Note of clarification of data in the paper entitled no association between XRCC1 gene Arg194Trp polymorphism and risk of lung cancer: evidence based on an updated cumulative meta-analysis

We read with great interest the paper entitled “No association between XRCC1 gene Arg194Trp polymorphism and risk of lung cancer: evidence based on an updated cumulative meta-analysis” published in Tumor Biol. 2014, 35: 5629–5635 [1]. Zhang et al. performed a meta-analysis to explore the association between X-ray repair cross-complementing group 1 (XRCC1) Arg194Trp polymorphism and lung cancer risk on the basis of 25 case-control studies with 8876 cases and 11,210 controls. The authors found that XRCC1 Arg194Trp polymorphism was not associated with lung cancer risk [odds ratio (OR) = 0.97 with 95 % confidence interval (95 %CI): 0.92–1.03 for Trp vs. Arg; OR = 0.92 with 95 %CI: 0.85–0.98 for Arg/Trp vs. Arg/Arg; OR = 1.07 with 95 %CI: 0.92–1.23 for Trp/Trp vs. Arg/Arg; OR = 0.93 with 95 %CI: 0.87–1.00 for Trp/Trp + Arg/Trp vs. Arg/Arg; and OR = 1.08 with 95 %CI: 0.94–1.25 for Trp/Trp vs. Arg/Trp + Arg/Arg]. The cumulative meta-analysis showed that the results maintained the same, while the ORs with 95 % CI were more stable with the accumulation of case-control studies. It is a valuable study.

Nevertheless, careful examination of the data provided by Zhang et al. [1] (shown in Table 1 in their original text) revealed two key issues that are worth noticing. Firstly, one overlapping paper [2] was not properly excluded from Zhang et al.’s study [1]. Secondly, the data reported by Zhang et al. [1] for the study by Wang et al. [3] do not seem in line with the data provided by Wang et al. [3] in their original publication. The numbers reported by Wang et al. [3] (shown in Table 1 in Wang et al.’s original paper) for Arg/Arg, Arg/Trp, and Trp/Trp, in cases and controls, are 89, 80, and 40 and 138, 90, and 28, respectively. Interestingly enough, after carefully examining the data reported by Zhang et al. [1], the numbers are 105, 83, and 21 in cases and 137, 96, and 23 in controls, respectively (supporting information). Therefore, the conclusions by Zhang et al. [1] are not entirely reliable. It is required to clarify the association between XRCC1 Arg194Trp polymorphism and lung cancer risk. We reassessed this association by performing a meta-analysis on the basis of a total of 30 studies with 9508 cases and 11,845 controls, which may provide comprehensive evidence for the association of XRCC1 Arg194Trp polymorphism with lung cancer risk.

Table 1 listed the general information of selected studies. Table 2 listed the summary odds ratios of the association between XRCC1 Arg194Trp polymorphism and lung cancer risk. Overall, we observed an increased lung cancer risk among subjects carrying XRCC1 codon 194 Trp/Trp genotype (OR = 1.26, 95 %CI: 1.10–1.45) compared with Arg/Arg genotype carriers in total population (Fig. 1a). We did not observe any association of Arg/Trp and Trp/Trp + Arg/Trp polymorphisms with lung cancer risk (OR = 0.96, 95 %CI: 0.86–1.08 for Arg/Trp vs. Arg/Arg and OR = 1.01, 95 %CI: 0.90–1.14 for Trp/Trp + Arg/Trp vs. Arg/Arg, respectively) (Fig. 1b, c). The cumulative meta-analysis accumulated the studies in the light of publication year and showed that there was still a significant association between XRCC1 codon 194 Trp/Trp polymorphism and lung cancer risk, the cumulative odds ratio was 1.26 with 95 %CI: 1.09–1.45 (Fig. 2). Limiting the analysis to the studies with controls in agreement with Hardy-Weinberg equilibrium (HWE), we observed an increased risk of lung cancer among subjects carrying Trp/Trp genotype, compared with Arg/Arg genotype (OR = 1.17, 95 %CI: 1.01–1.36) (Table 2). When the subgroup analysis was performed by ethnicity, we observed an increased lung cancer risk among subjects carrying XRCC1 codon 194 Trp/Trp genotype, compared with Arg/Arg genotype carries in Asians (OR = 1.28, 95 %CI: 1.11–1.47), but we observed a decreased lung cancer risk among subjects carrying XRCC1 codon 194 Arg/Trp and Arg/Trp + Trp/Trp genotypes compared with Arg/Arg genotype carries in Caucasians (OR = 0.85, 95 %CI: 0.73–0.99 for Arg/Trp vs. Arg/Arg and OR = 0.86, 95 %CI: 0.76–0.97 for Arg/Trp + Trp/Trp vs. Arg/Arg, respectively) (Table 2). In subgroup analysis by source of control, we observed an increased risk of XRCC1 codon Arg194Trp polymorphism for lung cancer in the genetic model of Trp/Trp vs. Arg/Arg based on population-based control and hospital-based control (OR = 1.28, 95%CI: 1.03–1.59 and OR = 1.25, 95 %CI: 1.05–1.49) (Table 2). A decreased lung cancer risk was observed among smokers carrying XRCC1 codon 194 Arg/Trp + Trp/Trp genotype compared with Arg/Arg genotype carries (OR = 0.83, 95 %CI: 0.71–0.98) when stratified by smoking status (Table 2). We did not observe any association between XRCC1 Arg194Trp polymorphism and lung cancer risk in additional subgroup analyses (Table 2).

Table 1 Characteristics of selected papers

Table 2 Summary of odds ratios for the relationship of XRCC1 Arg194Trp polymorphism with lung cancer risk

Fig. 1

Forest plots for the association of XRCC1 Arg194Trp polymorphism with lung cancer risk (a Trp/Trp vs. Arg/Arg, b Arg/Trp vs. Arg/Arg, and c: Arg/Trp + Trp/Trp vs. Arg/Arg)

Fig. 2

Forest plot for cumulative meta-analysis based on Trp/Trp vs. Arg/Arg

The shape of funnel plots seemed to be approximately symmetrical (Fig. 3a–c). Both Egger’s test and Begg’s test results suggested no evidence of publication biases existed in this meta-analysis (Table 2).

Fig. 3

Funnel plots for the association of XRCC1 Arg194Trp polymorphism with lung cancer risk (a Trp/Trp vs. Arg/Arg, b Arg/Trp vs. Arg/Arg, and c Arg/Trp + Trp/Trp vs. Arg/Arg)

Sensitivity analysis was performed to evaluate the root of heterogeneity. The combined estimates were not altered when the studies were lack of heterogeneity for Arg/Trp vs. Arg/Arg and Trp/Trp + Arg/Trp vs. Arg/Arg polymorphisms among total population by deleting Song et al.’s study [4], Du et al.’s study [5], and Buch et al.’s study [6] (data not shown).

In conclusion, the findings of Zhang et al.’s study [1] should be interpreted with caution. To draw a definitive conclusion, further well-designed studies with large sample size are still required to assess the association of XRCC1 Arg194Trp polymorphism with lung cancer risk. We hope that our remarks will contribute to a more accurate elaboration and substantiation of the results provided by Zhang et al. [1].