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Many epidemiological studies have found that leptin correlates to body fat extent and breast cancer. Leptin exerts its physiological action through the leptin receptor (LEPR). However, published data on the association between LEPR alleles and breast cancer occurrence have led to in contradictory results. A total of 10 studies were identified to the meta-analysis, including 4,644 cases and 5,485 controls for LEPR rs1137101 polymorphism, 5 studies with 2,759 cases and 4,464 controls for rs1137100 polymorphism, and 2 studies for rs8051542, rs8051542, and rs8051542 polymorphisms. The pooled odds ratios (OR) with 95 % confidence intervals (CI) for breast cancer risk associated with LEPR genotypes were estimated. Elevated breast cancer risk was associated with LEPR rs1137101 polymorphism when all studies were pooled in the meta-analysis (allele contrast model: OR = 0.71, 95 % CI = 0.551-0.997). In the stratified analysis by ethnicity, significantly increased risks were also found among Asians for allele contrast model (OR 0.414, 95 % CI 0.312-0.550) and dominant model (OR 0.537, 95 % CI 0.370-0.781); for Africans, significantly increased risks were also found for allele contrast model (OR 0.716, 95 % CI 0.595-0.861), homozygote codominant (OR 0.537, 95 % CI 0.370-0.781) and dominant model (OR 1.595, 95 % CI 1.207-2.108). And significantly elevated breast cancer risk was associated with LEPR rs1137100 polymorphism for allele contrast (OR = 0.666, 95 % CI = 0.603-0.720) and homozygote codominant models (OR = 0.344, 95 % CI = 0.282-0.421). For LEPR rs8179183, rs4655537, and rs3762274 polymorphisms, no significant associations were detected in all comparison models. This pooled analysis suggested that rs1137101 and rs1137100 polymorphisms were significantly correlated with breast cancer risk and the A allele of LEPR rs1137101 variant and the G allele of LEPR rs1137100 variant were low-penetrant risk factors for developing breast cancer. Further, no significant associations existed between LEPR rs8179183, rs4655537, and rs3762274 polymorphisms and risk of breast cancer.

We have read with great interest the article ‘‘Three common TP53 polymorphisms in susceptibility to breast cancer: evidence from meta-analysis’’ published in April 2010 issue of ‘‘Breast Cancer Research and Treatment’’ [1]. The results suggest that IVS3 16 bp Del/Ins is likely an important genetic marker contributing to the susceptibility of breast cancer, and codon 72 has a potential role in the association with breast cancer risk within certain populations or regions. Thus, some methodological issues need to be addressed concerning the data provided in the meta-analysis by Hu et al. [1]. We would like to comment and raise some concerns. The minor variants of IVS3 16 bp (rs17878362) polymorphism in the cases and controls were three and one, respectively [2]. However, a small number of subjects do not always indicate that they are minor variants in the meta-analysis. The data reported by Hu et al. [1] for the study did not seem in accordance with the data provided by Weston et al. [2] in their original publication. The numbers reported by Hu et al. [1] for RR, RP, and PP of codon 72 (rs1042522) polymorphism in the cases and controls were 32-27-6 and 72-42-3. Interestingly enough, after carefully studying the data presented by Weston et al. [2], the frequencies we retrieved were 6-27-32 and 3-42-72, which corresponded to the genotypes of 1-1, 1-2, and 2-2 [2]. In Weston’s research, the minor variants data were 32 and 72, indicating the large number of subjects. Similarly, the numbers reported by Hu et al. [1] for GG, GA, and AA of IVS6 ? 62A[G (rs1625895) polymorphism in the cases and controls were 43-20-2 and 95-22-0. The frequencies corresponding to the genotypes of 1-1, 1-2, and 2-2 [2] were 2-20-43 and 0-22-95. We can conclude that a small number of subjects do not always indicate that they are minor variants data for inclusion in a pooled analysis. Hu et al. [1] confused the original data and made the results not entirely credible. Thus, the odds ratio and the 95% confidence interval for codon 72 (rs1042522) and IVS6 ? 62A[G (rs1625895) polymorphisms in the metaanalysis significantly differed from those calculated by the original data of Weston’s research [2]. It would be valuable if the authors could provide a new and more accurate estimation of the pooled odds ratio after considering our comment. More importantly, the research by Weston et al. [2] was a nested case–control study involving 182 Caucasians, 56 Hispanics, and 46 African-Americans. This implies that the genotypes of 1-1, 1-2, and 2-2 by Hu et al. [1] were only subjects for Caucasians. The genotypes of 56 Hispanics and 46 African-Americans were not included even if they Pei-Hua Lu, Min-Bin Chen and Mu-Xin Wei contributed equally to this work and should be considered as co-first authors.

Trinucleotide repeat containing 9 (TNRC9) is a gene located at chromosome 16q12. Although of an uncertain function, it is a newly described risk factor for breast cancer. It contains a putative high-mobility group box motif, suggesting its possible role as transcription factor; it has been implicated in breast cancer metastasis. Published studies on the association between TNRC9 polymorphisms and breast cancer risk remain inconclusive, and a meta-analysis is required to verify the association. This pioneering research performed a meta-analysis of eight studies comprising a total of 25,828 cases and 36,177 controls. Significantly elevated breast cancer risk was associated with TNRC9 rs3803662 polymorphism when all studies were pooled in the meta-analysis (T vs. C allele contrast model: OR 1.18, 95% CI 1.09-1.28; TT vs. CC homozygote codominant model: OR 1.26, 95% CI 1.02-1.55; TT vs. CC+CT recessive model: OR 1.23, 95% CI 1.06-1.42). For TNRC9 rs12443621 polymorphism, no significant association was detected in all genetic models. For TNRC9 rs12443621 polymorphism, meanwhile, no significant association was observed in all comparison models. Conclusively, this meta-analysis suggests that TNRC9 rs3803662 polymorphism was significantly correlated with breast cancer risk and the variant T allele of TNRC9 rs3803662 polymorphism is a low-penetrant risk factor for developing breast cancer. There is no significant association between TNRC9 rs12443621 and rs8051542 polymorphisms and risk of breast cancer in current literature.

We have read with great interest the article ‘‘TNF-alpha polymorphisms and breast cancer’’ published in April 2011 issue of ‘‘Breast Cancer Research and Treatment’’. Yang et al. [1] identified a total of 17 studies with 44,442 breast cancer patients and 49,926 controls involved, and performed a meta-analysis to examine the association between tumor necrosis factor-alpha (TNF-alpha) gene polymorphisms and breast cancer susceptibility. The results indicated that the TNF-alpha-308, -238, -857, -863, -1031, and -1210 polymorphisms were not associated with the risk for BC in overall populations, whereas a negative association was found between TNF-alpha-308 polymorphism and BC in Caucasian populations. Nevertheless, some methodological issues need to be addressed concerning the data provided in the meta-analysis by Yang et al. [1]. We would like to comment and raise some concerns. First, the ethnicity reported by Yang et al. [1] for the studies Skerrett et al. [2] and Erdel et al. [3] do not seem in line with the ethnicity provided in their original publication. The research by Skerrett et al. was a case–control study, patients were obtained from tumor bank, the ethnicity for cases was as follows: 5.7% unknown, 65.5% White, 18.4% Hispanic, 8.0% Black, and 2.3% Asian. Controls were obtained from cord blood maternal donor samples randomly selected from the DNA banked, the ethnicity for cord bank were as follows: 10% African-American, 7% Asian-Pacific Island, 19% Hispanic, 5% other or mixed, and 61% Caucasian. Similarly, the study population of Erdel et al. contained 2.5% African-American and 2.5% Native American in both cases and controls. These data suggested that the ethnicity of the two studies were mixed population, not Caucasian. Furthermore, the recent meta-analysis that mainly regarding TNF-alpha-308, -238 polymorphisms and BC by Shen et al. [4] did not include these two studies. To address the reason, we have carefully read the original publications, which did not supply the genotype distributions of both cases and controls, this may be the possible explanation for these discrepancies. Yang et al. should indicate the source of the data or rule out these two studies. Second, the study by Mestiri et al. [5] was from Tunisia, Yang et al. [1] categorized the source of population from Tunisia into Arabs. It is generally accepted that both of Tunisia and Iran [6] belong to Arab world. We believed that the source of population from Iran goes more appropriate for the Arabs, rather than the Asian population. M.-B. Chen Department of Medical Oncology, Kunshan First People’s Hospital Affiliated to Jiangsu University, 91 Qianjin Road, Kunshan 215300, Jiangsu, China

We have read with great interest the article ‘‘No significant association between the TP53 codon 72 polymorphism and breast cancer risk: a meta-analysis of 21 studies involving 24,063 subjects’’ published online on May 23, 2010 issue of ‘‘Breast Cancer Research And Treatment’’ [1]. In conclusion, this meta-analysis with a large sample size provided strong evidence that TP53 codon 72 polymorphism was not associated with breast cancer risk [1]. The meta-analysis based on currently available evidence by Ma et al. [1] was aimed to derive a more precise assessment of the relationship between TP53 codon 72 polymorphism and breast cancer risk, but some methodological issues need to be addressed concerning this research. Ma et al. [1] concluded that no significant association was found between the TP53 codon 72 polymorphism and breast cancer risk when all the studies were pooled into the meta-analysis (Pro/Arg vs. Pro/Pro: OR 1.063, 95% CI 0.967–1.169; Arg/Arg vs. Pro/Pro: OR 1.245, 95% CI 0.997–1.554; dominant model: OR 1.146, 95% CI 0.979–1.340; recessive model: OR 1.179, 95% CI 1.020–1.362). Actually, the odds ratio of 1.179 and 95% confidence interval for odds ratio of 1.020–1.362 in recessive model demonstrated some evidence of association between TP53 codon 72 polymorphism and breast cancer risk. Similarly, Ma et al. [1] demonstrated that no significant association was observed for any of the genetic models in the stratified analysis by source of controls (Pro/Arg vs. Pro/Pro: OR 1.075, 95% CI 0.974–1.187; Arg/Arg vs. Pro/ Pro: OR 1.283, 95% CI 1.036–1.588; dominant model: OR 1.158, 95% CI 1.007–1.333; recessive model: OR 1.229, 95% CI 1.054–1.433). Obviously, significant associations were observed in the Arg/Arg vs. Pro/Pro, the dominant and the recessive models. Thus, the ongoing uncertainty still existed and the conclusion by Ma et al. [1] was not entirely credible. Importantly, several sizeable eligible studies (7,601 cases and 11,549 controls) have not been included in this meta-analysis [2–16], even though they satisfied the search criteria. Of note, there were 5 studies of Asians [2–6], 8 studies of Caucasians [7–14], and 2 studies of mixed populations [15, 16]. Among these eligible studies, 6 were population-based [2–4, 10, 13, 16], 7 were hospital-based [5, 8, 9, 11, 12, 14, 15], and 2 were not reported [6, 7]. Specifically, the study by Ohayon et al. [8] has provided separate data on among Ashkenazi Jews and non-Ashkenazi Jews subpopulations, and Menzel et al. [10] provided separate data on Tyrol and Prague subpopulations. Ma et al. [1] concluded that no significant association was found between the TP53 codon 72 polymorphism and breast cancer risk when all the studies were pooled into the meta-analysis and same conclusions were obtained in the Pei-Hua Lu, Guo-Qing Tao and Xiao Liu contributed equally to this work and should be considered as co-first authors.

Published data on the association between mitogen-activated protein kinase kinase kinase 1 (MAP3K1) gene rs889312 polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Crude ORs with 95% CIs were used to assess the strength of association between them. A total of seven eligible articles including 26,015 cases and 33,962 controls based on the search criteria were involved in this meta-analysis. We observed that the MAP3K1 rs889312 polymorphism was significantly correlated with breast cancer risk from the fixed effects model when all studies were pooled into the meta-analysis (the allele contrast model: OR 1.09, 95% CI 1.07–1.12; the homozygote codominant: OR 1.22, 95% CI 1.15–1.29; the heterozygote codominant: OR 1.07, 95% CI 1.04–1.11; the dominant model: OR 1.10, 95% CI 1.06–1.13; the recessive model: OR 1.18, 95% CI 1.12–1.25). No significant association was found in the BRCA1 mutation carriers in all genetic models. When stratified by BRCA2 mutation carriers status, statistically significantly elevated risk was found in this meta-analysis (C vs. A: OR 1.12, 95% CI 1.01–1.23; CC vs. AA: OR 1.35, 95% CI 1.06–1.71; the recessive model: OR 1.31, 95% CI 1.05–1.65). There was no evidence for significant association between MAP3K1 rs889312 polymorphism and breast cancer risk in BRCA1 and BRCA2 positive cohort for all comparison models. In conclusion, this meta-analysis suggests that the MAP3K1 rs889312 C allele is a low-penetrant risk factor for developing breast cancer, and there is limited evidence to indicate that MAP3K1 rs889312 polymorphism is associated with increased risk of breast cancer in BRCA1 mutation carriers.

Epidemiological studies have evaluated the association between ataxia telangiectasia mutated (ATM) gene polymorphisms and breast cancer risk. However, published data are still inconclusive. We performed a meta-analysis for the first time, based on currently available evidence, by searching PubMed, ISI Web of Knowledge, and Embase databases to derive a more precise assessment of the relationship. Following the inclusion and exclusion criteria, nine publications were included in this meta-analysis. Of these studies, one had a deviation from the Hardy–Weinberg equilibrium (HWE) at a statistical significance level of 0.01 in controls, and another two had no available data for HWE. We observed that the ATM 5557G>A polymorphism was significantly correlated with breast cancer risk when all studies were pooled into the meta-analysis (recessive model: odds ratio, OR = 0.67; 95% confidence interval (CI) 0.51–0.89). For the ATM IVS38-8T>C polymorphism, no significant association was found in the allele contrast, heterozygote codominant, and dominant models. There were no available data to perform this meta-analysis in the homozygote codominant and recessive models. For the ATM IVS1+19A>T polymorphism, a significant association with breast cancer risk was found in the allele contrast model (C vs. T: OR = 1.60; 95% CI 1.02–2.52). For the IVS34+60G>A polymorphism, no significant association was found in the allele contrast, codominant, dominant, and recessive models. Egger’s test did not suggest any evidence of publication bias (P = 0.47 for the recessive model). In conclusion, there is limited evidence to indicate that ATM polymorphisms are associated with increased risk of breast cancer.

Previous epidemiological studies have evaluated the association between the ABCB1 polymorphism and the risk of breast cancer with conflicting results. Hence, we conducted a meta-analysis of the ABCB1 gene and risk of breast cancer to obtain the most reliable estimate of the association. PubMed, Embase, and Web of Science databases were searched. A total of eight studies including 3,829 cases and 6,193 controls were identified. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were extracted and pooled to assess the strength of associations between the ABCB1 C3435T and rs2214102 G>A polymorphisms and risk of breast cancer. Of these studies, only one deviated from Hardy–Weinberg equilibrium. Summary estimates indicated that the ABCB1 C3435T polymorphism was not associated with increased risk of breast cancer in the allele contrast model (T vs. C, pooled OR = 1.15; 95% CI = 0.89–1.48); the co-dominant model (CT vs. CC, OR = 1.12 [0.86–1.46] and TT vs. CC, OR = 1.30 [0.79–2.15]); the dominant model (OR = 0.80 [0.63–1.02]; and the recessive model (OR = 0.83 [0.57–1.22]). In the sensitivity analysis by ethnicity, no statistically significant associations were detected in Asians. However, in Caucasian women the T allele contrast model and the TT genotype were each associated with increased risk: T vs. C, pooled OR (95% CI) = 1.26 (1.04–1.52) and TT vs. CC, OR = 1.48 (1.04–2.11). Accordingly, the dominant model yielded statistically significant results (pooled OR = 0.71, 95% CI: 0.52–0.96) but not with the allele contrast model or the co-dominant model. There was evidence of publication bias (P = 0.02 for recessive model). In conclusion, there is limited evidence to indicate that the ABCB1 C3435T and rs2214102 G>A polymorphisms are associated with increased risk of breast cancer.

We read with great interest the article ‘‘RAD51 135G[C polymorphism and breast cancer risk: a metaanalysis’’ published online in the July 2010 issue of ‘‘Breast Cancer Research And Treatment’’. Zhou et al. [1] have reached an important conclusion that RAD51 variant 135C homozygote is associated with elevated breast cancer risk among BRCA2 mutation carriers, but not in subgroup analysis according to specific ethnicity. Nevertheless, close inspection of the studies analyzed by the authors revealed some methodological issues that are worth mentioning and clarifying. After we adopt the same search strategy and end-of-search date as Zhou et al. [1], six relevant case–control studies in pubmed with a total number of 1,228 breast cancer cases and 1,127 controls [2–7] was not included in this meta-analysis. Of note, except for one study of mixed ethnicities [2], other five case–control studies were performed on Caucasian populations. Sub-analysis on Caucasian and Mixed subjects demonstrated no significant association between RAD51 135G[C polymorphism and breast cancer susceptibility by Zhou et al. [1]. This may imply that the original odds ratio for the eligible studies [2–7] not included in the sub-analysis on Caucasian and Mixed subjects may significantly differ from that calculated by Zhou et al. [1]. As a result, the conclusion by Zhou et al. [1] was not entirely credible. Meanwhile, meta-analysis based on currently available evidence, was to derive a more precise assessment of the relationship, but this research brought a new conflicting result in the subgroup analysis. Zhou et al. [1] demonstrated a significant association was found among BRCA2 mutation carriers in additive (OR = 4.92; 95% CI = 1.11–21.83) and the recessive models (OR = 4.88; 95% CI = 1.10–21.67), but not in BRCA1 mutation carriers in all genetic models. It was different from the meta-analysis result published in the July 17, 2010 issue of ‘‘Breast Cancer Research And Treatment’’ [8]. Jakubowska et al. [3] observed a significantly reduced risk of breast cancer among Polish female carriers of RAD51 135C allele and BRCA1 founder mutations. Gao et al. [8] demonstrated that no significant association was found in stratified analyses according to the BRCA1 or BRCA2 mutation status in the dominant comparison model tested. It can be secondarily noted that this significant association among BRCA2 mutation carriers by Zhou et al. [1] was just based on one study by Antoniou et al. [9]. We also found one relevant case–control study in pubmed, which have not been included in this meta-analysis [2]. The number of studies involved in the meta-analysis for RAD51 135G[C polymorphism among BRCA2 mutation carriers was relatively small, thus performing the subgroup analysis was met with difficulty. The study not included was P.-H. Lu (&) W. Shen M.-Y. Wu G.-Q. Tao (&) Department of General Surgery, Wuxi People’s Hospital of Nanjing Medical University, No. 299, Qingyang Road, Wuxi 214023, Jiangsu, China e-mail: lphty1_1@yahoo.com.cn

We have read with great interest the article ‘‘Lack of association between HER2 codon 655 polymorphism and breast cancer susceptibility: meta-analysis of 22 studies involving 19,341 subjects’’ published online in June 2010 issue of ‘‘Breast Cancer Research and Treatment’’ [1]. Ma et al. [1] did not demonstrate any significant associations between HER2 codon 655 polymorphism and breast cancer susceptibility, either at the overall or the ethnicity analyses (Caucasian and Asian). Nevertheless, some methodological issues need to be addressed concerning the meta-analysis by Ma et al. [1]. Importantly, four sizeable eligible studies [2–5] (1,745 cases and 1,921 controls) have not been included in this meta-analysis, even though they satisfied the search criteria. Specifically, the study by Millikan et al. [2] has provided separate data on African (754 cases and 676 controls) and Caucasian (1,261 cases and 1,132 controls) subpopulations. Of note, other three case–control studies were performed on Asian, African, and European populations. Under the light of the above, we put all studies into a new meta-analysis, including the four sizeable eligible studies [2–5], and we observed that the HER2 codon 655 polymorphism was significantly correlated with breast cancer risk in the Val versus Ile allele contrast model (OR 1.10, 95% CI 1.02–1.19, random effects model) and the dominant model (OR 1.10, 95% CI 1.01–1.19, random effects model). However, we did not find any associations in additive genetic model (the homozygote codominant: OR 1.15, 95% CI 0.93–1.43; the heterozygote codominant: OR 1.07, 95% CI 0.99–1.16; the recessive model: OR 1.11, 95% CI 0.90–1.35, random effects model). Conclusively, our pooled analysis suggested that the variant Val allele of HER2 codon 655 polymorphism was a low-penetrant risk factor for developing breast cancer, and there was limited evidence to indicate that HER2 Ile655Val polymorphism was associated with increased risk of breast cancer. Sub-analysis on Asian and Caucasian subjects demonstrated no significant association between HER2 codon 655 polymorphism and breast cancer susceptibility by Ma et al. [1]. But the eligible studies [2–5] were also not been included in the sub-analysis on Asian and Caucasian subjects. Moreover, the study by Ma et al. [1] has sorted the researches by Nelson et al. [6] and Kallel et al. [7] to mixed ethnicities. Actually, these two studies included ethnicities for Caucasian and African populations separately. In conclusion, the association between HER2 codon 655 polymorphism and breast cancer risk may well exist, further studies on race-specific populations are needed so as to validate the present results in larger sets of case–control studies.