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  • 1 Iran University of Medical Sciences, Iran
  • 2 Shahid Sadoughi University of Medical Sciences, Iran
  • 3 Shahid Beheshti University of Medical Sciences, Iran
  • 4 Shahid Sadoughi University of Medical Sciences, Iran
  • 5 Shahid Sadoughi University of Medical Sciences, Iran
  • 6 Shahid Sadoughi University of Medical Sciences, Iran
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The 18067 C>T polymorphism of XRCC3 gene has been considered to be implicated in the development of cervical and ovarian cancers, but the results are inconsistent. Thus, we conducted a meta-analysis to assess the association of XRCC3 18067 C>T polymorphism with risk of cervical and ovarian cancers. All studies on the association of XRCC3 18067 C>T polymorphism with cervical and ovarian cancers risk were retrieved. Finally, a total of 17 studies including 10 studies with 5,637 cases and 10,057 controls on ovarian cancer and 7 studies with 1,112 cases and 1,233 controls on cervical cancer were selected. Overall, pooled results showed that the XRCC3 18067 C>T polymorphism was significantly associated with increased risk of ovarian cancer (TC vs. CC: OR = 0.904, 95% CI = 0.841–0.972, p = 0.006; TT + TC vs. CC: OR = 0.914, 95% CI = 0.853–0.979, p = 0.010) and cervical cancer (TC vs. CC: OR = 1.00, 95% CI = 1.066–1.585, p = 0.009). Further subgroup analysis by ethnicity revealed an increased risk of cervical and ovarian cancer in Asians and Caucasians, respectively. The present meta-analysis inconsistent with the previous meta-analysis suggests that the XRCC3 18067 C>T polymorphism might be implicated in the pathogenesis of cervical and ovarian cancers.

Abstract

The 18067 C>T polymorphism of XRCC3 gene has been considered to be implicated in the development of cervical and ovarian cancers, but the results are inconsistent. Thus, we conducted a meta-analysis to assess the association of XRCC3 18067 C>T polymorphism with risk of cervical and ovarian cancers. All studies on the association of XRCC3 18067 C>T polymorphism with cervical and ovarian cancers risk were retrieved. Finally, a total of 17 studies including 10 studies with 5,637 cases and 10,057 controls on ovarian cancer and 7 studies with 1,112 cases and 1,233 controls on cervical cancer were selected. Overall, pooled results showed that the XRCC3 18067 C>T polymorphism was significantly associated with increased risk of ovarian cancer (TC vs. CC: OR = 0.904, 95% CI = 0.841–0.972, p = 0.006; TT + TC vs. CC: OR = 0.914, 95% CI = 0.853–0.979, p = 0.010) and cervical cancer (TC vs. CC: OR = 1.00, 95% CI = 1.066–1.585, p = 0.009). Further subgroup analysis by ethnicity revealed an increased risk of cervical and ovarian cancer in Asians and Caucasians, respectively. The present meta-analysis inconsistent with the previous meta-analysis suggests that the XRCC3 18067 C>T polymorphism might be implicated in the pathogenesis of cervical and ovarian cancers.

Introduction

Cervical and ovarian cancers remain two of the leading cause of cancer mortality worldwide among women and the most common site in several low-income countries [1, 2]. It is widely accepted that certain oncogenic types of human papilloma virus (HPV) are essential cause of cervical cancer development [3]. Almost 100% of women with a diagnosis of cervical cancer have been found to have had an HPV infection [4]. Ovarian cancer is characterized by few early symptoms, presentation at an advanced stage, and poor survival [5, 6]. The exact causes of ovarian cancer are not known. Relatively few risk factors for ovarian cancer have been identified, including age, parity, oral contraceptive use, lifestyle factors, and family history of breast or ovarian cancer, many of these are not easily modifiable on the population level [4, 7].

Genome-wide association studies have been extremely successful at finding susceptibility loci for cervical and ovarian cancers [8]. Molecular epidemiological studies have been conducted with the candidate gene approach to identify susceptibility genes for cervical and ovarian cancers, many of which have showed inconsistent result [9]. DNA repair plays an important role in the maintenance of genomic integrity by correcting DNA alterations caused by endogenous and exogenous genotoxic agents [10]. At present, several DNA repair genes (e.g., XPD, XPF, ERCC1, XRCC1, XRCC3, XPA, XPB, XPC, and hOGG1) have been reported to be associated with cervical and ovarian cancers, and the X-ray cross-complementing group 3 (XRCC3) gene has received an increasing attention [11, 12].

The human XRCC3 gene (MIM: 600675) is localized on chromosomes 14q32.3 [13]. It is involved in the homologous recombination repair (HR) pathway, responsible for DNA double-strand breaks [14]. XRCC3 is a polymorphic gene where many SNPs have been already described. Several polymorphisms in the XRCC3 gene have been described to affect the enzyme function and/or its interaction with other proteins involved in DNA damage and repair [13, 14]. Of these, C18607T transition (rs861539) at exon 7 resulting in an amino acid change at codon 241 (Thr241Met) has been studied frequently [13]. This polymorphism has been reported to be associated with the development of some cancers, such as bladder, skin, breast, lung, and colorectal cancers [15].

Several epidemiological studies were conducted in recent years to evaluate the association of the XRCC3 18067 C>T polymorphism with cervical and ovarian cancers [16, 17]. Some studies have shown a significant statistical correlation of this polymorphism with cervical and ovarian cancers, whereas others did not find any such association. Thus, these inconsistent results fail to clarify this complicated genetic relationship, presumably due to small sample size in each published study, various genetic backgrounds, and possible selection bias. To reliably demonstrate the effect of XRCC3 18067 C>T polymorphism on cervical and ovarian cancer risks, we performed a comprehensive systematic review and meta-analysis of all eligible studies to resolve this pivotal issue.

Materials and Methods

Study identification and selection

This meta-analysis conformed to the Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria. Two investigators independently searched the MEDLINE (PubMed), Google Scholar, Web of Science (Thomson-Reuters), Scientific Information Database (SID), Chinese National Knowledge Infrastructure (CNKI), the Chinese Wanfang, and the Chinese VIP databases for eligible articles examined the association of XRCC3 18067 C>T polymorphism with cervical and ovarian cancer risks published up to January 30, 2019. The following terms were utilized: (“ovarian cancer” OR “cervical cancer”) AND (“X-ray repair cross complementing 3” OR “XRCC3”) AND (“XRCC3 18067 C>T” OR “Thr241Met” OR “rs861539”) AND (“polymorphism”, OR “mutation” OR “variant” OR “gene” OR “genotype” OR “SNP” OR “allele”). The search was performed without any restrictions on language and was focused on studies that had been conducted in humans. In addition, manual searching of the references of eligible studies, reviews and related meta-analyses, and the abstracts presented at relevant conferences were performed to identify potentially relevant studies. If there were multiple reports of the same study or overlapping data, only the study with the largest sample sizes or the most recent one should be in the final analysis.

Data extraction

Information was carefully extracted from all eligible studies independently by two investigators according to the inclusion criteria listed above, and potential disagreements were resolved by consensus. The following data were collected from each study: name of first author, publication year, country where the study was conducted, racial descent (categorized as Asian, Caucasian, or mixed descent), polymorphisms, genotypic testing method, number of cases and controls, genotype frequency of cases and controls, minor allele frequencies in control subjects, and result of Hardy–Weinberg equilibrium (HWE) test in control subjects. In this meta-analysis, ethnicity was categorized as: Caucasian, Asian, and Mixed.

Inclusion and exclusion criteria

To be included in the meta-analysis, studies had to meet all the criteria: (1) use a case–control or cohort design; (2) assess the association of the XRCC3 18067 C>T polymorphism with ovarian and cervical cancers; and (3) provide sufficient data for estimating odds ratios (ORs) with 95% confidence intervals (CIs). The exclusion criteria were: (1) studies that could not offer the number of cases and controls or other essential information; (2) case only or studies without control group; (3) family based or linkage studies; (4) case reports, reviews, and studies; and (5) overlapping data. In the case of multiple studies by the same researchers involving the same or overlapping data sets, the most recent study with the largest number of participants was included in the meta-analysis.

Statistical analyses

The strength of association of the XRCC3 18067 C>T polymorphism with ovarian and cervical cancers susceptibility was assessed by OR with the corresponding 95% CI. The Z-test was performed to determine the significance of the pooled OR, with p < 0.05 defined as the significance threshold. The pooled ORs were calculated for the risk associated with the XRCC3 18067 C>T polymorphism in the allele model (T vs. C), homozygote model (TT vs. CC), heterozygote model (TC vs. CC), dominant model (TT + TC vs. CC), and recessive model (TT + TC vs. CC). The between-studies heterogeneity was tested using the Q statistic. If p < 0.10, the heterogeneity was considered statistically significant. Venice criteria for the I2 test included: I2 < 25% represents no heterogeneity, I2 = 25%–50% represents moderate heterogeneity, I2 = 50%–75% represents large heterogeneity, and I2 > 75% represents extreme heterogeneity. The p value of <0.05 for the Q-test indicated a lack of heterogeneity among studies, so that the pooled OR estimate of each study was calculated by the fixed-effects model (the Mantel–Haenszel method), otherwise the random effects model (the DerSimonian–Laird method) was utilized. Furthermore, to explore the source of between-study heterogeneity, the subgroup analyses were performed. The one-way sensitivity analyses were performed to survey the stability of the results, namely, a single study in the meta-analysis was omitted each time to reflect the influence of the individual data set to the pooled OR. Publication bias was assessed by visually examining the asymmetry of a funnel plot in which the log estimates were plotted against their standard errors. Furthermore, we also employed an Egger’s regression test in our analysis to calculate two-tailed p values for quantifying publication bias. A HWE test of the VDR gene polymorphisms in healthy subjects was examined using χ2 test. If p value > 0.05, the genotype distribution of the control group conformed to HWE. All the statistical analyses were performed by comprehensive meta-analysis version 2.0 software (Biostat, USA). All the p values were two sides and less than 0.05 were considered significant.

Results

Study selection and characteristics

A flow diagram schematizing the inclusion and exclusion process of identified articles with the inclusion criteria is presented in Fig. 1. After a comprehensive search, a total of 126 literatures were identified. Of these studies, the first screening excluded 47 were considered as duplicates or not relevant, leaving 79 studies for further selection. Finally, a total of 17 case–control studies (in 14 publications) were included in this meta-analysis [1831]. Of these, there were seven studies with 1,112 cases and 1,233 controls on cervical cancer [1824] and 10 studies with 5,637 cases and 9,267 controls on ovarian cancer [25, 2731]. The main characteristics of studies included in the present meta-analysis are presented in Table I. Of all the eligible studies, four were conducted in Asian, two were in Caucasians, and one was in mixed for cervical cancer; eight were conducted in Caucasians and two were in mixed for ovarian cancer. Twelve studies were population-based and four were hospital-based studies. One study in the present meta-analysis did not state the source of controls. Four genotyping methods were used, including AS-PCR, PCR-RFLP, PyrosequencingTM, and TaqMan assay. The genotype distributions among the controls in two studies were not consistent with HWE on ovarian cancer (Table I).

Table I.

Characteristics of studies included in the meta-analysis

First author (year)Country (ethnicity)SOCGenotyping techniqueCase/controlCasesControlsMAFsHWE
GenotypesAllelesGenotypesAlleles
CCCTTTCTCCCTTTCT
Cervical cancer
He (2008)China (Asian)PBAS-PCR200/20017719437327182171381190.0470.391
Xiao (2010)China (Asian)PBPCR-RFLP158/16482591722393115418271570.1730.097
Settheetham-Ishida (2011)Thailand (Asian)PBPCR-RFLP111/11810110021210106120224120.0500.560
Pérez (2013)Argentina (Caucasian)PBSequencing117/205505611156787895322511590.3870.730
Djansugurova (2013)Kazakhstan (Caucasian)PBAS-PCR217/160140572033797124324280400.1250.278
Colacino-Silva (2017)Brazil (Mixed)HBPCR-RFLP77/73432861144036307102440.3010.837
Al-Harbi (2017)Saudi Arabia (Asian)NSPCR-RFLP232/3137912627284180126145423972290.3650.977
Ovarian cancer
Auranen (2005a)UK (Caucasian)PBTaqMan1039/2614427468144132275610461231337333618920.3610.394
Auranen (2005b)USA (Caucasian)PBTaqMan270/34412511431364176130174404342540.3690.110
Auranen (2005c)Danish (Caucasian)PBTaqMan361/8911441684945626635839413911106720.3770.079
Webb (2005)Australia (Caucasian)HBPCR543/11252292387669639043853814914168340.3710.420
Beesley (2007a)Australia (Caucasian)PBPCR-RFLP504/9722072237463737137047113112117330.3770.326
Beesley (2007b)Australia (Caucasian)PBPCR-RFLP731/7472913391019215412883511089275670.3790.949
Quaye (2009)UK-USA-DK (Caucasian)PBSequencing1332/20245456121751702962784958282252615220.3760.695
Gonzalez-Hormazaba (2012)Chile (Mixed)PBTaqMan87/57045321012252335209238792610.2240.171
Monteiro (2014)Brazil (Mixed)HBPCR-RFLP70/703233597433233597430.3070.023
Michalska (2016)Poland (Caucasian)HBPCR-RFLP700/7001803401807007001503502006507500.5350.892

SOC: source of control; PB: population-based; HB: hospital-based; NA: not stated; PCR: polymerase chain reaction; ASPCR: allele-specific PCR; RFLP: restriction fragment length polymorphism; MAF: minor allele frequency; HWE: Hardy–Weinberg equilibrium

Fig. 1.
Fig. 1.

Flow diagram of selection of studies included in the current meta-analysis

Citation: Interventional Medicine and Applied Science IMAS 2020; 10.1556/1646.11.2019.21

Quantitative synthesis

Table II listed the main results of the meta-analysis of XRCC3 18067 C>T polymorphism with cervical and ovarian cancers risk. When all the eligible studies were pooled into meta-analysis, the results showed that XRCC3 18067 C>T polymorphism was not significantly associated with increased risk of cervical and ovarian cancers under all genetic models genetic models, i.e., allele (T vs. C: OR = 1.014, 95% CI = 0.930–1.106, p = 0.745), homozygote (TT vs. CC: OR =1.010, 95% = CI 0.855–1.194, p = 0.906), heterozygote (TC vs. CC: OR = 0.967, 95% CI = 0.876–1.067, p = 0.530), dominant (TT + TC vs. CC: OR = 0.993, 95% CI = 0.889–1.108, p = 0.897), and recessive (TT vs. TC + CC: OR = 1.028, 95% CI = 0.894–1.183, p = 0.700).

Table II

Results of the association of XRCC3 18067 C>T polymorphism with cervical and ovarian cancer risks

SubgroupGenetic modelType of modelHeterogeneityORPublication bias
I2 (%)PHOR95% CIZtestPORPBeggsPEggers
OverallT vs. CRandom61.030.0011.0140.930–1.1060.3260.7450.0910.112
TT vs. CCRandom51.700.0091.0100.855–1.1940.1180.9060.1620.079
TC vs. CCRandom39.280.0490.9670.876–1.067−0.6700.5300.2320.151
TT + TC vs. CCRandom54.910.0030.9930.889–1.108−0.1290.8970.2320.140
TT vs. TC + CCRandom43.090.0341.0280.894–1.1830.3850.7000.2240.099
Cervical cancerT vs. CRandom73.820.0011.2230.897–1.6691.2720.2031.0000.901
TT vs. CCRandom68.440.0071.4560.723–2.9321.0530.2920.7070.376
TC vs. CCFixed26.840.2241.3001.066–1.5852.5960.0090.5480.242
TT + TC vs. CCRandom58.550.0251.2700.935–1.7261.5300.1260.7630.452
TT vs. TC + CCRandom64.540.0151.3090.693–2.4700.8290.4070.4520.225
AsianT vs. CFixed60.390.0561.3021.076–1.5762.7160.0071.0000.862
TT vs. CCFixed58.940.0881.4570.918–2.3141.5950.1111.0000.446
TC vs. CCFixed14.620.3191.4411.113–1.8672.7680.0060.3080.474
TT + TC vs. CCFixed36.180.1951.4691.148–1.8803.0550.0020.7340.666
TT vs. TC + CCFixed61.310.0751.1650.754–1.8010.6890.4911.0000.375
CaucasiansT vs. CRandom91.870.001.2530.500–3.1380.4810.630NANA
TT vs. CCRandom89.450.0021.4840.188–11.7300.3740.708NANA
TC vs. CCFixed45.460.1761.2340.873–1.7431.1930.233NANA
TT + TC vs. CCRandom83.940.0131.2480.551–2.8260.5320.595NANA
TT vs. TC + CCRandom88.240.0041.4250.210–9.6550.3630.716NANA
Ovarian cancerT vs. CFixed4.190.4020.9560.910–1.003−1.8300.0670.2100.554
TT vs. CCFixed31.260.1580.9420.850–1.045−1.1300.2590.5910.313
TC vs. CCFixed0.000.6620.9040.841–0.972−2.7250.0061.0000.929
TT + TC vs. CCFixed0.000.5040.9140.853–0.979−2.5690.0101.0000.849
TT vs. TC + CCFixed25.210.2111.0100.994–1.092−0.1330.8940.3710.209
CaucasiansT vs. CFixed0.000.7630.9480.902–0.996−2.1370.0331.0000.171
TT vs. CCFixed0.000.7910.9220.831–1.024−1.5140.1300.9010.445
TC vs. CCFixed0.000.5670.8980.834–0.967−2.8530.0040.3860.221
TT + TC vs. CCFixed0.000.6380.9050.844–0.970−2.8180.0050.3860.133
TT vs. TC + CCFixed0.000.8040.9770.888–1.074−0.4800.6310.9010.963

OR: odds ratio; CI: confidence interval; NA: not applicable

The studies were further stratified by cancer type and ethnicity. When stratified by cancer, there was a significant association between XRCC3 18067 C>T polymorphism and increased risk of cervical cancer under the heterozygote model (TC vs. CC: OR = 1.00, 95% CI = 1.066–1.585, p = 0.009; Fig. 2A). Moreover, the XRCC3 18067 C>T polymorphism was significantly associated with increased risk of ovarian cancer under two genetic models, i.e., heterozygote (TC vs. CC: OR = 0.904, 95% CI = 0.841–0.972, p = 0.006) and dominant (TT + TC vs. CC: OR = 0.914, 95% CI = 0.853–0.979, p = 0.010; Fig. 2B).

Fig. 2.
Fig. 2.

Forest plots for association of XRCC3 Thr241Met polymorphism with cervical cancer and ovarian cancer. A: cervical cancer (heterozygote model: TC vs. CC); B: ovarian cancer (dominant model: TT + TC vs. CC)

Citation: Interventional Medicine and Applied Science IMAS 2020; 10.1556/1646.11.2019.21

Subgroup analysis by ethnicity showed that there was a significant association between XRCC3 18067 C>T polymorphism and cervical cancer in Asian under three genetic models, i.e., model (T vs. C: OR = 1.302, 95% CI = 1.076–1.576, p = 0.007), heterozygote (TC vs. CC: OR = 1.441, 95% CI = 1.113–1.867, p = 0.006) and dominant (TT + TC vs. CC: OR = 1.469, 95% CI =1.148–1.880, p = 0.002), but not in Caucasians. Moreover, subgroup analysis showed that there was a significant association between XRCC3 18067 C>T polymorphism and increased risk of ovarian cancer in Caucasians under two genetic models, i.e., heterozygote (TC vs. CC: OR = 0.898, 95% CI = 0.834–0.967, p = 0.004) and dominant (TT + TC vs. CC: OR = 0.905, 95% CI=0.844–0.970, p = 0.005). In the subgroup analyses by ethnicity, no studies were performed for ovarian cancer in Asians suggesting that our results might be not applicable for these populations.

Test of heterogeneity and sensitivity analyses

For cervical cancer, statistical significant heterogeneity among studies under four genetic models was observed when all eligible studies were pooled into the meta-analysis. However, the heterogeneity test showed that there was no significant heterogeneity in terms of the XRCC3 18067 C>T polymorphism association with ovarian cancer. Therefore, to explore the potential sources of heterogeneity across studies, we performed subgroup analysis under all models. To explore the sources of heterogeneity, we conducted subgroup analyses by ethnicity, genotyping methods, and source of controls. Subgroup analyses by ethnicity showed that the heterogeneity was still significant in Caucasians populations, indicating that ethnicity was the major source that contributed to heterogeneity for cervical cancer. In addition, we have performed sensitivity analyses to assess the influence of each individual study on the pooled ORs by sequential omission of individual studies. The results suggested that the sequential omission of individual studies did not significantly affect the pooled ORs for the XRCC3 18067 C>T polymorphism, the stability of the current meta-analysis results. For ovarian cancer, sensitivity analysis was further performed by excluded one HWE-violating study. However, the XRCC3 18067 C>T polymorphism association with ovarian cancer risk was not influenced by omitting the study.

Publication bias

Both Begg’s funnel plot and Egger’s test were performed to assess the publication bias of literatures in all genetic models and by ethnicity. The shape of the funnel plot did not reveal any evidence of obvious asymmetry in overall and by cancer type (Fig. 3). Then, we used the Egger’s test to provide statistical evidence of funnel plot symmetry. The results still did not suggest any evidence of publication bias in overall, by cancer type and ethnicity (Table II).

Fig. 3.
Fig. 3.

Begg’s funnel plot of publication bias test for XRCC3 Thr241Met polymorphism in overall under the allele model (A vs. G)

Citation: Interventional Medicine and Applied Science IMAS 2020; 10.1556/1646.11.2019.21

Discussion

The XRCC3 gene is one of the major genes involved in the restoration phase of DNA damage [14]. More than 300 validated single nucleotide polymorphisms in the XRCC3 gene were reported in the dbSNP database among them, 18067 C>T (rs861539) in XRCC3 codon 241 (Thr241Met) was the most extensively studied in different malignancies [16, 17]. There is evidence that XRCC3 18067 C>T polymorphism is a functional variant with potential to affect the capacity of DNA repair activity [15]. The association of this polymorphism with cervical and ovarian cancer risk has been assessed in several studies, which showed inconclusive results.

In the present meta-analysis, we examined the association of XRCC3 18067 C>T polymorphism with cervical and ovarian cancers risk. We found that the XRCC3 18067 C>T polymorphism was significantly associated with ovarian cancer risk. We also observed a significant relationship between the XRCC3 18067 C>T polymorphism and ovarian cancer in Caucasians. However, our results were inconsistent with previous meta-analysis. Yan et al. [16] in a meta-analysis of seven studies with 3,635 cases and 5,473 controls suggested that the XRCC3 18067 C>T polymorphism may not be associated with ovarian cancer in all five genetic models in overall and Caucasians population. In 2013, Qin et al. [17] in a meta-analysis of five case–control studies with a total of 806 cervical cancer cases and 850 controls estimated the association between XRCC3 18067 C>T polymorphism and cervical cancer risk. The results showed a significant association that XRCC3 18067 C>T polymorphism may contribute to the susceptibility of cervical cancer only under heterozygote model. The association was also confirmed by our meta-analysis, which involved seven studies with 1,112 cases and 1,233 controls only in the heterozygote model. Moreover, the previous [16] and the current meta-analyses findings confirmed that XRCC3 18067 C>T polymorphism is associated with the risk of cervical cancer among Asians, but not among Caucasians, suggesting that this polymorphism may modify the risk of cervical cancer in different ethnicities. Compared to the previous meta-analyses, the included studies to the current meta-analysis are most precise and comprehensive attributing to the largest sample size and accumulative meta-analysis method. Hence, our results are more precise and comprehensive on the association of XRCC3 18067 C>T polymorphism with cervical and ovarian cancers.

The heterogeneity plays an important role when performing meta-analysis and finding the source of heterogeneity is very important for the final result of meta-analysis. There were several sources bringing in heterogeneity, such as study design, age, sex distribution, sample size, genotyping methods, and ethnicity. Obviously, there was potential to moderate level heterogeneity in the current meta-analysis. Thus, we have performed meta-regression analysis to find source of heterogeneity. The heterogeneity between our studies was significantly reduced in the analysis of the cancer type and by ethnicity subgroups, indicating that the effect of XRCC3 18067 C>T polymorphism may be modified by cancer etiology and ethnicity backgrounds.

The main advantage of our meta-analysis that publication bias was not observed, which indicates that the whole pooled results, may be unbiased. However, several limitations in this meta-analysis should be addressed. First, the included studies only provided data toward Asians and Caucasians. The data regarding other ethnicities such as Africans were not found. Therefore, we cannot generalize these findings to every ethnic group. Second, there were only seven studies with a total of 1,112 cases and 1,233 controls that were finally included into the meta-analysis for cervical cancer. The number of included studies was relatively limited, which may increase the risk of bias in the meta-analysis, especially in the subgroup analysis by ethnicity. Thus, more studies with a larger sample size from different ethnicities should be performed in the future. Third, we have included only published studies in the meta-analysis, and non-significant or negative findings may be unpublished. Hence, any preexisting publication bias will be reflected in the findings; however, the statistical data may not show it. Fifth, the summary ORs were based on individual unadjusted estimates, while a more precise analysis might be performed if detailed individual data were available, which could allow for an adjusted estimation by age, obesity, hormone replacement therapy, reproductive history and infertility, gynecologic surgery, and environment factors. Lack of information for data analysis may cause serious confounding bias. Finally, gene–gene and gene–environment interactions may have influenced our findings, as ovarian and cervical cancers are mainly caused by genetic and environmental factors. However, these interactions were not tested in the current meta-analysis because of the lack of sufficient data.

In summary, our meta-analysis demonstrated that the XRCC3 18067 C>T polymorphism may be associated with increased risk of cervical and ovarian cancers. Moreover, the XRCC3 18067 C>T polymorphism might be a potential risk factor for cervical cancer among Asians and for ovarian cancer among Caucasians. However, to validate this association and our findings further, large and well-designed epidemiological studies are warranted.

Authors’ contribution

MK-Z and MM contributed to conception of the study, writing and editing the paper, and validation of the final version. HA, AH, and R-ST searched literature, selected study, and drafted the article. HN analyzed the data. HN and AJ contributed to interpretation of data, writing and editing of the paper, and validation of the final version of the manuscript.

Conflict of interest

The authors declare no competing interest.

Acknowledgements

The authors would like to thank Prof. Seyed Mehdi Kalantar for his intellectual guidance.

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    Ferguson LR , Chen H , Collins AR , Connell M , Damia G , Dasgupta S , Malhotra M , Meeker AK , Amedei A , Amin A , Ashraf SS , Aquilano K , Azmi AS , Bhakta D , Bilsland A , Boosani CS , Chen S , Ciriolo MR , Fujii H , Guha G , Halicka D , Helferich WG , Keith WN , Mohammed SI , Niccolai E , Yang X , Honoki K , Parslow VR , Prakash S , Rezazadeh S , Shackelford RE , Sidransky D , Tran PT , Yang ES , Maxwell CA : Genomic instability in human cancer: Molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition. Semin Cancer Biol 35, S5S24 (2015)

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  • 11.

    He X-F , Liu L-R , Wei W , Liu Y , Su J , Wang SL , Shen XL , Yang XB : Association between the XPG Asp1104His and XPF Arg415Gln polymorphisms and risk of cancer: A meta-analysis. Veitia RA, ed. PLoS One 9, e88490 (2014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Zhu M-L , Wang M , Cao Z-G , He J , Shi TY , Xia KQ , Wei Q : Association between the ERCC5 Asp1104His polymorphism and cancer risk: A meta-analysis. PLoS One 7, e36293 (2012)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Namazi A , Abedinzadeh M , Nourbaksh P , Neamatzadeh H : Association between the XRCC3 Thr241Met polymorphism and risk of colorectal cancer: A meta analysis of 5, 193 cases and 6, 645 controls. Asian Pac J Cancer Prev 16, 22632268 (2015)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Sobhan MR , Forat Yazdi M , Mazaheri M , Zare Shehneh M , Neamatzadeh H : Association between the DNA repair gene XRCC3 rs861539 polymorphism and risk of osteosarcoma: A systematic review and meta-analysis. Asian Pac J Cancer Prev 18, 549555 (2017)

    • Search Google Scholar
    • Export Citation
  • 15.

    Mucha B , Przybylowska-Sygut K , Dziki AJ , Dziki L , Sygut A , Majsterek I : Association of Thr241Met polymorphism of XRCC3 gene with risk of colorectal cancer in the Polish population. Pol J Pathol 64, 185190 (2013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Yan Y , Liang H , Li R , Xie L , Li M , Li S , Qin X : XRCC3 Thr241Met polymorphism and ovarian cancer risk: A meta-analysis. Tumour Biol 35(3), 27112715 (2014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Qin L-Y , Chen X , Li P , Yang Z , Mo W-N : Association between the XRCC3 Thr241Met polymorphism and cervical cancer risk: A meta-analysis. Asian Pac J Cancer Prev 14, 67036707 (2014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    He X , Ye F , Zhang J , Cheng Q , Shen J , Chen H : Susceptibility of XRCC3, XPD, and XPG genetic variants to cervical carcinoma. Pathobiology 75, 356363 (2008)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Xiao H : The association between XRCC3 gene polymorphism and cervical cancer risk. Jilin Med 31, 27312732 (2009)

  • 20.

    Settheetham-Ishida W , Yuenyao P , Natphopsuk S , Settheetham D , Ishida T : Genetic risk of DNA repair gene polymorphisms (XRCC1 and XRCC3) for high risk human papillomavirus negative cervical cancer in Northeast Thailand. Asian Pac J Cancer Prev 12, 963966 (2011)

    • Search Google Scholar
    • Export Citation
  • 21.

    Pérez LO , Crivaro A , Barbisan G , Poleri L , Golijow CD : XRCC2 R188H (rs3218536), XRCC3 T241M (rs861539) and R243H (rs77381814) single nucleotide polymorphisms in cervical cancer risk. Pathol Oncol Res 19, 553558 (2013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Djansugurova LB , Perfilyeva A V , Zhunusova GS , Djantaeva KB , Iksan OA , Khussainova EM : The determination of genetic markers of age-related cancer pathologies in populations from Kazakhstan. Front Genet 4, 70 (2013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Colacino-Silva F , Ferreira De Oliveira Kleine JP , Salzgeber MB , de Aquino Castro R , Girão MJBC , da Silva IDCG , D’Amora P : Polymorphic DNA repair genes XRCC1 and XRCC3 and the risk for cervical cancer in brazilian patients [Polimorfismos Nos Genes de Reparo Do DNA XRCC1 E XRCC3 E O Risco Para O Câncer Cervical Uterino Em Pacientes Brasileiras]. Braz J Oncol 13 (2017)

    • Search Google Scholar
    • Export Citation
  • 24.

    Al-Harbi NM , Bin Judia SS , Mishra KN , Shoukri MM , Alsbeih GA : Genetic predisposition to cervical cancer and the association with XRCC1 and TGFB1 polymorphisms. Int J Gynecol Cancer 27, 19491956 (2017)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Auranen A , Song H , Waterfall C , Dicioccio RA , Kuschel B , Kjaer SK , Hogdall E , Hogdall C , Stratton J , Whittemore AS , Easton DF , Ponder BA , Novik KL , Dunning AM , Gayther S , Pharoah PD : Polymorphisms in DNA repair genes and epithelial ovarian cancer risk. Int J Cancer 117, 611618 (2005)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Webb PM , Hopper JL , Newman B , Chen X , Kelemen L , Giles GG , Southey MC , Chenevix-Trench G , Spurdle AB : Double-strand break repair gene polymorphisms and risk of breast or ovarian cancer. Cancer Epidemiol Biomarkers Prev 14, 319323 (2005)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Beesley J , Jordan SJ , Spurdle AB , Song H , Ramus SJ , Kjaer SK , Hogdall E , DiCioccio RA , McGuire V , Whittemore AS , Gayther SA , Pharoah PD , Webb PM , Chenevix-Trench G : Association between single-nucleotide polymorphisms in hormone metabolism and DNA repair genes and epithelial ovarian cancer: Results from two Australian studies and an additional validation set. Cancer Epidemiol Biomarkers Prev 16, 25572565 (2007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Gonzalez-Hormazabal P , Reyes JM , Blanco R , Bravo T , Carrera I , Peralta O , Gomez F , Waugh E , Margarit S , Ibañez G , Santos JL , Jara L : The BARD1 Cys557Ser variant and risk of familial breast cancer in a South-American population. Mol Biol Rep 39, 80918098 (2012)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Monteiro MS , Vilas Boas DB , Gigliotti CB , Salvadori DMF : Association among XRCC1, XRCC3, and BLHX gene polymorphisms and chromosome instability in lymphocytes from patients with endometriosis and ovarian cancer. Genet Mol Res 13, 636648 (2014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Michalska MM , Samulak D , Romanowicz H , Jabłoński F , Smolarz B : Association between single nucleotide polymorphisms (SNPs) of XRCC2 and XRCC3 homologous recombination repair genes and ovarian cancer in Polish women. Exp Mol Pathol 100, 243247 (2016)

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    • Search Google Scholar
    • Export Citation
  • 31.

    Quaye L , Tyrer J , Ramus SJ , Song H , Wozniak E , DiCioccio RA , McGuire V , Høgdall E , Høgdall C , Blaakaer J , Goode EL , Schildkraut JM , Easton DF , Krüger-Kjaer S , Whittemore AS , Gayther SA , Pharoah PD : Association between common germline genetic variation in 94 candidate genes or regions and risks of invasive epithelial ovarian cancer. PLoS One 4, e5983 (2009)

    • Crossref
    • Search Google Scholar
    • Export Citation

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    Kamali M , Hamadani S , Neamatzadeh H , Mazaheri M , Zare Shehneh M , Modaress Gilani M , Haghighi F : Association of XRCC2 rs3218536 polymorphism with susceptibility of breast and ovarian cancer: A systematic review and meta-analysis. Asian Pac J Cancer Prev 18,17431749 (2017)

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    Chen D , Enroth S , Liu H , Sun Y , Wang H , Yu M , Deng L , Xu S , Gyllensten U : Pooled analysis of genome-wide association studies of cervical intraepithelial neoplasia 3 (CIN3) identifies a new susceptibility locus. Oncotarget 7, 4221642224 (2016)

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    Haruta S , Furukawa N , Yoshizawa Y , Tsunemi T , Nagai A , Kawaguchi R , Tanase Y , Yoshida S , Kobayashi H : Molecular genetics and epidemiology of epithelial ovarian cancer (Review). Oncol Rep 26, 13471356 (2011)

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    Ferguson LR , Chen H , Collins AR , Connell M , Damia G , Dasgupta S , Malhotra M , Meeker AK , Amedei A , Amin A , Ashraf SS , Aquilano K , Azmi AS , Bhakta D , Bilsland A , Boosani CS , Chen S , Ciriolo MR , Fujii H , Guha G , Halicka D , Helferich WG , Keith WN , Mohammed SI , Niccolai E , Yang X , Honoki K , Parslow VR , Prakash S , Rezazadeh S , Shackelford RE , Sidransky D , Tran PT , Yang ES , Maxwell CA : Genomic instability in human cancer: Molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition. Semin Cancer Biol 35, S5S24 (2015)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    He X-F , Liu L-R , Wei W , Liu Y , Su J , Wang SL , Shen XL , Yang XB : Association between the XPG Asp1104His and XPF Arg415Gln polymorphisms and risk of cancer: A meta-analysis. Veitia RA, ed. PLoS One 9, e88490 (2014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Zhu M-L , Wang M , Cao Z-G , He J , Shi TY , Xia KQ , Wei Q : Association between the ERCC5 Asp1104His polymorphism and cancer risk: A meta-analysis. PLoS One 7, e36293 (2012)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Namazi A , Abedinzadeh M , Nourbaksh P , Neamatzadeh H : Association between the XRCC3 Thr241Met polymorphism and risk of colorectal cancer: A meta analysis of 5, 193 cases and 6, 645 controls. Asian Pac J Cancer Prev 16, 22632268 (2015)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Sobhan MR , Forat Yazdi M , Mazaheri M , Zare Shehneh M , Neamatzadeh H : Association between the DNA repair gene XRCC3 rs861539 polymorphism and risk of osteosarcoma: A systematic review and meta-analysis. Asian Pac J Cancer Prev 18, 549555 (2017)

    • Search Google Scholar
    • Export Citation
  • 15.

    Mucha B , Przybylowska-Sygut K , Dziki AJ , Dziki L , Sygut A , Majsterek I : Association of Thr241Met polymorphism of XRCC3 gene with risk of colorectal cancer in the Polish population. Pol J Pathol 64, 185190 (2013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Yan Y , Liang H , Li R , Xie L , Li M , Li S , Qin X : XRCC3 Thr241Met polymorphism and ovarian cancer risk: A meta-analysis. Tumour Biol 35(3), 27112715 (2014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Qin L-Y , Chen X , Li P , Yang Z , Mo W-N : Association between the XRCC3 Thr241Met polymorphism and cervical cancer risk: A meta-analysis. Asian Pac J Cancer Prev 14, 67036707 (2014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    He X , Ye F , Zhang J , Cheng Q , Shen J , Chen H : Susceptibility of XRCC3, XPD, and XPG genetic variants to cervical carcinoma. Pathobiology 75, 356363 (2008)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Xiao H : The association between XRCC3 gene polymorphism and cervical cancer risk. Jilin Med 31, 27312732 (2009)

  • 20.

    Settheetham-Ishida W , Yuenyao P , Natphopsuk S , Settheetham D , Ishida T : Genetic risk of DNA repair gene polymorphisms (XRCC1 and XRCC3) for high risk human papillomavirus negative cervical cancer in Northeast Thailand. Asian Pac J Cancer Prev 12, 963966 (2011)

    • Search Google Scholar
    • Export Citation
  • 21.

    Pérez LO , Crivaro A , Barbisan G , Poleri L , Golijow CD : XRCC2 R188H (rs3218536), XRCC3 T241M (rs861539) and R243H (rs77381814) single nucleotide polymorphisms in cervical cancer risk. Pathol Oncol Res 19, 553558 (2013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Djansugurova LB , Perfilyeva A V , Zhunusova GS , Djantaeva KB , Iksan OA , Khussainova EM : The determination of genetic markers of age-related cancer pathologies in populations from Kazakhstan. Front Genet 4, 70 (2013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Colacino-Silva F , Ferreira De Oliveira Kleine JP , Salzgeber MB , de Aquino Castro R , Girão MJBC , da Silva IDCG , D’Amora P : Polymorphic DNA repair genes XRCC1 and XRCC3 and the risk for cervical cancer in brazilian patients [Polimorfismos Nos Genes de Reparo Do DNA XRCC1 E XRCC3 E O Risco Para O Câncer Cervical Uterino Em Pacientes Brasileiras]. Braz J Oncol 13 (2017)

    • Search Google Scholar
    • Export Citation
  • 24.

    Al-Harbi NM , Bin Judia SS , Mishra KN , Shoukri MM , Alsbeih GA : Genetic predisposition to cervical cancer and the association with XRCC1 and TGFB1 polymorphisms. Int J Gynecol Cancer 27, 19491956 (2017)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Auranen A , Song H , Waterfall C , Dicioccio RA , Kuschel B , Kjaer SK , Hogdall E , Hogdall C , Stratton J , Whittemore AS , Easton DF , Ponder BA , Novik KL , Dunning AM , Gayther S , Pharoah PD : Polymorphisms in DNA repair genes and epithelial ovarian cancer risk. Int J Cancer 117, 611618 (2005)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Webb PM , Hopper JL , Newman B , Chen X , Kelemen L , Giles GG , Southey MC , Chenevix-Trench G , Spurdle AB : Double-strand break repair gene polymorphisms and risk of breast or ovarian cancer. Cancer Epidemiol Biomarkers Prev 14, 319323 (2005)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Beesley J , Jordan SJ , Spurdle AB , Song H , Ramus SJ , Kjaer SK , Hogdall E , DiCioccio RA , McGuire V , Whittemore AS , Gayther SA , Pharoah PD , Webb PM , Chenevix-Trench G : Association between single-nucleotide polymorphisms in hormone metabolism and DNA repair genes and epithelial ovarian cancer: Results from two Australian studies and an additional validation set. Cancer Epidemiol Biomarkers Prev 16, 25572565 (2007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Gonzalez-Hormazabal P , Reyes JM , Blanco R , Bravo T , Carrera I , Peralta O , Gomez F , Waugh E , Margarit S , Ibañez G , Santos JL , Jara L : The BARD1 Cys557Ser variant and risk of familial breast cancer in a South-American population. Mol Biol Rep 39, 80918098 (2012)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Monteiro MS , Vilas Boas DB , Gigliotti CB , Salvadori DMF : Association among XRCC1, XRCC3, and BLHX gene polymorphisms and chromosome instability in lymphocytes from patients with endometriosis and ovarian cancer. Genet Mol Res 13, 636648 (2014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Michalska MM , Samulak D , Romanowicz H , Jabłoński F , Smolarz B : Association between single nucleotide polymorphisms (SNPs) of XRCC2 and XRCC3 homologous recombination repair genes and ovarian cancer in Polish women. Exp Mol Pathol 100, 243247 (2016)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Quaye L , Tyrer J , Ramus SJ , Song H , Wozniak E , DiCioccio RA , McGuire V , Høgdall E , Høgdall C , Blaakaer J , Goode EL , Schildkraut JM , Easton DF , Krüger-Kjaer S , Whittemore AS , Gayther SA , Pharoah PD : Association between common germline genetic variation in 94 candidate genes or regions and risks of invasive epithelial ovarian cancer. PLoS One 4, e5983 (2009)

    • Crossref
    • Search Google Scholar
    • Export Citation