Methylenetetrahydrofolate reductase polymorphisms and breast cancer risk: a meta-analysis from 41 studies with 16,480 cases and 22,388 controls

The association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and breast cancer risk has been widely reported, but results were inconsistent and underpowered. To clarify the effects of MTHFR polymorphisms on the risk of breast cancer, an updated meta-analysis of all available studies relating C677T and/or A1298C polymorphisms of MTHFR gene to the risk of breast cancer was conducted. Eligible articles were identified by search of databases including MEDLINE, PubMed, Web of Science, EMBASE and Chinese Biomedical Literature database (CBM) for the period up to January 2010. Finally, a total of 41 studies with 16,480 cases and 22,388 controls were included, all for C677T polymorphism and 20 with 12,170 cases and 15,865 controls for A1298C polymorphism. The pooled ORs were performed for the allele contrasts, additive genetic model, dominant genetic model, and recessive genetic model, respectively. Subgroup analyses were also performed by ethnicity and menopausal status. With respect to C677T polymorphism, significantly elevated breast cancer risk was found in overall analysis (T vs. C: OR = 1.041, 95% CI = 1.009–1.073; TT vs. CC: OR = 1.132, 95% CI = 1.019–1.259; TT vs. CC + CT: OR = 1.119, 95% CI = 1.014–1.236); in the subgroup analysis by ethnicity, significantly increased risk was found in East Asian population (T vs. C: OR = 1.121, 95% CI = 1.016–1.237; TT vs. CC: OR = 1.331, 95% CI = 1.073–1.650; TT vs. CC + CT: OR = 1.265, 95% CI = 1.058–1.513) but not in Caucasian population; in the subgroup analysis by menopausal status, no statistically significant association was found. With respect to A1298C polymorphism, no significant association with breast cancer risk was demonstrated in overall, ethnicity- and menopausal status-based population. It can be concluded that potentially functional MTHFR C677T polymorphism may play a low penetrance role in the development of breast cancer.     

Lack of association between CYP17 MspA1 polymorphism and breast cancer risk: a meta-analysis of 22,090 cases and 28,498 controls

Epidemiological studies have evaluated the association between CYP17 MspA1 polymorphism and breast cancer risk. However, the results remain conflicting rather than conclusive. To derive a more precise estimation of the relationship, we performed this meta-analysis. Systematic searches of the PubMed and Medline databases were performed. A total of 35 studies including 22,090 cases and 28,498 controls were identified. Genotype distributions of CYP17 in the controls of all studies were in agreement with Hardy–Weinberg equilibrium (HWE) except for three studies. When all 35 studies were pooled into the meta-analysis, there was no evidence for significant association between CYP17 MspA1 polymorphism and breast cancer risk (for A1/A2 vs. A1/A1: OR = 1.00, 95% CI = 0.96–1.04; for A2/A2 vs. A1/A1: OR = 1.03, 95% CI = 0.97–1.08; for dominant model: OR = 1.01, 95% CI = 0.97–1.05; for recessive model: OR = 1.03, 95% CI = 0.98–1.08). In the subgroup analyses by ethnicity, menopausal status and source of controls, no significant associations were found in all genetic models. When sensitivity analyses were performed by excluding HWE-violating studies, all the results were not materially altered. In summary, the meta-analysis strongly suggests that CYP17 MspA1 polymorphism is not associated with increased breast cancer risk.     

BRCA2 N372H polymorphism and breast cancer susceptibility: a meta-analysis involving 44,903 subjects

Published data on the association between BRCA2 N372H 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 22 studies including 22,515 cases and 22,388 controls were involved in this meta-analysis. Overall, no significant associations were found between BRCA2 N372H polymorphism and breast cancer risk when all studies pooled into the meta-analysis (NH versus NN: OR = 1.01, 95% CI = 0.97–1.05; HH versus NN: OR = 1.05, 95% CI = 0.97–1.13; dominant model: OR = 1.01, 95% CI = 0.98–1.05; and recessive model: OR = 1.05, 95% CI = 0.98–1.13). In the subgroup analysis by ethnicity, still no significant associations were found for Caucasians, Asians, or Africans. When stratified by study design, statistically significantly elevated risk was found for 372H allele based on population-based studies (HH versus NN: OR = 1.11, 95% CI = 1.01–1.21; dominant model: OR = 1.05, 95% CI = 1.00–1.10; recessive model: OR = 1.09, 95% CI = 1.00–1.18). In conclusion, this meta-analysis suggests that the BRCA2 372H allele may be a low-penetrant risk factor for developing breast cancer. However, large sample and representative population-based studies with homogeneous breast cancer patients and well matched controls are warranted to confirm this finding.     

The association between two polymorphisms of eNOS and breast cancer risk: a meta-analysis

Breast cancer is one of the most common malignant tumors worldwide. Endothelial nitric oxide synthase (eNOS) plays a key role in breast cancer development. The associations between the two eNOS polymorphisms (E298D rs1799983, −786T>C rs2070744) and breast cancer risk are inconclusive. A meta-analysis was performed in this study. By searching Medline, ISI Web of Knowledge, ScienceDirect, EBSCO, CNKI, and SinoMed database, six case–control studies were collected for the eNOS E298D polymorphism (3,038 cases and 2,508 controls) and three case–control studies were eligible for the eNOS −786T>C polymorphism. Crude ORs with 95% CIs were used to assess the strength of association between the two eNOS polymorphisms and breast cancer risk. The pooled ORs were performed for codominant model, dominant model, and recessive model, respectively. Overall, significantly decreased risk was observed for E298D (for EE vs. DD: OR = 0.74, 95% CI = 0.59–0.94; for ED vs. DD: OR = 0.78, 95% CI = 0.61–0.98; for dominant model: OR = 0.77, 95% CI = 0.61–0.96) and −786T > C (for TT vs. CC: OR = 0.60, 95% CI = 0.42–0.86; for dominant model: OR = 0.66, 95% CI = 0.47–0.94). In the subgroup analysis by ethnicity, significant decreased risks were found for E298D (for EE vs. DD: OR = 0.75, 95% CI = 0.56–0.99) and −786T>C (for TT vs. CC: OR = 0.53, 95% CI = 0.35–0.81; for dominant model: OR = 0.61, 95% CI = 0.41–0.91; for recessive model: OR = 0.70, 95% CI = 0.55–0.91) among Caucasians; significant decreased risks were observed for E298D (for ED vs. DD: OR = 0.12, 95% CI = 0.02–0.96; for dominant model: OR = 0.13, 95% CI = 0.02–1.00) among Asians. In conclusion, this meta-analysis suggests that both eNOS E298D and −786T>C polymorphisms are associated with reduced breast cancer risk.     

Transforming growth factor-β1 polymorphisms and breast cancer risk: a meta-analysis based on 27 case–control studies

The association between transforming growth factor-β1 (TGF-β1) gene polymorphisms and breast cancer risk has been widely reported, but results were somewhat controversial and underpowered. To derive a more precise estimation of the relationship between TGF-β1 polymorphisms and breast cancer risk, we conducted a meta-analysis of all available case–control studies relating the T869C and/or C-509T polymorphisms of the TGF-β1 gene to the risk of developing breast cancer. Eligible articles were identified by search of databases including MEDLINE, PubMed, Web of Science, EMBASE, and Chinese Biomedical Literature database (CBM) for the period up to March 2010. Finally, a total of 17 articles involving 27 case–control studies were identified, 25 with 20,022 cases and 24,423 controls for T869C polymorphism and eight with 10,633 cases and 13,648 controls for C-509T polymorphism. The pooled ORs were performed for the allele contrasts, additive genetic model, dominant genetic model and recessive genetic model, respectively. Subgroup analysis was also performed by ethnicity for T869C polymorphism. With respect to T869C polymorphism, no association was found in overall analysis (C vs. T: OR = 1.033, 95% CI = 0.996–1.072). In the subgroup analysis by ethnicity, significantly increased risk was found in Caucasian population (C vs. T: OR = 1.051, 95% CI = 1.018–1.085; CC vs. TT + TC: OR = 1.083, 95% CI = 1.019–1.151), but not in Asian population (C vs. T: OR = 1.054, 95% CI = 0.983–1.130). With respect to C-509T polymorphism, no significant association with breast cancer risk was demonstrated in overall analysis (T vs. C: OR = 0.986, 95% CI = 0.936–1.039). It can be concluded that potentially functional TGF-Β1 T869C polymorphism may play a low penetrance role in breast cancer susceptibility in an ethnicity-specific manner.     

Association between the p53 polymorphisms and breast cancer risk: meta-analysis based on case–control study

p53 is a tumor suppressor gene and plays an important role in the etiology of breast cancer. However, studies on the association between p53 polymorphisms and breast cancer risk have yielded conflicting results. We performed a meta-analysis to investigate the association between breast cancer and the p53 polymorphisms codon 72 (27,046 cases and 30,998 controls), IVS3 16 bp (3,332 cases and 3,700 controls) and IVS6+62A>G (8,787 cases and 9,869 controls) in different inheritance models. When all the eligible studies of codon 72 polymorphism were pooled into this meta-analysis, there was no evidence of significant association between breast cancer risk and p53 codon 72 polymorphism in any genetic model. However, in the stratified analysis for Indian population, significantly association was observed in additive model (OR = 0.62, 95% CI = 0.46–0.82, P value of heterogeneity test [P _h] = 0.153) and recessive model (OR = 0.70, 95% CI = 0.50–0.92, P _h = 0.463). IVS3 16 bp was significantly associated with breast cancer risk in a pooled 15 studies dataset (dominant model: OR = 1.14, 95% CI = 1.02–1.27, P _h = 0.30; recessive model: OR = 1.61, 95% CI = 1.21–2.25, P _h = 0.25; additive model: OR = 1.66, 95% CI = 1.24–2.21, P _h = 0.28). No significant association was found between IVS6+62A>G polymorphism and breast cancer risk in a total of 14 studies. In summary, these results indicate that IVS3 16 bp is likely an important genetic marker contributing to susceptibility of breast cancer, and codon 72 homozygous mutants may be associated with decreased breast cancer risk in Indian population.     

Current evidence on the relationship between HRAS1 polymorphism and breast cancer risk: a meta-analysis

Several molecular epidemiological studies were conducted in recent years to evaluate the association between NQO1 Pro187Ser polymorphism and breast cancer risk in diverse populations. However, the results remain conflicting rather than conclusive. This meta-analysis on 3177 cases with breast cancer and 4038 controls from seven published case–control studies showed that the 187Ser allele was not associated with a significantly increased risk of breast cancer (Ser versus Pro: P = 0.33, OR = 1.08, 95% CI = 0.92–1.28; Ser/Ser versus Pro/Pro: P = 0.58, OR = 1.16, 95% CI = 0.68–2.00; Ser/Ser versus Pro/Ser + Pro/Pro: P = 0.62, OR = 1.14, 95% CI = 0.68–1.90; Ser/Ser + Pro/Ser versus Pro/Pro: P = 0.30, OR = 1.07, 95% CI = 0.94–1.22). In the stratified analysis by ethnicity, we found that the Pro187Ser polymorphism was associated with increased breast cancer risk in Caucasians in the additive genetic model and dominant genetic model (P = 0.03, OR = 1.13, 95% CI = 1.01–1.26; P = 0.03, OR = 1.15, 95% CI = 1.01–1.30, respectively), whereas no significant in Asians (P = 0.44, OR = 0.94, 95% CI = 0.80–1.10) and postmenopausal women (P = 0.99, OR = 1.00, 95% CI = 0.84–1.19). The results suggest that NQO1 Pro187Ser polymorphism may contribute to breast cancer development in Caucasians.     

The hOGG1 Ser326Cys polymorphism and breast cancer risk: a meta-analysis

It was reported that the functional polymorphism Ser326Cys in the human 8-oxoguanine DNA glycosylase gene was associated with breast cancer risk; however, the published studies have inconsistent conclusions. To elucidate the effect of hOGG1 Ser326Cys on the susceptibility to breast cancer, all available studies were collected in this meta-analysis. We extracted the data from 10 case–control studies that were published in the PubMed database from 2003 to 2008 using the search phrases “human 8-oxoguanine DNA glycosylase, hOGG1, OGG1, OGG, polymorphism, genetic variation, and breast cancer.” This meta-analysis included 4,963 breast cancer cases and 4,776 control subjects. The results showed that individuals who carrying the hOGG1 326Cys allele in the additive model did not have significantly increased risk of breast cancer compared with those carrying the 326Ser allele (P = 0.47, OR = 1.02; 95% CI = 0.96–1.09); similarly, no significant association between the hOGG1 326Cys allele and breast cancer risk was found either in the recessive genetic model (P = 0.34, OR = 1.06; 95% CI = 0.94–1.18) for Cys/Cys versus Ser/Cys + Ser/Ser, or dominant genetic model (P = 0.78, OR = 1.01; 95% CI = 0.93–1.11) for Cys/Cys + Ser/Cys versus Ser/Ser. In the stratified analysis, the meta-analysis showed the association between hOGG1 326Cys allele in the additive model and breast cancer was significant in European subjects (P = 0.04, OR = 0.71; 95% CI = 0.51–0.98), and dominant genetic model (P = 0.004, OR = 0.44; 95% CI = 0.25–0.77). However, the association was not significant between this polymorphism and different menopausal status (premenopausal and postmenopausal) and the other ethnicities (Asians and Americans). The meta-analysis suggested that the hOGG1 326Cys allele plays a significant protective effect to breast cancer in European women.     

Lack of association of CYP1A2-164 A/C polymorphism with breast cancer susceptibility: a meta-analysis involving 17,600 subjects

Published data on the association between cytochrome P-450 1A2 (CYP1A2)-164 A/C polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Medline, PubMed, Embase, and Web of Science were searched. Crude ORs with 95% CIs were used to assess the strength of association between CYP1A2-164 A/C polymorphism and breast cancer risk. The pooled ORs were performed for co-dominant model (AC versus AA, CC versus AA), dominant model (CC + AC versus AA), and recessive model (CC versus AA + AC), respectively. A total of 9 studies including 7,580 cases and 10,020 controls were involved in this meta-analysis. Overall, no significantly elevated breast cancer risk was found in all genetic models when all studies were pooled into the meta-analysis (AC versus AA: OR = 1.02, 95% CI = 0.92–1.13; CC versus AA: OR = 1.17, 95% CI = 0.83–1.64; dominant model: OR = 1.07, 95% CI = 0.93–1.23; and recessive model: OR = 1.13, 95% CI = 0.82–1.55). In the subgroup analysis by ethnicity or source of controls, there was still no significant association detected in all genetic models. In conclusion, upto date, there is still no enough evidence to indicate the association of CYP1A2-164 A/C polymorphism and breast cancer development.     

Three common <Emphasis Type="Italic">TP53</Emphasis> polymorphisms in susceptibility to breast cancer,evidence from meta-analysis

The association of polymorphisms of tumor suppressor gene TP53 with breast cancer has widely been reported; however, the results are inconsistent. Here, we selected three commonly studied TP53 polymorphisms: codon 72 Arg > Pro, IVS3 16 bp Del/Ins, and IVS6 + 62A > G to explore their association with breast cancer risk by meta-analysis of published case–control studies. The results showed that codon 72 was not associated with breast cancer risk among 37 combined case–control studies (23,567 cases and 25,995 controls). However, a significant association with decreased risk of breast cancer was found in the Mediterranean studies (PP + PR vs. RR: OR = 0.32, 95% CI = 0.24−0.44, P < 0.001; PP vs. RR: OR = 0.35, 95% CI = 0.21−0.60, P < 0.001). IVS3 16 bp Del/Ins was significantly associated with an increased risk of developing breast cancer in a pooled 8 study dataset (2,470 cases and 2,825 controls; Ins/Ins + Del/Ins vs. Del/Del: OR = 1.15, 95% CI = 1.01−1.30, P = 0.04; Ins/Ins vs. Del/Del: OR = 1.75, 95% CI = 1.20−2.37, P = 0.003). No significant association was observed between IVS6 + 62A > G and breast cancer risk in a total of 10 studies (8,537 cases and 9,586 controls). These results suggest that IVS3 16 bp Del/Ins is likely an important genetic marker contributing to susceptibility of breast cancer, and codon 72 has a potential role in association with breast cancer risk within certain populations or regions.     

IGFBP3 A-202C polymorphism and breast cancer susceptibility: a meta-analysis involving 33,557 cases and 45,254 controls

Published data on the association between insulin-like growth factor binding protein 3 (IGFBP3) A-202C 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 27 studies including 33,557 cases and 45,254 controls were involved in this meta-analysis. Overall, significantly elevated breast cancer risk was associated with IGFBP3 C allele when all studies were pooled into the meta-analysis (CC vs. AA: OR = 1.06, 95% CI = 1.02–1.11; dominant model: OR = 1.04, 95% CI = 1.00–1.07). In the subgroup analysis by ethnicity, significantly increased risk was found for Caucasians (AC vs. AA: OR = 1.04, 95% CI = 1.00–1.08; CC vs. AA: OR = 1.05, 95% CI = 1.01–1.10; dominant model: OR = 1.04, 95% CI = 1.00–1.08) and Asians (CC vs. AA: OR = 1.35, 95% CI = 1.02–1.78; recessive model: OR = 1.38, 95% CI = 1.05–1.82). When stratified by study design, statistically significantly elevated risk was found among population-based studies (CC vs. AA: OR = 1.06, 95% CI = 1.01–1.11; dominant model: OR = 1.03, 95% CI = 1.00–1.07). In the subgroup analysis by menopausal status, no statistically significantly increased risk was found among premenopausal or postmenopausal women. In conclusion, this meta-analysis suggests that the IGFBP3 C allele is a low-penetrant risk factor for developing breast cancer.     

MTHFR C677T polymorphism associated with breast cancer susceptibility: a meta-analysis involving 15,260 cases and 20,411 controls

Published data on the association between MTHFR C677T polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Medline, PubMed, Embase, and Web of Science were searched. Crude ORs with 95% CIs were used to assess the strength of association between the MTHFR C677T polymorphism and breast cancer risk. The pooled ORs were performed with co-dominant model (CT vs. CC, TT vs. CC), dominant model (CT + TT vs. CC), and recessive model (TT vs. CC + CT), respectively. A total of 37 studies including 15,260 cases and 20,411 controls were involved in this meta-analysis. Overall, significantly elevated breast cancer risk was associated with TT variant genotype in homozygote comparison and dominant genetic model when all studies were pooled into the meta-analysis (TT vs. CC: OR = 1.11, 95% CI = 1.01–1.23; dominant model: OR = 1.04, 95% CI = 1.00–1.09). In the subgroup analysis by ethnicity, significantly increased risks were found for TT allele carriers among Asians (TT vs. CC: OR = 1.18, 95% CI = 1.04–1.35; recessive model: OR = 1.15, 95% CI = 1.03–1.29). When stratified by study design, statistically significantly elevated risk was found in hospital-based studies (TT vs. CC: OR = 1.18, 95% CI = 1.02–1.38; recessive model: OR = 1.17, 95% CI = 1.05–1.29). In the subgroup analysis by menopausal status, statistically significantly increased risk was found among postmenopausal women (CT vs. CC: OR = 1.12, 95% CI = 1.02–1.23; dominant model: OR = 1.11, 95% CI = 1.01–1.22). In conclusion, this meta-analysis suggests that the MTHFR T allele is a low-penetrant risk factor for developing breast cancer.     

SULT1A1 R213H polymorphism and breast cancer risk: a meta-analysis based on 8,454 cases and 11,800 controls

The SULT1A1 R213H polymorphism is suggested to be implicated in the development and progression of breast cancer. However, the published findings are inconsistent. We therefore performed a meta-analysis of 8,454 breast cancer cases and 11,800 controls from 14 published case–control studies. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association of the R213H polymorphism with breast cancer risk. Overall, our results suggested that there is no significant relationship between SULT1A1 R213H polymorphism and the risk of breast cancer. However, further ethnic population analysis revealed a significantly increased risk of breast cancer for HH allele carriers among Asians (for HH vs. RR: OR = 2.27, 95% CI = 1.11–4.63, P _{heterogeneity} = 0.63; for the recessive model: OR = 2.03, 95% CI = 1.00–4.41, P _{heterogeneity} = 0.62). Taken together, this meta-analysis suggests that the SULT1A1 R213H may be a low-penetrant risk factor for developing breast cancer in Asian population.     

Association between <Emphasis Type="Italic">EGF</Emphasis> promoter polymorphisms and cancer risk: a meta-analysis

EGF promoter polymorphisms are observed to modulate EGF levels and thought to have effect on susceptibility to various carcinomas but the results are inconsistent. In this meta-analysis, we assessed published studies of the association between three EGF polymorphisms and cancer risk from 21 studies with 14,609 subjects for EGF G61A, from two studies with 2,535 subjects for G-1380A and A-1744G, respectively. For EGF G61A, the contrast of homozygote (OR = 0.80, 95% CI = 0.65–0.98), allele (OR = 0.90, 95% CI = 0.81–0.99) and dominant model (OR = 0.86, 95% CI = 0.74–0.99) produced significant association among 21 studies with relatively large heterogeneity (P _{heterogeneity} < 0.001). Through the stratified analysis, heterogeneity decreased significantly. In the stratified analysis by racial descent, the significant risks were found among Asians for homozygote contrast (OR = 0.83, 95% CI = 0.69–0.99, P _{heterogeneity} = 0.506) and Americans for the contrast of homozygote (OR = 0.50, 95% CI = 0.30–0.84, P _{heterogeneity} = 0.051), allele (OR = 0.70, 95% CI = 0.51–0.96, P _{heterogeneity} = 0.008) and dominant model (OR = 0.57, 95% CI = 0.42–0.77, P _{heterogeneity} = 0.28). No significant associations were found in all Caucasians genetic models. In the subgroup analyses by cancer types, for gastric cancer and esophageal cancer significant associations were found in all genetic models without heterogeneity. Significant risk was also found in the contrast of homozygote (OR = 0.41, 95% CI = 0.20–0.81, P _{heterogeneity} = 0.184) and recessive model (OR = 0.53, 95% CI = 0.33–0.85, P _{heterogeneity} = 0.384) for hepatoma and recessive model (OR = 0.72, 95% CI = 0.53–0.99, P _{heterogeneity} = 0.474) for glioma. For EGF G-1380A and A-1744G, no significant associations were found in all genetic models. This meta-analysis suggests that the EGF G61A polymorphism most likely contributes to decreased susceptibility to cancers among Asians and Americans, and A allele may be a protective factor for gastric cancer, esophageal cancer, hepatoma and glioma. Both EGF G-1380A and A-1744G is marginally associated with cancer susceptibility.     

Association of genetic polymorphisms of <Emphasis Type="Italic">ER-α</Emphasis> and the estradiol-synthesizing enzyme genes <Emphasis Type="Italic">CYP17</Emphasis> and <Emphasis Type="Italic">CYP19</Emphasis> with breast cancer risk in Chinese women

Estrogen plays a role in breast cancer development, and genetic polymorphisms in estrogen receptor gene ER-α and genes regulating estrogen biosynthesis and metabolisms are associated with the risk of breast cancer in women in western countries. Therefore, we hypothesized that SNPs in ER-α and other estrogen-metabolizing genes contribute to breast cancer risk in Chinese women. In this study, we genotyped polymorphisms in the regulatory regions of ER-α (rs3798577) and other two estrogen-metabolizing enzyme genes CYP17 (rs743572) and CYP19 (rs10046) among 300 breast cancer cases and 390 controls in a Chinese population. Crude and adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression analyses to estimate breast cancer risk associated with these polymorphisms. We found that the T allele frequency of ER-α was significantly higher in cases (59.8%) than controls (54.5%) (P = 0.047), but no significant difference was found in the genotype distribution. However, postmenopausal breast cancer risk was associated with the CYP17 TC genotype (aOR = 1.77, 95% CI = 1.11–2.83) compared with the TT genotype. The CYP19 variant TC + TT genotypes were associated with both overall cancer risk (TT + TC vs. TT aOR = 1.73, 95% CI = 1.13–2.65) and premenopausal cancer risk (TT + TC vs. TT aOR = 1.78, 95% CI = 1.03–3.09), particularly for ER +/PR + tumors. Furthermore, there were joint effects between CYP19 T and ER-α T varint genotypes (aOR = 1.67, 95% CI = 1.03–2.69 for CYP19 TC + TT vs. CC among ER-α T variant carriers) and between CYP19 T and CYP17 C variant genotypes (aOR = 1.77, 95% CI = 1.11–2.83 for CYP19 TC + TT vs. CC among CYP17 variant C carriers). This study provides evidence that polymorphisms CYP17 rs743572, CYP19 rs10046 and ER-α rs3798577 are associated with breast cancer risk among Chinese women.     

No association between SOD2 Val16Ala polymorphism and breast cancer susceptibility: a meta-analysis based on 9,710 cases and 11,041 controls

Breast cancer is the most common cancer in women worldwide, but its etiology is still unclear. It is believed that oxidative stress plays an essential role in the development of breast cancer, while SOD2 is one of the primary enzymes that directly convert potential harmful oxidizing species to harmless metabolites. The association of SOD2 Val16Ala polymorphism and breast cancer risk has been widely reported, but results of previous studies were somewhat contradictory and underpowered. To overcome the limitations of individual study and to understand the real situation, we conducted a systematic review and meta-analysis toward the association between SOD2 Val16Ala polymorphism and breast cancer. Through retrieving MEDLINE, PubMed, Embase, and Web of Science, a total of 17 studies with 9,710 cases and 11,041 controls were identified. The results showed that no significant associations were found for the allele contrast (allele Ala vs. allele Val: OR = 1.020, 95% CI = 0.979–1.062), additive genetic model (Ala/Ala vs. Val/Val: OR = 1.091, 95% CI = 0.969–1.229), dominant genetic model (Ala/Ala +Ala/Val vs. Val/Val: OR = 1.045, 95% CI = 0.961–1.136), and recessive genetic model (Ala/Ala vs. Val/Val +Ala/Val: OR = 1.027, 95% CI = 0.956–1.102). In the stratified analysis by ethnicity and menopausal status, significant associations were also not detected in all genetic models. Conclusively, this meta-analysis strongly suggests that SOD2 Val16Ala polymorphism is not associated with breast cancer susceptibility.     

Erratum to: Genetic polymorphisms in phase I and phase II enzymes and breast cancer risk associated with menopausal hormone therapy in postmenopausal women

Recent findings indicate a greater risk of postmenopausal breast cancer with estrogen–progestagen therapy than estrogen monotherapy, and more so for current than past use. Few studies have examined individual genetic susceptibility to the effects of menopausal hormone therapy. We used two population-based case-control studies with 3,155 postmenopausal breast cancer patients and 5,496 controls to evaluate modification of breast cancer risk associated with duration of hormone use by genes involved in hormone metabolism and detoxification. Twenty-eight polymorphisms in eight genes of phase I (CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP3A4, CYP3A5, CYP3A7) and nine genes of phase II enzymes (COMT, GSTM1, GSTM3, GSTP1, GSTT1, SULT1A1, UGT1A1, UGT1A6, UGT2B7) were genotyped. The risk associated with duration of use of combined estrogen–progestagen therapy was significantly modified by genetic polymorphisms located in CYP1B1, GSTP1, and GSTT1. In homozygote carriers of the CYP1B1_142_G and the CYP1B1_355 _T variant alleles, adjusted odds ratios (OR) per year of use were 1.06 (95% confidence interval (CI) = 1.02–1.09) and 1.06 (95% CI = 1.03–1.09), respectively, compared with 1.02 (95% CI = 1.01–1.03) in non-carriers of either polymorphism (p _interaction = 0.01). Carriers of the functional GSTT1 allele and the GSTP1_341_T allele were at significantly higher risks associated with hormone use compared with non-carriers (p _interaction = 0.0001 and 0.02). CYP1A1_2452_C>A significantly reduced the risk associated with duration of use of estrogen monotherapy (p _interaction = 0.01). The finding regarding GSTT1 was still statistically significant after corrections for multiple comparisons. Postmenopausal breast cancer risk associated with hormone therapy may be modified by genetically determined variations in phase I and II enzymes involved in steroid hormone metabolism.     

TNFα ?308 G/A polymorphism is associated with breast cancer risk: a meta-analysis involving 10,184 cases and 12,911 controls

Tumor necrosis factor α (TNFα) is a pleiotropic cytokine which can regulate a wide variety of cellular responses. Low concentrations of TNFα seem to increase tumor growth and progression. The −308 G/A polymorphism in TNFα has been implicated in breast cancer risk but the published data remain inconclusive. In order to derive a more precise estimation of the relationship, a meta-analysis was performed by searching PubMed, Web of Science, ScienceDirect, EBSCO, CNKI, and Chinese Biomedicine Database. 11 studies including 10,184 cases and 12,911 controls were collected for TNFα −308 G/A polymorphism. Crude ORs with 95% CIs were used to assess the strength of association between the TNFα −308 G/A polymorphism and breast cancer risk. The pooled ORs were performed for codominant model (GG versus AA; GA versus AA), dominant model (GG + GA versus AA), recessive model (GG versus GA + AA), and G allele versus A allele, respectively. Overall, significantly elevated breast cancer risk was found for recessive model (OR = 1.10, 95% CI = 1.04–1.17) and for G allele versus A allele (OR = 1.08, 95% CI = 1.02–1.14). In the subgroup analysis by ethnicity, significantly increased risks were also found among Caucasians for recessive model and for G allele versus A allele (for recessive model: OR = 1.10, 95% CI = 1.04–1.17; for G allele versus A allele: OR = 1.09, 95% CI = 1.03–1.14). However, no significant associations were found among Asians for all genetic models. In conclusion, this meta-analysis suggests that the TNFα −308 G allele is a risk factor for developing breast cancer, especially for Caucasians.     

TGFB1 L10P polymorphism is associated with breast cancer susceptibility: evidence from a meta-analysis involving 47,817 subjects

Published data on the association between TGFB1 L10P polymorphism and breast cancer risk are inconclusive. In order 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 30 studies including 20,401 cases and 27,416 controls were involved in this meta-analysis. Overall, significantly elevated breast cancer risk was associated with TGFB1 10P allele when all studies were pooled into the meta-analysis (LP vs. LL: OR = 1.046, 95% CI = 1.003–1.090; dominant model: OR = 1.052, 95% CI = 1.012–1.095). In the subgroup analysis by ethnicity, statistically significantly elevated risk was found in Caucasians (dominant model: OR = 1.045, 95% CI = 1.001–1.091). When stratified by study design, statistically significantly elevated risk was found based on population-based studies (dominant model: OR = 1.076, 95% CI = 1.019–1.136). In conclusion, this meta-analysis suggests that the TGFB1 10P allele may be a low-penetrant risk factor for developing breast cancer. However, large sample and representative population-based studies with homogeneous breast cancer patients and well-matched controls are warranted to confirm this finding.     

A <Emphasis Type="Italic">CYP19</Emphasis> (aromatase) polymorphism is associated with increased premenopausal breast cancer risk

Due to the established association between estrogen levels and breast cancer risk, polymorphic variation in genes regulating estrogen levels is thought to be related to breast cancer risk. Aromatase, the protein product of the CYP19 gene, is involved in the production of endogenous estrogens via androgen conversion. We examined whether polymorphic variation in CYP19 associated with increased breast cancer risk in a population based case-control study. We examined two single nucleotide polymorphisms (SNP), rs1008805 (A/G) and rs730154 (C/T), which have been shown to tag SNPs within two different haplotype blocks in CYP19. Among premenopausal women, the presence of at least one G allele at rs1008805 was significantly associated with an increase in the risk of breast cancer (OR = 1.72 [95% CI, 1.20–2.49]), especially with estrogen and progesterone receptor negative breast cancer (OR = 3.89 [1.74–8.70] and OR = 2.52 [1.26–5.05], respectively). No association was observed among postmenopausal women (OR = 1.06 [0.82–1.36]). There was no significant association between rs730154 and breast cancer, regardless of menopausal status. Our results suggest that premenopausal women carrying the G allele at CYP19 rs1008805 have increased risk of breast cancer. The finding supports the potential role of variation in estrogen biosynthesis genes in premenopausal breast cancer risk.