These authors have contributed equally to this work
This article was submitted to Cancer Genetics and Oncogenomics, a section of the journal Frontiers in Genetics
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Head and neck squamous cell carcinomas (HNSCC), heterogeneous collection of malignancies of the upper aerodigestive tract, salivary glands and thyroid, constitute 90% of cancers that arise in the head and neck (
Two major classes of DNA repair pathways are base excision repair (BER) and single-strand break repair (SSBR). The primary defense mechanism against oxidative DNA damage is BER (
Several studies have investigated that XRCC1 gene polymorphisms (Arg399Gln and Arg194Trp) increase the risk of HNSCC (
We conducted a systematic computerized search in PubMed, Web of Science, EMBASE, Wanfang, and Chinese National Knowledge Infrastructure (CNKI) databases 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). Articles published between 1992 and 2022 were considered for study inclusion. The latest search was conducted on 1 June 2022.
According to the PICOS (patients, intervention, comparison, outcomes, and study design) principles, the inclusion criteria of the meta-analysis were as follows: 1) Population: patients of any age diagnosed with HNSCC; 2) Intervention: expression of XRCC1 in HNSCC was assessed by immunohistochemical (IHC) analysis. The target gene polymorphisms for XRCC1 were Arg399Gln (rs25487) and/or Arg194Trp (rs1799782) and assessed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP); 3) Comparison: HNSCC patients without concentration on high XRCC1 expression or without concentration on XRCC1 Arg399Gln (rs25487) and/or Arg194Trp (rs1799782); 4) Outcomes: overall survival (OS) between XRCC1 and HNSCC as a primary outcome. Progression-free survival (PFS) between XRCC1 and HNSCC as a secondary outcome; 5) Study design: Any human-based studies; 6) including hazard ratios (HR) and the 95% confidence interval (CI) directly, or
The criteria of exclusion included: 1) abstract-only publications, letters, case reports, meta-analyses, comments, conference articles, on-going or unavailable literature; 2) studies with insufficient original data or focused only on odds ratio without HR values. In case of the same population reported by several publications, the latest literature gained the priority.
Two researchers (Jing-cai Chen and Yao Luo) independently conducted the electronic search. Data were carefully extracted and cross-checked by two independent researchers (Liu-qing Zhou and Fan Yang) to minimize variation. If there were divergences, the senior researcher (Yan-Jun Wang) participated in the progress of data extraction for achieving a consensus. To begin with, we removed duplicate literature. After manual screening titles and abstracts, publications were eligible for full-text perusal. Finally, studies that meet the selection criteria were included in this meta-analysis. The following information was extracted from each included study: the name of the first author, year of publication, country, cancer type, sample size, age, gender, stage, follow-up time, survival outcomes, method, HR. The Newcastle–Ottawa Scale (NOS) was used to assess the quality of the included publications. A star system (maximum is nine stars) of NOS concentrated in three domains: comparability of study groups, selection of participants and ascertainment of outcomes of interest. Studies with NOS ≥6 were high-quality (
HRs and 95% CIs are effect measures which were obtained directly from the original data in the selected publications or estimated by
Heterogeneity was assessed by the Cochran-based Q test and the I2 test (
As shown in
Flow diagram of the selection of relevant studies included in the meta-analysis. CNKI, Chinese National Knowledge Infrastructure; XRCC1, X-ray repair cross-complementary group 1; HNSCC, head and neck squamous cell carcinoma; HR, hazard ratios.
The characteristics of the enrolled studies were summarized in
Characteristics of the studies included in the meta-analysis. NR, not reported; IHC, Immunohistochemistry; PCR-RFLP, polymerase chain reaction restriction fragment length polymorphism; HNSCC, head and neck squamous cell carcinoma; LSCC, laryngeal squamous cell carcinoma; OSCC, oral squamous cell carcinomas; NPC, nasopharyngeal carcinoma; OPSCC, oropharyngeal squamous cell carcinoma.
Author | Year | Country | Cancer type | Sample size | Age | Gender: Male/female | Stage | Follow-up time | Survival | Method | HR | NOS/REMARK score |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Fandino | 2006 | Canada | HNSCC | 103 | 60.09 (39.09–94.00) | 97/6 | NR | 22.5 (9–51) | OS | PCR-RFLP | Estimated | 8/16 |
Csejtei | 2009 | Hungary | HNSCC | 108 | 56.7 | 97/11 | I-IV | 60 | OS | PCR-RFLP | Estimated | 6/13 |
Ang | 2011 | America | HNSCC | 77 | 56 (39–61) | 51/26 | I-IV | 66 (39–87) | OS, PFS | IHC | Reported | 7/14 |
Azad | 2012 | Canada | HNSCC | 531 | 63 (33–86) | 420/111 | I-II | 100.52 | OS | PCR-RFLP | Reported | 7/14 |
Jin | 2014 | China | NPC | 75 | 45 (22–72) | 57/18 | II-IV | 25 (5–46) | PFS | PCR-RFLP IHC | Reported | 7/14 |
Costa1 | 2016 | Brazil | OPSCC | 125 | 57 (33–85) | 113/12 | IV | 24.5 (1.5–116.7) | OS, PFS | PCR-RFLP | Reported | 7/16 |
Costa2 | 2016 | Brazil | OPSCC | 125 | 57 (33–85) | 113/12 | IV | 24.5 (1.5–116.7) | OS, PFS | PCR-RFLP | Reported | 7/16 |
Hirakawa | 2020 | Japan | HNSCC | 225 | 67 (41–91) | 200/25 | I-IV | 48 (3–146) | OS | PCR-RFLP | Estimated | 6/14 |
Raturi | 2020 | Japan | LSCC | 134 | 56 (32–64) | 108/26 | III-IV | 33 | OS, PFS | PCR-RFLP | Reported | 6/14 |
Bold | 2021 | Germany | HNSCC | 519 | NR | NR | NR | 60 | OS | IHC | Estimated | 6/13 |
Wang | 2021 | China | OSCC | 98 | 51 (31–76) | 92/6 | I-IV | 40 (2.4–137.4) | OS | IHC | Reported | 7/15 |
Ten articles with 1995 patients included in this meta-analysis evaluated the survival association between XRCC1 and HNSCC. Nine studies including 1920 patients evaluated OS between XRCC1 and HNSCC and four studies including 411 patients evaluated PFS between XRCC1 and HNSCC. The results showed that XRCC1 Arg399Gln (HR = 1.31, 95% CIs: 1.03-1.66,
Forest plot indicating the overall survival association between XRCC1 gene polymorphisms (Arg194Trp and Arg399Gln)/high XRCC1 protein expression and HNSCC.
Forest plot indicating the association between XRCC1 and progression-free survival in HNSCC.
The sensitivity analysis was conducted to evaluate the effects of each single study on the overall effect. We conducted a leave-one-out sensitivity analysis to evaluate the effect of each single data point against the aggregate. The recalculated outcomes (
The sensitivity analysis was conducted to evaluate the effects of each single study on the overall effect.
Begg’s funnel plot and Egger’s test were applied to validate potential bias from searched publications. We observed that two sides of the Begg’s funnel plot were asymmetric. The Egger’s test indicated publication bias existed (
Publication bias and trim and fill analysis of the enrolled analysis:
In the present meta-analysis, we included ten studies with 1995 HNSCC patients. Results indicated that the XRCC1 gene polymorphism Arg399Gln and XRCC1 high protein expression were significantly associated with poor OS for HNSCC patients and XRCC1 was significantly associated with poor PFS. There was large heterogeneity in our study (I2 = 56.7%,
Anti-cancer drug therapy for HNSCC has been widely used in the clinic and has recently been shown to be effective. In a previous study, oncogene genes in HNSCC were identified through extensive DNA sequencing and genetic analysis (2015). 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 (
Studies have investigated the association between XRCC1 Arg399Gln/XRCC1 Arg194Trp polymorphisms and HNSCC risk (
This meta-analysis prospectively evaluated XRCC1 as a bio-predictor of survival outcomes in patients with HNSCC. There is no doubt that our study is the first meta-analysis including ten published studies with 1995 patients to comprehensively evaluate the survival value of XRCC1 (SNPs and high protein expression) in HNSCC. It might offer useful information for clinical decision-making in HNSCC.
After analyzing and summarizing all selected data, the results indicated that high protein expression and Arg399Gln SNPs of XRCC1 significantly predicted poor OS in HNSCC patients with HRs of 2.32 and 1.31. These findings confirmed that XRCC1 could be widely applied as a diagnostic marker and therapeutic target in HNSCC patients. As a genetic-associated study, the Hardy-Weinberg (HWE) principle was used to avoid methodological weaknesses, such as biased selection of subjects or genotyping errors. The enrolled studies in our meta-analysis were all in agreement with HWE principle.
This meta-analysis should be interpreted within the context of its limitations. First, all included studies are published with English languages only. Therefore, publication bias is very likely to occur. 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, larger scale and comprehensive studies are needed to achieve a more persuasive conclusion. Third, large heterogeneity was observed in this meta-analysis. The heterogeneity of the included studies was likely due to differences of the baseline characteristics in patients or different sites of HNSCC or tumor treatments or HRs calculated by Parmer’s methods or other parameters. A random-effects model was conducted to minimize the effects of these differences. Forth, studies with positive results are more likely to be published and thus more likely to be enrolled. Hence, the survival association of XRCC1 in HNSCC may to some extent has been overestimated in this meta-analysis.
In conclusion, our meta-analysis demonstrated that XRCC1 gene polymorphism Arg399Gln and high protein expression of XRCC1 were associated with poor OS in HNSCC patients. And XRCC1 was significantly associated with poor PFS in HNSCC patients. This current meta-analysis might provide favorable data for future application of XRCC1 as bio-predictor for HNSCC treatment. Larger prospective studies should be conducted in the future to further verify the results in the present study.
JC and YL collected the data. FY and LZ analyzed the data and wrote the paper. LZ and YW conceived and designed this study. All authors read and approved the final manuscript.
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.wj 2021M250).
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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