055; heterozygote: P =0.012) and rs1799796 (allele: P =0.194; dominant: P =0.372; recessive: P =0.032; homozygote: P =0.011; heterozygote: P =0.122) indicated a risk of publication bias.
|Figure 4: The funnel plot of X-ray repair cross-complementing group 3 rs1799794 polymorphism for the test of publication bias under the 5 genetic models|
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|Figure 5: The funnel plot of X-ray repair cross-complementing group 3 rs1799796 polymorphism for the test of publication bias under the 5 genetic models|
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| > Discussion|| |
Our study showed that XRCC3 rs1799794 was significantly related to increased breast cancer risk. In addition, the risk of breast cancer increased significantly in population-based studies, and we also found that Caucasian individuals were more likely to develop breast cancer. By contrast, there was a significant correlation between the rs1799796 polymorphism and reduced risk of breast cancer. When we removed the articles that did not conform to HWE and reanalyzed the data, only rs1799796 was associated with breast cancer.
Our results were partially consistent with those of previous meta-analyses on the associations between XRCC3 polymorphisms and breast cancer risk. For rs1799794, our combined results were consistent with those of Qiu et al.; rs1799794 was associated with a statistically significant increase in cancer risk in the dominant model. However, after limiting the analysis to studies where the control group conformed to the HWE, the combined results were consistent with those of He et al., that is, there was no association between rs1799794 and breast cancer. For rs1799796, our combined results were consistent with those of Qiu et al.; AA carriers had a lower risk of breast cancer. Compared with previous studies, we included more case–control studies and combined analyses of the five genetic models. In addition, we performed subgroup analyses to identify sources of heterogeneity.
Moderate heterogeneity was found in this meta-analysis. As shown in [Table 2], heterogeneity in the subgroup stratified by ethnicity increased in Arabian, and Caucasian, suggesting that ethnicity may have been a factor in the heterogeneity; similar effects were seen in the subgroups stratified by cancer type, method, and source of control. Ethnicity, cancer type, method, and source of control were thus potential sources of inter-study heterogeneity. In addition, the shapes of the funnel plots and the results of Egger's test showed a risk of publication bias; this may also have been a source of heterogeneity.
Despite the advantages of a large sample size and stratified analyses, the meta-analysis had several limitations. First, heterogeneity existed among some studies; this was possibly derived from differences in ethnicity, source of control, and cancer type. Second, the studies were limited to those published in English; this may have been one of the reasons for publication bias. Third, we did not evaluate potential gene–environment interactions, which may affect cancer risk, owing to a lack of relevant data across the included studies.
| > Conclusion|| |
The results of this meta-analysis suggest that the variant G allele of the XRCC3 rs1799794 polymorphism is a low-penetrant risk factor for developing breast cancer, while the variant G allele of the XRCC3 rs1799796 polymorphism has a protective effect against breast cancer development, especially in Caucasian individuals.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]