Association of XRCC1 rs1799782 and ERCC2 rs13181 Polymorphisms with Glioma Risk: A Systematic Review and Meta-Analysis

of nervous system hereditary factors roles in the development of gliomas with mutations and single nucleotide polymorphisms (SNPs) prominent among the genetic changes. this systematic review and meta-analysis assess the association of XRCC1 (rs1799782) and ERCC2 (rs13181) gene polymorphisms and glioma risk. Of the eleven articles on XRCC1 rs1799782, nine were based on Asian populations. Of the studies on ERCC2 rs13181, ve were based on Caucasian populations, four were based on Asian populations, and one was based on both Caucasians and Asians. Only one study was conducted using a Latin-American population (Brazilian) to evaluate the XRCC1 rs1799782 SNP (Table 2).


Background
Gliomas are the most common primary tumors of the central nervous system, representing approximately 80% of all malignant central nervous system tumors. There are four histological subtypes of which astrocytomas are the most prevalent. According to the World Health Organization (WHO) 2010 classi cation, astrocytomas can be strati ed into four grades with grades I and II being low grade or benign and grades III and IV being high grade or malignant. The latter grades are highly aggressive and present a poor prognosis, even when adequately treated with surgical resection, chemotherapy, and radiotherapy [1][2][3][4][5].
Many environmental and lifestyle factors are considered to be associated with increased risk for the development of gliomas, including some occupations, exposure to ionizing radiation, and smoking, among others. Hereditary factors may also play an important role in the development of gliomas as genetic studies have identi ed several genes that may be associated with the onset and/or growth of these tumors [5][6][7].
Among several genetic changes, mutations and polymorphisms stand out and may result in inter-individual differences in susceptibility to diseases and response variations to drugs and environmental factors. Single nucleotide polymorphisms (SNPs) are the simplest and most common form of polymorphism, characterized as the change of a single nitrogenous base at a frequency greater than 1% and is sometimes associated with the insertion or deletion of one or more nucleotides [8].
Multiple genes encode proteins involved in correcting possible DNA errors, including the X-ray repair crosscomplementing group 1 (XRCC1) and excision repair cross-complementation group 2 (ERCC2). XRCC1 encodes proteins that repair base excisions and single-strand breaks in DNA while the ERCC2 gene encodes proteins that are involved in transcription-coupled nucleotide excision repair. These represent three of the main mechanisms of DNA repair, preventing mutations that can lead to the development of cancer in different organs. However, the presence of SNPs in these genes can alter or inhibit repair mechanisms, resulting in mutations and increased risks for the development of gliomas [8,9].
Numerous studies have been published on these genes and their various polymorphisms, but they often contain con icting results. There is a need for greater understanding of the pathways involved in the regulation of the aberrant growth of glial neoplasms. This need led us to conduct a systematic review of the literature and to perform a meta-analysis regarding XRCC1 rs1799782 and ERCC2 rs13181 polymorphisms in effort to determine their association with the risk of healthy individuals developing gliomas.

Methods
This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) standards and used a targeted search to identify and retrieve relevant articles [9]. The Population, Intervention, Comparison, Outcome and Study design (PICOS) model was used for developing the inclusion criteria and search terms. This review was recorded at PROSPERO International prospective register of systematic reviews, ID 196173.

Literature search
The PUBMED and EMBASE databases were searched for case-controls articles published between January 2005 and April 2020 with an association of XRCC1 rs1799782 or ERCC2 rs13181 (intervention) and increased or decreased risk (comparison) of developing gliomas (outcome) in healthy individuals (population). The following search terms and Booleans were used: ("SNP" OR "polymorphism" OR "single nucleotide polymorphism") AND ("gliomas" OR "glioma" OR "astrocytoma" OR "glioblastoma") AND ("XRCC1 gene" OR "ERCC2 gene"). The search process included only articles in English.

Selection Criteria
The inclusion criteria were: a) case-control studies, b) articles on the risk of developing gliomas for participants free from the disease, c) studies of human beings, and d) studies on SNPs of the XRCC1 and ERCC2 genes. The exclusion criteria were: a) irrelevant studies, b) repeated publications, c) articles with only abstract being available, d) case reports/case series, e) editorials, f) comments, g) literature reviews, h) polymorphisms in tumors other than gliomas, i) polymorphisms of the XRCC1 gene other than rs1799782, j) polymorphisms of the ERCC2 gene other than rs13181, and l) letters to the editor.
To expand the scope of the evaluation, all articles were inspected by two experienced investigators. The data were extracted and compiled by one reviewer using a standardized abstraction form and independently veri ed by the second reviewer. In the event of any disagreements, the issues were resolved by consulting with two additional reviewers for consensus.

Quality assesment
The quality of the methodology used in the published reports included in our study was assessed using the Quality Assessment Tool for Quantitative Studies [10]. This tool globally rated the studies as weak, moderate, or strong by evaluating potential selection bias, study design, confounding factors, concealment, data collection methodology, and withdrawal and dropout reports. Component ratings were scored according to the criteria speci ed in the dictionary accompanying the assessment tool [10]. The global quality assessment rating of each study was determined by evaluating the six component classi cations [10]. The studies without any weak ratings and with at least four strong ratings were considered strong. Those with one weak and less than four strong ratings were considered moderate. Finally, those with two or more weak ratings were considered weak.

Data analysis
Statistical analysis was conducted using the META-MAR V2.7.0 meta-analysis calculator and p-values < 0.05 were considered statistically signi cant. Dichotomous data are presented as odds ratios (OR) with a 95% con dence interval (CI). Statistical heterogeneity was measured using the I 2 test and I 2 > 50% were regarded as high heterogeneity. Funnel plots, Begg (BT) and Egger Tests (ET) were used to assess publication bias with signi cance level established at p < 0.1.

Results
A total of 933 published articles were identi ed by searching the PUBMED and EMBASE databases; however, only 160 of the articles met the inclusion criteria. After being evaluated by the two reviewers, 139 studies were excluded and only 21 were included in the systematic review. Ten of the included papers were on ERCC2 rs13181 and eleven were on XRCC1 rs1799782 (Fig. 1). All the studies included in our analysis were considered to be of moderate quality according to the evaluation tool (Table 1).  All the published articles evaluated in our study used serum samples to investigate the peripheral nervous system except one, which used oral mucosa specimens. The method used to detect polymorphisms for all the published studies was polymerase chain reaction (Table 2).
Of the studies on XRCC1 rs1799782, four reported no relationship with the risk of developing gliomas while the other seven reported an association, especially in the presence of the TT genotype and/or the Trp allele ( Table 2). Of the studies on ERCC2 rs13181, six reported no association with the risk of gliomas, two reported an increased risk, and the other two reported a decreased risk in the presence of the AGC haplotype or C allele (Table 3). Five articles reported an increased risk for gliomas for Asian populations in the presence of XRCC1 rs1799782 and two articles reported an increase in the presence of ERCC2 rs13181. For Caucasian populations, two articles reported an increased risk for gliomas in the presence of the XRCC1 rs1799782 SNP and two articles reported a decreased risk in the presence of ERCC2 rs13181 ( Table 2 and Table 3).
The meta-analysis identi ed an increased risk of gliomas for only the TT genotype of XRCC1 rs1799782 (OR:  (Fig. 2 through Fig. 7).
Among the genotypes of the polymorphisms that showed an increased risk for glioma development, only in the study in Asians with ERCC2 rs13181 AC was not possible to perform the tests of publication bias due to the small number of studies (< 3 an asymmetric distribution, denoting no publication bias (Fig. 8).

Discussion
There are four main pathways involved in repairing DNA damage, nucleotide excision repair (NER), base excision repair (BER), double-strand break repair (DSBR), and mismatch repair (MMR). XRCC1 and ERCC2 encode proteins that are involved in the BER and NER pathways, respectively, and polymorphisms in these genes may change a cell's DNA repair e ciency. This in turn may be related to the development of several types of cancers, including lung, colorectal, breast, ovary, and thyroid cancers, esophageal carcinoma, and even brain tumors [9][10][11].
The XRCC group is an important component of the BER system, which is the predominant DNA repair pathway for small errors resulting from oxidation and alkylation damage. The proper functioning of the BER system may prevent the activation of oncogenes or the inactivation of tumor suppression genes and thereby reduce the risk of cancer development. The XRCC1 gene is located on chromosome 19q13.2-13.2, is 33 kb in size, and consists of 17 exons. The XRCC1 protein coordinates several protein-protein interactions, including those between DNA ligase III, DNA polymerase, and poly ADP-ribose polymerase, which together play an important role in DNA repair.
Our current systematic review included eleven published articles on XRCC1 rs1799782, which contained contradictory ndings. For instance, studies by Gao et al. [7], Li et al. [10], Zhou et al. [14] and Wang et al. [15] reported no association between the XRCC1 rs1799782 SNP and the risk of developing gliomas. However, other studies reported an increased risk, including those by Hu et al. [16] and Rajaraman et al. [17]. Mean while, Liu et al. [18], Xu et al. [9] and Pan et al. [12] reported an increased risk for glioma speci c for the TT genotypes in an Asian population. Custodio et al. [20] reported an increased risk for gliomas in Caucasians with the XRCC1 rs1799782 SNP (Brazilian population), but they also observed improved survival in the presence of the 194Trp allele. Finally, in the study published by Fan et al. [8] there was an increased risk for gliomas in participants that had TT or CT + TT genotypes (Table 2) [14][15][16][17][18][19][20][21][22][23][24].
Due to the discrepancies in the published results, we performed this meta-analysis and found for healthy individuals an increased risk for the development of glial tumors only in Asians with the TT genotype of the XRCC1 rs1799782 as an association was not observed with the CT and/or CT + TT genotypes. These results were similar to the meta-analyses by Li et al. [21], He et al. [22], and Zhang et al. [23]. However, in none of those studies was the data analysis broken down by observed population type [25][26][27]. Contrary to our study, a review by Sun et al. [5], reported an increased risk associated with the TT genotype in the general population, but no association when individually analyzed in the Asian and Caucasian populations [28].
Lu et al. [24] reviewed sixteen published papers and reported increased risk only for Asians with TT and TT + CT genotype in their meta-analysis. Xu et al. [25] found an increased risk only in Asians with CT + TT genotype and in both Asians and Caucasians with TT genotype. There are currently also systematic reviews in the literature that include meta-analysis and report a relationship between the XRCC1 rs1799782 polymorphism and its genotypes with the development of glial tumors [31][32][33].
The ERCC2 gene is located on chromosome 19q13.3 and encodes a protein responsible for DNA repair as part of the NER pathway. There are published reports on the relationship between some ERCC2 SNPs and the risk of systemic tumors with the most studied being ERCC2 Lys751Gln (rs13181). This polymorphism is characterized by the replacement of thymine (T) by guanine (G) at the locus 751, which changes the enzymatic activity of some encoded proteins, such as helicase, and can be associated with several types of cancers, including gastric, esophageal, hepatocellular carcinoma, non-small cell lung, prostate, skin, and bladder cancers, as well as gliomas [6]. Our current study reviewed and analyzed ten published reports that included ve based on Asian populations, four based on Caucasian populations, and one that included both populations and the genotypes studied in these reports were AC, CC, GG, and TG.
Similar to the results regarding the XRCC1 polymorphisms, the ndings for ERCC2 rs13181 polymorphisms are highly contradictory. Six reports demonstrate no relationship between ERCC2 rs13181 polymorphisms and the risk of developing glial tumors. However, the studies by Gao et al. [7] and Chen et al. [29] reported increased risks of gliomas while the reports by McKean-Cowdin [30] and Rodriguez-Hernandez et al. [11] showed a decrease risk in the presence of the AGC haplotype and C allele, respectively.
Based on meta-analysis, the AC genotypes of ERCC2 rs13181 in Asians and Caucasians and the CC genotypes in Caucasians were associated to an increased risk of gliomas. This result corroborates the ndings reported by Qian et al. [6], who reviewed fteen studies and conducted a meta-analysis [38]. These investigators reported increased risks for the development of glial cell tumors only in Asians with the CC and AC genotypes (Figs. 2 and   3).
In our current review and analysis, the GG and TG genotypes showed no relationship with the development of glial tumors, corroborating the studies by Xin et al. [31] and Zhou et al. [32] (Fig. 2 and Fig. 3). However, contrary results were described in the reviews and meta-analyses by Cui et al. [33] and Jia et al. [34], who found increased risks only in Asian populations and with the TG genotype. On the other hand, Huang et al. [35] found increased risks in the general population for patients with either TG or GG genotypes.
Although the meta-analysis shows the importance of SNPs XRCC1 rs1799782 TT, ERCC2 rs13181 AC and CC in the development of gliomas in certain populations, the high heterogeneity between studies and the presence of publication biases evidenced in some Plot Funnel, show the need for further multicenter studies with larger samples, more uniform methodologies and research with different ethnic groups in order to establish the association of these polymorphisms with the risk of developing gliomas.
The studies presented in our current review and analysis had limitations, which thereby contributed to limitations of our study. These included the fact that most all of them used only one population type, which prevents the extrapolation of the results to other ethnic groups. Furthermore, in most of the studies, the samples were collected from only a single hospital, increasing the potential for selection bias. Finally, in most of the studies the interactions between genes, environmental factors, and even the loci of the polymorphisms were not considered, which are factors that may in uence the risk of developing gliomas.

Conclusion
In the present study, TT genotypes of XRCC1 rs1799782 in Asians and ERCC2 rs13181 polymorphisms with AC genotypes in Asians and Caucasians and CC genotypes in Caucasians are associated with increased risk for gliomas that may bene t these patients with early diagnostic and therapeutic strategies.

Availability of data and materials
All data generated in this analysis are available from the corresponding author.

Competing interests
The authors declare that they have no competing interests.

Funding
No funding was obtained for this study.
Author Contributions CB and BB conceived and designed the study; FA and EJ provided study materials and tools; RJ, LC, VC , AC, EB, RO, CB BB were responsible for the collection and assembly of data, data analysis, and interpretation; FC, PV, dos AR, AL was involved in writing the manuscript; CB, BB and LH revised the manuscript.
all authors have read and approved the manuscript