The XRCC1 Arg194Trp polymorphism was associated with the risk of head and neck squamous cell carcinoma development: Results from a systematic review and meta‐analysis

Abstract Background The X‐ray repair cross complementing group 1 (XRCC1) is a DNA repair gene. Various studies have examined the association between XRCC1 Arg194Trp polymorphism and head and neck squamous cell carcinoma (HNSCC) susceptibility with contradictory results. So, this systematic review and meta‐analysis aimed to assess whether variants of this polymorphism increase the HNSCC risk or not. Recent findings Thirty three studies consisting of 14282 subjects (6012 cases and 8270 controls) were included in this meta‐analysis. Variants of XRCC1 Arg194Trp polymorphism were associated with increased HNSCC risk and the associations were significant based on heterozygous and dominant models (heterozygous model: OR = 1.182, 95%CI = 1.015–1.377, P = 0.032; homozygous model: OR = 1.274, 95%CI = 0.940–1.727, P = 0.119; dominant model: OR = 1.194, 95%CI = 1.027–1.388, P = 0.021; recessive model: OR = 1.181, 95%CI = 0.885–1.576, P = 0.119). There were significant associations between variants of this polymorphism and HNSCC risk based on Asian ethnicity under dominant model, hospital control source under different genetic models, PCR‐RFLP genotyping method under dominant model and oral cavity tumor site under heterozygous and dominant models. Objective The X‐ray repair cross complementing group 1 (XRCC1) is a DNA repair gene. Various studies have examined the association between XRCC1 Arg194Trp polymorphism and head and neck squamous cell carcinoma (HNSCC) susceptibility with contradictory results. So, this systematic review and meta‐analysis aimed to assess whether variants of this polymorphism increase the HNSCC risk or not. Methods A systematic search of the literatures published till April 2022 was conducted using Google Scholar, Scopus, PubMed, Web of Science, Cochrane Library and Embase databases. The heterogeneity was assessed with the I‐Square statistic. A random effects model or fixed effects model was used to analyze the data. Data were reported by odds ratio (OR) and 95% confidence interval (CI). The p value was considered significant if p < .05. Results Thirty three studies consisting of 14 282 subjects (6012 cases and 8270 controls) were included in this meta‐analysis. Variants of XRCC1 Arg194Trp polymorphism were associated with increased HNSCC risk and the associations were significant based on heterozygous and dominant models (heterozygous model: OR = 1.182, 95%CI = 1.015–1.377, p = .032; homozygous model: OR = 1.274, 95%CI = 0.940–1.727, p = .119; dominant model: OR = 1.194, 95%CI = 1.027–1.388, p = .021; recessive model: OR = 1.181, 95%CI = 0.885–1.576, p = .119). There were significant associations between variants of this polymorphism and HNSCC risk based on Asian ethnicity under dominant model, hospital control source under different genetic models, PCR‐RFLP genotyping method under dominant model and oral cavity tumor site under heterozygous and dominant models. Conclusion Variants of XRCC1 Arg194Trp polymorphism were significantly associated with increased risk of HNSCC development based on heterozygous and dominant genetic models.

this may induce apoptosis or may lead to uncontrolled cell proliferation and consequently cancer. 1,2 The DNA repair genes play an important role in maintaining the genomic integrity by repairing the DNA. So, the mutation of DNA repair genes may increase the risk of HNSCC. 3 The X-ray repair crosscomplementing group 1 (XRCC1) gene is involved in the base excision repair (BER) pathway and protects DNA from the harmful effects of carcinogens. XRCC1 protein plays a significant role in repairing singlestranded DNA fractures. 3,4 The XRCC genes have important roles in different DNA repair processes which prevent genomic instability. Genetic polymorphisms in DNA repair genes such as XRCC1 may change the DNA repair capacity which subsequently has impacts on cancer susceptibility. [1][2][3][4] Several studies have assessed the association between XRCC1 polymorphisms and cancer risk and prognosis; they have shown that individual susceptibility to cancer is different because of XRCC1 gene polymorphisms in lung, breast, stomach, esophageal and nasopharyngeal cancers. 4 It has been hypothesized that XRCC1 gene polymorphisms may alter HNSCC risk. However, the results of several studies that have examined this hypothesis are contradictory. 1,2,4 One of the most common single nucleotide polymorphisms in the XRCC1 gene is Arg194Trp (C to T transition at exon 6 which results in arginine [Arg] to tryptophan [Trp] amino acid change). 4 So, this systematic review and meta-analysis aimed to assess whether variants of XRCC1 Arg194Trp polymorphism increase the risk of development of HNSCC or not.

| MATERIALS AND METHODS
This meta-analysis has been registered in PROSPERO (ID: CRD42022336289). The search process was based on the MeSH terms as keywords using the following algorithm:

| Searched sources
The sources searched included Google Scholar, Scopus, PubMed, Web of Science, Cochrane Library, and Embase databases.

| Inclusion and exclusion criteria
This meta-analysis included all studies that had been published up to April 2022 regarding the association of XRCC1 Arg194Trp polymorphism with HNSCC risk and contained the required information including the frequency of different alleles and genotypes of the XRCC1 Arg194Trp polymorphism. There was no restriction on the language of the article.
In cases where the full text of the article could not be accessed and the required information was not available in the abstract of the article, that study was excluded from the meta-analysis. Case report, review and letters to the editor articles were excluded from the meta-analysis. Studies that did not have the required quality after risk of quality assessment were also excluded (e.g., score below 60%).

| Data extraction
The systematic search and article selection was done by two independent researchers. In cases where there was disagreement between the two researchers, the disagreement was resolved by consensus, or in the absence of consensus, the final decision was made by referring to another third researcher.
All initial searched articles were first screened by their titles; articles with unrelated titles to the aim of this meta-analysis as well as articles with duplicate titles were excluded. In the next step, the remained searched articles were screened by their abstracts.
At final step, the screening process was completed by assessing the full-texts of articles. EndNote X7 software was used to manage the data.

| Risk of bias (quality) assessment
Quality assessment was done through evaluation of the following items: quality of methodology, accuracy of study, and external validity.
In this meta-analysis, the Joanna Briggs Institute (JBI) checklist for case control studies 5 was used to assess the quality of the studies in terms of clear criteria for inclusion, detail description of study subject and setting, reliability and validity of study tools, used standard criteria or objective, identify cofounding factor, strategy dealing with cofounders, outcome measured in a valid way, appropriate statistical analysis. Articles with a score below than 60% according to this checklist would be excluded.
Risk of bias (quality) assessment was done by two independent researchers. The disagreement between these two researchers was being resolved by consensus or referral to a third reviewer.          In Hu et al., 39 Huang et al., 40 4,46 In the present meta-analysis, there was also no significant association between this polymorphism and pharyngeal carcinomas. Table 3 summarizes the results of above-mentioned metaanalyses for ease of comparison.

| Limitations
Among the limitations of the present meta-analysis was the lack of sufficient information in some studies about variables such as age and sex. writingreview and editing (equal). Khadijeh Najafi-Ghobadi: conception and design of the study (equal); data collection and analysis (equal); data interpretation and drafting the manuscript (equal); critical revision of the manuscript (equal). Hamid Abbaszadeh: conception and design of the study (equal); data collection and analysis (equal); data interpretation and drafting the manuscript (equal); critical revision of the manuscript (equal).