Genetic polymorphisms of the methylenetetrahydrofolate reductase gene, plasma folate levels and breast cancer susceptibility: a case-control study in Taiwan

Methylenetetrahydrofolate reductase (MTHFR) balances the pool of folate coenzymes in one-carbon metabolism for DNA synthesis and methylation, both are implicated in carcinogenesis. Two common variants in the MTHFR gene (C677T and A1298C) have been associated with reduced enzyme activity, thereby making MTHFR polymorphisms a potential candidate cancer-predisposing factor. To evaluate the C677T and A1298C functional polymorphisms in the MTHFR gene and their associations with breast cancer risk, as well as the potential modifying effect by plasma folate status on the MTHFR-associated risk, a hospital-based case-control study was conducted on a Taiwanese population consisting of 146 histologically confirmed incident breast cancer cases and their 285 age-matched controls without a history of cancer. A PCR-RFLP method was used for MTHFR polymorphism genotyping and RIA was used to measure the plasma folate. Statistical evaluations were performed using logistic regression analysis. The plasma folate level was inversely associated with breast cancer risk with an adjusted odds ratio (OR) of 0.52 [95% confidence interval (CI): 0.26-1.05] observed among women who were in the highest plasma folate tertile. The MTHFR 677T and 1298C variant alleles were associated with decreased risk for breast cancer [adjusted ORs were 0.81 (95% CI: 0.54-1.21) and 0.57 (95% CI: 0.36-0.89) for 677CT + TT genotypes and 1298AC + CC genotypes, respectively]. Furthermore, compound heterozygote and homozygote variants (677CT + TT and 1298AC + CC) had greater reduced risk (adjusted OR: 0.11, 95% CI: 0.03-0.43) among women with lower plasma folate levels. These results provide support for the important role of folate metabolism in breast tumorigenesis. Further mechanistic studies are warranted to investigate how MTHFR combined genotypes exert their effect on cancer susceptibility.     

Methylenetetrahydrofolate Reductase Polymorphisms and Susceptibility to Esophageal Cancer in Chinese Populations:a Meta-analysis

Although many epidemiologic studies investigated the methylenetetrahydrofolate reductase (MTHFR)polymorphisms and their associations with esophageal cancer, definite conclusions could not be drawn. To clarifythe effects of MTHFR polymorphisms on the risk of esophageal cancer, a meta-analysis was here performed inChinese populations. A total of 16 studies including 3,040 cases and 4,127 controls were involved in this metaanalysis.Overall, significant associations were found between the MTHFR C677T polymorphism and esophagealcancer risk when all studies in Chinese populations were pooled into the meta-analysis (T vs. C, OR = 1.19, 95%CI = 1.06–1.34; TT vs. CC, OR = 1.35, 95% CI = 1.07–1.70; TT+ CT vs. CC, OR = 1.29, 95% CI = 1.08–1.54;TT vs. CC + CT, OR = 1.19, 95% CI = 1.03–1.37). In subgroup analyses stratified by ethnicity and source ofcontrols, the same results were found in Kazakh (TT vs. CC, OR = 1.38, 95% CI = 1.02-1.87; TT + CT vs. CC,OR = 1.50, 95% CI = 1.03-2.18), in not stated populations (T vs. C, OR = 1.24, 95% CI = 1.08-1.42; TT vs. CC,OR = 1.47, 95% CI = 1.10-1.96; TT + CT vs. CC, OR = 1.30, 95% CI = 1.05-1.60; TT vs. CC + CT, OR = 1.32,95% CI = 1.12-1.56), and in hospital-based studies (T vs. C, OR = 1.34, 95% CI = 1.19-1.51; TT vs. CC, OR =1.81, 95% CI = 1.37-2.39; TT + CT vs. CC, OR = 1.51, 95% CI = 1.26-1.83; and TT vs. CC + CT, OR = 1.39,95% CI = 1.13-1.70). In conclusion, this meta-analysis provides evidence that the MTHFR C677T polymorphismcontributes to esophageal cancer development in Chinese populations.     

One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancer

Accumulating evidence from epidemiologic studies suggests that risk of breast cancer is reduced in relation to increased consumption of folate and related B vitamins. We investigated independent and joint effects of B vitamin intake as well as two polymorphisms of a key one-carbon metabolizing gene [i.e., methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C] on breast cancer risk. The study uses the resources of a population-based case-control study, which includes 1,481 cases and 1,518 controls. Significant inverse associations between B vitamin intake and breast cancer risk were observed among non-supplement users. The greatest reduction in breast cancer risk was observed among non-supplement users in the highest quintile of dietary folate intake [odds ratio (OR), 0.61; 95% confidence interval (95% CI), 0.41-0.93] as compared with non-supplement users in the lowest quintile of dietary folate intake (high-risk individuals). The MTHFR 677T variant allele was associated with increased risk of breast cancer (P, trend = 0.03) with a multivariate-adjusted OR of 1.37 (95% CI, 1.06-1.78) for the 677TT genotype. The 1298C variant allele was inversely associated with breast cancer risk (P, trend = 0.03), and was likely due to the linkage of this allele to the low-risk allele of 677C. The MTHFR-breast cancer associations were more prominent among women who did not use multivitamin supplements. Compared with 677CC individuals with high folate intake, elevation of breast cancer risk was most pronounced among 677TT women who consumed the lowest levels of dietary folate (OR, 1.83; 95% CI, 1.13-2.96) or total folate intake (OR, 1.71; 95% CI, 1.08-2.71). From a public heath perspective, it is important to identify risk factors, such as low B vitamin consumption, that may guide an effective prevention strategy against the disease.     

One-carbon metabolism-related gene polymorphisms and risk of breast cancer

Environmental exposures and/or genetic background in Japanese population, which might contribute to the relatively low breast cancer incidence rates in Japan, have not been clarified in detail. Folate plays an essential role in DNA methylation and synthesis, and thus may be involved in the development of breast cancer. Functional polymorphisms in genes encoding one-carbon metabolism enzymes, methylenetetrahydrofolate reductase (MTHFR C677T), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G) and thymidylate synthase (TS), influence folate metabolism, but epidemiological studies have yielded inconsistent findings. We therefore conducted a case-control study to clarify their associations with breast cancer risk. A total of 456 breast cancer cases and 912 age-matched and menopausal status-matched non-cancer controls were genotyped for the polymorphisms. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using conditional logistic models adjusted for potential confounders and gene-environment interactions between the polymorphisms and folate consumption were also evaluated. We observed an increased risk of postmenopausal breast cancer with the MTHFR 677TT genotype (OR = 1.83, 95% CI: 1.08-3.11) with a menopausal status-based analysis. In combination analysis, a significantly elevated OR was found among postmenopausal women with the MTHFR 677TT genotype and lower intake of dietary folate compared with those with 677CC genotype and adequate folate consumption (OR = 2.80, 95% CI: 1.11-7.07). In addition, interaction between the MTRR A66G polymorphism and folate intake for risk of postmenopausal breast cancer was observed (interaction P = 0.008). Our findings indicated that the MTHFR and MTRR polymorphisms were associated with individual susceptibility to breast cancer among postmenopausal women.     

5,10-Methylenetetrahydrofolate reductase polymorphisms and acute lymphoblastic leukemia risk: a meta-analysis.

There is evidence supporting a role for 5-10 methylenetetrahydrofolate reductase (MTHFR) gene variants in acute lymphoblastic leukemia (ALL). To provide a more robust estimate of the effect of MTHFR polymorphisms on the risk of ALL, we did a meta-analysis to reevaluate the association between the two most commonly studied MTHFR polymorphisms (C677T and A1298C) and ALL risk. All case-control studies investigating an association between the C677T or A1298C polymorphisms and risk of ALL were included. We applied both fixed-effects and random-effects models to combine odds ratio (OR) and 95% confidence intervals (95% CI). Q-statistic was used to evaluate the homogeneity and both Egger and Begg-Mazumdar tests were used to assess publication bias. The meta-analysis of the C677T polymorphism and risk of childhood ALL included 13 studies with a total of 4,894 individuals. Under a fixed-effects model, the TT genotype failed to be associated with a statistically significant reduction of childhood ALL risk (TT versus CT + CC: OR, 0.88; 95% CI, 0.73-1.06; P = 0.18). However, individuals homozygous for the 677T allele exhibited a 2.2-fold decrease in risk of adult ALL (TT versus CT + CC: OR, 0.45; 95% CI, 0.26-0.77; P = 0.004). In both cases, no evidence of heterogeneity was observed. No association between the A1298C variant and susceptibility to both adult and childhood ALL was disclosed. Our findings support the proposal that the common genetic C677T polymorphism in the MTHFR contributes to the risk of adult ALL, but not to the childhood ALL susceptibility.     

Associations between methylenetetrahydrofolate reductase polymorphisms and hepatocellular carcinoma risk in Chinese population

Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene are considered to have some influence on both folate metabolism and cancer risk. Previous studies on the associations of MTHFR genetic polymorphisms with hepatocellular carcinoma (HCC) risk in Chinese population reported inconsistent results. We performed this meta-analysis to comprehensively assess the associations. Finally, 12 individual case–control studies were included into the meta-analysis. There were seven studies (6,384 subjects) on the MTHFR C677T polymorphism and five studies (4,502 subjects) on the MTHFR A1298C polymorphism. Overall, MTHFR C677T polymorphism was significantly associated with susceptibility to HCC in Chinese population (T versus C, odds ratio (OR)?=?1.09, 95 % confidence interval (95 % CI) 1.01–1.17; TT versus CC, OR?=?1.17, 95 % CI 1.00–1.38; TT/CT versus CC, OR?=?1.12, 95 % CI 1.00–1.26). MTHFR A1298C polymorphism was conversely associated with HCC risk in Chinese population (CC versus AA, OR?=?0.65, 95 % CI 0.46–0.91; CC versus AA/AC, OR?=?0.64, 95 % CI 0.46–0.90). The sensitivity analysis confirmed the reliability and stability of the meta-analysis. Thus, the findings from our meta-analysis support the associations of MTHFR C677T and A1298C polymorphisms with HCC risk in Chinese population.     

Association of polymorphisms in one-carbon metabolizing genes with breast cancer risk in Syrian women

Dietary folate status as well as polymorphisms in one-carbon metabolism genes may affect the risk of breast cancer through aberrant DNA methylation and altered nucleotide synthesis and DNA repair. A large number of studies investigated the role of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms in breast cancer with inconsistent results. Association between multiple polymorphisms in one-carbon metabolism genes and breast cancer was not studied before in an Arab population. The purpose of the present study is to test the hypothesis that polymorphisms in one-carbon metabolism genes are associated with breast cancer susceptibility in Syrian breast cancer women patients. A total of 245 subjects (119 breast cancer women patients and 126 healthy controls) were genotyped for MTHFR C677T and A1298C and MTRR A66G polymorphisms. Association was tested for under numerous genetic models. A statistically significant association was found for MTHFR A1298C polymorphism especially under the allele contrast model (odds ratio (OR) = 1.68, 95% confidence interval (CI) (1.16-2.45), P = 0.006). On the other hand, no significant association was found for MTHFR C677T or MTRR A66G under any of the genetic models tested. The effects of the compound genotypes were also examined. The 66GG genotype was found to be protective against breast cancer when combined with the 677CT or 1298AC genotype (OR = 0.18, 95% CI (0.04-0.82), P = 0.014; OR = 0.3, 95% CI (0.08-1.11), P = 0.058). In conclusion, our study supports the hypothesis that polymorphisms in one-carbon gene metabolisms modulate the risk for breast cancer, particularly the A1298C polymorphism of the MTHFR gene.     

MTHFR polymorphisms, folate intake and carcinogen DNA adducts in the lung

The methylenetetrahydrofolate reductase (MTHFR) genes and folate in one-carbon metabolism are essential for DNA methylation and synthesis. However, their role in carcinogen DNA damage in target lung tissue, a dosimeter for cancer risk, is not known. Our study aimed to investigate the association between genetic and nutritional one-carbon metabolism factors and DNA adducts in target lung. Data on 135 lung cancer cases from the Massachusetts General Hospital were studied. Genotyping was completed for MTHFR C677T (rs1801133) and A1298C (rs1801131). Information on dietary intake for one-carbon related micronutrients, folate and other B vitamin was derived from a validated food frequency questionnaire. DNA adducts in lung were measured by (32) P-postlabeling. After adjusting for potential confounders, DNA adduct levels in lung significantly increased by 69.2% [95% confidence interval (CI), 5.5% to 171.5%] for the MTHFR 1298AC+CC genotype. The high risk group, combining the A1298C (AC+CC) plus C677T (CT+TT) genotypes, had significantly enhanced levels of lung adducts by 210.7% (95% CI, 21.4% to 695.2%) in contrast to the A1298C (AA) plus C677T (CC) genotypes. Elevation of DNA adduct was pronounced-111.3% (95% CI, -3.0 to 360.5%) among 1298AC+CC patients, who consumed the lowest level of folate intake as compared to 1298AA individuals with highest tertile of intake. These results indicate that DNA adducts levels are influenced by MTHFR polymorphisms and low folate consumption, suggesting an important role of genetic and nutritional factors in protecting DNA damage from lung carcinogen in at-risk populations.     

The methylenetetrahydrofolate reductase 677C-->T polymorphism and distal colorectal adenoma risk.

A common polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, where a cytosine at nucleotide 677 is replaced by a thymine (677C-->T), is associated with enzyme thermolability and a reduction in the conversion of 5,10-methyltetrahydrofolate (5,10-MTHF) into 5-methyltetrahydrofolate. We assessed the association between homozygosity for the MTHFR 677CT genotype (TT) and colorectal adenoma risk in a large sigmoidoscopy-based case-control study of members of a prepaid health plan in Los Angeles. MTHFR genotype was determined for 471 cases and 510 age-, sex-, clinic-, and sigmoidoscopy-date-matched controls. Information on RBC and plasma folate levels were analyzed for 331 cases and 350 controls. When compared with the presence of at least one wild-type allele (CT/CC), the odds ratio (OR) for the TT genotype was 1.19 [95% confidence interval (CI), 0.77-1.76] after adjusting for race and the matching factors. Compared with those in the lowest quartiles of RBC and plasma folate and a wild-type allele, adenoma risk was increased for TT homozygotes in the lowest folate quartiles (genotype: OR, 2.04 and 95% CI, 0.6-7.0; OR, 1.84 and 95% CI, 0.6-7.0 for RBCs and plasma folate, respectively) and decreased in TT homozygotes in the highest quartiles (genotype: OR, 0.82 and 95% CI, 0.32-2.10; OR, 0.65 and 95% CI, 0.22-1.95, respectively). There was also a significant interaction between TT genotype and the increased adenoma risk associated with alcohol. These data are consistent with an interaction between MTHFR genotype and folate availability.     

Quantitative assessment of the association between MTHFR C677T polymorphism and colorectal cancer risk in East Asians

A great number of studies regarding the association between MTHFR C677T polymorphism and risk of colorectal cancer (CRC) in East Asians were published, but the results were inconsistent. Thus, a meta-analysis was performed to investigate the association. PubMed, Embase, and CBM databases were searched for eligible publications. Pooled odds ratios (ORs) with 95?% confidence intervals (95?% CIs) were calculated using random or fixed effect models. Finally, 24 case?Ccontrol studies with a total of 7,230 CRC cases and 9,285 controls were included. Meta-analyses of a total of 24 studies showed there was a statistically significant association between MTHFR C677T polymorphism and decreased CRC risk in East Asians under four genetic models (T versus C, OR?=?0.92, 95?% CI 0.85?C0.99; TT versus CC, OR?=?0.80, 95?% CI 0.69?C0.94; TT versus CT/CC, OR?=?0.82, 95?% CI 0.71?C0.95; TT/CT versus CC, OR?=?0.92, 95?% CI 0.86?C0.98). The cumulative meta-analyses for the allele contrast (T versus C), homozygote (TT versus CC), dominant (TT/CT versus CC), and recessive (TT versus CT/CC) models all showed a trend of more obvious association as information accumulated by year. Subgroup analyses by country further identified this association in Korea and Japan. This meta-analysis suggests that MTHFR C677T polymorphism is associated with decreased risk of colorectal cancer in East Asians, and MTHFR 677T variant has a protective effect on colorectal cancer.     

Significant association between MTHFR C677T polymorphism and hepatocellular carcinoma risk: a meta-analysis

Previous studies investigated the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and hepatocellular carcinoma risk, but the impact of MTHFR C677T polymorphism on hepatocellular carcinoma was still unclear, owing to the obvious inconsistence from those studies. This study aimed to quantify the strength of the association between MTHFR C677T polymorphism and hepatocellular carcinoma risk by performing a meta-analysis. We searched the PubMed and Wanfang databases for studies on the association between MTHFR C677T polymorphism and hepatocellular carcinoma risk. We estimated the pooled odds ratios (ORs) with their 95 % confidence intervals (95 % CIs) to assess the association. Fifteen studies with 8,625 participants were finally included into the meta-analysis. Meta-analyses of total 15 studies suggested that MTHFR C677T polymorphism was significantly associated with an increased risk of hepatocellular carcinoma under two main genetic models (for TT versus CC, OR?=?1.19, 95 % CI 1.03–1.37, P?=?0.016; for TT versus CT/CC, OR?=?1.14, 95 % CI 1.01–1.28, P?=?0.032). Subgroup meta-analyses suggested that MTHFR C677T polymorphism was associated with an increased risk of hepatocellular carcinoma in Asians, but not in Caucasians. Thus, individuals with homozygote genotype TT of MTHFR C677T have obviously increased risk of hepatocellular carcinoma.     

5,10-methylenetetrahydrofolate reductase 677 and 1298 polymorphisms, folate intake, and microsatellite instability in colon cancer.

The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene plays a critical role in folate metabolism. Studies on the association between MTHFR polymorphisms and length changes in short tandem repeat DNA sequences [microsatellite instability (MSI)] are inconsistent. Using data from colon cancer cases (n=503) enrolled as part of an existing population-based case-control study, we investigated the association between MTHFR 677 and MTHFR 1298 polymorphisms and MSI. We also examined whether the association was modified by folate intake. Participants were case subjects enrolled as part of the North Carolina Colon Cancer Study. Consenting cases provided information about lifestyle and diet during in-home interviews as well as blood specimens and permission to obtain tumor blocks. DNA from normal and tumor tissue sections was used to determine microsatellite status (MSI). Tumors were classified as MSI if two or more microsatellite markers (BAT25, BAT26, D5S346, D2S123, and D17S250) had changes in the number of DNA sequence repeats compared with matched nontumor tissue. Tumors with one positive marker (MSI-low) or no positive markers (microsatellite stable) were grouped together as non-MSI tumors (microsatellite stable). MTHFR 677 and MTHFR 1298 genotypes were determined by real-time PCR using the 5' exonuclease (Taqman) assay. Logistic regression was used to calculate odds ratio (OR) and 95% confidence intervals (95% CI). MSI was more common in proximal tumors (OR, 3.8; 95% CI, 1.7-8.4) and in current smokers (OR, 4.0; 95% CI, 1.6-9.7). Compared with MTHFR 677 CC referent, MTHFR 677 CT/TT genotype was inversely associated with MSI among White cases (OR, 0.36; 95% CI, 0.16-0.81) but not significant among African Americans. Although not statistically significant, a similar inverse association was observed between MTHFR 677 CT/TT genotype and MSI among the entire case subjects (OR, 0.54; 95% CI, 0.26-1.10). Among those with adequate folate intake (>400 microg total folate), we found strong inverse associations between combined MTHFR genotypes and MSI (677 CC+1298 AC/CC, OR, 0.09; 95% CI, 0.01-0.59; 677 CT/TT+1298 AA, OR, 0.13; 95% CI, 0.02-0.85) compared with the combined wild-type genotypes (677 CC+1298 AA). This protective effect was not evident among those with low folate (<400 microg total folate) intake. Our results suggest that MTHFR variant genotypes are associated with reduced risk of MSI tumors under conditions of adequate folate intake, although the data are imprecise due to small numbers. These results indicate that the relationship between MTHFR genotypes and MSI is influenced by folate status.     

Methylenetetrahydrofolate reductase polymorphisms and breast cancer risk in Chinese population: a meta-analysis of 22 case–control studies

The association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and breast cancer risk in the Chinese population has been widely reported, but results were inconsistent. In order to derive a more precise estimation of the relationship, a meta-analysis was performed. Eligible articles were identified through search of databases including Medline, PubMed, Web of Science, Embase, Chinese Biomedical Literature Database (CBM, Chinese), China National Knowledge Infrastructure (CNKI, Chinese), and Wangfang Database (Chinese). The association between the MTHFR polymorphism and breast cancer risk was conducted using odds ratios (ORs) and 95 % confidence intervals (95 % CIs). Finally, a total of 22 studies with 6,103 cases and 7,913 controls were included in our meta-analysis: 13 studies with 3,273 cases and 4,419 controls for C677T polymorphism and 9 studies with 2,830 cases and 3,494 controls for A1298C polymorphism. With regard to C677T polymorphism, significant association was found with breast cancer risk under three models (T vs. C: OR?=?1.12, 95 % CI?=?1.02–1.23, P?=?0.015; TT vs. CC: OR?=?1.35, 95 % CI?=?1.10–1.67, P?=?0.005; TT vs. CC/CT: OR?=?1.37, 95 % CI?=?1.11–1.70, P?=?0.004). There was no significant association found between A1298C polymorphism and breast cancer risk under all genetic models (C vs. A: OR?=?0.96, 95 % CI?=?0.89–1.03, P?=?0.268; CC vs. AA: OR?=?0.98, 95 % CI?=?0.77–1.26, P?=?0.899; AC vs. AA: OR?=?0.95, 95 % CI?=?0.88–1.02, P?=?0.174; CC vs. AC/AA: OR?=?1.00, 95 % CI?=?0.78–1.28, P?=?0.996, CC/AC vs. AA: OR?=?0.96, 95 % CI?=?0.89–1.02, P?=?0.196). In summary, during this meta-analysis, we found that MTHFR C677T polymorphism was significantly associated with breast cancer risk in the Chinese population. Meanwhile, MTHFR A1298C polymorphism was not associated with breast cancer risk in the Chinese population.     

Evaluation of the MTHFR C677T Polymorphism as a Risk Factor for Colorectal Cancer in Asian Populations

Background: Genetic and environmental factors play important roles in pathogenesis of digestive tract cancers like those in the esophagus, stomach and colorectum. Folate deficiency and methylenetetrahydrofolate reductase (MTHFR) as an important enzyme of folate and methionine metabolism are considered crucial for DNA synthesis and methylation. MTHFR variants may cause genomic hypomethylation, which may lead to the development of cancer, and MTHFR gene polymorphisms (especially C677T and A1298C) are known to influence predispositions for cancer development. Several case control association studies of MTHFR C677T polymorphisms and colorectal cancer (CRC) have been reported in different populations with contrasting results, possibly reflecting inadequate statistical power. Aim: The present meta-analysis was conducted to investigate the association between the C677T polymorphism and the risk of colorectal cancer. Materials and Methods: A literature search of the PubMed, Google Scholar, Springer link and Elsevier databases was carried out for potential relevant articles. Pooled odds ratio (OR) with corresponding 95 % confidence interval (95 % CI) was calculated to assess the association of MTHFR C677T with the susceptibility to CRC. Cochran’s Q statistic and the inconsistency index (I2) were used to check study heterogeneity. Egger’s test and funnel plots were applied to assess publication bias. All statistical analyses were conducted by with MetaAnalyst and MIX version 1.7. Results: Thirty four case-control studies involving a total of 9,143 cases and 11,357 controls were retrieved according to the inclusion criteria. Overall, no significant association was found between the MTHFR C677T polymorphism and colorectal cancer in Asian populations (for T vs. C: OR=1.03; 95% CI= 0.92 1.5; p= 0.64; for TT vs CC: OR=0.88; 95%CI= 0.74-1.04; p= 0.04; for CT vs. CC: OR = 1.02; 95%CI= 0.93-1.12; p=0.59; for TT+ CT vs. CC: OR=1.07; 95%CI= 0.94-1.22; p=0.87). Conclusions: Evidence from the current meta-analysis indicated that the C677T polymorphism is not associated with CRC risk in Asian populations. Further investigations are needed to offer better insight into any role of this polymorphism in colorectal carcinogenesis.     

Folate Pathway Gene MTHFR C677T Polymorphism and Risk of Lung Cancer in Asian Populations

Background: Previous studies concerning the association between the 5,10-methylenetetrahydrofolatereductase (MTHFR) C677T gene polymorphism with lung cancer in Asian populations have provided inconclusivefindings. Aim: A meta-analysis was performed to investigate a more reliable association between MTHFR C677Tpolymorphism and lung cancer in Asians. Materials and Methods: A comprehensive search was conducted toidentify all case-control studies of MTHFR polymorphisms and lung cancer in Asia, using odds ratios (ORs) with95% confidence intervals (CIs) to assess the strength of any association. Results: Meta-analysis results suggestedthat the MTHFR C677T polymorphism contributed to an increased lung cancer risk in Asian populations (forT vs C: OR=1.11, 95%CI=1.0-1.23; for CT vs CC: OR= 1.1, 95%CI= 0.95-1.2 ; for TT+CT vs CC: OR=1.13,95%CI=1.0-1.30; for TT vs CC: OR=1.25, 95%CI=1.01-1.30; for TT vs CT+CC: OR=1.16, 95%CI=1.0-1.36).Conclusions: MTHFR C677T polymorphism is significantly associated with lung cancer in Asians.     

Meta-analysis of the Relationship between the Metholenetetrahydrofolate Reductase C677T Genetic Polymorphism,Folate Intake and Esophageal Cancer

Objective: To evaluate the effect of the methylenetetrahydrofolate reductase C677T genetic polymorphism(MTHFR C677T) and folate intake on the risk of esophageal cancer. Methods: A total of 17 studies (3,277 casesand 4,661 controls) regarding MTHFR C677T and 6 studies (1,817 cases and 7,678 controls) regarding folateintake published between 2001 and 2011 were identified through researching MEDLINE, EMBASE and theChinese Biomedical Database. The data of the last search was February 2011. A meta-analysis was performedto obtain summary estimated odd ratios and 95% confidence intervals of folate intake and MTHFR C677T foresophageal cancer. Results: A significant association was seen between MTHFR 677 CT [adjusted OR (95%CI)=1.55(1.28-1.88)] and TT [crude OR (95% CI)=1.63(1.24-2.15)] genotypes and esophageal cancer. Folateintake was seen to have a preventive effect on esophageal cancer [OR (95% CI)=0.60(0.50-0.70)]. Non-drinkerswith MTHFR 677 CT and TT showed light esophageal cancer risk, and higher esophageal cancer risk was foundamong smokers. Also, the MTHFR 677 CT and TT genotypes were associated with light esophageal cancer riskin non-drinkers and a higher risk in drinkers. The meta-regression analysis showed the effect of MTHFR 677CT and TT increased with the level of alcohol and tobacco consumption. The MTHFR 677 TT genotype showeda decreased risk of esophageal cancer in the high folate intake group. Conclusion: MTHFR 677CT/TT increasethe risk of esophageal cancer, and the effects are greatly modified by alcohol, tobacco and folate intake. Folateintake was seen to have a preventive effect on developing esophageal cancer.     

Involvement of microRNA-423 Gene Variability in Breast Cancer Progression in Saudi Arabia

Aim: microRNA-423 is an oncogenic factor which is frequently upregulated in cancer. However, associations withbreast cancer risk remain inconsistent. Therefore, we investigated the prevalence of microRNA-423 rs6505162C>Tgene variation with breast cancer susceptibility in Saudi women. Methodology: This study was conducted on 100breast cancer patients and 124 matched healthy individuals. Genotyping of the microRNA-423 rs6505162C/T genevariation was performed by using the amplification refractory mutation system PCR method (ARMS-PCR). Results:A significant difference was observed in the genotype distribution between the breast cancer cases and controls(p=0.0001), the frequencies of the genotypes CC,CT and TT being 25%, 52% and 23% in patients and 65%,20% and15% respectively, in controls. The microRNA-423 C>T variant was associated with an increased risk of breast cancerin codominant models for (OR = 6.73, 95 % CI, 3.50-12.97; RR 2.35(1.67-3.30, p=0.0001) the microRNA-423TTgenotype and (OR = 4.14, 95 % CI, 1.93-8.87; p=0.0003) microRNA-423CT (OR= 6.73, 95% CI, 3.50-12.97; p=0.0001)and also with the dominant model (OR 5.6(3.14-1.01), p=0.0001) CT+TT vs CC) with a non-significant association forthe recessive model (OR=1.75, 95%CI=0.08-3.44, P=0.139, TT vs CC+CT). The T allele significantly increased therisk of breast cancer (OR =2.63, 95 % CI, 1.77-3.91; p=0.001) compared to the C allele. Some 6.73 ,4.14 and 2.63 foldincreased risk of developing breast cancer was associated with TT and CT genotypes and the T allele of microRNA-423in the northwestern region of Saudi Arabia. Conclusion: Our findings indicate that the microRNA-423 TT genotypeand the T allele are associated with an increased susceptibility, metastasis and advanced stage of breast cancer in SaudiArabian patients. Further studies with larger sample sizes are necessary to confirm our findings.     

The Methylenetetrahydrofolate Reductase C677T Polymorphism and Breast Cancer Risk in Asian Populations

Background: Methylenetetrahydrofolate (MTHFR) is the key enzyme of the folate metabolic pathway andseveral studies have pointed to association between the MTHFR C677T polymorphism and breast cancer risk.Although significant association was observed in some studies, in others no clear link could be established.Objective: A meta-analysis of published Asian case control studies was therefor carried out to shed further lighton any C677T breast cancer association. Materials and Methods: PubMed, Springer Link, Google Scholar andElsevier databases were searched for case control studies of associations between MTHFR C677T polymorphismand breast cancer risk. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess theassociation. A total of 36 studies including 8,040 cases and 10,008 controls were included in the present metaanalysis.Results: Overall, a significantly elevated breast cancer risk was associated with the T allele and TTgenotype in homozygote comparison and dominant genetic models when all studies were pooled into the metaanalysis(T vs C (allele contrast model): OR=1,23, 95%CI=1.13-1.37, p=0.000 ; TT vs CC(homozygote model):OR=1.38, 95%CI=1.16-1.63, p=0.0003; TT+CT vs CC (dominant model): OR=1.12, 95%CI=1.01-1.23, p=0.02).Conclusions: The present meta-analysis strongly suggested a significant association between the MTHFR C677Tpolymorphism and risk of breast cancer in Asian populations.     

Impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on methotrexate-induced toxicities in acute lymphoblastic leukemia: a meta-analysis

The associations between methylenetetrahydrofolate reductase (MTHFR) polymorphism and methotrexate (MTX)-induced toxicities in patients with acute lymphoblastic leukemia (ALL) have been evaluated in various populations, with the results remained conflicting. 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 were searched until 21 September 2011 to identify eligible studies. A total of 14 studies were included, with all studies investigating MTHFR C677T polymorphism while nine of them investigating MTHFR A1298C polymorphism only. Results suggested that MTHFR C677T polymorphism was associated with significantly increased risk of MTX-induced toxicity, specifically liver toxicity (TT/CT vs. CC: odds ratio (OR)?=?1.70, 95?% confidence interval (CI)?=?1.05?C2.75), myelosuppression (TT vs. CT/CC: OR?=?2.82, 95?%CI?=?1.25?C6.34), oral mucositis (TT/CT vs. CC: OR?=?3.68, 95?%CI?=?1.73?C7.85), gastrointestinal toxicity (TT/CT vs. CC: OR?=?2.36, 95?%CI?=?1.36?C4.11), and skin toxicity (T vs. C: OR?=?2.26, 95?%CI?=?1.07?C4.74). MTHFR A1298C polymorphism was found to be associated with decreased risk of skin toxicity (CC/AC vs. AA: OR?=?0.11, 95?%CI?=?0.01?C0.85). Genotyping of MTHFR polymorphism, C677T particularly, prior to treatment for ALL is likely to be useful with the aim of tailoring MTX therapy and thus reducing the MTX-related toxicities. However, further studies with larger data set and well-designed models are required to validate our findings.     

Genetic susceptibility of methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C, and G1793A polymorphisms with risk for bladder transitional cell carcinoma in men

We performed a case-control study of 158 bladder transitional cell carcinoma (TCC) cases and 316 controls to investigate the association between methylenetetrahydrofolate reductase (MTHFR) C677T, A1298G, and G1793A polymorphisms and bladder cancer susceptibility by polymerase chain reaction restriction fragment length polymorphism (PCR-RLFP) technique. The controls were frequency-matched to the cases by age (± 5 years), ethnicity, and smoking status. We also measured serum levels of total homocysteine (tHcy), folate, and vitamin B12. It was found that the 1298AC (odds ratio, OR = 3.74; 95% confidence interval, CI = 2.34-5.47; P = 0.001) and 1298CC (OR = 3.46, 95% CI = 2.37-5.52; P = 0.001) genotypes of MTHFR A1298C were significantly associated with increased risk of bladder TCC. The MTHFR C677T and G1793A polymorphisms were not associated with bladder TCC. After stratification for grade and stage, we observed that the 677TT (OR = 4.47, 95% CI = 2.74-6.72; P = 0.001) and MTHFR 1298CC (OR = 4.78, 95% CI = 2.82-6.89; P = 0.001) genotypes of MTHFR were associated with increased risk of muscle-invasive bladder TCC. We also found that the MTHFR 677CT+1298AA genotypes were associated with an approximately 70% reduction in risk of bladder cancer (OR = 0.31; 95% CI = 0.15-0.68) compared to the combined referent genotype. There were 8 haplotypes and 16 haplotype genotypes based on these three variants. When we used the haplotypes and assumed that the 677T, 1298C, and 1793G alleles were risk alleles, the adjusted odds ratios increased as the number of risk alleles increased: 1.00 for 0-1 variant, 1.88 (1.4-2.7) for any two risk alleles and 2.07 (1.6-2.8) for any three risk alleles. Serum tHcy levels were significantly higher in carriers of the 677T, 1298C, and 1793G alleles compared to noncarriers (all P < 0.01). There was no significant correlation between serum levels of tHcy and folate and bladder cancer risk. Further studies in larger samples size and different ethnicity are required to confirm our findings.