Numerous case-control studies on the association between polymorphisms of key genes involved in methionine remethylation [methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS)] and the susceptibility of cervical intraepithelial neoplasia (CIN) and cervical cancer have provided inconclusive results. The aim of the present meta-analysis was to determine the effects of two MTHFR (C677T and A1298C) and one MS gene polymorphism (A2756G) on the risk of CIN II/III or cervical cancer. Relevant data were retrieved following a systematic search in PubMed, Web of Science, MEDLINE and Wanfang Data up to November 2012. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated from eligible studies by meta-analysis with subgroup analyses stratified by ethnicity. A total of 13 studies with 1,936 cases and 2,858 controls were included in the present meta‑analysis. An increased risk of cervical cancer was found in Asian women with the MTHFR 677T allele (TT vs. CC: OR=1.41, 95% CI=1.07‑1.86, P=0.01; TT vs. CC+CT: OR=1.38, 95% CI=1.08-1.75, P=0.008), while a decreased risk was observed in Caucasian women (TT vs. CC: OR=0.65, 95% CI=0.45-0.93, P=0.02; TT+CT vs. CC: OR=0.7, 95% CI=0.58-0.86, P=0.0005). No effects of MTHFR C677T polymorphism on CIN II/III risk and MTHFR A1298C or MS A2756G polymorphisms on cervical cancer risk were detected. The sensitivity analysis suggested stability of this meta-analysis and no publication bias was detected. The MTHFR 677T allele may enhance the risk of cervical cancer in the Asian female population and play a protective role in Caucasian females. However, limited association is suggested between MTHFR A1298C and MS A2756G polymorphisms with cervical tumorigenesis.

Isocitrate dehydrogenase (IDH) genes 1 and 2 are frequently mutated in acute myeloid leukaemia (AML), low-grade glioma, cholangiocarcinoma (CC) and chondrosarcoma (CS). For AML, low-grade glioma and CC, mutant IDH status is associated with a DNA hypermethylation phenotype, implicating altered epigenome dynamics in the aetiology of these cancers. Here we show that the IDH variants in CS are also associated with a hypermethylation phenotype and display increased production of the oncometabolite 2-hydroxyglutarate, supporting the role of mutant IDH-produced 2-hydroxyglutarate as an inhibitor of TET-mediated DNA demethylation. Meta-analysis of the acute myeloid leukaemia, low-grade glioma, cholangiocarcinoma and CS methylation data identifies cancer-specific effectors within the retinoic acid receptor activation pathway among the hypermethylated targets. By analysing sequence motifs surrounding hypermethylated sites across the four cancer types, and using chromatin immunoprecipitation and western blotting, we identify the transcription factor EBF1 (early B-cell factor 1) as an interaction partner for TET2, suggesting a sequence-specific mechanism for regulating DNA methylation.

Studies investigating the association between single-nucleotide polymorphisms (SNPs) of the cytochrome P450 1B1 (CYP1B1) and prostate cancer (PCa) risk report conflicting results. To derive a more precise estimation of the relationship between CYP1B1 polymorphisms and PCa risk, a meta-analysis was performed.

Mitochondrial dysfunction has been long proposed to play a major role in tumorigenesis. Mitochondrial DNA (mtDNA) mutations, especially the mtDNA 4,977 bp deletion has been found in patients of various types of cancer. In order to comprehend the mtDNA 4,977 bp deletion status in various cancer types, we performed a meta-analysis composed of 33 publications, in which a total of 1613 cancer cases, 1516 adjacent normals and 638 healthy controls were included. When all studies were pooled, we found that cancerous tissue carried a lower mtDNA 4,977 bp deletion frequency than adjacent non-cancerous tissue (OR = 0.43, 95% CI = 0.20-0.92, P = 0.03 for heterogeneity test, I(2) = 91.5%) among various types of cancer. In the stratified analysis by cancer type the deletion frequency was even lower in tumor tissue than in adjacent normal tissue of breast cancer (OR = 0.19, 95% CI = 0.06-0.61, P = 0.005 for heterogeneity test, I(2)= 82.7%). Interestingly, this observation became more significant in the stratified studies with larger sample sizes (OR = 0.70, 95% CI = 0.58-0.86, P = 0.0005 for heterogeneity test, I(2) = 95.1%). Furthermore, when compared with the normal tissue from the matched healthy controls, increased deletion frequencies were observed in both adjacent non-cancerous tissue (OR = 3.02, 95% CI = 2.13-4.28, P<0.00001 for heterogeneity test, I(2)= 53.7%), and cancerous tissue (OR = 1.36, 95% CI = 1.04-1.77, P = 0.02 for heterogeneity test, I(2)= 83.5%). This meta-analysis suggests that the mtDNA 4,977 bp deletion is often found in cancerous tissue and thus has the potential to be a biomarker for cancer occurrence in the tissue, but at the same time being selected against in various types of carcinoma tissues. Larger and better-designed studies are still warranted to confirm these findings.

Cytochrome P450 1A1 (CYP1A1) A4889G polymorphism was supposed to be associated with endometrial cancer risk, but previous studies reported conflicting results. We therefore performed a meta-analysis of all relevant studies to get a comprehensive assessment of the association between CYP1A1 A4889G polymorphism and endometrial cancer risk. The pooled odds ratios (OR) with the corresponding 95% confidence interval (95% CI) was calculated to assess the association. Finally, ten studies with a total of 1,682 endometrial cancer cases and 2,510 controls were finally included into the meta-analysis. Meta-analysis of the total ten studies showed that CYP1A1 A4889G polymorphism was not associated with endometrial cancer risk (ORG versus A = 1.14, 95% CI 0.83-1.57, P OR = 0.417; ORGG versus AA = 1.23, 95% CI 0.70-2.18, P OR = 0.470; ORGG versus AA/AG = 1.03, 95% CI 0.59-1.81, P OR = 0.919; ORGG/AG versus AA = 1.22, 95% CI 0.82-1.81, P OR = 0.336). Subgroup analyses by ethnicity further showed that there was also no obvious association between CYP1A1 A4889G polymorphism and endometrial cancer risk in both Caucasians and Asians. Sensitivity analysis by excluding single study in turns showed that the pooled estimations were not stable. Therefore, evidence for currently available data suggests that CYP1A1 A4889G polymorphism is not associated with endometrial cancer risk. However, more studies with large number of participants are needed to further assess the association precisely.

P53 codon 72 Arg/Pro is a C/G variation upstream of the p53 gene on human chromosome 17p13. Many case-control studies have investigated the association between p53 codon 72 Arg/Pro polymorphism and glioma risk but provided inconsistent findings. To better understand the pathogenesis of glioma, we performed the current meta-analysis by pooling data from all available individual studies. According to the inclusion criteria, ten independent publications with 11 case-control studies were included into this meta-analysis. The pooled odds ratio (OR) with 95 % confidence interval (95 % CI) was calculated to estimate the effect of p53 codon 72 Arg/Pro variant on the development of glioma. Overall, no appreciable correlation was observed among the total studies in all gene models (ORPro allele vs. Arg allele = 1.04, 95 % CI = 0.90-1.20, P OR = 0.581; ORPro/Pro vs. Arg/Arg = 0.95, 95 % CI = 0.80-1.14, P OR = 0.614; ORPro/Arg vs. Arg/Arg = 1.01, 95 % CI = 0.79-1.29, P OR = 0.993; ORPro/Arg + Pro/Pro vs. Arg/Arg = 1.03, 95 % CI = 0.82-1.29, P OR = 0.799; ORPro/Pro vs. Arg/Arg + Pro/Arg = 1.02, 95 % CI = 0.86-1.22, P OR = 0.785). In stratified analyses by ethnicity, source of controls, and glioma subtypes, the p53 codon 72 Arg/Pro polymorphism did not alter the risk for glioma in population-based, hospital-based, astrocytoma, and oligodendroglioma studies among Caucasian. Interestingly, the Pro/Pro genotype seemed to be negatively associated with the glioma risk among patients with glioblastoma (ORPro/Pro vs. Arg/Arg = 0.68, 95 % CI = 0.48-0.95, P OR = 0.026). Our study suggests that the polymorphism of p53 codon 72 Arg/Pro may play a protective role in the development of glioblastoma. The relationship of p53 codon 72 Arg/Pro polymorphism with the susceptibility to glioma needs further estimation by more individual studies with high quality across ethnicities.

Evidence is increasingly emerging about multiple roles for the NAD(P)H quinone oxidoreductase 1 enzyme in cancer. The C609T (rs1800566, Pro187Ser) null polymorphism of the NQO1 gene contributes significantly to the variation in enzymatic activity across different populations. NQO1 C609T polymorphism was thoroughly investigated with respect to cancer susceptibility. The results were inconsistent partly due to low sample sizes. The aim of the present work was to perform a meta-analysis to assess association for all common cancer sites separately and in combination.

The associations between hypoxia-inducible factor-1 alpha (HIF-1α) and clinicopathological characteristics of cancers have been evaluated in various studies, with the conflicting results. Therefore, we conducted a meta-analysis by combining available data to derive a more precise estimation of the association. PubMed, Embase, and China National Knowledge Infrastructure (CNKI) were searched until February 2013 to identify eligible studies. A total of 25 studies were included, with all studies investigating the role of HIF-1α C1772T polymorphism in clinicopathological parameters in cancers while 17 of them investigating HIF-1α G1790A polymorphism only. Results suggested that HIF-1α C1772T polymorphism was associated with histological grade of cancer (T/T + C/T vs. C/C, grade 3 vs. grade 2: OR = 1.51, 95% CI = 1.08-2.13; grade 2 vs. grade 1: OR = 0.67, 95% CI = 0.46-0.97) and increased risk of lymph node metastasis (T/T + C/T vs. C/C: OR = 1.38, 95% CI = 1.13-1.68). HIF-1α G1790A polymorphism was found to be associated with increased risk of larger tumor size (G/G + G/A vs. A/A: OR = 1.64, 95% CI = 1.04-2.58) and borderline significant risk of lymph node metastasis (G/G + G/A vs. A/A: OR = 1.33, 95% CI = 1.00-1.78). Therefore, HIF-1α polymorphisms could be a potential prognostic factor for cancer. Further studies with larger data set and well-designed models are required to validate our findings.

The polymorphism of X-ray repair cross-complementing group 1 (XRCC1) Arg194Trp, a substitution of Arg to Gln at position 194, has been implicated in the development of colorectal cancer (CRC) in a number of case-control studies with contradictory and inconclusive findings. The current meta-analysis of all currently available publications was conducted to assess the gene susceptibility to CRC and improve our understanding of the CRC pathogenesis. The pooled odds ratio (OR) with corresponding 95 % confidence interval (95 % CI) was calculated by use of fixed-effects model or random-effects model when appropriate. A total of 15 eligible case-control studies with 4,501 cases and 8,038 controls were retrieved after a comprehensive search of the PubMed, Embase, Web of science, and Chinese Biomedicine (CBM) databases up to December 2012. The overall meta-analysis identified a positive but not statistically significant association between the XRCC1 Arg194Trp polymorphism and CRC risk under all genetic contrast models (ORTrp vs. Arg = 1.07, 95 % CI 0.90-1.26, P OR = 0.441; ORTrpTrp vs. ArgArg = 1.28, 95 % CI 0.91-1.81, P OR = 0.163; ORArgTrp vs. ArgArg = 1.00, 95 % CI 0.85-1.19, P OR = 0.956; ORArgTrp + TrpTrp vs. ArgArg = 1.06, 95 % CI 0.90-1.24, P OR = 0.502; ORTrpTrp vs. ArgArg + ArgTrp = 1.11, 95 % CI 0.91-1.34, P OR = 0.306). The genotype TrpTrp carriers among Caucasians were more susceptible to CRC, although lack statistical evidence (ORTrpTrp vs. ArgArg = 2.69, 95 % CI 0.97-7.49, P OR = 0.058; ORTrpTrp vs. ArgArg + ArgTrp = 2.77, 95 % CI 0.99-7.72, P OR = 0.051). Interestingly, the XRCC1 Arg194Trp variant was significantly associated with an increased risk of colon cancer. The present meta-analysis suggests that the XRCC1 Arg194Trp polymorphism may modify the risk for CRC, particularly colon cancer. However, the precise genetic association needs to be further estimated in future studies.

No clear consensus has been reached on the

Increasing scientific evidences suggest that common polymorphisms in the CYP1A1 and CYP11A1 genes may contribute to the development and progression of polycystic ovary syndrome (PCOS), but many existing studies have yielded inconclusive results. The aim of this study was to perform a meta-analysis of published studies on the associations between common polymorphisms in the CYP1A1 and CYP11A1 genes and susceptibility to PCOS.

Emerging evidence suggests that common functional polymorphisms in the CYP1A1 gene are involved in the regulation of the activities of cytochrome P450 enzymes, thereby increasing an individual's susceptibility to polycystic ovary syndrome (PCOS), but individually published results are inconclusive. This meta-analysis aimed to derive a more precise estimation of the relationship between CYP1A1 gene polymorphisms and PCOS risk.

Methylenetetrahydrofolate reductase (MTHFR) gene plays key roles not only in folate metabolism but also in carcinogenesis. The single nucleotide polymorphism MTHFR C677T has been indicated in the development of various tumors. The effect of the MTHFR C677T polymorphism on brain tumors remains poorly understood. We performed the present meta-analysis and aimed to provide a better understanding of the pathogenesis of brain tumors. A literature search of the PubMed, Embase, Web of Science, and Wanfang databases was carried out for potential relevant publications. We calculated the pooled odds ratio (OR) with corresponding 95% confidence interval (95% CI) to assess the association of MTHFR C677T with the susceptibility to brain tumors. We also performed stratified analysis and sensitivity analysis to further estimate the genetic association. All statistical analyses were conducted by the use of STATA 11.0 (STATA Corporation, College Station, TX, USA). Eight case-control studies involving a total of 3,059 cases and 3,324 controls were retrieved according to the inclusion criteria. The overall ORs suggested that the MTHFR C677T variant can exert a risk effect on brain tumor development under the following contrast models (OR(TC vs. CC) = 1.14, 95% CI 1.02-1.27, P OR = 0.018; OR(TT + TC vs. CC)= 1.23, 95% CI 1.01-1.51, P(OR) = 0.043). No significant correlation was identified among the Caucasians, but not among the Asians. In addition, the TC genotype carriers were more susceptible to meningioma when compared with the CC genotype carriers (OR(TC vs. CC) = 1.38, 95% CI 1.15-1.65, P(OR) < 0.001). The MTHFR C677T polymorphism seemed to exert no effect on glioma risk. The current meta-analysis firstly provides evidence that the MTHFR C677T polymorphism may modify the risk for brain tumors, particularly meningioma. The role of the MTHFR C677T variant in brain tumor pathogenesis across diverse ethnicities needs further elucidation by more future studies with large sample size.

Tuberous sclerosis (TS) is caused by mutation of the tumor suppressor genes, tuberous sclerosis complex 1 (TSC1) or 2 (TSC2). The aim of the present study was to compare the frequency and types of TSC1 and TSC2 mutations in American, British, Polish and Taiwanese populations. A meta‑analysis of 380 TS patients was performed. Significant differences were analyzed using the Chi-square test and one-way ANOVA analysis. Results showed a difference in frequency for the four populations analyzed. The frequency of TSC1 mutations was twice as high in the American and British populations. However, there were no significant differences in the types of mutations, with insertions of >1 nucleotide being the least frequent. Additionally, in an analysis of the complexity of nucleotide sequences it was demonstrated that the level of sequence complexity in the Polish population was significant higher compared to the remaining populations. Concerning strand bias, in the case of two types of substitutions, C>G/G>C and C>T/G>A, the ratio of corresponding mutations on the two DNA strands was approximately 3:1 and 2:1. In the present study, an increased frequency of C>G/G>C and C>T/G>A mutations in the coding strand was found in the analyzed populations. However, additional studies and larger patient cohorts are required to verify these results.

The angiotensinogen (AGT) gene has been considered to be implicated in the development of cancer. However, the results have been inconsistent. In this study, we performed a meta-analysis to clarify the association of AGT M235T variant with cancer risk.

Breast cancer cells respond to estrogen in a concentration dependent fashion, resulting in proliferation or apoptosis. The mechanism of this concentration dependent differential outcome is not well understood yet.

The methionine synthase (MTR) gene polymorphism A2756G has been linked to the risk of developing breast cancer, but the available results were inconsistent and underpowered. To derive a more precise estimation of the association between A2756G and breast cancer risk, an updated meta-analysis of 16 available studies with 9866 cases and 11,702 controls estimating the association between MTR A2756G and breast cancer risk was conducted. The quality of these studies was generally good except 2 studies with a lowest score 4 according to the Newcastle-Ottawa Scale (NOS). The results suggested that there is no significant association between A2756G and breast cancer risk in overall results. In the stratified analysis by ethnicity, source of controls (population or hospital-based), Hardy-Weinberg equilibrium (HWE) in controls, sample size (≥1000 and <1000 subjects), and menopausal status, the 2756G allele was associated with a decreased risk in Caucasians, PB (population-based) subgroup, and large studies. But the associations disappeared after removing the studies not in HWE. On the contrary, an increased risk was found in small studies. In conclusion, the findings suggest that MTR A2756G polymorphism is not associated with altered susceptibility to breast cancer, while the observed decreased risk in Caucasians, PB subgroup, and large studies and increased risk in small studies may be due to selection bias or other unknown factors.

The p53 tumor suppressor gene Arg72Pro polymorphism has been associated with esophageal cancer. However, the results were not consistent. Herein, this meta-analysis was performed to estimate the association between p53 Arg72Pro polymorphism and esophageal cancer.

DNA damage and replication checkpoints mediated by the ATR-CHEK1 pathway are key to the maintenance of genome stability, and both ATR and CHEK1 have been proposed as potential breast cancer susceptibility genes. Many novel variants recently identified by the large resequencing projects have not yet been thoroughly tested in genome-wide association studies for breast cancer susceptibility. We therefore used a tagging SNP (tagSNP) approach based on recent SNP data available from the 1000 genomes projects, to investigate the roles of ATR and CHEK1 in breast cancer risk and survival. ATR and CHEK1 tagSNPs were genotyped in the Sheffield Breast Cancer Study (SBCS; 1011 cases and 1024 controls) using Illumina GoldenGate assays. Untyped SNPs were imputed using IMPUTE2, and associations between genotype and breast cancer risk and survival were evaluated using logistic and Cox proportional hazard regression models respectively on a per allele basis. Significant associations were further examined in a meta-analysis of published data or confirmed in the Utah Breast Cancer Study (UBCS). The most significant associations for breast cancer risk in SBCS came from rs6805118 in ATR (p=7.6 x 10(-5)) and rs2155388 in CHEK1 (p=3.1 x 10(-6)), but neither remained significant after meta-analysis with other studies. However, meta-analysis of published data revealed a weak association between the ATR SNP rs1802904 (minor allele frequency is 12%) and breast cancer risk, with a summary odds ratio (confidence interval) of 0.90 (0.83-0.98) [p=0.0185] for the minor allele. Further replication of this SNP in larger studies is warranted since it is located in the target region of 2 microRNAs. No evidence of any survival effects of ATR or CHEK1 SNPs were identified. We conclude that common alleles of ATR and CHEK1 are not implicated in breast cancer risk or survival, but we cannot exclude effects of rare alleles and of common alleles with very small effect sizes.

Numerous epidemiological studies have evaluated the association between the glutathione S-transferases P1 (GSTP1) Ile105Val polymorphisms and prostate cancer (PCa) risk. However, these studies have yielded conflicting results. A comprehensive search was conducted through researching MEDLINE, PubMed, Web of Science, and EMBASE, and a total of 13 studies including 3,227 cases and 3,945 controls were identified. A meta-analysis was performed to obtain a summary of estimated odds ratios (ORs) and 95% confidence intervals (CIs) of GSTP1 polymorphisms for PCa, with attention to study quality and publication bias. The GSTP1 Ile158Val variant genotypes are less associated with increased risk of PCa for the homozygote model (Val/Val vs Ile/Ile: OR = 1.42; I(2) = 63.7%; 95% CI = 1.02-1.97) and the recessive model (OR = 1.41; I(2) = 45.5%; 95% CI = 1.10-1.80). However, no associations were detected for other genetic models. In the stratified analysis by ethnicity, significant associations between GSTP1 Ile105Val polymorphism and PCa risk were also found among Caucasians for Val/Val vs Ile/Ile comparison (OR = 1.22; I(2) = 0.0 %; 95 % CI = 1.02-1.47) and for the recessive model (OR = 1.26; I(2) = 0.0%; 95% CI = 1.06-1.49), while there were no associations found for other genetic models. However, no associations were found in Asians and African-Americans for all genetic models when stratified by ethnicity. In conclusion, our meta-analysis provides evidence that GSTP1 Ile105Val gene polymorphisms contributed to PCa susceptibility.