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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

The XRCC1 Arg194Trp polymorphism was associated with the risk of head and neck squamous cell... INTRODUCTIONHead and neck squamous cell carcinomas (HNSCCs) consist of the SCCs of the oral cavity, pharynx, and larynx. HNSCC is the fifth most common cancer worldwide, with severe morbidity and mortality and a poor overall survival rate.1 Development of HNSCC is a multifactorial process. Varied risk factors have been involved in the carcinogenesis process. Tobacco use and alcohol drinking are among the major risk factors for HNSCC.1–3 These carcinogens can cause DNA damage; this may induce apoptosis or may lead to uncontrolled cell proliferation and consequently cancer.1,2The 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 cross‐complementing 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 single‐stranded 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.1–4Several 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.1,2,4One 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).4So, 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 METHODSThis meta‐analysis has been registered in PROSPERO (ID: CRD42022336289).Search strategyWe used Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines for the systematic review reporting. PRISMA flow diagram was used for systematic identification and selection of studies (Figure 1).1FIGUREPRISMA flow diagram representing process of identification of studies through databasesThe search strategy was based on the research question (PICO):Do variants of XRCC1 Arg194Trp polymorphism increase the risk of development of HNSCC?P = Population/Patient: HNSCC patients; I = Intervention: presence of gene polymorphism; C = comparator: individuals without polymorphism; O = outcome: risk or susceptibility.The search process was based on the MeSH terms as keywords using the following algorithm:(“Genetic polymorphism” OR “single nucleotide polymorphism” OR “genetic variation”) AND (“X‐ray repair cross complementing protein 1” OR “DNA repair” OR “rs 1 799 782”) AND (“disease susceptibility” OR “risk”) AND (“head and neck neoplasms” OR “squamous cell carcinoma of head and neck” OR “mouth neoplasms” OR “nasopharyngeal carcinoma” OR “laryngeal neoplasms” OR “pharyngeal neoplasms”)Searched sourcesThe sources searched included Google Scholar, Scopus, PubMed, Web of Science, Cochrane Library, and Embase databases.Inclusion and exclusion criteriaThis 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 extractionThe 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.A designed form in Microsoft Excel 2016 software was used as a data collection tool. This form contained the following information: author, publication year, country, ethnicity, control source, tumor site, genotyping methods, sample size (case/control), frequency of Arg allele (case/control), frequency of Trp allele (case/control), frequency of Arg/Arg genotype (case/control), frequency of Arg/Trp genotype (case/control), frequency of Trp/Trp genotype (case/control), Hardy–Weinberg Equilibrium (HWE) p value, and quality score.Risk of bias (quality) assessmentQuality 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 studies5 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.Data analysesPublication bias was assessed using funnel plot and Begg's test (p value <.05 was considered as having publication bias). I2 statistic (significance level ≥25%) was used to identify statistical heterogeneity. If there was heterogeneity, the random effects model was used to analyze the data; otherwise the fixed effects model was used. Subgroup analysis was used to deal with the heterogeneity. There was no adjustment for multiple comparisons. The p value was considered significant if p < .05.All analyses were performed by Stata 12 statistical software and Comprehensive Meta‐Analysis Software.RESULTSOf initial 627 searched articles, 33 studies were eligible to include in this meta‐analysis. All of these studies had a quality score of higher than 60%. These 33 studies consisted of 14 282 subjects including 6012 cases and 8270 controls. The sex distribution ranged from 63.5% to 100% for male HNSCC patients and 0%–36.5% for female HNSCC patients. The sex distribution in control group ranged from 49.3% to 100% for male individuals and 0%–50.7% for female individuals. The age distribution ranged from 12 to 89 years old for HNSCC patients. The age distribution in control individuals ranged from 20 to 84 years old.Table 1 summarizes the characteristics of the studies included in this meta‐analysis.1TABLECharacteristics of the studies included in this meta‐analysisFirst Author, yearEthnicityControl sourceTumor siteGenotyping methodsSample size (case/control)Sex (male/female)Mean age (years)Sturgis, 19996CaucasianHospitalOral cavity, larynx, pharynxPCR‐RFLP203/424Case: 137/66Control: 269/155Case: 59.8Control: 60.1Olshan, 20027CaucasianHospitalOral cavity, larynx, pharynxPCR‐RFLP98/161Case: 71/27Control: 90/71Case: 61.8Control: 57.6Varzim, 20038CaucasianHealthyLarynxPCR‐RFLP88/178Case: 83/5Control: 128/50Case: 62.8Control: 43.02Tae, 20049AsianHospitalOral cavity, larynx, pharynxSequence129/157NSNSDemokan, 200510CaucasianHealthyOral cavity, larynx, pharynxPCR‐RFLP95/98Case: 83/12Control: 51/47Case: 59.6Control: 47.2Majumder, 200511AsianHospitalOral cavityPCR‐RFLP310/348Case: 197/113Control: 265/83Case: 55Control: 50.4Rydzanicz, 200512CaucasianHealthyOral cavity, larynx, pharynxPCR‐RFLP182/143Case: 178/4Control: 143/0Case: 61.2Control: 53.1Gajecka, 200513CaucasianHealthyLarynxPCR‐RFLP293/319Case: 293/0Control: 319/0NSKietthubthew, 200614AsianHealthyOral cavityPCR‐RFLP106/164Case: 77/29Control: 91/73Case: 67.1Control: 68.4Matullo, 200615CaucasianHealthyOral cavity, larynx, pharynxTaqman82/1094NSNSCao, 200616AsianHealthyPharynxPCR‐RFLP425/501Case: 339/123Control: 252/259Case: 45.9Control: 45.7Ramachandran, 200617AsianHospitalOral cavityPCR‐RFLP110/110NSNSMajumder, 200718AsianHospitalOral cavityPCR‐RFLP309/387Case: 198/112Control: 302/87Case: 55Control: 49Yang, 200719AsianHealthyPharynxPCR‐RFLP153/168Case: 110/43Control: 118/50Case: 48.7Control: 47.9Yen, 200820AsianHospitalOral cavityPCR‐RFLP103/98Case: 100/3Control: 49/49Case: 53.6Control: 40.5Harth, 200821CaucasianHospitalOral cavity, larynx, pharynxPCR‐RFLP310/300Case: 250/60Control: 176/124Case: 59.7Control: 47.2Csejtei, 200922CaucasianHealthyOral cavity, larynx, pharynxPCR‐RFLP108/102Case: 97/11Control: NSCase: 56.7Control: NSKowalski, 200923CaucasianHealthyOral cavity, larynx, pharynxPCR‐RFLP92/124Case: 50/42Control: 63/61Case: 48.7Control: 44.47Applebaum, 200924CaucasianHealthyOral cavity, larynx, pharynxPCR‐RFLP483/547Case: 359/124Control: 401/146Case: 59.5Control: 61Gugatschka, 201125CaucasianHealthyOral cavity, larynx, pharynxTaqman168/463Case: 148/20Control: 234/229Case: 65Control: 58Laantri, 201126AfricanHospitalPharynxTaqman512/477NSNSKumar, 201227AsianHealthyOral cavity, larynx, pharynxPCR‐RFLP278/278Case: 278/0Control: 278/0Case: 50Control: 52Dos Reis, 201328MixedHealthyOral cavityPCR‐RFLP150/150Case: 122/28Control: 122/28Case: 57.52Control: 57.27Curioni, 201329MixedHospitalOral cavityPCR‐RFLP92/244Case: 81/11Control: 225/19Case: 53Control: 53.6Zhu, 201430AsianHealthyPharynxPCR‐RFLP87/94NSNSMutlu, 201531CaucasianHealthyOral cavity, larynx, pharynxPCR‐RFLP55/69NSNSYang, 201532AsianHospitalOral cavityPCR‐RFLP103/98Case: 100/3Control: 49/49NSCosta, 201633MixedHospitalpharynxPCR‐RFLP200/200Case: 183/17Control: NSCase: 57Control: 53Alimu, 201834AsianHealthyLarynxPCR‐RFLP58/116Case: 49/9Control: NSCase: 62Control: 58Borkotoky, 202035AsianHealthyOral cavityPCR‐RFLP152/190Case: 109/43Control: NSCase: 52.96Control: NSKabzinski, 202136CaucasianHealthyOral cavityTaqman353/343Case: 204/149Control: NSCase: 63Control: NSSeifi, 202237AsianHealthyOral cavityPCR‐RFLP50/59Case: 36/14Control: 35/24Case: 62.04Control: 54.15Tata, 202238AsianHospitalOral cavityPCR‐RFLP75/75Case: 51/24Control: 54/21Case: 54.88Control: NSAbbreviation: NS, not specified.Publication biasResults of Begg's test showed no publication bias except for subgroup analyses in Asian ethnicity under allelic genetic model (p value = .038), Taqman genotyping method under heterozygous and dominant genetic models (p values = .042) and oral cavity tumor site under allelic genetic model (p value = .016).Meta‐analysis resultsTable 2 summarizes the results of meta‐analysis on the association of XRCC1 Arg194Trp polymorphism with HNSCC risk in different subgroups.2TABLEThe association of XRCC1 Arg194Trp polymorphism with HNSCC risk in different subgroupsStatistic SubgroupOR (95%CI)p ValueHeterogeneity (I2 Statistic [%])Genetic modelAllelic0.86 (0.75–0.98).02964.5Heterozygous1.182 (1.015–1.377).03258.7Homozygous1.274 (0.940–1.727).11936.2Dominant1.194(1.027–1.388).02161.2Recessive1.181 (0.885–1.576).25834.2EthnicityAsianAllelic.764 (.613–.952).01679Heterozygous1.256(0.973–1.620).08072.1Homozygous1.447 (0.908–2.307).12165.3Dominant1.329 (1.033–1.710).02775.6Recessive1.350 (0.897–2.032).15056.9CaucasianAllelic1.040 (0.916–1.180).5480Heterozygous1.038 (0.851–1.267).71331Homozygous0.985 (0.674–1.438).9360Dominant1.033(0.889–1.200).6708.7Recessive0.737 (0.529–1.026).0710MixedAllelic0.748 (0.413–1.354).33767.8Heterozygous1.589 (0.927–2.721).09254.3Homozygous0.650 (0.195–2.167).4830Dominant1.479 (0.833–2.627).18152.7Recessive0.615 (0.184–2.055).4290Control sourceHealthyAllelic0.988 (0.841–1.160).88059.2Heterozygous1.079 (0.887–1.313).44657.5Homozygous1.017 (0.709–1.458).92731Dominant1.065 (0.874–1.296).53361.2Recessive0.811 (0.650–1.013).06516.3HospitalAllelic0.715 (0.595–0.860)<.00151.7Heterozygous1.350 (1.075–1.697).01054.2Homozygous1.869 (1.306–2.674).00110Dominant1.401 (1.155–1.700).00144.8Recessive1.781 (1.253–2.532).00113.4Genotyping methodPCR‐RFLPAllelic0.853 (0.737–0.988).03363.1Heterozygous1.166 (0.992–1.370).06254.6Homozygous1.223 (0.861–1.737).26038.5Dominant1.187 (1.013–1.391).03457.9Recessive1.184 (0.866–1.619).28928.1TaqmanAllelic1.063 (0.749–1.509).73260.4Heterozygous1.040 (0.633–1.707).87871.9Homozygous1.037 (0.666–1.617).8711.9Dominant1.049 (0.690–1.596).82363.7Recessive1.131 (0.413–3.100).81139.7SmokingOnly smokingAllelic0.891 (0.628–1.265).52066Heterozygous1.154 (0.843–1.580).37148.1Homozygous0.951 (0.381–2.369).91326.1Dominant1.143 (0.806–1.622).45260.4Recessive0.967 (0.497–1.882).92214.5Tumor siteOral cavityAllelic0.732 (0.602–0.891).00259.7Heterozygous1.471 (1.172–1.846).00149.3Homozygous1.460 (0.942–2.265).09141.8Dominant1.462 (1.208–1.769)<.00135.7Recessive1.279 (0.773–2.116).33859.1PharynxAllelic0.828 (0.536–1.277).39386.1Heterozygous1.229 (0.813–1.857).32977Homozygous1.288 (0.381–4.359).68475.7Dominant1.235 (0.768–1.985).38483.5Recessive1.189 (0.424–3.330).74267LarynxAllelic1.107 (0.790–1.551).5560Heterozygous0.844 (0.579–1.231).3780Homozygous1.400 (0.415–4.730).5880Dominant0.874 (0.606–1.262).4720Recessive1.514 (0.452–5.068).5010Abbreviations: CI, confidence interval; OR, odds ratio; PCR‐RFLP, Polymerase chain reaction‐restriction fragment length polymorphism.The association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on different genetic modelsVariants of XRCC1 Arg194Trp polymorphism were associated with increased risk of HNSCC development based on different genetic models; the associations were significant under heterozygous and dominant genetic models (p values <.05).Figure 2 shows forest plot for the association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on dominant model.2FIGUREForest plot for the association of XRCC1 Arg194Trp polymorphism with head and neck squamous cell carcinoma (HNSCC) risk based on dominant modelThe association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on different ethnicitiesThere were not significant associations between XRCC1 Arg194Trp polymorphism with HNSCC risk based on Caucasian or mixed ethnicity under different genetic models (p values >.05); the association was significant for Asian ethnicity under dominant genetic model so that the Trp/Trp + Arg/Trp variant was significantly associated with increased HNSCC risk compared to Arg/Arg variant.Figure 3 shows forest plot for the association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on Asian ethnicity under dominant model.3FIGUREForest plot for the association of XRCC1 Arg194Trp polymorphism with head and neck squamous cell carcinoma (HNSCC) risk based on Asian ethnicity under dominant modelThe association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on control sourceThere was significant association between XRCC1 Arg194Trp polymorphism with HNSCC risk based on hospital‐based control source under different genetic model (p values <.05); variants of this polymorphism increased the HNSCC risk compared to corresponding reference variant.There were not any significant associations between XRCC1 Arg194Trp polymorphism with HNSCC risk based on healthy control source under different genetic models.Figure 4 shows forest plot for the association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on hospital‐based control source under dominant model.4FIGUREForest plot for the association of XRCC1 Arg194Trp polymorphism with head and neck squamous cell carcinoma (HNSCC) risk based on hospital‐based control source under dominant modelThe association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on genotyping methodThere were not any significant associations between XRCC1 Arg194Trp polymorphism with HNSCC risk based on Taqman genotyping method under different genetic models (p values >.05).There was significant association between XRCC1 Arg194Trp polymorphism with HNSCC risk based on Polymerase Chain Reaction‐Restriction Fragment Length Polymorphism (PCR‐RFLP) genotyping method under dominant genetic model (p values <.05).Figure 5 shows forest plot for the association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on PCR‐RFLP genotyping method under dominant model.5FIGUREForest plot for the association of XRCC1 Arg194Trp polymorphism with head and neck squamous cell carcinoma (HNSCC) risk based on Polymerase Chain Reaction‐Restriction Fragment Length Polymorphism (PCR‐RFLP) genotyping method under dominant modelThe association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on smoking participantsThere were not any significant associations between XRCC1 Arg194Trp polymorphism with HNSCC risk based on only smoking participants under different genetic models (p value >.001).The association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on tumor siteThere was significant association between XRCC1 Arg194Trp polymorphism with HNSCC risk based on oral cavity tumor site under heterozygous and dominant models (p values <.05); the Arg/Trp + Trp/Trp (CT + TT) genotypes were significantly associated with increased risk of HNSCC development compared to Arg/Arg (CC) genotype (dominant model); also, the Arg/Trp variant significantly increased the HNSCC risk compared to Arg/Arg (heterozygous model); the associations were not significant under other genetic models (p value >.05).There were not significant associations between XRCC1 Arg194Trp polymorphism with HNSCC risk based on pharyngeal or laryngeal tumor sites under different genetic models (p values >.001).Figure 6 shows forest plot for the association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on oral cavity tumor site under dominant model.6FIGUREforest plot for the association of XRCC1 Arg194Trp polymorphism with head and neck squamous cell carcinoma (HNSCC) risk based on oral cavity tumor site under dominant modelDISCUSSIONThis meta‐analysis showed that variants of XRCC1 Arg194Trp polymorphism significantly increased the risk of HNSCC development under heterozygous and dominant genetic models; of course, it should be noted that although variants of this polymorphism was associated with increased risk of HNSCC development under homozygous and recessive genetic models, the association was not significant; subgroup analyses showed that 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.The presence of associations between XRCC1 Arg194Trp polymorphism and HNSCC risk under heterozygous and dominant genetic models shows that this polymorphism may play a role in individual differences in susceptibility to HNSCCs. Therefore, one of the ways to prevent head and neck cancer can be to identify genetically susceptible people (e.g., with unfavorable polymorphic variants of XRCC1 Arg194Trp polymorphism) and undergo continuous and regular monitoring to prevent them from developing cancer and if head and neck cancer occurs, they can be diagnosed in the early stages. The insignificant results under homozygous and recessive genetic models show that these genetic models fail to identify relatively small effects of this single nucleotide polymorphism on HNSCC development against a complex background of biological factors or large‐scale population‐based studies are needed to reveal such an effect under these genetic models.In Hu et al.,39 Huang et al.,40 and Feng et al.41 and meta‐analyses on the XRCC1 Arg194Trp polymorphism and risk of cancer, this polymorphism was identified as a biomarker of cancer risk. In Hu et al. meta‐analysis, under dominant genetic model, the Trp/Trp + Arg/Trp genotypes was significantly associated with decreased cancer risk compared to Arg/Arg genotype (OR = 0.89 [95% CI: 0.81–0.98]) for all tumor types (breast, lung, etc.); subgroup analysis in head and neck cancers showed similar results (OR = 0.85 [95%CI: 0.59–1.23])39; their results are inconsistent with the results of present meta‐analysis; the reason for this inconsistency may be due to the very small number of available studies on HNSCC in their meta‐analysis compared to a much larger number of the same studies in the present meta‐analysis. Huang et al. observed in their meta‐analysis that XRCC1 Arg194Trp polymorphism is a cancer risk factor among Chinese population so that a significantly increased risk was found under recessive model (OR = 1.31; 95%CI: 1.13–1.53); in the subgroup analysis, this association was observed for lung and esophageal cancers; among the head and neck cancers, only nasopharyngeal carcinoma was present in their stratification which had no significant association with this polymorphism40; their general results on all type of cancers are consistent with the results of present meta‐analysis except for genetic model. In Feng et al. met‐analysis, a significant increased risk was found under recessive, homozygous and additive models; their results are consistent with the results of present meta‐analysis except for genetic models.41In Flores‐Obando et al. meta‐analysis, there was a significant association between XRCC1 Arg194Trp polymorphism with head and neck cancer risk2 which is consistent with the results of the present meta‐analysis; of course, in their meta‐analysis, the increased OR (OR = 1.69, 95% CI: 1.10–2.58) was observed under the homozygous model; in our meta‐analysis the significant association was observed under heterozygous and dominant genetic models; in their meta‐analysis, a significant increase in HNSCC risk was observed for Asian ethnicity which is consistent with the results of the present meta‐analysis. In both meta‐analyses, no significant association was found for Caucasians ethnicity under heterozygous, homozygous and dominant models. In their meta‐analysis, a significantly increased risk was observed for oral cancers; this is consistent with the results of the present meta‐analysis, although in their meta‐analysis, a significant association was obtained under heterozygous model; in the present meta‐analysis, this association was significant under heterozygous and dominant model.In the three meta‐analyses conducted by Lou et al.,1 Wu et al.,42 and Zhou et al.,43 there were not significant association between XRCC1 Arg194Trp polymorphism and the HNSCC risk under different genetic models; these findings are inconsistent with results of present meta‐analysis; the reason for these inconsistencies can be attributed to the smaller number of studies and the smaller number of cases and controls in their meta‐analysis. In Lou et al. and Wu et al. meta‐analyses, stratification analyses based on ethnicity and genotyping method; these findings are again inconsistent with results of present meta‐analysis. Variants of this polymorphism was significantly associated with a decreased risk of oral cavity cancer under recessive genetic model in Lou et al. meta‐analysis; the direction of results was inconsistent between our meta‐analysis and Lou et al. meta‐analysis in the field of oral cancers. Variants of this polymorphism was significantly associated with an increased risk of oral cavity cancer under the allelic, heterozygote, and dominant models in Wu et al. meta‐analysis; these findings of Wu et al. meta‐analysis are consistent with results of present meta‐analysis. In Lou et al. meta‐analysis,1 subgroup analysis for smoking showed significantly increased risk under homozygous model but in the present meta‐analysis no such association was found. In Zhou et al. meta‐analysis, stratification by ethnicity showed significant association in Asian ethnicity under heterozygous and recessive models43; their finding is consistent with the results of present meta‐analysis except for genetic model.In Zhou et al. meta‐analysis, oral cancer susceptibility was not associated with XRCC1 Arg194Trp polymorphisms, although there was significant increase in the risk of oral cancer in Asian ethnicity under allelic, homozygous, and dominant models.44 In contrast, there was significant association between this polymorphism with oral cavity cancer susceptibility under heterozygous and dominant models in the present meta‐analysis; the reason for the discrepancy could be related to a much larger number of cases and controls in the present meta‐analysis.In Mozaffari et al. and Zhang et al. meta‐analyses on the association of XRCC1 Arg194Trp with oral cancer risk, there were significant increased associations between this polymorphism and oral cancer risk under allelic, heterozygote, and recessive models in Mozaffari et al. meta‐analysis and under dominant model in Zhang et al. met‐analysis.3,45 These results are consistent with the result of the present meta‐analysis. Subgroup analysis according to ethnicity in Zhang et al. meta‐analysis showed that this polymorphism was associated with significantly increased risk of oral cancer in Asians ethnicity under allelic, homozygous, and dominant genetic models.In Lin et al. and Deng et al. meta‐analyses, there were no significant associations between XRCC1 Arg194Trp polymorphism and nasopharyngeal carcinoma under all genetic models.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 meta‐analyses for ease of comparison.3TABLEThe results of existing meta‐analyses on the association of XRCC1 Arg194Trp polymorphism with cancer riskFirst author, yearType of cancerResultsNumber ofSubgroup analysis with significant resultCommentsNon‐significantSignificantStudyCaseControlIncreased riskDecreased riskHu, 200539All cancer types‐‐√3811 95714 174‐Significant results under dominant genetic modelHead and neck‐‐√47231045‐Huang, 201140All cancer types‐√‐34937412 111‐Only Chinese people analyzed; significant results under recessive modelNasopharynx√‐‐37901013‐Feng, 201441All cancer types‐√‐20159 22781 587‐Significant results under recessive, homozygous and additive modelsFlores‐Obando, 20102Head and neck‐√‐1523303834Asian ethnicity (increased risk)Significant results under the homozygous modelOral cavity‐√‐5724818‐Significant results under heterozygous modelLou, 20131Head and neck√‐‐2244786873Smoking (increased risk)Significant results under homozygous modelOral cavity‐‐√69151412‐Significant results under recessive modelWu, 201442Head and neck√‐‐2137716144‐‐Oral cavity‐√‐712251760‐Significant results under the allelic, heterozygote, and dominant modelsZhou, 201443Head and neck√‐‐2033625796Asian ethnicity (increased risk)Significant results under heterozygous and recessive modelsZhou, 200944Oral cavity√‐‐813623130Asian ethnicity (increased risk)Significant results under allelic, homozygous and dominant modelsMozaffari, 20213Oral cavity‐√‐710671602‐Significant results under allelic, heterozygote, and recessive modelsZhang, 201345Oral cavity‐√‐68281412Asian ethnicity (increased risk)Significant results under dominant modelLin, 20184Nasopharynx√‐‐514281519‐‐Deng, 201746Nasopharynx√‐‐48771007‐Restricted to Chinese populationPresent meta‐analysisHead and neck√‐‐3360128270Ethnicity/smoking/genotyping method (all non‐significant)‐Oral cavity‐√‐1219132266Significant result under dominant modelLimitationsAmong the limitations of the present meta‐analysis was the lack of sufficient information in some studies about variables such as age and sex.CONCLUSIONVariants of XRCC1 Arg194Trp polymorphism were associated with increased risk of HNSCC development under different genetic models; the associations were significant under heterozygous and dominant genetic models. There were significant associations between variants of this polymorphism and HNSCC risk based on Asian ethnicity, hospital control source, PCR‐RFLP genotyping method and oral cavity tumor site. Variants of this polymorphism were not significantly associated with increased risk of HNSCC development under different genetic models although they were associated with borderline decreased risk of HNSCC development under recessive genetic model.AUTHOR CONTRIBUTIONSNooshin Mohtasham: Conceptualization (equal); supervision (equal); writing – review 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).ACKNOWLEDGEMENTNone.CONFLICT OF INTERESTThe authors have stated explicitly that there are no conflicts of interest in connection with this article.DATA AVAILABILITY STATEMENTThe data related to this study is within the text.ETHNIC STATEMENTNot applicable.REFERENCESLou Y, Peng WJ, Cao DS, Xie J, Li HH, Jiang ZX. DNA repair gene XRCC1 polymorphisms and head and neck cancer risk: an updated meta‐analysis including 16344 subjects. PLoS One. 2013;8(9):e74059.Flores‐Obando RE, Gollin SM, Ragin CC. Polymorphisms in DNA damage response genes and head and neck cancer risk. Biomarkers. 2010;15(5):379‐399.Mozaffari HR, Rostamnia M, Sharifi R, et al. 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Int J Clin Exp Med. 2017;10(1):418‐425. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Reports Wiley

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

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Abstract

INTRODUCTIONHead and neck squamous cell carcinomas (HNSCCs) consist of the SCCs of the oral cavity, pharynx, and larynx. HNSCC is the fifth most common cancer worldwide, with severe morbidity and mortality and a poor overall survival rate.1 Development of HNSCC is a multifactorial process. Varied risk factors have been involved in the carcinogenesis process. Tobacco use and alcohol drinking are among the major risk factors for HNSCC.1–3 These carcinogens can cause DNA damage; this may induce apoptosis or may lead to uncontrolled cell proliferation and consequently cancer.1,2The 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 cross‐complementing 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 single‐stranded 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.1–4Several 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.1,2,4One 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).4So, 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 METHODSThis meta‐analysis has been registered in PROSPERO (ID: CRD42022336289).Search strategyWe used Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines for the systematic review reporting. PRISMA flow diagram was used for systematic identification and selection of studies (Figure 1).1FIGUREPRISMA flow diagram representing process of identification of studies through databasesThe search strategy was based on the research question (PICO):Do variants of XRCC1 Arg194Trp polymorphism increase the risk of development of HNSCC?P = Population/Patient: HNSCC patients; I = Intervention: presence of gene polymorphism; C = comparator: individuals without polymorphism; O = outcome: risk or susceptibility.The search process was based on the MeSH terms as keywords using the following algorithm:(“Genetic polymorphism” OR “single nucleotide polymorphism” OR “genetic variation”) AND (“X‐ray repair cross complementing protein 1” OR “DNA repair” OR “rs 1 799 782”) AND (“disease susceptibility” OR “risk”) AND (“head and neck neoplasms” OR “squamous cell carcinoma of head and neck” OR “mouth neoplasms” OR “nasopharyngeal carcinoma” OR “laryngeal neoplasms” OR “pharyngeal neoplasms”)Searched sourcesThe sources searched included Google Scholar, Scopus, PubMed, Web of Science, Cochrane Library, and Embase databases.Inclusion and exclusion criteriaThis 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 extractionThe 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.A designed form in Microsoft Excel 2016 software was used as a data collection tool. This form contained the following information: author, publication year, country, ethnicity, control source, tumor site, genotyping methods, sample size (case/control), frequency of Arg allele (case/control), frequency of Trp allele (case/control), frequency of Arg/Arg genotype (case/control), frequency of Arg/Trp genotype (case/control), frequency of Trp/Trp genotype (case/control), Hardy–Weinberg Equilibrium (HWE) p value, and quality score.Risk of bias (quality) assessmentQuality 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 studies5 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.Data analysesPublication bias was assessed using funnel plot and Begg's test (p value <.05 was considered as having publication bias). I2 statistic (significance level ≥25%) was used to identify statistical heterogeneity. If there was heterogeneity, the random effects model was used to analyze the data; otherwise the fixed effects model was used. Subgroup analysis was used to deal with the heterogeneity. There was no adjustment for multiple comparisons. The p value was considered significant if p < .05.All analyses were performed by Stata 12 statistical software and Comprehensive Meta‐Analysis Software.RESULTSOf initial 627 searched articles, 33 studies were eligible to include in this meta‐analysis. All of these studies had a quality score of higher than 60%. These 33 studies consisted of 14 282 subjects including 6012 cases and 8270 controls. The sex distribution ranged from 63.5% to 100% for male HNSCC patients and 0%–36.5% for female HNSCC patients. The sex distribution in control group ranged from 49.3% to 100% for male individuals and 0%–50.7% for female individuals. The age distribution ranged from 12 to 89 years old for HNSCC patients. The age distribution in control individuals ranged from 20 to 84 years old.Table 1 summarizes the characteristics of the studies included in this meta‐analysis.1TABLECharacteristics of the studies included in this meta‐analysisFirst Author, yearEthnicityControl sourceTumor siteGenotyping methodsSample size (case/control)Sex (male/female)Mean age (years)Sturgis, 19996CaucasianHospitalOral cavity, larynx, pharynxPCR‐RFLP203/424Case: 137/66Control: 269/155Case: 59.8Control: 60.1Olshan, 20027CaucasianHospitalOral cavity, larynx, pharynxPCR‐RFLP98/161Case: 71/27Control: 90/71Case: 61.8Control: 57.6Varzim, 20038CaucasianHealthyLarynxPCR‐RFLP88/178Case: 83/5Control: 128/50Case: 62.8Control: 43.02Tae, 20049AsianHospitalOral cavity, larynx, pharynxSequence129/157NSNSDemokan, 200510CaucasianHealthyOral cavity, larynx, pharynxPCR‐RFLP95/98Case: 83/12Control: 51/47Case: 59.6Control: 47.2Majumder, 200511AsianHospitalOral cavityPCR‐RFLP310/348Case: 197/113Control: 265/83Case: 55Control: 50.4Rydzanicz, 200512CaucasianHealthyOral cavity, larynx, pharynxPCR‐RFLP182/143Case: 178/4Control: 143/0Case: 61.2Control: 53.1Gajecka, 200513CaucasianHealthyLarynxPCR‐RFLP293/319Case: 293/0Control: 319/0NSKietthubthew, 200614AsianHealthyOral cavityPCR‐RFLP106/164Case: 77/29Control: 91/73Case: 67.1Control: 68.4Matullo, 200615CaucasianHealthyOral cavity, larynx, pharynxTaqman82/1094NSNSCao, 200616AsianHealthyPharynxPCR‐RFLP425/501Case: 339/123Control: 252/259Case: 45.9Control: 45.7Ramachandran, 200617AsianHospitalOral cavityPCR‐RFLP110/110NSNSMajumder, 200718AsianHospitalOral cavityPCR‐RFLP309/387Case: 198/112Control: 302/87Case: 55Control: 49Yang, 200719AsianHealthyPharynxPCR‐RFLP153/168Case: 110/43Control: 118/50Case: 48.7Control: 47.9Yen, 200820AsianHospitalOral cavityPCR‐RFLP103/98Case: 100/3Control: 49/49Case: 53.6Control: 40.5Harth, 200821CaucasianHospitalOral cavity, larynx, pharynxPCR‐RFLP310/300Case: 250/60Control: 176/124Case: 59.7Control: 47.2Csejtei, 200922CaucasianHealthyOral cavity, larynx, pharynxPCR‐RFLP108/102Case: 97/11Control: NSCase: 56.7Control: NSKowalski, 200923CaucasianHealthyOral cavity, larynx, pharynxPCR‐RFLP92/124Case: 50/42Control: 63/61Case: 48.7Control: 44.47Applebaum, 200924CaucasianHealthyOral cavity, larynx, pharynxPCR‐RFLP483/547Case: 359/124Control: 401/146Case: 59.5Control: 61Gugatschka, 201125CaucasianHealthyOral cavity, larynx, pharynxTaqman168/463Case: 148/20Control: 234/229Case: 65Control: 58Laantri, 201126AfricanHospitalPharynxTaqman512/477NSNSKumar, 201227AsianHealthyOral cavity, larynx, pharynxPCR‐RFLP278/278Case: 278/0Control: 278/0Case: 50Control: 52Dos Reis, 201328MixedHealthyOral cavityPCR‐RFLP150/150Case: 122/28Control: 122/28Case: 57.52Control: 57.27Curioni, 201329MixedHospitalOral cavityPCR‐RFLP92/244Case: 81/11Control: 225/19Case: 53Control: 53.6Zhu, 201430AsianHealthyPharynxPCR‐RFLP87/94NSNSMutlu, 201531CaucasianHealthyOral cavity, larynx, pharynxPCR‐RFLP55/69NSNSYang, 201532AsianHospitalOral cavityPCR‐RFLP103/98Case: 100/3Control: 49/49NSCosta, 201633MixedHospitalpharynxPCR‐RFLP200/200Case: 183/17Control: NSCase: 57Control: 53Alimu, 201834AsianHealthyLarynxPCR‐RFLP58/116Case: 49/9Control: NSCase: 62Control: 58Borkotoky, 202035AsianHealthyOral cavityPCR‐RFLP152/190Case: 109/43Control: NSCase: 52.96Control: NSKabzinski, 202136CaucasianHealthyOral cavityTaqman353/343Case: 204/149Control: NSCase: 63Control: NSSeifi, 202237AsianHealthyOral cavityPCR‐RFLP50/59Case: 36/14Control: 35/24Case: 62.04Control: 54.15Tata, 202238AsianHospitalOral cavityPCR‐RFLP75/75Case: 51/24Control: 54/21Case: 54.88Control: NSAbbreviation: NS, not specified.Publication biasResults of Begg's test showed no publication bias except for subgroup analyses in Asian ethnicity under allelic genetic model (p value = .038), Taqman genotyping method under heterozygous and dominant genetic models (p values = .042) and oral cavity tumor site under allelic genetic model (p value = .016).Meta‐analysis resultsTable 2 summarizes the results of meta‐analysis on the association of XRCC1 Arg194Trp polymorphism with HNSCC risk in different subgroups.2TABLEThe association of XRCC1 Arg194Trp polymorphism with HNSCC risk in different subgroupsStatistic SubgroupOR (95%CI)p ValueHeterogeneity (I2 Statistic [%])Genetic modelAllelic0.86 (0.75–0.98).02964.5Heterozygous1.182 (1.015–1.377).03258.7Homozygous1.274 (0.940–1.727).11936.2Dominant1.194(1.027–1.388).02161.2Recessive1.181 (0.885–1.576).25834.2EthnicityAsianAllelic.764 (.613–.952).01679Heterozygous1.256(0.973–1.620).08072.1Homozygous1.447 (0.908–2.307).12165.3Dominant1.329 (1.033–1.710).02775.6Recessive1.350 (0.897–2.032).15056.9CaucasianAllelic1.040 (0.916–1.180).5480Heterozygous1.038 (0.851–1.267).71331Homozygous0.985 (0.674–1.438).9360Dominant1.033(0.889–1.200).6708.7Recessive0.737 (0.529–1.026).0710MixedAllelic0.748 (0.413–1.354).33767.8Heterozygous1.589 (0.927–2.721).09254.3Homozygous0.650 (0.195–2.167).4830Dominant1.479 (0.833–2.627).18152.7Recessive0.615 (0.184–2.055).4290Control sourceHealthyAllelic0.988 (0.841–1.160).88059.2Heterozygous1.079 (0.887–1.313).44657.5Homozygous1.017 (0.709–1.458).92731Dominant1.065 (0.874–1.296).53361.2Recessive0.811 (0.650–1.013).06516.3HospitalAllelic0.715 (0.595–0.860)<.00151.7Heterozygous1.350 (1.075–1.697).01054.2Homozygous1.869 (1.306–2.674).00110Dominant1.401 (1.155–1.700).00144.8Recessive1.781 (1.253–2.532).00113.4Genotyping methodPCR‐RFLPAllelic0.853 (0.737–0.988).03363.1Heterozygous1.166 (0.992–1.370).06254.6Homozygous1.223 (0.861–1.737).26038.5Dominant1.187 (1.013–1.391).03457.9Recessive1.184 (0.866–1.619).28928.1TaqmanAllelic1.063 (0.749–1.509).73260.4Heterozygous1.040 (0.633–1.707).87871.9Homozygous1.037 (0.666–1.617).8711.9Dominant1.049 (0.690–1.596).82363.7Recessive1.131 (0.413–3.100).81139.7SmokingOnly smokingAllelic0.891 (0.628–1.265).52066Heterozygous1.154 (0.843–1.580).37148.1Homozygous0.951 (0.381–2.369).91326.1Dominant1.143 (0.806–1.622).45260.4Recessive0.967 (0.497–1.882).92214.5Tumor siteOral cavityAllelic0.732 (0.602–0.891).00259.7Heterozygous1.471 (1.172–1.846).00149.3Homozygous1.460 (0.942–2.265).09141.8Dominant1.462 (1.208–1.769)<.00135.7Recessive1.279 (0.773–2.116).33859.1PharynxAllelic0.828 (0.536–1.277).39386.1Heterozygous1.229 (0.813–1.857).32977Homozygous1.288 (0.381–4.359).68475.7Dominant1.235 (0.768–1.985).38483.5Recessive1.189 (0.424–3.330).74267LarynxAllelic1.107 (0.790–1.551).5560Heterozygous0.844 (0.579–1.231).3780Homozygous1.400 (0.415–4.730).5880Dominant0.874 (0.606–1.262).4720Recessive1.514 (0.452–5.068).5010Abbreviations: CI, confidence interval; OR, odds ratio; PCR‐RFLP, Polymerase chain reaction‐restriction fragment length polymorphism.The association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on different genetic modelsVariants of XRCC1 Arg194Trp polymorphism were associated with increased risk of HNSCC development based on different genetic models; the associations were significant under heterozygous and dominant genetic models (p values <.05).Figure 2 shows forest plot for the association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on dominant model.2FIGUREForest plot for the association of XRCC1 Arg194Trp polymorphism with head and neck squamous cell carcinoma (HNSCC) risk based on dominant modelThe association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on different ethnicitiesThere were not significant associations between XRCC1 Arg194Trp polymorphism with HNSCC risk based on Caucasian or mixed ethnicity under different genetic models (p values >.05); the association was significant for Asian ethnicity under dominant genetic model so that the Trp/Trp + Arg/Trp variant was significantly associated with increased HNSCC risk compared to Arg/Arg variant.Figure 3 shows forest plot for the association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on Asian ethnicity under dominant model.3FIGUREForest plot for the association of XRCC1 Arg194Trp polymorphism with head and neck squamous cell carcinoma (HNSCC) risk based on Asian ethnicity under dominant modelThe association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on control sourceThere was significant association between XRCC1 Arg194Trp polymorphism with HNSCC risk based on hospital‐based control source under different genetic model (p values <.05); variants of this polymorphism increased the HNSCC risk compared to corresponding reference variant.There were not any significant associations between XRCC1 Arg194Trp polymorphism with HNSCC risk based on healthy control source under different genetic models.Figure 4 shows forest plot for the association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on hospital‐based control source under dominant model.4FIGUREForest plot for the association of XRCC1 Arg194Trp polymorphism with head and neck squamous cell carcinoma (HNSCC) risk based on hospital‐based control source under dominant modelThe association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on genotyping methodThere were not any significant associations between XRCC1 Arg194Trp polymorphism with HNSCC risk based on Taqman genotyping method under different genetic models (p values >.05).There was significant association between XRCC1 Arg194Trp polymorphism with HNSCC risk based on Polymerase Chain Reaction‐Restriction Fragment Length Polymorphism (PCR‐RFLP) genotyping method under dominant genetic model (p values <.05).Figure 5 shows forest plot for the association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on PCR‐RFLP genotyping method under dominant model.5FIGUREForest plot for the association of XRCC1 Arg194Trp polymorphism with head and neck squamous cell carcinoma (HNSCC) risk based on Polymerase Chain Reaction‐Restriction Fragment Length Polymorphism (PCR‐RFLP) genotyping method under dominant modelThe association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on smoking participantsThere were not any significant associations between XRCC1 Arg194Trp polymorphism with HNSCC risk based on only smoking participants under different genetic models (p value >.001).The association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on tumor siteThere was significant association between XRCC1 Arg194Trp polymorphism with HNSCC risk based on oral cavity tumor site under heterozygous and dominant models (p values <.05); the Arg/Trp + Trp/Trp (CT + TT) genotypes were significantly associated with increased risk of HNSCC development compared to Arg/Arg (CC) genotype (dominant model); also, the Arg/Trp variant significantly increased the HNSCC risk compared to Arg/Arg (heterozygous model); the associations were not significant under other genetic models (p value >.05).There were not significant associations between XRCC1 Arg194Trp polymorphism with HNSCC risk based on pharyngeal or laryngeal tumor sites under different genetic models (p values >.001).Figure 6 shows forest plot for the association of XRCC1 Arg194Trp polymorphism with HNSCC risk based on oral cavity tumor site under dominant model.6FIGUREforest plot for the association of XRCC1 Arg194Trp polymorphism with head and neck squamous cell carcinoma (HNSCC) risk based on oral cavity tumor site under dominant modelDISCUSSIONThis meta‐analysis showed that variants of XRCC1 Arg194Trp polymorphism significantly increased the risk of HNSCC development under heterozygous and dominant genetic models; of course, it should be noted that although variants of this polymorphism was associated with increased risk of HNSCC development under homozygous and recessive genetic models, the association was not significant; subgroup analyses showed that 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.The presence of associations between XRCC1 Arg194Trp polymorphism and HNSCC risk under heterozygous and dominant genetic models shows that this polymorphism may play a role in individual differences in susceptibility to HNSCCs. Therefore, one of the ways to prevent head and neck cancer can be to identify genetically susceptible people (e.g., with unfavorable polymorphic variants of XRCC1 Arg194Trp polymorphism) and undergo continuous and regular monitoring to prevent them from developing cancer and if head and neck cancer occurs, they can be diagnosed in the early stages. The insignificant results under homozygous and recessive genetic models show that these genetic models fail to identify relatively small effects of this single nucleotide polymorphism on HNSCC development against a complex background of biological factors or large‐scale population‐based studies are needed to reveal such an effect under these genetic models.In Hu et al.,39 Huang et al.,40 and Feng et al.41 and meta‐analyses on the XRCC1 Arg194Trp polymorphism and risk of cancer, this polymorphism was identified as a biomarker of cancer risk. In Hu et al. meta‐analysis, under dominant genetic model, the Trp/Trp + Arg/Trp genotypes was significantly associated with decreased cancer risk compared to Arg/Arg genotype (OR = 0.89 [95% CI: 0.81–0.98]) for all tumor types (breast, lung, etc.); subgroup analysis in head and neck cancers showed similar results (OR = 0.85 [95%CI: 0.59–1.23])39; their results are inconsistent with the results of present meta‐analysis; the reason for this inconsistency may be due to the very small number of available studies on HNSCC in their meta‐analysis compared to a much larger number of the same studies in the present meta‐analysis. Huang et al. observed in their meta‐analysis that XRCC1 Arg194Trp polymorphism is a cancer risk factor among Chinese population so that a significantly increased risk was found under recessive model (OR = 1.31; 95%CI: 1.13–1.53); in the subgroup analysis, this association was observed for lung and esophageal cancers; among the head and neck cancers, only nasopharyngeal carcinoma was present in their stratification which had no significant association with this polymorphism40; their general results on all type of cancers are consistent with the results of present meta‐analysis except for genetic model. In Feng et al. met‐analysis, a significant increased risk was found under recessive, homozygous and additive models; their results are consistent with the results of present meta‐analysis except for genetic models.41In Flores‐Obando et al. meta‐analysis, there was a significant association between XRCC1 Arg194Trp polymorphism with head and neck cancer risk2 which is consistent with the results of the present meta‐analysis; of course, in their meta‐analysis, the increased OR (OR = 1.69, 95% CI: 1.10–2.58) was observed under the homozygous model; in our meta‐analysis the significant association was observed under heterozygous and dominant genetic models; in their meta‐analysis, a significant increase in HNSCC risk was observed for Asian ethnicity which is consistent with the results of the present meta‐analysis. In both meta‐analyses, no significant association was found for Caucasians ethnicity under heterozygous, homozygous and dominant models. In their meta‐analysis, a significantly increased risk was observed for oral cancers; this is consistent with the results of the present meta‐analysis, although in their meta‐analysis, a significant association was obtained under heterozygous model; in the present meta‐analysis, this association was significant under heterozygous and dominant model.In the three meta‐analyses conducted by Lou et al.,1 Wu et al.,42 and Zhou et al.,43 there were not significant association between XRCC1 Arg194Trp polymorphism and the HNSCC risk under different genetic models; these findings are inconsistent with results of present meta‐analysis; the reason for these inconsistencies can be attributed to the smaller number of studies and the smaller number of cases and controls in their meta‐analysis. In Lou et al. and Wu et al. meta‐analyses, stratification analyses based on ethnicity and genotyping method; these findings are again inconsistent with results of present meta‐analysis. Variants of this polymorphism was significantly associated with a decreased risk of oral cavity cancer under recessive genetic model in Lou et al. meta‐analysis; the direction of results was inconsistent between our meta‐analysis and Lou et al. meta‐analysis in the field of oral cancers. Variants of this polymorphism was significantly associated with an increased risk of oral cavity cancer under the allelic, heterozygote, and dominant models in Wu et al. meta‐analysis; these findings of Wu et al. meta‐analysis are consistent with results of present meta‐analysis. In Lou et al. meta‐analysis,1 subgroup analysis for smoking showed significantly increased risk under homozygous model but in the present meta‐analysis no such association was found. In Zhou et al. meta‐analysis, stratification by ethnicity showed significant association in Asian ethnicity under heterozygous and recessive models43; their finding is consistent with the results of present meta‐analysis except for genetic model.In Zhou et al. meta‐analysis, oral cancer susceptibility was not associated with XRCC1 Arg194Trp polymorphisms, although there was significant increase in the risk of oral cancer in Asian ethnicity under allelic, homozygous, and dominant models.44 In contrast, there was significant association between this polymorphism with oral cavity cancer susceptibility under heterozygous and dominant models in the present meta‐analysis; the reason for the discrepancy could be related to a much larger number of cases and controls in the present meta‐analysis.In Mozaffari et al. and Zhang et al. meta‐analyses on the association of XRCC1 Arg194Trp with oral cancer risk, there were significant increased associations between this polymorphism and oral cancer risk under allelic, heterozygote, and recessive models in Mozaffari et al. meta‐analysis and under dominant model in Zhang et al. met‐analysis.3,45 These results are consistent with the result of the present meta‐analysis. Subgroup analysis according to ethnicity in Zhang et al. meta‐analysis showed that this polymorphism was associated with significantly increased risk of oral cancer in Asians ethnicity under allelic, homozygous, and dominant genetic models.In Lin et al. and Deng et al. meta‐analyses, there were no significant associations between XRCC1 Arg194Trp polymorphism and nasopharyngeal carcinoma under all genetic models.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 meta‐analyses for ease of comparison.3TABLEThe results of existing meta‐analyses on the association of XRCC1 Arg194Trp polymorphism with cancer riskFirst author, yearType of cancerResultsNumber ofSubgroup analysis with significant resultCommentsNon‐significantSignificantStudyCaseControlIncreased riskDecreased riskHu, 200539All cancer types‐‐√3811 95714 174‐Significant results under dominant genetic modelHead and neck‐‐√47231045‐Huang, 201140All cancer types‐√‐34937412 111‐Only Chinese people analyzed; significant results under recessive modelNasopharynx√‐‐37901013‐Feng, 201441All cancer types‐√‐20159 22781 587‐Significant results under recessive, homozygous and additive modelsFlores‐Obando, 20102Head and neck‐√‐1523303834Asian ethnicity (increased risk)Significant results under the homozygous modelOral cavity‐√‐5724818‐Significant results under heterozygous modelLou, 20131Head and neck√‐‐2244786873Smoking (increased risk)Significant results under homozygous modelOral cavity‐‐√69151412‐Significant results under recessive modelWu, 201442Head and neck√‐‐2137716144‐‐Oral cavity‐√‐712251760‐Significant results under the allelic, heterozygote, and dominant modelsZhou, 201443Head and neck√‐‐2033625796Asian ethnicity (increased risk)Significant results under heterozygous and recessive modelsZhou, 200944Oral cavity√‐‐813623130Asian ethnicity (increased risk)Significant results under allelic, homozygous and dominant modelsMozaffari, 20213Oral cavity‐√‐710671602‐Significant results under allelic, heterozygote, and recessive modelsZhang, 201345Oral cavity‐√‐68281412Asian ethnicity (increased risk)Significant results under dominant modelLin, 20184Nasopharynx√‐‐514281519‐‐Deng, 201746Nasopharynx√‐‐48771007‐Restricted to Chinese populationPresent meta‐analysisHead and neck√‐‐3360128270Ethnicity/smoking/genotyping method (all non‐significant)‐Oral cavity‐√‐1219132266Significant result under dominant modelLimitationsAmong the limitations of the present meta‐analysis was the lack of sufficient information in some studies about variables such as age and sex.CONCLUSIONVariants of XRCC1 Arg194Trp polymorphism were associated with increased risk of HNSCC development under different genetic models; the associations were significant under heterozygous and dominant genetic models. There were significant associations between variants of this polymorphism and HNSCC risk based on Asian ethnicity, hospital control source, PCR‐RFLP genotyping method and oral cavity tumor site. Variants of this polymorphism were not significantly associated with increased risk of HNSCC development under different genetic models although they were associated with borderline decreased risk of HNSCC development under recessive genetic model.AUTHOR CONTRIBUTIONSNooshin Mohtasham: Conceptualization (equal); supervision (equal); writing – review 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). 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Journal

Cancer Reports – Wiley

Published: Mar 1, 2023

Keywords: genetic polymorphism; squamous cell carcinoma of head and neck; X‐ray repair cross complementing protein 1

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