Glutathione S-transferase T1 polymorphism is associated with breast cancer susceptibility

The association between present/null polymorphism of glutathione S-transferase T1 (GSTT1) and breast cancer risk are still inconclusive. We performed a meta-analysis to derive a more precise estimation of the relationship. A total of 48 studies including 17,254 cases and 21,163 controls were involved in this meta-analysis. When all studies were pooled into the meta-analysis, significantly elevated breast cancer risk was associated with null genotype (OR = 1.138, 95% CI = 1.051–1.232). When stratified by ethnicity, significantly increased risks were found for Caucasians (OR = 1.185, 95% CI = 1.075–1.306), but no statistically significantly increased risks were found in Asians (OR = 1.017, 95% CI = 0.846–1.223) and Africans (OR = 1.160, 95% CI = 0.815–1.650). In the subgroup analysis by controls source, statistically significantly elevated risks were both found in population-based studies (OR = 1.123, 95% CI = 1.014–1.243) and hospital-based studies (OR = 1.181, 95% CI = 1.056–1.321). When stratified by menopausal status, no statistically significantly increased risks were found in premenopausal women (OR = 1.115, 95% CI = 0.925–1.345) and postmenopausal women (OR = 1.077, 95% CI = 0.992–1.169). In summary, this meta-analysis suggests that the GSTT1 null genotype is a risk allele for breast cancer development. However, large sample and representative population-based studies with homogeneous breast cancer patients and well matched controls are warranted to confirm this finding.     

Prognostic and clinical significance of focal adhesion kinase expression in breast cancer: A systematic review and meta-analysis

BackgroundThe prognostic significance of focal adhesion kinase (FAK) in breast cancer remains controversial. Here, we conducted a meta-analysis to explore the prognostic value of FAK expression in breast cancer.Materials and methodsPossible prognostic significance of protein or mRNA expression of FAK in breast cancer was investigated with searches of electronic databases for relevant publications. Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were extracted from eligible studies.ResultsA total of eight eligible studies which included 2604 participants were analyzed in this meta-analysis. Increased expression of FAK protein was found to significantly correlate with shorter overall survival (OS) (HR = 1.43, 95% CI: 1.12–1.83; P = 0.004), and not with disease-free survival (HR = 1.31, 95% CI: 0.92–1.85; P = 0.14). Elevated FAK protein expression was also associated with negative estrogen receptor (ER) expression (OR, 1.34; 95% CI, 1.06–1.68; P = 0.01), negative progesterone receptor (PR) expression (OR, 1.54; 95% CI, 1.22–1.93; P < 0.001), positive human epidermal growth factor receptor 2 (HER2) expression (OR, 1.64; 95% CI, 1.28–2.09; P < 0.001), triple-negative breast cancer (TNBC) (OR, 1.57; 95% CI, 1.14–2.17; P = 0.006), high nuclear grade (OR, 1.70; 95% CI, 1.05–2.78; P = 0.03), high Ki-67 expression level (OR, 2.87; 95% CI, 1.94–4.24; P < 0.001), and positive p53 status (OR, 2.28; 95% CI, 1.58–3.29; P < 0.001).ConclusionOur meta-analysis identifies an association between increased FAK protein expression and worse OS among breast cancer patients. Moreover, enhanced FAK expression is associated with negative ER expression, negative PR expression, positive HER2 expression, TNBC, high nuclear grade, high Ki-67 expression level, and positive p53 status in breast carcinoma.     

Association of excision repair cross-complimentary group 1 gene polymorphisms with breast and ovarian cancer susceptibility

The role of excision repair cross-complimentary group 1 (ERCC1) gene polymorphisms in breast and ovarian cancer development has long been controversial and existing data were inconsistent. Here, we conducted a comprehensive meta-analysis to better clarify the association. Case-control studies published from December 2008 to November 2018 were assessed. The statistical analyses of the pooled odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated. Fifteen articles with 24 case-control studies and 3 ERCC1 polymorphisms were enrolled. A total of 20 923 participants including 9896 cases and 11 027 controls were analyzed. The results showed that C to T variation in the ERCC1 rs11615 (C/T) polymorphisms was correlated with breast cancer susceptibility (T vs C: OR = 1.19, 95% CI = 1.02-1.38; TT + CT vs CC: OR = 1.24, 95% CI = 1.12-1.36). ERCC1 rs3212986 (C/A) polymorphisms posed an increased risk for breast and ovarian cancer as whole (A vs C: OR = 1.12, 95% CI = 1.01-1.25; AA + CA vs CC: OR = 1.11, 95% CI = 1.02-1.22), and presented especially higher risk for ovarian cancer (A vs C: OR = 1.31, 95% CI = 1.05-1.63; AA vs CA + CC: OR = 1.66, 95% CI = 1.12-2.47; AA vs CC: OR = 1.72, 95% CI = 1.12-2.64). Meanwhile, neither overall group analyses nor stratified analyses displayed any association of ERCC1 rs2298881 (A/C) polymorphisms in breast and ovarian cancer susceptibility. This meta-analysis suggested that ERCC1 rs11615 (C/T) polymorphisms were associated with breast cancer susceptibility and rs3212986 (C/A) polymorphisms were especially correlated with ovarian cancer risk. More case-control studies with well-adjusted data and diverse populations are essential for validation of our conclusion.     

miR-196a2 C allele is a low-penetrant risk factor for cancer development

Published data on the association between miR-196a2 T/C polymorphism and cancer susceptibility are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 21 studies including 10,441 cases and 12,353 controls were involved in this meta-analysis. Overall, significantly elevated cancer risk was associated with miR-196a2 C allele when all studies were pooled into the meta-analysis (TC vs. TT: OR=1.23, 95% CI=1.11-1.36; CC vs. TT: OR=1.30, 95% CI=1.14-1.48; dominant model: OR=1.25, 95% CI=1.13-1.38). In the subgroup analysis by ethnicity, significantly increased risks were found in Asains (TC vs. TT: OR=1.24, 95% CI=1.10-1.40; CC vs. TT: OR=1.31, 95% CI=1.13-1.52; dominant model: OR=1.26, 95% CI=1.12-1.41) but with bordline statistical significance in Caucasians (TC vs. TT: OR=1.15, 95% CI=1.00-1.31). In the subgroup analysis by cancer type, statistically significantly increased risks were found for breast cancer (TC vs. TT: OR=1.15, 95% CI=1.01-1.31; CC vs. TT: OR=1.30, 95% CI=1.01-1.68; dominant model: OR=1.22, 95% CI=1.00-1.50; and recessive model: OR=1.11, 95% CI=1.01-1.23) and lung cancer (CC vs. TT: OR=1.30, 95% CI=1.10-1.54; and recessive model: OR=1.18, 95% CI=1.02-1.36). When stratified by study design, statistically significantly elevated risk was found in hospital-based studies (TC vs. TT: OR=1.30, 95% CI=1.13-1.49; CC vs. TT: OR=1.37, 95% CI=1.14-1.66; dominant model: OR=1.32, 95% CI=1.15-1.53) and population-based studies (CC vs. TT: OR=1.19, 95% CI=1.06-1.35; dominant model: OR=1.13, 95% CI=1.01-1.25). Despite some limitations, this meta-analysis suggests that the miR-196a2 C allele is a low-penetrant risk factor for cancer development.     

Lack of association between miR-149 C>T polymorphism and cancer susceptibility: a meta-analysis based on 4,677 cases and 4,830 controls

To derive a more precise estimation of the relationship between miR-149 C>T polymorphism and cancer risk, a meta-analysis was performed. A total of 8 studies including 4,677 cases and 4,830 controls were involved in this meta-analysis. Overall, no significantly elevated cancer risk was associated with miR-149 T allele when all studies were pooled into the meta-analysis (CT vs. CC: OR = 0.977, 95 % CI = 0.882-1.082; TT vs. CC: OR = 0.985, 95 % CI = 0.857-1.132; dominant model: OR = 0.984, 95 % CI = 0.893-1.084; recessive model: OR = 1.026, 95 % CI = 0.931-1.132). In the subgroup analysis by ethnicity or study design, no significantly increased risks were found under all models. When stratified by cancer type, there were no significant cancer risk changes for lung cancer, breast cancer or colorectal cancer when miR-149 T allele was included. In conclusion, this meta-analysis suggests that the miR-149 C>T polymorphism may not contribute to cancer susceptibility.     

miR-499 rs3746444 polymorphism is associated with cancer development among Asians and related to breast cancer susceptibility

To derive a more precise estimation of the relationship between miR-499 rs3746444 polymorphism (A>G) and cancer risk, a meta-analysis was performed. A total of 9 studies including 6,077 cases and 7,199 controls were involved in this meta-analysis. Overall, no significantly elevated cancer risk was associated with miR-499 G allele when all studies were pooled into the meta-analysis (AG vs. AA: OR?=?1.14, 95?% CI?=?0.98–1.32; GG vs. AA: OR?=?1.12, 95?% CI?=?0.95–1.33; dominant model: OR?=?1.13, 95?% CI?=?0.99–1.29; recessive model: OR?=?1.05, 95?% CI?=?0.83–1.33). In the subgroup analysis by ethnicity, significantly increased risk was only found for Asians (dominant model: OR?=?1.22, 95?% CI?=?1.02–1.46). When stratified by study design, no statistically significantly elevated risks were found in hospital-based studies or population-based studies. In the subgroup analysis by cancer type, significant cancer risk change was only found for breast cancer when miR-499 G allele was included (dominant model: OR?=?1.13, 95?% CI?=?1.01–1.26). In conclusion, this meta-analysis suggests that the miR-499 rs3746444 polymorphism (A>G) is a low-penetrant risk factor for cancer development among Asians and may contribute to breast cancer susceptibility.     

An updated meta-analysis of the p53 codon 72 polymorphism and gastric cancer risk

To investigate the association between p53 codon 72 polymorphisms and gastric cancer risk, a meta-analysis published in 2007 was updated with new data. Relevant literature was retrieved by searching PubMed and statistical analysis conducted using Review Manager software. Twenty-eight case-control studies were included in this meta-analysis, with 6,859 cases and 9,277 controls. The pooled results for all included studies showed that patients with gastric cancer had a borderline lower frequency of the Arg/Arg phenotype (odds ratio (OR) = 0.91, 95 % CI = 0.83-1.00, p = 0.04). When stratified for race, the difference in Arg/Arg frequency was significant among Asians (OR = 0.87, 95 % CI = 0.78-0.97, p = 0.01). On stratifying the various studies we found that, among Asians: (i) patients with cardial gastric cancer had a significantly higher frequency of the Pro/Pro genotype (OR = 1.35, 95 % CI = 1.03-1.77, p = 0.04) than those with non-cardial gastric cancer; (ii) patients with advanced (stage III/IV) gastric cancer had a significantly higher frequency of Arg/Arg (OR = 1.30, 95 % CI = 1.06-1.61, p = 0.01) than those with early (stage I/II) cancer; and (iii) patients with metastasis had a significantly higher frequency of Pro/Pro (OR = 3.31, 95 % CI = 1.31-8.41) than those without metastasis. Our study suggests that, among Asians, the p53 codon 72 Arg/Arg genotype is associated with a modestly decreased risk of gastric cancer, and that this difference in genotype distribution may be associated with cancer stage, location, differentiation and metastasis.     

Lack of association between methylenetetrahydrofolate reductase gene A1298C polymorphism and breast cancer susceptibility

Published data on the association between methylenetetrahydrofolate reductase gene (MTHFR) A1298C 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 A1298C polymorphism and breast cancer risk. The pooled ORs were performed for co-dominant model (AC vs. AA, CC vs. AA), dominant model (CC+AC vs. AA), and recessive model (CC vs. AC+AA), respectively. A total of 26 studies including 12,244 cases and 15,873 controls were involved in this meta-analysis. Overall, no significant associations were found between MTHFR A1298C polymorphism and breast cancer risk when all studies pooled into the meta-analysis (AC vs. AA: OR=0.99, 95% CI 0.94-1.05; CC vs. AA: OR 0.99, 95% CI 0.90-1.09; dominant model: OR=0.99, 95% CI 0.95-1.04; and recessive model: OR=0.98, 95% CI 0.90-1.08). In the subgroup analysis by ethnicity or study design, still no significant associations were found for all comparison models. In conclusion, this meta-analysis suggests that the MTHFR A1298C polymorphism may be not associated with breast cancer development. However, large sample and representative population-based studies with homogeneous breast cancer patients and well matched controls are warranted to confirm this finding.     

Association between SHBG Asp327Asn (rs6259) polymorphism and breast cancer risk: a meta-analysis of 10,454 cases and 13,111 controls

Sex hormone-binding globulin (SHBG) is a plasma glycoprotein that plays an important role in breast cancer pathophysiology and risk definition, since it regulates the bioavailable fraction of circulating estradiol. Epidemiological studies have evaluated the association between SHBG Asp327Asn polymorphism and breast cancer risk in diverse populations. However, the results remain conflicting rather than conclusive. This meta-analysis of literatures was performed to derive a more precise estimation of the relationship. A total of 10 studies were identified for the meta-analysis, including 10,454 cases and 13,111 controls for SHBG Asp327Asn polymorphism. When all studies were pooled into the meta-analysis, there was no evidence for significant association between SHBG Asp327Asn polymorphism and breast cancer risk (for Asn/Asn vs. Asp/Asp: OR = 1.20, 95 % CI = 0.94-1.55; for Asp/Asn vs. Asp/Asp: OR = 0.94, 95 % CI = 0.87-1.01; for dominant model: OR = 0.95, 95 % CI = 0.90-1.02; for recessive model: OR = 1.22, 95 % CI = 0.95-1.57). In the subgroup analyses by ethnicity, menopausal status, and source of controls, no significant associations were found in all genetic models. Interestingly, further analyses stratified by menopausal status in different ethnicities revealed that this polymorphism might provide protective effects against breast cancer risk in postmenopausal Asian women (for dominant model: OR = 0.83, 95 % CI = 0.70-0.97). Sensitivity analyses were performed by sequential removal of individual studies and cumulative statistics have showed combined ORs were not materially altered by any individual study under all comparisons. In summary, this meta-analysis suggests that SHBG Asp327Asn polymorphism is not associated with breast cancer risk overall, while it might be an important genetic susceptibility factor in postmenopausal Asian women for developing breast cancer. Larger and well-designed studies are warranted to confirm our findings in the future.     

Prediction of Poor Prognosis in Breast Cancer Patients Based on MicroRNA-21 Expression: A Meta-Analysis

BackgroundMicroRNA-21 (miRNA-21 or miR-21) may act as a prognostic biomarker of cancer. However, the available evidence is controversial. Therefore, the present meta-analysis summarizes this evidence and evaluates the prognostic role of this gene in breast cancer.MethodsThe meta-analysis was conducted by searching the databases of PubMed, EMBASE, Web of Science and Chinese database-China National Knowledge Infrastructure (CNKI). Data were extracted from studies that investigated the association between miR-21 expression and survival outcomes in breast cancer patients. With respect to survival outcomes, the pooled hazard ratios (HRs) of miR-21 were calculated given a 95% confidence interval (CI).ResultsOur meta-analysis identified a total of 10 studies involving 1,439 cases. Further investigation demonstrated that a high miR-21 expression can predict poor overall survival (OS) (HR = 2.57, 95% CI: 1.37—4.81, P = 0.003) and shortened disease-free/recurrence-free survival (DFS/RFS) (HR = 1.45, 95% CI: 1.16—1.82, P = 0.001) in breast cancer patients. Moreover, high miR-21 expression was significantly correlated with lowered OS in the Asian group (HR = 5.07, 95% CI: 2.89—8.92, P < 0.001), but not in the Caucasian cohort (HR = 1.44, 95% CI: 0.99—2.10, P = 0.058). Furthermore, odds ratios (ORs) showed that up-regulated miR-21 levels were associated with multiple clinical characteristics.ConclusionOur results indicated that miR-21 can predict unfavorable prognoses in breast cancer patients, especially in Asians.     

The Role of Adiponectin in Breast Cancer: A Meta-Analysis

Published results suggests that high adiponectin level may decrease the risk of breast cancer. However, available evidence on breast cancer is conflicting. Therefore a meta-analysis was performed to assess the association between blood adiponectin and breast cancer risk. PubMed database, Web of Science, Elsevier Science, Springer Link and bibliographies of retrieved articles were searched for epidemiological studies published up to March 2013. Meta-analysis was performed on the combined effect values (OR) as well as standardized mean difference (SMD) including 17 studies. Fixed or random effect pooled measure was selected on the basis of homogeneity test among studies. The publication bias was assessed by the Egger’s regression asymmetry test and Begg’s rank correlation test with Begg’s funnel plot. Subgroup analyses and sensitivity analysis were also performed. A total of 13 studies involving 3578 breast cancer cases and 4363 controls contributed to the OR analysis. The high adiponectin level did not significantly affect breast cancer risk (OR=0.902, 95% CI=0.773–1.053). After excluding articles that were the key contributors to between-study heterogeneity, the OR of high adiponectin level was associated with decreased breast cancer risk (OR=0.838, 95% CI=0.744–0.943). There was a significantly association between high adiponectin level and postmenopausal breast cancer women (OR=0.752, 95%CI=0.604-0.936); and it was not associated with premenopausal breast cancer women (OR=0.895, 95%CI=0.638-1.256). The result of pooled measure on SMD was that the high adiponectin level was associated with decreased breast cancer risk (SMD= -0.348, 95% CI= -0.533--0.614) after excluding articles which were the key contributors to between-study heterogeneity. Our findings indicate that high adiponectin level might decrease the risk of postmenopausal breast cancer. More randomized clinical trials and observational studies are needed to confirm this association with underlying biological mechanisms in the future.     

Clinicopathological Characteristics of Gynecological Cancer Associated with Hypoxia-Inducible Factor 1α Expression: A Meta-Analysis Including 6,612 Subjects

BackgroundGynecological cancer is characterized by tumor hypoxia. However, the role of hypoxia-inducible factor 1α (HIF-1α) in gynecological cancer remains unclear.MethodElectronic databases including Cochrane Library, PUBMED, Web of Knowledge and clinical trial registries were searched from inception through October 2014 for published, case-control studies assessing the association between HIF-1α and the clinicopathological characteristics of gynecological cancer. We pooled results from 59 studies using fixed or random-effects models and present results as odds ratios (ORs) following the PRISMA guidelines.ResultsOur meta-analysis, which included 6,612 women, demonstrated that the expression of HIF-1α was associated with the clinicopathological characteristics of gynecological cancer. The expression of HIF-1α in cancer or borderline tissue was significantly higher than that in normal tissue (cancer vs. normal: odds ratio (OR) =9.59, 95% confidence interval (CI): 5.97, 15.39, p<0.00001; borderline vs. normal: OR=4.13, 95% (CI): 2.43, 7.02, p<0.00001; cancer vs. borderline: OR=2.70, 95% (CI): 1.69, 4.31, p<0.0001). The expression of HIF-1α in III‒IV stage or lymph node metastasis was significantly higher than that in I‒II stage or that without lymph node metastasis, respectively (OR=2.66, 95% (CI): 1.87,3.79, p<0.00001; OR= 3.98, 95% (CI): 2.10,12.89, p<0.0001). HIF-1α was associated with histological grade of cancer (Grade 3 vs. Grade 1: OR=3.77, 95% (CI): 2.76,5.16, p<0.00001; Grade 3 vs. Grade 2: OR=1.62, 95% (CI): 1.20,2.19, p=0.002; Grade 2 vs. Grade 1: OR=2.34, 95% (CI): 1.82,3.00, p<0.00001),5-years disease free survival (DFS) rates (OR=2.93, 95% (CI):1.43,6.01, p=0.001) and 5-years overall survival (OS) rates (OR=5.53, 95% (CI): 2.48,12.31, p<0.0001).ConclusionHIF-1α is associated with the malignant degree, FIGO stage, histological grade, lymph node metastasis, 5-years survival rate and recurrence rate of gynecological cancer. It may play an important role in clinical treatment and prognostic evaluation.     

The association between common genetic variant of microRNA-146a and cancer susceptibility

Published data on the association between microRNA-146a (miR-146a) G/C polymorphism and cancer susceptibility are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 23 studies including 10,585 cases and 12,183 controls were used in the meta-analysis. Overall, no significant associations were found between miR-146a G/C polymorphism and cancer risk when all studies pooled into the meta-analysis (GC vs. CC: OR=1.08, 95% CI=0.94-1.24; GG vs. CC: OR=1.13, 95% CI=0.93-1.37; dominant model: OR=1.09, 95% CI=0.94-1.26). In the subgroup analysis by ethnicity, still no significant associations were found. In the subgroup analysis by cancer type, statistically significantly increased risks were found for papillary thyroid carcinoma (GC vs. CC: OR=3.44, 95% CI=1.86-6.34; GG vs. CC: OR=2.20, 95% CI=1.22-3.99; dominant model: OR=2.68, 95% CI=1.48-4.83). In the subgroup analysis by population-based controls or hospital-based controls, no statistically significantly increased risks were found. Despite some limitations, this meta-analysis suggests that the miR-146a G allele is a low-penetrant risk factor for papillary thyroid carcinoma development.     

HIF-1α 1772 C/T and 1790 G/A Polymorphisms Are Significantly Associated with Higher Cancer Risk: An Updated Meta-Analysis from 34 Case-Control Studies

Background

HIF-1 activates various genes in cancer progression and metastasis. HIF-1α 1772 C/T and 1790 G/A polymorphisms are reportedly associated with cancer risk; however, the results are inconclusive.

Methodology/Principal Findings

A meta-analysis of 34 studies that involved 7522 cases and 9847 controls for 1772 C/T and 24 studies that involved 4884 cases and 8154 controls for 1790 G/A was conducted to identify the association of C/T and G/A polymorphisms with cancer risk. Odds ratio (OR) and 95% confidence intervals (95% CI) were used to assess the strength of association.HIF-1α 1772 C/T and 1790 G/A polymorphisms were associated with higher cancer risk in homozygote comparison (1772C/T: TT vs. CC: OR = 2.45, 95% CI: 1.52, 3.96; P _{heterogeneity} = 0.028; 1790G/A: AA vs. GG: OR=4.74, 95% CI: 1.78, 12.6; P _{heterogeneity} < 0.01), dominant model (1772C/T: TT/CT vs. CC: OR = 1.27, 95% CI: 1.04, 1.55; P _{heterogeneity} < 0.01, 1790G/A: AA/GA vs. GG: OR = 1.65, 95% CI: 1.05, 2.60; P _{heterogeneity} < 0.01), T allele versus C allele (T vs. C: OR = 1.42, 95% CI: 1.18, 1.70; P _{heterogeneity} < 0.01), and A allele versus G allele (A vs. G: OR = 1.83, 95% CI: 1.13, 2.96; P _{heterogeneity} < 0.01). On a subgroup analysis, the 1772 C/T polymorphism was significantly linked to higher risks for breast cancer, lung cancer, prostate cancer, and cervical cancer, whereas the 1790 G/A polymorphism was significantly linked to higher risks for lung cancer and prostate cancer. A significantly increased cancer risk was found in both Asians and Caucasians for 1772C/T polymorphism, whereas a significantly increased cancer risk was found in Caucasians in the heterozygote comparison and recessive model for 1790G/A polymorphism.

Conclusions

HIF-1α 1772 C/T and 1790 G/A polymorphisms are significantly associated with higher cancer risk.     

APEX Nuclease (Multifunctional DNA Repair Enzyme) 1 Gene Asp148Glu Polymorphism and Cancer Risk: A Meta-Analysis Involving 58 Articles and 48903 Participants

Background

Polymorphisms in the APEX nuclease (multifunctional DNA repair enzyme) 1 gene (APEX1) may be involved in the carcinogenesis by affecting DNA repair. We aimed to summarize available data on the association of the APEX1 Asp148Glu (rs1130409) polymorphism with risk of multiple types of cancer via a meta-analysis.

Methods and Results

In total, 58 qualified articles including 22,398 cancer patients and 26,505 controls were analyzed, and the data were extracted independently by two investigators. Analyses of the full data set indicated a marginally significant association of the APEX1 Asp148Glu polymorphism with cancer risk under allelic (odds ratio (OR)=1.05; 95% confidence interval (95% CI): 0.99-1.11; P=0.071), dominant (OR=1.09; 95% CI: 1.01-1.17; P=0.028), and heterozygous genotypic (OR=1.08; 95% CI: 1.01-1.16; P=0.026) models, with significant heterogeneity and publication bias. In subgroup analyses by cancer type, with a Bonferroni corrected alpha of 0.05/6, significant association was observed for gastric cancer under both dominant (OR=1.74; 95% CI: 1.2-2.51; P=0.003) and heterozygous genotypic (OR=1.66; 95% CI: 1.2-2.31; P=0.002) models. In subgroup analysis by ethnicity, risk estimates were augmented in Caucasians, especially under dominant (OR=1.11; 95% CI: 1.0-1.24; P=0.049) and heterozygous genotypic (OR=1.11; 95% CI: 0.99-1.24; P=0.063) models. By study design, there were no significant differences between population-based and hospital-based studies. In subgroup analysis by sample size, risk estimates were remarkably overestimated in small studies, and no significance was reached in large studies except under the heterozygous genotypic model (OR=1.23; 95% CI: 1.06-1.43; P=0.006, significant at a Bonferroni corrected alpha of 0.05/2). By quality score, the risk estimates, albeit nonsignificant, were higher in low-quality studies than in high-quality studies. Further meta-regression analyses failed to identify any contributory confounders for the associated risk estimates.

Conclusions

Our findings suggest that APEX1 Asp148Glu polymorphism might be a genetic risk factor for the development of gastric cancer. Further investigations on large populations are warranted.     

糖尿病对乳腺癌患者预后影响的Meta 分析

目的：评价中国地区糖尿病对乳腺癌患者预后的影响，为临床工作提供依据。方法：检索万方、中国知网、维普、Medline、 Pubmed、Embase数据库有关糖尿病对乳腺癌患者预后影响的文章，收集数据，进行meta 分析，以合并OR 值作为效应指标。结果： meta 分析共纳入11 篇文献，总共有28589 个病例；合并糖尿病对乳腺癌患者5 年无病生存率有影响[OR=2.48，95%CI （1.81~3.40）；I2=0%，P(Q)=0.42]；合并糖尿病对乳腺癌患者5 年总生存率有影响[OR=2.40，95%CI（1.75~3.29）；I2=81.67%，P(Q)<0. 01]。结论：糖尿病对乳腺癌患者预后有影响，造成生存率降低。     

Promoter Methylation of the Retinoic Acid Receptor Beta2 (RARβ2) Is Associated with Increased Risk of Breast Cancer: A PRISMA Compliant Meta-Analysis

Background

Epigenetic studies demonstrate that an association may exist between methylation of the retinoic acid receptor beta2 (RARβ2) gene promoter and breast cancer onset risk, tumor stage, and histological grade, however the results of these studies are not consistent. Hence, we performed this meta-analysis to ascertain a more comprehensive and accurate association.

Materials and Methods

Relevant studies were retrieved from the PubMed, Embase and Chinese National Knowledge Infrastructure databases up to February 28, 2015. After two independent reviewers screened the studies and extracted the necessary data, meta-analysis was performed using Review Manager 5.2 software.

Results

Nineteen eligible articles, including 20 studies, were included in our analysis. Compared to non-cancerous controls, the frequency of RARβ2 methylation was 7.27 times higher in patients with breast cancer (odds ratio (OR) = 7.27, 95% confidence interval (CI) = 3.01–17.52). Compared to late-stage RARβ2 methylated patients, the pooled OR of early-stage ones was 0.81 (OR = 0.81, 95% CI = 0.55–1.17). The OR of low-grade RARβ2 methylated patients was 0.96 (OR = 0.96, 95% CI = 0.74–1.25) compared to high-grade RARβ2 methylated patients.

Conclusion

RARβ2 methylation is significantly increased in breast cancer samples when compared to non-cancerous controls. RARβ2 could serve as a potential epigenetic marker for breast cancer detection and management.     

MicroRNA Related Polymorphisms and Breast Cancer Risk

Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88–0.96), rs1052532 (OR 0.97; 95% CI: 0.95–0.99), rs10719 (OR 0.97; 95% CI: 0.94–0.99), rs4687554 (OR 0.97; 95% CI: 0.95–0.99, and rs3134615 (OR 1.03; 95% CI: 1.01–1.05) located in the 3′ UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.     

CYP1A1 Ile462Val is a risk factor for ovarian cancer development

Published data on the association between CYP1A1 gene polymorphism and ovarian cancer risk are conflicting and heterogeneous. To derive a more precise estimation of the relationship, a meta-analysis was performed. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were performed for heterozygous, homozygous, dominant model, recessive model and allele, respectively. A total of 15 case-control studies were identified, among which, 13 studies (1815 cases and 3501 controls) were eligible for CYP1A1 Ile(462)Val and nine studies (2495 cases and 3553 controls) were eligible for CYP1A1 Msp1. Overall, Ile(462)Val was significantly associated with ovarian cancer, with homozygous carriers (Val/Val vs. Ile/Ile: OR=2.64; 95% CI: 1.63-4.28) and recessive model (Val/Val vs. Ile/Ile and Ile/Val: OR=2.30; 95% CI: 1.45-3.65) being risk factors for ovarian cancer development. In the subgroup analysis by ethnicity, significantly increased risks were found for Caucasians (homozygous carriers: OR=4.91; 95% CI: 2.07-11.66; recessive model: OR=3.26; 95% CI: 1.41-7.50) and Asians (homozygous carriers: OR=3.06; 95% CI: 1.48-6.33; recessive model: OR=2.75; 95% CI: 1.40-5.41; Val allele: OR=1.67; 95% CI: 1.19-2.35). However, no significant associations were found between Msp1 and ovarian cancer in the overall analyses or the subgroup analyses by ethnicity. This meta-analysis denotes the importance for in-depth research regarding of gene-gene, gene-environment interactions, race-specific and histological subtypes specific to obtain a more conclusive response about the function of CYP1A1 in ovarian cancer.     

Prognostic Role of Phospho-STAT3 in Patients with Cancers of the Digestive System: A Systematic Review and Meta-Analysis

ObjectiveThe definite prognostic role of p-STAT3 has not been well defined. We performed a meta-analysis evaluating the prognostic role of p-STAT3 expression in patients with digestive system cancers.MethodsWe searched the available articles reporting the prognostic value of p-STAT3 in patients with cancers of the digestive system, mainly including colorectal cancer, gastric cancer, hepatocellular carcinoma, esophagus cancer and pancreatic cancer. The pooled hazard ratios (HRs) with 95 % confidence intervals (95 % CIs) of overall survival (OS) and disease-free survival (DFS) were used to assess the prognostic role of p-STAT3 expression level in cancer tissues. And the association between p-STAT3 expression and clinicopathological characteristics was evaluated.ResultsA total of 22 studies with 3585 patients were finally enrolled in the meta-analysis. The results showed that elevated p-STAT3 expression level predicted inferior OS (HR=1.809, 95% CI: 1.442-2.270, P<0.001) and DFS (HR=1.481, 95% CI: 1.028-2.133, P= 0.035) in patients with malignant cancers of the digestive system. Increased expression of p-STAT3 is significantly related with tumor cell differentiation (Odds ratio (OR) =1.895, 95% CI: 1.364-2.632, P<0.001) and lymph node metastases (OR=2.108, 95% CI: 1.104-4.024, P=0.024). Sensitivity analysis suggested that the pooled HR was stable and omitting a single study did not change the significance of the pooled HR. Funnel plots and Egger’s tests revealed there was no significant publication bias in the meta-analysis.ConclusionPhospho-STAT3 might be a prognostic factor of patients with digestive system cancers. More well designed studies with adequate follow-up are needed to gain a thorough understanding of the prognostic role of p-STAT3.