Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 17  |  Issue : 5  |  Page : 1225-1233

Associations of rs1799794 and rs1799796 polymorphisms with risk of breast cancer: A meta-analysis


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 Submission28-Jan-2021
Date of Decision03-Sep-2021
Date of Acceptance17-Sep-2021
Date of Web Publication27-Nov-2021

Correspondence Address:
Heng Niu
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
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.331305

Rights and Permissions
 > Abstract 


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

How to cite this URL:
Niu H, Yang J, Chen X. Associations of rs1799794 and rs1799796 polymorphisms with risk of breast cancer: A meta-analysis. J Can Res Ther [serial online] 2021 [cited 2022 May 26];17:1225-33. Available from: https://www.cancerjournal.net/text.asp?2021/17/5/1225/331305




 > Introduction Top


Breast cancer represents the majority of all female-related cancers and has a high morbidity and mortality rate.[1] 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.[2] In addition, studies have shown that homologous recombination (HR) and NHEJ pathways participate in these repair processes.[3] 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.[4] 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;[5] 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.[1] These studies include case–control studies and meta-analyses.[2],[3],[4],[5],[6],[7],[8],[9],[10] However, the three meta-studies on rs1799794 and rs1799796 and breast cancer susceptibility reported inconsistent results.[2],[7],[11] 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 Top


Search strategies

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.

Selection criteria

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).[12] 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.



Statistical analysis

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%),[13] 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 Top


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[4],[14],[15],[16],[17],[18],[19],[20],[21] and seven articles reporting 10 studies of SNP rs1799796.[4],[14],[15],[16],[17],[19],[20]
Figure 1: Flow chart of study selection

Click here to view


The main characteristics of the nine articles (13 studies) are shown in [Table 1]. For SNP rs1799794, two studies were conducted in Arabian populations,[18],[19] two in Asian populations,[16],[19] and nine in Caucasian populations.[4],[14],[15],[16],[17],[21] In addition, in terms of the source of controls, six studies were hospital-based,[16],[17],[18],[19],[20],[21] six were population-based,[4],[14],[15],[16] and one was nested.[16] For SNP rs1799796, seven studies were conducted in Caucasian populations,[4],[14],[15],[16],[17] one in an Asian population,[19] and one in an Arabian population.[20] In addition, in terms of source of controls, four studies were hospital-based,[16],[17],[19],[20] five were population-based,[4],[14],[15],[16] and one was nested.[16] Two case–control studies did not conform to the HWE,[19],[20] 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

Click here to view


Meta-analysis results

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

Click here to view
Table 2: Results of meta-analysis for polymorphisms in and cancer susceptibility

Click here to view


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

Click here to view


Publication bias

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

Click here to view
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

Click here to view



 > Discussion Top


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.;[11] 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.,[7] that is, there was no association between rs1799794 and breast cancer. For rs1799796, our combined results were consistent with those of Qiu et al.;[11] 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 Top


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

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Auranen A, Song H, Waterfall C, Dicioccio RA, Kuschel B, Kjaer SK, et al. Polymorphisms in DNA repair genes and epithelial ovarian cancer risk. Int J Cancer 2005;117:611-8.  Back to cited text no. 1
    
2.
Han S, Zhang HT, Wang Z, Xie Y, Tang R, Mao Y, et al. DNA repair gene XRCC3 polymorphisms and cancer risk: A meta-analysis of 48 case-control studies. Eur J Hum Genet 2006;14:1136-44.  Back to cited text no. 2
    
3.
Dashti S, Taherian-Esfahani Z, Keshtkar A, Ghafouri-Fard S. Associations between XRCC3 Thr241Met polymorphisms and breast cancer risk: Systematic-review and meta-analysis of 55 case-control studies. BMC Med Genet 2019;20:79.  Back to cited text no. 3
    
4.
García-Closas M, Egan KM, Newcomb PA, Brinton LA, Titus-Ernstoff L, Chanock S, et al. Polymorphisms in DNA double-strand break repair genes and risk of breast cancer: Two population-based studies in USA and Poland, and meta-analyses. Hum Genet 2006;119:376-88.  Back to cited text no. 4
    
5.
Lee SA, Lee KM, Park SK, Choi JY, Kim B, Nam J, et al. Genetic polymorphism of XRCC3 Thr241Met and breast cancer risk: Case-control study in Korean women and meta-analysis of 12 studies. Breast Cancer Res Treat 2007;103:71-6.  Back to cited text no. 5
    
6.
Economopoulos KP, Sergentanis TN. XRCC3 Thr241Met polymorphism and breast cancer risk: A meta-analysis. Breast Cancer Res Treat 2010;121:439-43.  Back to cited text no. 6
    
7.
He XF, Wei W, Su J, Yang ZX, Liu Y, Zhang Y, et al. Association between the XRCC3 polymorphisms and breast cancer risk: Meta-analysis based on case-control studies. Mol Biol Rep 2012;39:5125-34.  Back to cited text no. 7
    
8.
He XF, Wei W, Li JL, Shen XL, Ding DP, Wang SL, et al. Association between the XRCC3 T241M polymorphism and risk of cancer: Evidence from 157 case-control studies. Gene 2013;523:10-9.  Back to cited text no. 8
    
9.
Mao CF, Qian WY, Wu JZ, Sun DW, Tang JH. Association between the XRCC3 Thr241Met polymorphism and breast cancer risk: An updated meta-analysis of 36 case-control studies. Asian Pac J Cancer Prev 2014;15:6613-8.  Back to cited text no. 9
    
10.
Chai F, Liang Y, Chen L, Zhang F, Jiang J. Association between XRCC3 Thr241Met polymorphism and risk of breast cancer: Meta-analysis of 23 case-control studies. Med Sci Monit 2015;21:3231-40.  Back to cited text no. 10
    
11.
Qiu LX, Mao C, Yao L, Yu KD, Zhan P, Chen B, et al. XRCC3 5'-UTR and IVS5-14 polymorphisms and breast cancer susceptibility: A meta-analysis. Breast Cancer Res Treat 2010;122:489-93.  Back to cited text no. 11
    
12.
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:603-5.  Back to cited text no. 12
    
13.
Attia J, Thakkinstian A, D'Este C. Meta-analyses of molecular association studies: Methodologic lessons for genetic epidemiology. J Clin Epidemiol 2003;56:297-303.  Back to cited text no. 13
    
14.
Kuschel B, Auranen A, McBride S, Novik KL, Antoniou A, Lipscombe JM, et al. Variants in DNA double-strand break repair genes and breast cancer susceptibility. Hum Mol Genet 2002;11:1399-407.  Back to cited text no. 14
    
15.
Tranah GJ, Giovannucci E, Ma J, Fuchs C, Hankinson SE, Hunter DJ. XRCC2 and XRCC3, polymorphisms are not associated with risk of colorectal adenoma. Cancer Epidemiol Biomark Prev 2004;13:1090-1.  Back to cited text no. 15
    
16.
Breast Cancer Association Consortium. Commonly studied single-nucleotide polymorphisms and breast cancer: Results from the breast cancer association consortium. J Natl Cancer Inst 2006;98:1382-96.  Back to cited text no. 16
    
17.
Vral A, Willems P, Claes K, Poppe B, Perletti G, Thierens H. Combined effect of polymorphisms in Rad51 and Xrcc3 on breast cancer risk and chromosomal radiosensitivity. Mol Med Rep 2011;4:901-12.  Back to cited text no. 17
    
18.
Al Zoubi MS. X-ray repair cross-complementing protein 1 and 3 polymorphisms and susceptibility of breast cancer in a Jordanian population. Saudi Med J 2015;36:1163-7.  Back to cited text no. 18
    
19.
Su CH, Chang WS, Hu PS, Hsiao CL, Ji HX, Liao CH, et al. Contribution of DNA double-strand break repair gene XRCC3 genotypes to triple-negative breast cancer risk. Cancer Genomics Proteomics 2015;12:359-67.  Back to cited text no. 19
    
20.
Ali AM, AbdulKareem H, Al Anazi M, Reddy Parine N, Shaik JP, Alamri A, et al. Polymorphisms in DNA Repair Gene XRCC3 and Susceptibility to Breast Cancer in Saudi Females. Biomed Res Int. 2016;2016:8721052. doi: 10.1155/2016/8721052.  Back to cited text no. 20
    
21.
Al Zoubi MS, Zavaglia K, Mazanti C, Al Hamad M, Al Batayneh K, Aljabali AA, et al. Polymorphisms and mutations in GSTP1, RAD51, XRCC1 and XRCC3 genes in breast cancer patients. Int J Biol Markers 2017;32:e337-43.  Back to cited text no. 21
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>Methods>Results>Discussion>Conclusion>Article Figures>Article Tables
  In this article
>References

 Article Access Statistics
    Viewed534    
    Printed14    
    Emailed0    
    PDF Downloaded69    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]