Prospective Evaluation of XRCC-1 as a Biopredictor for Survival Outcomes in Patients of Head and Neck Squamous Cell Carcinoma (HNSCC): A Meta-analysis

Prospective Evaluation of XRCC-1 as a Biopredictor for Survival Outcomes in Patients of Head and Neck Squamous Cell Carcinoma (HNSCC): A Meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Prospective Evaluation of XRCC-1 as a Biopredictor for Survival Outcomes in Patients of Head and Neck Squamous Cell Carcinoma (HNSCC): A Meta-analysis Fan Yang, Liu-qing Zhou, Yan-jun Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-698406/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Epidemiologic studies have demonstrated that X-ray repair cross-complementary group 1 (XRCC1) is one of the susceptibility factors in head and neck squamous cell carcinoma(HNSCC) patients. However, its clinical prognostic impact remains controversial. Thus, a meta-analysis was performed to clarify the survival value of XRCC1 in HNSCC patients. Methods: Following the Preferred Reporting Items or Systematic Reviews Meta Analyses (PRISMA) 2020 guidelines, literature searches were systematically performed by PubMed, EMBASE and Web of Science with a manual retreive to evaluate the prognostic consequence of XRCC1 in HNSCC patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) were collected to estimate the correlation between XRCC1 and the survival outcomes of HNSCC patients. Results: Ten studies including 2086 HNSCC patients who satisfied the inclusion and exclusion criteria were included in this meta-analysis. The meta-analysis showed that high XRCC1 expression and Arg399Gln and Arg194Trp were significantly correlated with poorer overall survival (OS), with HRs of 1.97 (95% CI, 1.36–2.84, P<0.001), 1.30 (95% CI, 1.12–1.51, P<0.001), and 1.65 (95% CI, 1.18–2.32 P<0.05), respectively. Conclusion: XRCC1 was associated with poorer survival outcomes in HNSCC patients. Hence, XRCC1 is a potential therapeutic target for HNSCC. Cancer Biology XRCC1 HNSCC Prognosis Meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Head and neck squamous cell carcinomas (HNSCC) is the fifth most common cancer in the world and accounts for approximately 3% of new cancer cases annually. It is a malignant disease of the upper aerodigestive tract, including oral, pharyngeal and laryngeal regions. Current treatment strategies for patients with HNSCC involve surgery, chemotherapy, immunotherapy, radiotherapy and so on. However, with such treatments, the survival results of HNSCC patients were still not satisfactory. The survival of HNSCC patients remain unsatisfactory. Specifically, the five-year survival rate of HNSCC patients is estimated to be near 50% due to high mortality and early disease recurrence. Therefore, there is an urgent need to identify new predictive biomarkers to improve the overall survival (OS) of HNSCC patients. Epidemiologic data showed that tobacco and alcohol consumption are the main etiological factors in the carcinogenesis of HNSCC. These risk factors, such as benzo(a)pyrene from tobacco, can induce an increase in reactive oxygen species levels that leads to oxidative DNA damage in the epithelial cells of the head and neck region, which stimulates HNSCC occurrence. However, not all individuals with these risk factors develop HNSCC, suggesting that individual susceptibility might also play a role in HNSCC carcinogenesis. The DNA repair pathway can generally correct base lesions. In contrast, defects in the DNA repair system can also result in genetic instability and carcinogenesis. Single-nucleotide polymorphisms (SNPs) are genetic variants that are related to cancer susceptibility[ 1 ]. Hence, common genetic polymorphisms in genes involved in DNA repair capacity may play key roles in individual susceptibility and prognosis in HNSCC. The primary DNA repair pathway that corrects base lesions is the base excision repair. X-ray repair cross-complementary group 1 (XRCC1) is a master DNA repair gene involved in base excision repair[ 2 ]. The capacity to repair damaged cells with XRCC1 is encoded by polymorphic genes that may modify the expression of encoded proteins and proteins. Consequently, the DNA repair ability is modified. Recently, XRCC1 gene SNPs within conserved sequences have been identified. Arg399Gln (rs25487) and Arg194Trp (rs1799782) are the main variant alleles [ 3 , 4 ]. A number of studies have investigated the association between XRCC1 polymorphisms and HNSCC risk. However, the association between XRCC1 SNPs or expression and the survival outcomes in HNSCC patients is still largely controversial or unknown. Thus, a meta-analysis including a total of 10 studies with 2086 patients was performed by systematically searching for relevant publications from the PubMed, EMBASE, and Web of Science databases to provide a systematic evaluation of the diagnostic and prognostic role of XRCC1 polymorphisms and expression in HNSCC patients. Methods Search strategy Comprehensively searches in PubMed, Web of Science and EMBASE were performed using the following search terms: (XRCC1 or X-ray repair cross-complementing 1) and (prognosis OR outcome OR mortality OR survival OR progression OR recurrence) and (head and neck or laryngeal or tonsil or oropharyngeal or oral or oropharynx or nasopharyngeal) and (squamous cell cancer or carcinoma).Related papers published from September 2006 to March 2021 were selected. Selection criteria The inclusion criteria of the meta-analysis were as follows: 1) all patients diagnosed with HNSCC; 2) the study revealed the association between XRCC1 and survival of HNSCC; 3) selected the English language of publications only; 4) including hazard ratios (HR) with prognostic endpoints and the 95% confidence interval(CI) directly, or other data such as Kaplan- Meier survival curves that can be estimate for OS. The criteria of exclusion included: 1) studies without exsiting HR and 95% CI data for meta-analysis, or other outcomes for OS such as Kaplan- Meier survival curves. 2) Other text formats: abstracts, reviews, letters and case reports; and 3) The data of the article has nothing to do with HNSCC or XRCC1. In case of the same cohort reported by several publications, Latest literature gained the priority . Data extraction Following the Preferred Reporting Items or Systematic Reviews Meta Analyses (PRISMA) 2021 guidelines [ 5 ], electronic searches for relevant studies were performed in PubMed, EMBASE and Web of Science databases till March 1, 2021. Data were carefully extracted and tabulated by two independent researchers (LQ Zhou and Fan Yang) to minimize variation. In order to achieve a consensus, disagreements were solved by adjustments of the third researcher(YJ Wang). The following information was extracted from the studies: author, year, country, ethnicity, cancer type, sample size, age, follow-up, method, and HR value. The Newcastle–Ottawa Scale (NOS) was included to assess the quality of the included publications, and a star system (maximum is nine stars) was adopted to evaluate a study in three domains: comparability of study groups, selection of participants and ascertainment of outcomes of interest. Scores of NOS ≥ 6 indicated high-quality studies[ 6 ]. Reporting recommendations for tumor marker prognostic studies (REMARK) were also applied to evaluate study quality in cancer-related meta-analyses[ 7 ]. Statistical analysis The value of survival outcome between XRCC1 polymorphisms or expression and HNSCC was measured by HR and 95% CI, which were obtained directly or estimated from the primary publications or estimated by p values and other published data following Parmer’s methods[ 8 ]. Heterogeneity was assessed by the χ 2 -based Q test and the I 2 test. The fixed-effects model was employed for analysis without obvious statistical heterogeneity between studies (P > 0.10, I 2 < 50%). Otherwise, the random-effects model was applied. Moreover, we performed subgroup analysis to explore the potential source of heterogeneity. Sensitivity analysis was also enrolled to investigate the influence of each individual study on the overall pooled results. Publication bias was assessed by Begg’s and Egger’s. All of the statistical tests used in this meta-analysis were performed with Stata version 12.0 (StataCorp, College Station, TX, USA). Results Study selection and characteristics As shown in Fig. 1, 231 published articles were identified by searching the electronic databases. Out of 231 studies, duplicates (n = 131), reviews, abstracts and letters (n = 16) and the studies not related to the topics (n = 44 )were excluded. The retrieved publications(n = 40) were further evaluated by reading their full texts, and 30 studies were discarded due to the lack of specific data regarding HNSCC or XRCC1. Finally, 10 studies with 2086 HNSCC patients were selected. The characteristics of the enrolled studies were summarized in Table 1. Six for HNSCC, one for laryngeal squamous cell carcinoma (LSCC), one for oral squamous cell carcinomas (OSCC),one for nasopharyngeal carcinoma (NPC) and one for oropharyngeal squamous cell carcinoma (OPSCC) were included. Sample sizes of the publications ranged from 75 to 531. Two publications enrolled > 500 patients. XRCC1 SNPs were explored by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and immunohistochemical (IHC) staining of XRCC1 protein technology were applied for XRCC1 protein expression. In the original literature, half of the studies reported the HR and 95% CI directly, and the remaining studies only provided Kaplan-Meier survival curves. All of the publications’ NOS scores were above 6 and the REMARK scores were between 13 and 16. Table 1 Characteristics of the studies examined in the meta-analysis Author Year Country Ethnicity Cancer type Sample size Age Follow-up （ month ） Method HR NOS/REMARK score Azad [9 ] 2012 Canada Non-Asian HNSCC 531 63 (33–86) 100.52 PCR-RFLP Reported 7/14 Costa[2] 2016 Brazil Non-Asian OPSCC 200 57(33-85) 24.5（1.5-116.7） RT‑PCR Reported 7/16 Hirakawa [4] 2020 Japan Asian HNSCC 225 67（41-91） 48（3-146） PCR-RFLP Estimated 6/14 Jin [10] 2014 China Asian NPC 75 45(22–72) 25(5-46) IHC Reported 7/14 Fandino [1] 2006 Spain Non-Asian HNSCC 103 60.09(39.09-94.00) 22.5(9-51) PCR-RFLP Estimated 8/15 Ang [11] 2011 America Non-Asian HNSCC 77 56(39-61) 66（39-87） IHC Reported 7/14 Bold [12] 2021 German Non-Asian HNSCC 519 NR 60 IHC Estimated 7/14 Wang1 [13] 2021 China Asian OSCC 98 51(31-76) 40(2.4-137.4) IHC Reported 8/16 Wang2 [13] 2021 China Asian OSCC 98 51(31-76) 40(2.4-137.4) IHC Reported 7/15 Csejtei [3] 2009 Hungary Non-Asian HNSCC 108 56.7 60 PCR-RFLP Estimated 6/13 Raturi [14] 2020 Japan Asian LSCC 150 56(32-64) 33 PCR-RFLP Reported 6/14 Association between XRCC1 and survival in HNSCC patients Ten articles with 2086 patients in the meta-analysis evluated the survival value of XRCC1 for patients with HNSCC. The pooled HR for high XRCC1 expression was 1.97 (95%CI, 1.36–2.84, P < 0.001), for the XRCC1 Arg399Gln was 1.30 (95% CI, 1.12–1.51, P < 0.001) and for the XRCC1 Arg194Trp was 1.65 (95% CI, 1.18–2.32, P < 0.005). The heterogeneity between high XRCC1 expression and OS (I 2 = 16.1%, P heterogeneity = 0.304) was slight, and moderate heterogeneity was noted between XRCC1Arg194Trp and OS. (I 2 = 53.0%, P heterogeneity =0.119), while the heterogeneity between XRCC1 Arg399Gln and OS was low (I 2 = 46.2%, P heterogeneity = 0.115) (Fig. 2). Sensitivity analysis During the process of comprehensive comparisons, we conducted sensitivity analyses to evaluate the effect of each single data point against the aggregate. The recalculated outcomes (Fig. 3)were not substantially influenced, suggesting that the combined effect size of the meta-analysis results was stable and reliable. Publication bias Begg's funnel plots and Egger's test were applied to validate potential bias from searched publications. The result indicates bias existed (p = 0.014). Therefore, “trim and fill” analysis was further utilized, and the pooled HR of 1.253 (95% CI: 1.115–1.408) remained statistically significant (Figure. 4),overall, the results are relatively reliable in spite of the significant publication bias. Discussion Head and neck cancers are a heterogeneous group of secondary cancers[ 9 ], with a high rate of early recurrence and mortality. However, radiotherapy and chemotherapy have been widely used in the clinic and have recently been shown to be effective. The survival rates of advanced HNSCC are approximately 50% and have not changed significantly in recent years. This may be due to the individual's treatment response controlled by intrinsic genetics. In a previous study, oncogene genes in HNSCC were identified through extensive DNA sequencing and genetic analysis[ 10 ]. Therefore, it is reasonable to quest potential biomarkers of treatment by analyzing genomic features. DNA repair genes have been considered driver genes of HNSCC due to their frequent mutation. Defects in DNA repair promote genomic instability and carcinogenesis [ 11 ]. DNA repair systems play an indispensable role in protecting cells against carcinogenic agents from internal and external stimuli[ 12 ]. Statistical analyses indicated that the DNA repair status of a tumor is associated with poor prognosis in cancer [ 13 , 14 ]. XRCC1 is a major DNA repair gene involved in base excision repair (BER) for small base lesions resulting from oxidation and alkylation damage[ 15 , 16 ]. More than 300 validated SNPs in the XRCC1 gene were reported in the dbSNP database ( http://www.ncbi.nlm.nih.gov/SNP ). Among them, the XRCC1 genes Arg194Trp and Arg399Gln, which occur within conserved sequences, are the most frequently mutated genes and the most extensively studied. Studies have investigated the association between XRCC1 Arg399Gln/XRCC1 Arg194Trp polymorphisms and HNSCC risk [ 17 – 23 ]. However, these results were contradictory. Wang [ 24 ] conducted a meta-analysis on the association of XRCC1 Arg399Gln polymorphisms with HNSCC risk. Nevertheless, they did not observe any precise estimation of this relationship based on 18 published studies. Sturgis [ 25 ] reported a reduced risk between XRCC1 Arg194Trp and HNSCC while Andrew[ 26 ] found a weak elevation between HNSCC risk and the XRCC1 Arg194Trp polymorphism. XRCC1 protein is involved in BER [ 27 , 28 ], and its protein expression alters the sensitivity of cells to radiation and chemotherapeutic agents [ 29 ]. It was reported that high protein expression levels of XRCC1 may be a risk factor for HNSCC [ 30 , 31 ]. In addition, XRCC1 protein expression is common in HNSCC, and high XRCC1 protein expression may confer poorer survival, regardless of the primary tumor site or stage [ 31 , 32 ]. In summary, these results either contrast with each other or are not accurate conclusions. In addition, this systematic review or meta-analysis prospectively evaluated XRCC1 as a biopredictor of survival outcomes in patients with HNSCC. There is no doubt that our study is the first meta-analysis including 10 published studies with 2086 patients to comprehensively evaluate the value of XRCC1 (SNPs and protein expression) and offer useful information for clinical decision-making in HNSCC. After analyzing and summarizing all of the selected data, the results indicate that high expression and SNPs (Arg194Trp and Arg399Gln) of XRCC1 significantly predicted poorer OS in HNSCC patients with HRs of 1.97, 1.65, and 1.30, respectively. These findings confirmed that XRCC1 could be widely applied as a diagnostic marker and therapeutic target in HNSCC patients. As a genetic association literature, the Hardy-Weinberg (HWE) principle is also considered to avoid methodological weaknesses, such as biased selection of subjects or genotyping errors. The enrolled studies were all in agreement with HWE. This meta-analysis should be interpreted within the context of its limitations. First, studies containing only English languages and only published articles were included, which may contribute to additional bias. Therefore, publication bias is very likely to occur. In light of Begg's funnel plots and Egger's test, no significant publication bias was present in this meta-analysis. Second, the number of articles was limited, and the sample size was relatively small in the present meta-analysis. False-positive or false-negative findings may have occurred in small sample sizes. Therefore, our results of the survival value in analyses might have occurred by chance, and more large-scale and comprehensive studies are needed to achieve a more persuasive conclusion. Third, the method of HR extrapolation from the Kaplan-Meier graph may also generate heterogeneity because the HRs of the five records enrolled were calculated by Parmer's methods and not directly reported. Last, studies with positive results are more likely to be published and thus more likely to be enrolled. Hence, the survival value of XRCC1 in HNSCC may to some extent have been overestimated in this meta-analysis. In summary, our systematic review or meta-analysis was conducted to identify XRCC1 from all primary relevant articles and to evaluate the potential prognostic value of XRCC1 in HNSCC. The results demonstrated that both XRCC1 polymorphisms (Arg194Trp and Arg399Gln) and XRCC1 protein high expression exhibited poor survival in HNSCC patients. The prognostic value of XRCC1 in HNSCC patients is undoubtedly known. However, larger prospective studies should be conducted in the future to further verify the outcomes from this current meta-analysis Declarations Acknowledgements This study was supported by grants from the National 12th-Five Year Research Program of China (no.2012BAI12B02)and Health Commission of Hubei Province scientific research project (no.wj2021M250). Ethics approval and consent to participate: Not applicable. Consent for publication: I agree that the text and any pictures or videos published in the article will be freely available on the internet and may be seen by the general public. The pictures, videos and text may also appear on other websites or in print, may be translated into other languages or used for commercial purposes. Availability of data and materials: All data generated or analyzed during this study are included in this published article [and its supplementary information files]. Competing interests: The author(s) declare(s) that they have no competing interests. Funding: Not applicable. Authors' contributions: YF and LZ collected and analyzed the data, wrote the paper. LZ, YF and JW analyzed the data and wrote the paper. LZ and JW conceived and designed this study, analyzed the data, wrote the paper. All authors read and approved the final manuscript. Acknowledgements: Not applicable. Data availability statements All data generated or analyzed during this study are included in this published article [and its supplementary information files]. The data that support the findings of this study are available from the corresponding author upon reasonable request. References Quintela-Fandino, M., et al., DNA-repair gene polymorphisms predict favorable clinical outcome among patients with advanced squamous cell carcinoma of the head and neck treated with cisplatin-based induction chemotherapy . J Clin Oncol, 2006. 24 (26): p. 4333–9. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-698406","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":39348407,"identity":"803c9dee-2fde-4fff-b704-c7b8e5610669","order_by":0,"name":"Fan Yang","email":"","orcid":"","institution":"Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Fan","middleName":"","lastName":"Yang","suffix":""},{"id":39348410,"identity":"ad4a50e8-9a43-4328-86b6-453e5d4eb0f4","order_by":1,"name":"Liu-qing Zhou","email":"","orcid":"","institution":"Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Liu-qing","middleName":"","lastName":"Zhou","suffix":""},{"id":39348412,"identity":"ca95f981-2bd1-44f8-8874-22a44b48a1b5","order_by":2,"name":"Yan-jun Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIie3LvQrCMBDA8SsBp1bXSkF9hIhjxWdpCOgmgtC5k1PR1eJLFATnlICTNmugDvoGgiDFD7DqbuommP9w3MH9AHS6n4w9R9d7H5XypF8QVJq84l8QnGzap9FFDLEQDI4+h9oiUBC26TjRNBtjScGYpxzsHVORbexYYUZiiQBZEw7Y9pRkebXClMSCA7qXJCvHzBmJGQVklCF1Js6uFVASSYqTMB2YtlSQqlzTzLz1yFQkh33uu43aXEFakgEYk/dRrGB+/i9qzoJi3pR/Op1O9889AKmcTpjNmcvhAAAAAElFTkSuQmCC","orcid":"","institution":"Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yan-jun","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2021-07-08 11:59:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-698406/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-698406/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":11495360,"identity":"bf979ab6-a98e-418c-b4a1-32334a2a9c51","added_by":"auto","created_at":"2021-07-15 15:23:07","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":22476,"visible":true,"origin":"","legend":"Flow diagram of the selection of relevant studies included in the meta-analysis","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-698406/v1/45c74ca897488c3180980bad.png"},{"id":11495361,"identity":"a87cb717-6740-4b90-b478-5a5693288174","added_by":"auto","created_at":"2021-07-15 15:23:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":67506,"visible":true,"origin":"","legend":"Forest plot indicating the association between XRCC1 polymorphisms (Arg194Trp and Arg399Gln) / high XRCC1 protein expression and OS in HNSCC ","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-698406/v1/aecaa3ffe0eeac4163c0806c.png"},{"id":11495905,"identity":"7bbb1ff6-76a1-4e03-a356-da7e88c70e2d","added_by":"auto","created_at":"2021-07-15 15:26:07","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":23149,"visible":true,"origin":"","legend":"The sensitivity analyses were conducted to evaluate the effects of each single study on the overall effect ","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-698406/v1/56442e5652f97d45408800bd.png"},{"id":11495362,"identity":"654ce5b2-eda8-4ef3-a245-553255d8f46c","added_by":"auto","created_at":"2021-07-15 15:23:07","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":144482,"visible":true,"origin":"","legend":"Publication bias and trim and fill analysis of the enrolled analysis. a The Begg’s funnel plots; b The Egger’s test. c Trim and fill analysis ","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-698406/v1/d909f59216e22d0adb34ebed.png"},{"id":15526197,"identity":"080a7f0e-1441-4ba6-8aa2-c940bbd30854","added_by":"auto","created_at":"2021-11-15 00:14:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":468539,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-698406/v1/4d6a42e6-5f4f-4797-aabd-30a5737d14c6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eProspective Evaluation of XRCC-1 as a Biopredictor for Survival Outcomes in Patients of Head and Neck Squamous Cell Carcinoma (HNSCC): A Meta-analysis\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHead and neck squamous cell carcinomas (HNSCC) is the fifth most common cancer in the world and accounts for approximately 3% of new cancer cases annually. It is a malignant disease of the upper aerodigestive tract, including oral, pharyngeal and laryngeal regions. Current treatment strategies for patients with HNSCC involve surgery, chemotherapy, immunotherapy, radiotherapy and so on. However, with such treatments, the survival results of HNSCC patients were still not satisfactory. The survival of HNSCC patients remain unsatisfactory. Specifically, the five-year survival rate of HNSCC patients is estimated to be near 50% due to high mortality and early disease recurrence. Therefore, there is an urgent need to identify new predictive biomarkers to improve the overall survival (OS) of HNSCC patients. Epidemiologic data showed that tobacco and alcohol consumption are the main etiological factors in the carcinogenesis of HNSCC. These risk factors, such as benzo(a)pyrene from tobacco, can induce an increase in reactive oxygen species levels that leads to oxidative DNA damage in the epithelial cells of the head and neck region, which stimulates HNSCC occurrence. However, not all individuals with these risk factors develop HNSCC, suggesting that individual susceptibility might also play a role in HNSCC carcinogenesis.\u003c/p\u003e \u003cp\u003eThe DNA repair pathway can generally correct base lesions. In contrast, defects in the DNA repair system can also result in genetic instability and carcinogenesis. Single-nucleotide polymorphisms (SNPs) are genetic variants that are related to cancer susceptibility[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Hence, common genetic polymorphisms in genes involved in DNA repair capacity may play key roles in individual susceptibility and prognosis in HNSCC.\u003c/p\u003e \u003cp\u003eThe primary DNA repair pathway that corrects base lesions is the base excision repair. X-ray repair cross-complementary group 1 (XRCC1) is a master DNA repair gene involved in base excision repair[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The capacity to repair damaged cells with XRCC1 is encoded by polymorphic genes that may modify the expression of encoded proteins and proteins. Consequently, the DNA repair ability is modified. Recently, XRCC1 gene SNPs within conserved sequences have been identified. Arg399Gln (rs25487) and Arg194Trp (rs1799782) are the main variant alleles [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA number of studies have investigated the association between XRCC1 polymorphisms and HNSCC risk. However, the association between XRCC1 SNPs or expression and the survival outcomes in HNSCC patients is still largely controversial or unknown. Thus, a meta-analysis including a total of 10 studies with 2086 patients was performed by systematically searching for relevant publications from the PubMed, EMBASE, and Web of Science databases to provide a systematic evaluation of the diagnostic and prognostic role of XRCC1 polymorphisms and expression in HNSCC patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch strategy\u003c/h2\u003e \u003cp\u003eComprehensively searches in PubMed, Web of Science and EMBASE were performed using the following search terms: (XRCC1 or X-ray repair cross-complementing 1) and (prognosis OR outcome OR mortality OR survival OR progression OR recurrence) and (head and neck or laryngeal or tonsil or oropharyngeal or oral or oropharynx or nasopharyngeal) and (squamous cell cancer or carcinoma).Related papers published from September 2006 to March 2021 were selected.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSelection criteria\u003c/h2\u003e \u003cp\u003eThe inclusion criteria of the meta-analysis were as follows: 1) all patients diagnosed with HNSCC; 2) the study revealed the association between XRCC1 and survival of HNSCC; 3) selected the English language of publications only; 4) including hazard ratios (HR) with prognostic endpoints and the 95% confidence interval(CI) directly, or other data such as Kaplan- Meier survival curves that can be estimate for OS. The criteria of exclusion included: 1) studies without exsiting HR and 95% CI data for meta-analysis, or other outcomes for OS such as Kaplan- Meier survival curves. 2) Other text formats: abstracts, reviews, letters and case reports; and 3) The data of the article has nothing to do with HNSCC or XRCC1. In case of the same cohort reported by several publications, Latest literature gained the priority .\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData extraction\u003c/h2\u003e \u003cp\u003eFollowing the Preferred Reporting Items or Systematic Reviews Meta Analyses (PRISMA) 2021 guidelines [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], electronic searches for relevant studies were performed in PubMed, EMBASE and Web of Science databases till March 1, 2021. Data were carefully extracted and tabulated by two independent researchers (LQ Zhou and Fan Yang) to minimize variation. In order to achieve a consensus, disagreements were solved by adjustments of the third researcher(YJ Wang). The following information was extracted from the studies: author, year, country, ethnicity, cancer type, sample size, age, follow-up, method, and HR value. The Newcastle\u0026ndash;Ottawa Scale (NOS) was included to assess the quality of the included publications, and a star system (maximum is nine stars) was adopted to evaluate a study in three domains: comparability of study groups, selection of participants and ascertainment of outcomes of interest. Scores of NOS\u0026thinsp;\u0026ge;\u0026thinsp;6 indicated high-quality studies[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Reporting recommendations for tumor marker prognostic studies (REMARK) were also applied to evaluate study quality in cancer-related meta-analyses[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe value of survival outcome between XRCC1 polymorphisms or expression and HNSCC was measured by HR and 95% CI, which were obtained directly or estimated from the primary publications or estimated by \u003cem\u003ep\u003c/em\u003e values and other published data following Parmer\u0026rsquo;s methods[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Heterogeneity was assessed by the χ\u003csup\u003e2\u003c/sup\u003e-based Q test and the I\u003csup\u003e2\u003c/sup\u003e test. The fixed-effects model was employed for analysis without obvious statistical heterogeneity between studies (P\u0026thinsp;\u0026gt;\u0026thinsp;0.10, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026lt;\u0026thinsp;50%). Otherwise, the random-effects model was applied. Moreover, we performed subgroup analysis to explore the potential source of heterogeneity. Sensitivity analysis was also enrolled to investigate the influence of each individual study on the overall pooled results. Publication bias was assessed by Begg\u0026rsquo;s and Egger\u0026rsquo;s. All of the statistical tests used in this meta-analysis were performed with Stata version 12.0 (StataCorp, College Station, TX, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv class=\"Section2\" id=\"Sec8\"\u003e\n \u003ch2\u003eStudy selection and characteristics\u003c/h2\u003e\n \u003cp\u003eAs shown in Fig.\u0026nbsp;1, 231 published articles were identified by searching the electronic databases. Out of 231 studies, duplicates (n\u0026thinsp;=\u0026thinsp;131), reviews, abstracts and letters (n\u0026thinsp;=\u0026thinsp;16) and the studies not related to the topics (n\u0026thinsp;=\u0026thinsp;44 )were excluded. The retrieved publications(n\u0026thinsp;=\u0026thinsp;40) were further evaluated by reading their full texts, and 30 studies were discarded due to the lack of specific data regarding HNSCC or XRCC1. Finally, 10 studies with 2086 HNSCC patients were selected.\u003c/p\u003e\n \u003cp\u003eThe characteristics of the enrolled studies were summarized in Table\u0026nbsp;1. Six for HNSCC, one for laryngeal squamous cell carcinoma (LSCC), one for oral squamous cell carcinomas (OSCC),one for nasopharyngeal carcinoma (NPC) and one for oropharyngeal squamous cell carcinoma (OPSCC) were included. Sample sizes of the publications ranged from 75 to 531. Two publications enrolled\u0026thinsp;\u0026gt;\u0026thinsp;500 patients. XRCC1 SNPs were explored by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and immunohistochemical (IHC) staining of XRCC1 protein technology were applied for XRCC1 protein expression. In the original literature, half of the studies reported the HR and 95% CI directly, and the remaining studies only provided Kaplan-Meier survival curves. All of the publications\u0026rsquo; NOS scores were above 6 and the REMARK scores were between 13 and 16.\u003c/p\u003e\n \u003cp style=\"text-align: center;\"\u003eTable 1\u003c/p\u003e\n \u003cp style=\"text-align: center;\"\u003eCharacteristics of the studies examined in the meta-analysis\u003c/p\u003e\n \u003ctable align=\"left\" border=\"0\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" width=\"8.755760368663594%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAuthor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"4.23963133640553%\"\u003e\n \u003cp\u003e\u003cstrong\u003eYear\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"5.43778801843318%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCountry\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"7.28110599078341%\"\u003e\n \u003cp\u003e\u003cstrong\u003eEthnicity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"9.03225806451613%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCancer type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"7.8341013824884795%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSample size\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"12.258064516129032%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"12.995391705069125%\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003emonth\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"7.557603686635945%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMethod\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"9.953917050691244%\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" width=\"14.654377880184331%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNOS/REMARK score\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.755760368663594%\"\u003e\n \u003cp\u003eAzad\u0026nbsp;[9\u0026nbsp;]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.23963133640553%\"\u003e\n \u003cp\u003e2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.43778801843318%\"\u003e\n \u003cp\u003eCanada\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.28110599078341%\"\u003e\n \u003cp\u003eNon-Asian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.03225806451613%\"\u003e\n \u003cp\u003eHNSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.8341013824884795%\"\u003e\n \u003cp\u003e531\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.258064516129032%\"\u003e\n \u003cp\u003e63 (33\u0026ndash;86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.995391705069125%\"\u003e\n \u003cp\u003e100.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.557603686635945%\"\u003e\n \u003cp\u003ePCR-RFLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.953917050691244%\"\u003e\n \u003cp\u003eReported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.654377880184331%\"\u003e\n \u003cp\u003e7/14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.755760368663594%\"\u003e\n \u003cp\u003eCosta[2]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.23963133640553%\"\u003e\n \u003cp\u003e2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.43778801843318%\"\u003e\n \u003cp\u003eBrazil\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.28110599078341%\"\u003e\n \u003cp\u003eNon-Asian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.03225806451613%\"\u003e\n \u003cp\u003eOPSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.8341013824884795%\"\u003e\n \u003cp\u003e200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.258064516129032%\"\u003e\n \u003cp\u003e57(33-85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.995391705069125%\"\u003e\n \u003cp\u003e24.5（1.5-116.7）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.557603686635945%\"\u003e\n \u003cp\u003eRT‑PCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.953917050691244%\"\u003e\n \u003cp\u003eReported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.654377880184331%\"\u003e\n \u003cp\u003e7/16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.755760368663594%\"\u003e\n \u003cp\u003eHirakawa\u0026nbsp;[4]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.23963133640553%\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.43778801843318%\"\u003e\n \u003cp\u003eJapan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.28110599078341%\"\u003e\n \u003cp\u003eAsian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.03225806451613%\"\u003e\n \u003cp\u003eHNSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.8341013824884795%\"\u003e\n \u003cp\u003e225\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.258064516129032%\"\u003e\n \u003cp\u003e67（41-91）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.995391705069125%\"\u003e\n \u003cp\u003e48（3-146）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.557603686635945%\"\u003e\n \u003cp\u003ePCR-RFLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.953917050691244%\"\u003e\n \u003cp\u003eEstimated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.654377880184331%\"\u003e\n \u003cp\u003e6/14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.755760368663594%\"\u003e\n \u003cp\u003eJin\u0026nbsp;[10]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.23963133640553%\"\u003e\n \u003cp\u003e2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.43778801843318%\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.28110599078341%\"\u003e\n \u003cp\u003eAsian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.03225806451613%\"\u003e\n \u003cp\u003eNPC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.8341013824884795%\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.258064516129032%\"\u003e\n \u003cp\u003e45(22\u0026ndash;72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.995391705069125%\"\u003e\n \u003cp\u003e25(5-46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.557603686635945%\"\u003e\n \u003cp\u003eIHC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.953917050691244%\"\u003e\n \u003cp\u003eReported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.654377880184331%\"\u003e\n \u003cp\u003e7/14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.755760368663594%\"\u003e\n \u003cp\u003eFandino\u0026nbsp;[1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.23963133640553%\"\u003e\n \u003cp\u003e2006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.43778801843318%\"\u003e\n \u003cp\u003eSpain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.28110599078341%\"\u003e\n \u003cp\u003eNon-Asian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.03225806451613%\"\u003e\n \u003cp\u003eHNSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.8341013824884795%\"\u003e\n \u003cp\u003e103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.258064516129032%\"\u003e\n \u003cp\u003e60.09(39.09-94.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.995391705069125%\"\u003e\n \u003cp\u003e22.5(9-51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.557603686635945%\"\u003e\n \u003cp\u003ePCR-RFLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.953917050691244%\"\u003e\n \u003cp\u003eEstimated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.654377880184331%\"\u003e\n \u003cp\u003e8/15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.755760368663594%\"\u003e\n \u003cp\u003eAng\u0026nbsp;[11]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.23963133640553%\"\u003e\n \u003cp\u003e2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.43778801843318%\"\u003e\n \u003cp\u003eAmerica\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.28110599078341%\"\u003e\n \u003cp\u003eNon-Asian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.03225806451613%\"\u003e\n \u003cp\u003eHNSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.8341013824884795%\"\u003e\n \u003cp\u003e77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.258064516129032%\"\u003e\n \u003cp\u003e56(39-61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.995391705069125%\"\u003e\n \u003cp\u003e66（39-87）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.557603686635945%\"\u003e\n \u003cp\u003eIHC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.953917050691244%\"\u003e\n \u003cp\u003eReported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.654377880184331%\"\u003e\n \u003cp\u003e7/14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.755760368663594%\"\u003e\n \u003cp\u003eBold\u0026nbsp;[12]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.23963133640553%\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.43778801843318%\"\u003e\n \u003cp\u003eGerman\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.28110599078341%\"\u003e\n \u003cp\u003eNon-Asian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.03225806451613%\"\u003e\n \u003cp\u003eHNSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.8341013824884795%\"\u003e\n \u003cp\u003e519\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.258064516129032%\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.995391705069125%\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.557603686635945%\"\u003e\n \u003cp\u003eIHC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.953917050691244%\"\u003e\n \u003cp\u003eEstimated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.654377880184331%\"\u003e\n \u003cp\u003e7/14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.755760368663594%\"\u003e\n \u003cp\u003eWang1\u0026nbsp;[13]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.23963133640553%\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.43778801843318%\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.28110599078341%\"\u003e\n \u003cp\u003eAsian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.03225806451613%\"\u003e\n \u003cp\u003eOSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.8341013824884795%\"\u003e\n \u003cp\u003e98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.258064516129032%\"\u003e\n \u003cp\u003e51(31-76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.995391705069125%\"\u003e\n \u003cp\u003e40(2.4-137.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.557603686635945%\"\u003e\n \u003cp\u003eIHC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.953917050691244%\"\u003e\n \u003cp\u003eReported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.654377880184331%\"\u003e\n \u003cp\u003e8/16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.755760368663594%\"\u003e\n \u003cp\u003eWang2\u0026nbsp;[13]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.23963133640553%\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.43778801843318%\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.28110599078341%\"\u003e\n \u003cp\u003eAsian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.03225806451613%\"\u003e\n \u003cp\u003eOSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.8341013824884795%\"\u003e\n \u003cp\u003e98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.258064516129032%\"\u003e\n \u003cp\u003e51(31-76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.995391705069125%\"\u003e\n \u003cp\u003e40(2.4-137.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.557603686635945%\"\u003e\n \u003cp\u003eIHC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.953917050691244%\"\u003e\n \u003cp\u003eReported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.654377880184331%\"\u003e\n \u003cp\u003e7/15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.755760368663594%\"\u003e\n \u003cp\u003eCsejtei\u0026nbsp;[3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.23963133640553%\"\u003e\n \u003cp\u003e2009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.43778801843318%\"\u003e\n \u003cp\u003eHungary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.28110599078341%\"\u003e\n \u003cp\u003eNon-Asian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.03225806451613%\"\u003e\n \u003cp\u003eHNSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.8341013824884795%\"\u003e\n \u003cp\u003e108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.258064516129032%\"\u003e\n \u003cp\u003e56.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.995391705069125%\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.557603686635945%\"\u003e\n \u003cp\u003ePCR-RFLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.953917050691244%\"\u003e\n \u003cp\u003eEstimated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.654377880184331%\"\u003e\n \u003cp\u003e6/13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.755760368663594%\"\u003e\n \u003cp\u003eRaturi\u0026nbsp;[14]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.23963133640553%\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.43778801843318%\"\u003e\n \u003cp\u003eJapan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.28110599078341%\"\u003e\n \u003cp\u003eAsian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.03225806451613%\"\u003e\n \u003cp\u003eLSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.8341013824884795%\"\u003e\n \u003cp\u003e150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.258064516129032%\"\u003e\n \u003cp\u003e56(32-64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.995391705069125%\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.557603686635945%\"\u003e\n \u003cp\u003ePCR-RFLP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.953917050691244%\"\u003e\n \u003cp\u003eReported\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.654377880184331%\"\u003e\n \u003cp\u003e6/14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec9\"\u003e\n \u003ch2\u003eAssociation between XRCC1 and survival in HNSCC patients\u003c/h2\u003e\n \u003cp\u003eTen articles with 2086 patients in the meta-analysis evluated the survival value of XRCC1 for patients with HNSCC. The pooled HR for high XRCC1 expression was 1.97 (95%CI, 1.36\u0026ndash;2.84, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), for the XRCC1 Arg399Gln was 1.30 (95% CI, 1.12\u0026ndash;1.51, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and for the XRCC1 Arg194Trp was 1.65 (95% CI, 1.18\u0026ndash;2.32, P\u0026thinsp;\u0026lt;\u0026thinsp;0.005). The heterogeneity between high XRCC1 expression and OS (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;16.1%, P\u003csub\u003eheterogeneity\u003c/sub\u003e= 0.304) was slight, and moderate heterogeneity was noted between XRCC1Arg194Trp and OS. (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;53.0%, P\u003csub\u003eheterogeneity\u003c/sub\u003e=0.119), while the heterogeneity between XRCC1 Arg399Gln and OS was low (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;46.2%, P\u003csub\u003eheterogeneity\u003c/sub\u003e= 0.115) (Fig.\u0026nbsp;2).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec10\"\u003e\n \u003ch2\u003eSensitivity analysis\u003c/h2\u003e\n \u003cp\u003eDuring the process of comprehensive comparisons, we conducted sensitivity analyses to evaluate the effect of each single data point against the aggregate. The recalculated outcomes (Fig.\u0026nbsp;3)were not substantially influenced, suggesting that the combined effect size of the meta-analysis results was stable and reliable.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec11\"\u003e\n \u003ch2\u003ePublication bias\u003c/h2\u003e\n \u003cp\u003eBegg\u0026apos;s funnel plots and Egger\u0026apos;s test were applied to validate potential bias from searched publications. The result indicates bias existed (p\u0026thinsp;=\u0026thinsp;0.014). Therefore, \u0026ldquo;trim and fill\u0026rdquo; analysis was further utilized, and the pooled HR of 1.253 (95% CI: 1.115\u0026ndash;1.408) remained statistically significant (Figure. 4),overall, the results are relatively reliable in spite of the significant publication bias.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eHead and neck cancers are a heterogeneous group of secondary cancers[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], with a high rate of early recurrence and mortality. However, radiotherapy and chemotherapy have been widely used in the clinic and have recently been shown to be effective. The survival rates of advanced HNSCC are approximately 50% and have not changed significantly in recent years. This may be due to the individual's treatment response controlled by intrinsic genetics. In a previous study, oncogene genes in HNSCC were identified through extensive DNA sequencing and genetic analysis[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Therefore, it is reasonable to quest potential biomarkers of treatment by analyzing genomic features.\u003c/p\u003e \u003cp\u003eDNA repair genes have been considered driver genes of HNSCC due to their frequent mutation. Defects in DNA repair promote genomic instability and carcinogenesis [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. DNA repair systems play an indispensable role in protecting cells against carcinogenic agents from internal and external stimuli[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Statistical analyses indicated that the DNA repair status of a tumor is associated with poor prognosis in cancer [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. XRCC1 is a major DNA repair gene involved in base excision repair (BER) for small base lesions resulting from oxidation and alkylation damage[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. More than 300 validated SNPs in the XRCC1 gene were reported in the dbSNP database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ncbi.nlm.nih.gov/SNP\u003c/span\u003e\u003c/span\u003e). Among them, the XRCC1 genes Arg194Trp and Arg399Gln, which occur within conserved sequences, are the most frequently mutated genes and the most extensively studied.\u003c/p\u003e \u003cp\u003eStudies have investigated the association between XRCC1 Arg399Gln/XRCC1 Arg194Trp polymorphisms and HNSCC risk [\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. However, these results were contradictory. Wang [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] conducted a meta-analysis on the association of XRCC1 Arg399Gln polymorphisms with HNSCC risk. Nevertheless, they did not observe any precise estimation of this relationship based on 18 published studies. Sturgis [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] reported a reduced risk between XRCC1 Arg194Trp and HNSCC while Andrew[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] found a weak elevation between HNSCC risk and the XRCC1 Arg194Trp polymorphism. XRCC1 protein is involved in BER [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], and its protein expression alters the sensitivity of cells to radiation and chemotherapeutic agents [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. It was reported that high protein expression levels of XRCC1 may be a risk factor for HNSCC [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. In addition, XRCC1 protein expression is common in HNSCC, and high XRCC1 protein expression may confer poorer survival, regardless of the primary tumor site or stage [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. In summary, these results either contrast with each other or are not accurate conclusions.\u003c/p\u003e \u003cp\u003eIn addition, this systematic review or meta-analysis prospectively evaluated XRCC1 as a biopredictor of survival outcomes in patients with HNSCC. There is no doubt that our study is the first meta-analysis including 10 published studies with 2086 patients to comprehensively evaluate the value of XRCC1 (SNPs and protein expression) and offer useful information for clinical decision-making in HNSCC.\u003c/p\u003e \u003cp\u003eAfter analyzing and summarizing all of the selected data, the results indicate that high expression and SNPs (Arg194Trp and Arg399Gln) of XRCC1 significantly predicted poorer OS in HNSCC patients with HRs of 1.97, 1.65, and 1.30, respectively. These findings confirmed that XRCC1 could be widely applied as a diagnostic marker and therapeutic target in HNSCC patients. As a genetic association literature, the Hardy-Weinberg (HWE) principle is also considered to avoid methodological weaknesses, such as biased selection of subjects or genotyping errors. The enrolled studies were all in agreement with HWE.\u003c/p\u003e \u003cp\u003eThis meta-analysis should be interpreted within the context of its limitations. First, studies containing only English languages and only published articles were included, which may contribute to additional bias. Therefore, publication bias is very likely to occur. In light of Begg's funnel plots and Egger's test, no significant publication bias was present in this meta-analysis. Second, the number of articles was limited, and the sample size was relatively small in the present meta-analysis. False-positive or false-negative findings may have occurred in small sample sizes. Therefore, our results of the survival value in analyses might have occurred by chance, and more large-scale and comprehensive studies are needed to achieve a more persuasive conclusion. Third, the method of HR extrapolation from the Kaplan-Meier graph may also generate heterogeneity because the HRs of the five records enrolled were calculated by Parmer's methods and not directly reported. Last, studies with positive results are more likely to be published and thus more likely to be enrolled. Hence, the survival value of XRCC1 in HNSCC may to some extent have been overestimated in this meta-analysis.\u003c/p\u003e \u003cp\u003eIn summary, our systematic review or meta-analysis was conducted to identify XRCC1 from all primary relevant articles and to evaluate the potential prognostic value of XRCC1 in HNSCC. The results demonstrated that both XRCC1 polymorphisms (Arg194Trp and Arg399Gln) and XRCC1 protein high expression exhibited poor survival in HNSCC patients. The prognostic value of XRCC1 in HNSCC patients is undoubtedly known. However, larger prospective studies should be conducted in the future to further verify the outcomes from this current meta-analysis\u003c/p\u003e "},{"header":"Declarations","content":"\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eThis study was supported by grants from the National 12th-Five Year Research Program of China (no.2012BAI12B02)and Health Commission of Hubei Province scientific research project (no.wj2021M250).\u003c/p\u003e\n\u003ch2\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eConsent for publication:\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eI agree that the text and any pictures or videos published in the article will be freely available on the internet and may be seen by the general public. The pictures, videos and text may also appear on other websites or in print, may be translated into other languages or used for commercial purposes.\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials:\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article [and its supplementary information files].\u003c/p\u003e\n\u003ch2\u003eCompeting interests:\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eThe author(s) declare(s) that they have no competing interests.\u003c/p\u003e\n\u003ch2\u003eFunding:\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eAuthors\u0026apos; contributions:\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eYF and LZ collected and analyzed the data, wrote the paper. LZ, YF and JW analyzed the data and wrote the paper. LZ and JW conceived and designed this study, analyzed the data, wrote the paper. All authors read and approved the final manuscript.\u003cbr\u003e\u0026nbsp;Acknowledgements: Not applicable.\u003c/p\u003e\n\u003ch2\u003eData availability statements\u003c/h2\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article [and its supplementary information files].\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eQuintela-Fandino, M., et al., \u003cem\u003eDNA-repair gene polymorphisms predict favorable clinical outcome among patients with advanced squamous cell carcinoma of the head and neck treated with cisplatin-based induction chemotherapy\u003c/em\u003e. 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Oncol Lett, 2021. \u003cb\u003e21\u003c/b\u003e(6): p.\u0026nbsp;450.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAng, M.K., et al., \u003cem\u003eHigh XRCC1 protein expression is associated with poorer survival in patients with head and neck squamous cell carcinoma\u003c/em\u003e. Clin Cancer Res, 2011. \u003cb\u003e17\u003c/b\u003e(20): p.\u0026nbsp;6542\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBold, I.T., et al., \u003cem\u003eDNA Damage Response during Replication Correlates with CIN70 Score and Determines Survival in HNSCC Patients\u003c/em\u003e. Cancers (Basel), 2021. \u003cb\u003e13\u003c/b\u003e(6).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"XRCC1, HNSCC, Prognosis, Meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-698406/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-698406/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Epidemiologic studies have demonstrated that X-ray repair cross-complementary group 1 (XRCC1) is one of the susceptibility factors in head and neck squamous cell carcinoma(HNSCC) patients. However, its clinical prognostic impact remains controversial. Thus, a meta-analysis was performed to clarify the survival value of XRCC1 in HNSCC patients.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eFollowing the Preferred Reporting Items or Systematic Reviews Meta Analyses (PRISMA) 2020 guidelines, literature searches were systematically performed by PubMed, EMBASE and Web of Science with a manual retreive to\u0026nbsp;evaluate the prognostic consequence of XRCC1 in HNSCC patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) were collected to estimate the correlation between XRCC1 and the survival outcomes of HNSCC patients.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eTen studies including 2086 HNSCC patients who satisfied the inclusion and exclusion criteria were included in this meta-analysis. The meta-analysis showed that high XRCC1 expression and Arg399Gln and Arg194Trp were significantly correlated with poorer overall survival (OS), with HRs of 1.97 (95% CI, 1.36–2.84, P\u0026lt;0.001), 1.30 (95% CI, 1.12–1.51, P\u0026lt;0.001), and 1.65 (95% CI, 1.18–2.32 P\u0026lt;0.05), respectively.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eXRCC1 was associated with poorer survival outcomes in HNSCC patients. Hence, XRCC1 is a potential therapeutic target for HNSCC.\u003c/p\u003e","manuscriptTitle":"Prospective Evaluation of XRCC-1 as a Biopredictor for Survival Outcomes in Patients of Head and Neck Squamous Cell Carcinoma (HNSCC): A Meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-07-15 15:23:05","doi":"10.21203/rs.3.rs-698406/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6068b0e9-ca8d-40af-8cd1-b8da85514d1a","owner":[],"postedDate":"July 15th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":5742866,"name":"Cancer Biology"}],"tags":[],"updatedAt":"2021-11-15T00:14:06+00:00","versionOfRecord":[],"versionCreatedAt":"2021-07-15 15:23:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-698406","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-698406","identity":"rs-698406","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}