We read with great interest the recent paper entitled “Methylenetetrahydrofolate reductase polymorphisms and breast cancer risk in Chinese population: a meta-analysis of 22 case-control studies” published online in Tumor Biology, 2014, 35: 1695–1701 [1]. Liang et al. conducted a meta-analysis to investigate the association between methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphisms and breast cancer risk in the Chinese population on the basis of 13 case-control studies with 3272 cases and 4419 controls. The authors found that MTHFR C677T polymorphism was significantly associated with breast cancer risk in the Chinese population under three genetic models [T vs. C: odds ratio (OR) = 1.12, 95 % confidence interval (95 % CI) = 1.02–1.23, P = 0.015; TT vs. CC: OR = 1.35, 95 % CI = 1.10–1.67, P = 0.005; TT vs. CC + CT: OR = 1.37, 95 % CI = 1.11–1.70, P = 0.004]. It is an extremely valuable study.

Nevertheless, after carefully examining the data provided by Liang et al. (shown in Table 1 in their original text) [1], we found that three key issues should be worth noticing. Firstly, one overlapping paper [2] was not properly excluded from the study of Liang et al. [1]. Secondly, the meta-analysis of Liang et al. failed in including two eligible articles [3, 4] that were available at the time their meta-analysis was performed. Thirdly, the data reported by Liang et al. [1] for the study of Gao et al. [5] did not seem in line with the data provided by Gao et al. [5] in their original publication. The numbers reported by Gao et al. [5] (shown in Table 2 of the original paper of Gao et al.) for CC, CT, and TT, in cases and controls, are 202-305-117 and 235-301-88, respectively. Interestingly enough, after carefully examining the data reported by Liang et al. [1], the numbers are 217-327-125 in cases and 257-329-96 in controls, respectively. Therefore, the conclusions by Liang et al. are not entirely reliable. It is required to clarify the association between MTHFR C677T polymorphisms and the risk of breast cancer in Chinese population comprehensively and objectively. We reassessed this association by performing an updated meta-analysis on the basis of a total of 18 studies with 6808 cases and 7872 controls. Further subgroup analysis was conducted in this study stratified by source of control and Hardy-Weinberg equilibrium (HWE) in controls. In addition, cumulative meta-analysis was carried out to examine the tendency of results by accumulating single study year by year, which could be used to determine whether new relevant studies are needed or not. We hope that our results are able to provide comprehensive and objective evidence for the association of MTHFR C677T polymorphisms with breast cancer risk in Chinese population.

Table 1 Main characteristics of selected studies in this meta-analysis
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Table 2 The summary odds ratio for the association of MTHFR C677T polymorphisms with breast cancer risk in Chinese population
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Table 1 listed the main characteristics of selected studies in this meta-analysis. Table 2 listed the summary odds ratios of the association between MTHFR C677T polymorphisms and the risk of breast cancer in Chinese population. Overall, we observed an increased risk of breast cancer among the subjects carrying MTHFR C677T TT and CT + TT genotypes (OR = 1.57, 95 % CI 1.26–1.97 and OR = 1.12, 95 % CI 1.00–1.25, respectively) compared with those carrying CC genotype in total Chinese population (Fig. 1a, b). We also observed an increased risk of breast cancer among the subjects carrying MTHFR C677T T-allele (OR = 1.20, 95 % CI 1.08–1.34) compared with those carrying C-allele in total Chinese population (Fig. 1c). We did not observe the association of MTHFR C677T polymorphism with breast cancer risk under the genetic model of CT vs. CC (OR = 1.03, 95 % CI 0.95–1.10) (Fig. 1d). The cumulative meta-analysis accumulated the studies in the light of the year of publications, and the results showed that there were still significant associations between MTHFR C677T polymorphisms and breast cancer risk under the genetic models of TT vs. CC, CT + TT vs. CC, and T-allele vs. C-allele; the cumulative ORs were 1.57 with 95 % CI 1.26–1.97, 1.12 with 95 % CI 1.00–1.25, and 1.20 with 95 % CI 1.08–1.34, respectively (Fig. 2a–c). When limiting the analysis to the studies with controls in agreement with HWE, we observed an increased risk of breast cancer among the subjects carrying TT genotype compared with those carrying CC genotype (OR = 1.51, 95 % CI 1.15–1.98) and among the subjects carrying T-allele compared with those carrying C-allele (OR = 1.16, 95 % CI 1.03–1.31) (Table 2). In a subgroup analysis by source of control, we observed an increased risk of MTHFR C677T polymorphisms for breast cancer under the genetic models of TT vs. CC, CT + TT vs. CC and T-allele vs. C-allele on the basis of hospital-based controls (OR = 1.75 with 95 % CI 1.33–2.29, OR = 1.18 with 95 % CI 1.03–1.36 and OR = 1.29 with 95 % CI 1.12–1.48, respectively) (Table 2). We did not observe any association between MTHFR C677T polymorphisms and breast cancer risk on the basis of population-based controls (Table 2).

Fig. 1
figure 1

Forest plots of the odds ratio for MTHFR C677T polymorphisms associated with breast cancer risk (a TT vs. CC, b CT + TT vs. CC, c T-allele vs. C-allele, and d CT vs. CC)

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Fig. 2
figure 2

Forest plots for cumulative meta-analysis of odds ratio for MTHFR C677T polymorphisms associated with breast cancer risk (a TT vs. CC, b CT + TT vs. CC, c T-allele vs. C-allele, and d CT vs. CC)

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The shape of funnel plots seemed to be approximately symmetrical among total population (Fig. 3a–d). Both Egger’s test and Begg’s test results suggested that no evidence of publication bias existed in this meta-analysis (Table 2). To evaluate the stability of the results of the meta-analysis, we performed a sensitivity analysis through sequentially removing each individual study. The sensitivity analysis showed that the results were robust and were not influenced by any single study (Fig. 4).

Fig. 3
figure 3

Funnel plot analysis to detect publication bias for MTHFR C677T polymorphisms associated with breast cancer risk (a TT vs. CC, b CT + TT vs. CC, c T-allele vs. C-allele, and d CT vs. CC)

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Fig. 4
figure 4

Sensitivity analysis on the association between MTHFR C677T polymorphisms and breast cancer risk (T-allele vs. C-allele)

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In summary, the results of the study by Liang et al. [1] should be expounded with caution. To reach a definitive conclusion, further well-designed and larger sample size studies are still needed to evaluate the association between MTHFR C677T polymorphisms and breast cancer risk in Chinese population. We hope that our remarks will contribute to more accurate elaboration and substantiation of the results provided by Liang et al. [1].