Folate intake, methylenetetrahydrofolate reductase polymorphisms, and risk of esophageal cancer

Aim: Genetic and environmental factors may play roles in the pathogenesis of esophageal cancer and susceptibility may be modified by functional polymorphisms in folate metabolic genes, such as methylenetetrahydrofolate reductase (MTHFR). We here evaluated associations of the MTHFR C677T polymorphism and folate intake with esophageal cancer. Methods: A matched hospital-based case-control study with 155 esophageal cancer and 310 non-cancer controls was conducted in a Chinese population with gene-environment interactions evaluated between the MTHFR C667T polymorphism and drinking and smoking, as well as folate intake. Results: Individuals carrying MTHFR 667CT [adjusted odds ratio (OR), 1.95; 95% confidence interval (CI), 1.23-2.62] and TT [adjusted odds ratio (OR), 3.36; 95% confidence interval (CI), 1.46-8.74] had significantly increased esophageal cancer risk compared with those with MTHFR 667CC genotype. Folate intake was seen to have non-significant preventive effect. In former, moderate and heavy drinkers, a high esophageal cancer risk was observed for those with an MTHFR 677T allele genotype [ORs: 5.0(1.29-18.88), 3.70(1.83-7.66) and 5.77(2.11-15.72), respectively]. Significant interaction was found for moderate-heavy drinking and the MTHFR 677T allele genotype for esophageal cancer risk (p<0.05). Significant increased risk was also found in moderate and heavy smokers with the two genotypes [ORs: 3.58(1.64-7.80) and 4.51(1.15-17.78), respectively]. High folate intake and MTHFR 677TT was associated with a non-significant tendency for decreased esophageal cancer risk. Conclusion: Our finding supports the hypothesis that MTHFR C667T polymorphisms play a role in pathogenesis of esophageal cancer in the Chinese population.     

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.     

Methylenetetrahydrofolate Reductase Genetic Polymorphisms and Esophageal Squamous Cell Carcinoma Susceptibility: A Meta-analysis of Case-control Studies

Background: Genetic factors and environmental factors play a role in pathogenesis of esophageal squamouscell carcinoma (ESCC). Previous studies regarding the association of folate intake and Methylenetetrahydrofolatereductase C677T polymorphism with ESCC was conflicting. We conducted a meta-analysis to investigate theassociation of MTHFR C677T and folate intake with esophageal cancer risk. Methods: MEDLINE, EMBASEand the Chinese Biomedical Database were searched in our study. The quality of studies were evaluated bypredefined scale, and The association of polymorphisms of MTHFR C677T and folate intake and ESCC riskwas estimated by Odds ratio (ORs) with 95% confidence intervals (CIs). Results: 19 studies (4239 cases and5575 controls) were included for meta-analysis. A significant association was seen between individuals withMTHFR 677 CT [OR(95%)=1.47(1.32-1.63)] and TT [OR(95%)=1.69(1.49-1.91)] genotypes and ESCC risk(p<0.05). Low intake of folate had significantly higher risk of esophageal cancer among individuals with CT/TTgenotype [OR(95%)=1.65(1.1-2.49)], while high intake of folate did not find significant high risk of esophagealcancer among individuals with CT/TT genotype [OR(95%)=1.64 (0.82-3.26)]. Conclusions: Our meta-analysisindicated the folate intake and MTHFR 677CT/TT are associated with the risk of ESCC, and folate showed asignificant interaction with polymorphism of MTHFR C677T.     

The Methylenetetrahydrofolate Reductase C677T Polymorphism Influences Risk of Esophageal Cancer in Chinese

Methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism. This study with381 esophageal cancer patients and 432 healthy controls was conducted to examine the association of MTHFRC677T and A1298C polymorphisms with susceptibility to esophageal cancer (EC) in a Chinese population.Compared with the CC genotype of MTHFR C677T, subjects carrying homozygote TT and variant genotypes(CT+TT) demonstrated reduced risk of EC with adjusted ORs (95% CI) of 0.44 (0.28-0.71) and 0.57 (0.37-0.88),respectively. However, no association was found between the MTHFR A1298C polymorphism and the risk ofEC. Comparing to haplotype CA, haplotypes TA and TC could reduce the susceptibility to EC with adjustedORs (95% CI) of 0.61(0.47-0.79) and 0.06 (0.01-0.43), respectively. In conclusion, the present study suggestedthat the MTHFR C677T polymorphism can markedly influence the risk of EC in Chinese.     

Systematic review on the relationship between genetic polymorphisms of methylenetetrahydrofolate reductase and esophageal squamous cell carcinoma

Background: Both genetic and environmental factors play roles in pathogenesis of esophageal squamouscell carcinoma (ESCC) and susceptibility may be modified by functional polymorphisms in folate metabolicgenes, such as methylenetetrahydrofolate reductase (MTHFR). We here aimed to evaluate associations ofMTHFR C677T and A1298C polymorphisms with ESCC. Methods: We searched MEDLINE, EMBASE andthe Chinese Biomedical Database and 2 evaluators independently reviewed all the articles identified accordingto predetermined criteria. Results: A total of 15 case-control studies published between 2001 and 2010 wereincluded. When all the studies were pooled, the crude odds ratio (95% CI) of ESCC for individuals carryingMTHFR 677 CT and TT genotypes, as compared to CC, were 1.39 (1.11-1.75) and 1.79 (1.31-2.43), respectively.Individuals with MTHFR 1298CC showed non-significantly increased risk of ESCC, with an OR (95%CI) of3.31(0.90-12.17). In smokers, a significantly increased risk of ESCC was observed for those with the MTHFR677T allele (OR (95% CI)=2.2 (1.31-2.41)). Chinese carrying MTHFR 677T and MTHFR 1298C alleles had agreater increase in ESCC risk than other ethnicities. Conclusions: The present meta-analysis provided evidencethat MTHFR 677CT/TT plays a carcinogenic role in ESCC, and its effect is modified by tobacco and ethnicity.The small number of subjects with the MTHFR 1299C allele genotype in published studies limits conclusionsregarding this polymorphism.     

MTHFR polymorphisms, dietary folate intake, and breast cancer risk: results from the Shanghai Breast Cancer Study.

Folate plays an important role in DNA methylation, synthesis, and repair; intake has been associated with breast cancer. The folate-metabolizing enzyme, methylenetetrahydrofolate reductase (MTHFR) is polymorphic at nucleotides 677 (C-->T) and 1298 (A-->C), resulting in allozymes with decreased activity. We evaluated these two common polymorphisms and their effects on the folate intake and breast cancer risk association in a population-based case-control study of 1144 breast cancer cases and 1236 controls using a PCR-RFLP-based assay. All subjects completed in-person interviews, which included a food frequency questionnaire. Unconditional logistic regression models were used to calculate odds ratios and their 95% confidence intervals, after adjusting for potential confounding factors. Cases and controls were similar in the distribution of MTHFR polymorphisms at codons 677 (41.4% cases and 41.8% controls carried the T allele) and 1298 (17.6% cases and 17.5% controls carried the C allele). An inverse association of breast cancer risk with folate intake was observed in all genotype groups, particularly among subjects with the 677TT genotype. Compared with those with the 677CC genotype and high folate, the adjusted odds ratios (95% confidence intervals) associated with low folate intake were 1.94 (1.15-3.26), 2.17 (1.34-3.51), and 2.51 (1.37-4.60) for subjects who had CC, CT, and TT genotypes (p for interaction, 0.05). No modifying effect of A1298C genotypes on the association of folate intake with breast cancer risk was observed. Results of this study suggest that the MTHFR C677T polymorphisms may modify the association between dietary folate intake and breast cancer risk.     

Polymorphisms of folate metabolic genes and susceptibility to bladder cancer: a case-control study

Epidemiological studies have shown an association between low folate intake and an increased cancer risk. Major genes involved in folate metabolism include methylene-tetrahydrofolate reductase (MTHFR) and methionine synthase (MS). We investigated joint effects of polymorphisms of the MTHFR (677 C-->T, 1298A-->C) and MS genes (2756 A-->G), dietary folate intake and cigarette smoking on the risk of bladder cancer in a case-control study. The study population consisted of 457 bladder cancer patients and 457 healthy controls, matched to the cases in terms of age, gender and ethnicity. Genotype data were analyzed in a subset of 410 Caucasian cases and 410 controls. Compared with individuals carrying the MTHFR 677 wild-type (CC) and reporting a high folate intake, those carrying the variant genotype (CT or TT) and reporting a low folate intake were at a significantly 3.51-fold increased risk of bladder cancer (95% CI: 1.59-6.52). In contrast, individuals carrying a variant genotype and reporting a high folate intake were at only a 1.39-fold increased risk (95% CI: 0.71-2.70), and those carrying the wild-type and reporting a low folate intake were at only 1.56-fold increased risk (95% CI: 0.82-2.97). The interaction between genetic polymorphisms and folate intake was significant on the multiplicative scale (P = 0.01). When analyzed in the context of smoking status, compared with never smokers with the MTHFR 677 wild-type, the risk increased to 6.56-fold (95% CI: 3.28-13.12) in current smokers carrying the variant genotype. Analyses of the MTHFR 1298, MS 2756 genes revealed similar results. In addition, age at cancer onset in former smokers increased as the proportion of the heteromorphic haplotype in the individual increased (P = 0.005). Our results strongly suggest that polymorphisms of the MTHFR and MS genes act together with low folate intake and smoking to increase bladder cancer risk. These results have important implications for cancer prevention in susceptible populations.     

Diet Folate,DNA Methylation and Polymorphisms in Methylenetetrahydrofolate Reductase in Association with the Susceptibility to Gastric Cancer

Methylenetetrahydrofolate reductase (MTHFR) has been reported to be associated with DNA methylation, anepigenetic feature frequently found in gastric cancer. We conducted a case-control study to explore the associationof MTHFR C677T polymorphisms with gastric cancer risk and its relation with the DNA methylation of COX-2,MGMT, and hMLH1 genes. Genotyping of P16, MGMT and HMLH1 was determined by methylation-specificPCR after sodium bisulfate modification of DNA, and genotyping of MTHFR C677T was conducted by TaqManassays using the ABI Prism 7911HT Sequence Detection System. Folate intake was calculated with the aid ofa questionnaire. Compared with the MTHFR 677CC genotype, the TT genotype was significantly associatedwith 2.08 fold risk of gastric cancer when adjusting for potential risk factors. Individuals who had an intakeof folate above 310 μg/day showed protective effects against gastric cancer risk. The effect of MTHFR C677Tpolymorphisms on the risk of gastric cancer was modified by folate intake and methylation status of MGMT (Pfor interaction <0.05).     

Polymorphisms of 5,10-methylenetetrahydrofolate reductase and risk of gastric cancer in a Chinese population: a case-control study

Low dietary folate intake has been associated with increased risk of gastric cancer. The 5,10-methylenetetrahydrofolate reductase (MTHFR) involved in folate metabolism has 2 variants, C677T and A1298C, that result in decreased MTHFR activity and lower plasma folate levels. Therefore, we hypothesized that these 2 variants play a role in gastric carcinogenesis. We tested this hypothesis in a Chinese population-based case-control study of 187 histopathologically confirmed gastric cancer cases and 166 healthy controls frequency-matched by age (+/-5 years), gender and residential area. The 677TT genotype was associated with increased risk for gastric cancer [adjusted odds ratio (OR) = 1.87, 95% confidence interval (CI) = 1.00-3.48] compared to the 677CC genotype. This association was more pronounced for gastric cardia cancer (adjusted OR = 2.47, 95% CI = 1.14-5.32). However, no evidence was found for risk associated with the MTHFR A1298C polymorphism. Our findings support the hypothesis that MTHFR C677T variants contribute to gastric carcinogenesis, particularly in gastric cardia. Larger studies incorporating dietary folate intake and serum levels are needed to confirm our findings.     

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.     

Polymorphisms of methylene-tetrahydrofolate reductase and risk of lung cancer: a case-control study.

Previous studies have suggested that low folate intake is associated with increased risk of lung cancer. Methylene-tetrahydrofolate reductase (MTHFR) is one of the enzymes involved in folate metabolism and is thought to influence DNA methylation and nucleotide synthesis. MTHFR is highly polymorphic, and the variant genotypes result in decreased MTHFR enzyme activity and lower plasma folate level. Therefore, we hypothesized that these variant genotypes may play a role in the etiology of lung cancer. To test this hypothesis, we investigated the association between two common MTHFR polymorphisms (C677T and A1298C) and risk of lung cancer in a non-population-based case-control study of 550 histologically confirmed lung cancer cases and 554 healthy controls. The subjects were non-Hispanic whites, and the controls were frequency-matched to the cases by age (+ or -5 years), sex, and smoking status (ever or never). Folate intake and alcohol consumption were estimated from a self-administered food-frequency questionnaire. The cases consumed significantly less folate (162 microg/day/1000 kcal) than the controls did (172 microg/day/1000 kcal; P = 0.033). However, we found no evidence for an association between the MTHFR C677T and A1298C polymorphisms and risk of lung cancer in either all of the subjects or the low folate intake subgroup; nor did we find evidence for an interaction between these two MTHFR polymorphisms and dietary folate intake or alcohol use. In multivariate logistic regression analysis, the adjusted odds ratios and 95% confidence intervals for MTHFR C677T were 1.1 (0.8-1.4) for 677CT versus 677CC wild type and 1.1 (0.7-1.7) for 677TT versus 677CC, and for MTHFR A1298C, they were 1.0 (0.8-1.3) for 1298AC versus 1298AA wild type and 1.1 (0.7-1.8) for 1298CC versus 1298AA. These results suggest that the MTHFR C677T and A1298C polymorphisms by themselves do not play an important role in the etiology of lung cancer.     

Diets, polymorphisms of methylenetetrahydrofolate reductase, and the susceptibility of colon cancer and rectal cancer

The aim of this study was to investigate the association of environmental factors (dietary folate, methionine and drinking status) and polymorphisms in the methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) gene, as well as the combination of these factors, with the risk of colon cancer and rectal cancer. A case-control study of 53 colon cancer patients, 73 rectal cancer patients and 343 healthy controls was conducted. Genotypes of C677T and A1298C polymorphisms were analyzed by PCR-RFLP. The dietary folate and methionine intakes were assessed using food-frequency questionnaires and food consumption tables. Unconditional logistic regression was applied to estimate the odds ratios (ORs) and their 95% confidence intervals (CIs). The frequency of MTHFR 677T and 1298C alleles in healthy population were 39.4 and 17.2%, respectively. After adjustment for specific variants, the MTHFR 677TT genotype showed a significantly reduced risk of colon cancer compared with the wild type (OR=0.22, 95% CI: 0.50-0.98), and 1298C allele-carrier showed an inverse association with the risk of rectal cancer compared to the wild type (OR=0.52, 95% CI: 0.28-0.98). Adequate intake of folate was a protective factor from colon cancer (OR=0.32, 95% CI: 0.12-0.88) and MTHFR C677T polymorphism showed a statistically significant effect (OR=0.25, 95% CI: 0.06-0.93), reducing the risk of colon cancer in groups that have an intake of folate exceeding 115.64ng per 1000kcal per day. This study suggests that MTHFR C677T and A1298C polymorphisms are associated with the reduced risk of colon and rectal cancers, respectively. Adequate folate intake shows an inverse association with the risk of colon cancer. There is a significant interaction between MTHFR C677T polymorphism and folate intake in reducing the risk of colon cancer.     

MTHFR C677T and A1298C polymorphisms: diet, estrogen, and risk of colon cancer.

5,10-methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism, diverting metabolites toward methylation reactions or nucleotide synthesis. Using data from an incident case-control study (1608 cases and 1972 controls) we investigated two polymorphisms in the MTHFR gene, C677T and A1298C, and their associations with risk of colon cancer. All of the combined genotypes were evaluated separately, and the 1298AA/677CC (wild-type/wild-type) group was considered the reference group. Among both men and women, the 677TT/1298AA (variant/wild-type) genotype was associated with a small reduction in risk [men: odds ratio (OR), 0.7, 95% confidence interval (CI), 0.5-1.0; women: OR, 0.8, 95% CI, 0.5-1.2]. However, the 677CC/1298CC (wild-type/variant) genotype was associated with a statistically significant lower risk among women (OR, 0.6; 95% CI, 0.4-0.9) but not men. When the polymorphisms were considered individually, for A1298C a significant risk reduction associated with the homozygous variant CC genotype was seen among women only (OR, 0.6; 95% CI, 0.5-0.9), and nonstatistically significant reduced risks were observed for the variant 677 TT genotypes among both men and women. Stratification by nutrient intakes showed inverse associations with higher intakes of folate, vitamin B(2), B(6), B(12), and methionine among women with the MTHFR 677CC/1298AA genotypes, but not those with 677TT/1298AA. We observed opposite risk trends for both MTHFR variants, depending on whether women used hormone-replacement therapy or not (P for interaction = <.01). In summary, this study supports recent findings that the MTHFR A1298C polymorphism may be a predictor of colon cancer risk and have functional relevance. The possible interaction with hormone-replacement therapy warrants additional investigation.     

The MTHFR 1298A>C polymorphism and genomic DNA methylation in human lymphocytes.

Methylenetetrahydrofolate reductase (MTHFR) balances the pool of folate coenzymes in one-carbon metabolism for DNA synthesis and methylation, both implicated in carcinogenesis. Epidemiologic studies have shown that two functional polymorphisms in MTHFR gene, 677C>T and 1298A>C, are related to increased cancer risk. We aimed to analyze lymphocyte DNA from 198 subjects to evaluate the MTHFR 1298A>C polymorphism and folate status affecting genomic DNA methylation as a possible mechanism underlying the relationship between MTHFR polymorphisms and cancer susceptibility. Carriers of the 1298AA wild-type genotype showed lower genomic DNA methylation compared with 1298AC or 1298CC genotypes [3.72 versus 8.59 or 6.79 ng 5-methyl-2'-deoxycytidine (5-mCyt)/microg DNA, P < 0.0001 and P = 0.007, respectively]. When DNA methylation was evaluated according to plasma folate status, only 1298AA with low folate levels revealed diminished DNA methylation (P < 0.0001). Moreover, when the two MTHFR polymorphisms were concomitantly evaluated at the low folate status, DNA methylation was reduced only in 1298AA/677TT compared with 1298AA/677CC (3.11 versus 7.29 ng 5-mCyt/microg DNA, P = 0.001) and 1298CC/677CC genotypes (3.11 versus 7.14 ng 5-mCyt/microg DNA, P = 0.004). However, the high prevalence of 677TT mutants within the 1298AA group (79%) and the similar biochemical features of 1298AA/677CC and 1298CC/677CC combined genotypes suggest that the gene-nutrient interaction affecting DNA methylation in 1298AA is mainly due to the coexistence of the 677TT genotype and that the 1298A>C polymorphism may convey its protective effect not through this interaction but through another pathway in one-carbon metabolism. Further mechanistic studies are warranted to investigate how single polymorphisms as well as MTHFR combined genotypes exert their effect on cancer susceptibility.     

Sex differences in risk of lung cancer associated with methylene-tetrahydrofolate reductase polymorphisms.

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the metabolism of folate and nucleotides needed for DNA synthesis and repair. Variations in MTHFR functions likely play roles in the etiology of lung cancer. The MTHFR gene has three nonsynonymous single nucleotide polymorphisms (i.e., C677T, A1298C, and G1793A) that have a minor allele frequency of >5%. We investigated the associations between the frequencies of MTHFR variant genotypes and risk of lung cancer in a hospital-based case-control study of 1,051 lung cancer patients and 1,141 cancer-free controls in a non-Hispanic White population. We found that compared with the MTHFR 1298AA genotype, the 1298CC genotype was associated with a significantly increased risk of lung cancer in women [(odds ratio (OR), 2.09; 95% confidence interval (95% CI), 1.32-3.29)] but not in men (OR, 0.95; 95% CI, 0.62-1.45). The MTHFR 677TT genotype was associated with a significantly decreased risk of lung cancer in women (OR, 0.60; 95% CI, 0.40-0.92) but not in men. No association was found between the MTHFR G1793A polymorphism and risk of lung cancer. Further analysis suggested evidence of gene-dietary interactions between the MTHFR C677T polymorphism and dietary intake of vitamin B6, vitamin B12, and methionine in women and evidence of gene-environment interactions between the MTHFR C677T and A1298C polymorphisms and tobacco smoking in men. In conclusion, the polymorphisms of MTHFR may contribute to the risk of lung cancer in non-Hispanic Whites and modify the risk associated with the dietary and environmental exposure in a sex-specific manner.     

Gene-environment interactions between alcohol drinking and the MTHFR C677T polymorphism impact on esophageal cancer risk: results of a case-control study in Japan

Folate takes part in two biological pathways involved in DNA methylation and synthesis, and a potential protective influence of this nutrient chemical against carcinogenicity has been recognized in several sites, including the esophagus. Therefore, the functional polymorphisms in genes encoding folate metabolizing enzymes, MTHFR C677T and MTR A2756G, might be suspected of impacting on esophageal cancer risk. We therefore conducted a matched case-control study of 165 esophageal cancer cases and 495 non-cancer controls to clarify associations among folate intake, MTHFR C677T and MTR A2756G polymorphisms, and esophageal cancer risk. Gene-environment interactions between the two polymorphisms, and drinking and smoking were also evaluated. Folate consumption and MTHFR 677TT were associated with a non-significant tendency for decreased risk while the MTR genotypes did not show any links in themselves; further, when analysis was limited to heavy drinkers, the MTHFR TT genotype significantly decreased esophageal cancer risk [odds ratio (OR) = 0.27, 95% confidence interval (CI), 0.09-0.76]. The OR for the gene-environment interaction between heavy drinking and the 677TT genotype in the case-only design was 0.31 (95% CI, 0.10-0.94), indicating risk with heavy drinking to be 69% decreased in individuals harboring the 677TT genotype. We failed to find any significant interaction between either of the polymorphisms and smoking.     

Allele and Genotype Frequencies of the Polymorphic Methylenetetrahydrofolate Reductase and Colorectal Cancer among Jordanian Population

Background: Methylenetetrahydrofolate reductase (MTHFR) is involved in DNA synthesis and repair. We hereaimed to investigate two common polymorphisms, C677T and A1298C, with genotype and haplotype frequenciesin colorectal cancer (CRC) cases among Jordanian. Materials and Methods: 131 CRC cases were studied forMTHFR C677T and A1298C polymorphisms, compared to 117 controls taken from the general population,employing the PCR-RFLP technique. Results: We found the frequency of the three different genotypes of MTHFRC677T among Jordanians to be CC: 61.7%, CT: 35.2%, and TT 3.1% among CRC cases and 50.9%, 38.8% and10.3% among controls. Carriers of the TT genotype were less likely to have CRC (OR=0.25; 95%CI: 0.076-0.811;p=0.021) as compared to those with the CC genotype. Genotype analysis of MTHFR A12987C revealed AA:38.9%, AC: 45%, and CC 16% among CRC cases and 37.4%, 50.4% and 12.2% among controls. There wasno significant association between genetic polymorphism at this site and CRC. Haplotype analysis of MTHFRpolymorphism at the two loci showed differential distribution of the TA haplotype (677T-1298A) between casesand controls. The TA haplotype was associated with a decreased risk for colorectal cancer (OR=0.6; 95% CI:0.4-0.9, p=0.03). Conclusions: The genetic polymorphism of MTHFR at 677 and the TA haplotype may modulatethe risk for CRC development among the Jordanian population. Our findings may reflect an importance of genesinvolved in folate metabolism in cancer risk.     

Mutational analysis of the MTHFR gene in breast cancer patients of Pakistani population

Objectives: Since methylenetetrahydrofolatereductase (MTHFR) maintains the balance of circulating folate and methionine and blocks the formation of homocysteine, its regulation in relation to different cancers has extensively been studied in different populations. However, information on Pakistani breast cancer patients is lacking. The MTHFR gene has two most common mutations that are single nucleotide additions which result in change of amino acids C677T to Ala222val and A1298C to Glu429Ala. Methodology: 110 sporadic breast patients with no prior family history of cancer or any other type of genetic disorders along with 110 normal individuals were screened for mutations in exons 1 to exon 9 using single strand conformational polymorphism, RFLP and sequencing analyzer. Results: The p values for the 677CC, 677CT, and 677TT genotypes were 0.223, 0.006, and 0.077, respectively. Those for the 1298AA, 1298AC, and 1298CC genotypes were 0.555, 0.009, and 0.003, respectively. Conclusions: We found an overall a significant, weak inverse association between breast cancer risk and the 677TT genotype and an inverse association with the 1298C variant. These results for MTHFR polymorphism might be population specific in sporadic breast cancer affected patients but many other factors need to be excluded before making final conclusions including folate intake, population and disease heterogeneity.     

Methylenetetrahydrofolate reductase 677C>T polymorphism and gastric cancer susceptibility in Mexico

This study investigated whether methylenetetrahydrofolate reductase MTHFR 677C>T polymorphism modified gastric cancer (GC) risk independently as well as in combination with folate intake and alcohol consumption. A hospital-based case-control study of 201 cases and 427 controls was conducted in three geographical areas of Mexico, between 1994 and 1996. The MTHFR 677T allele frequency was 51.0% in cases compared with 45.3% in controls. After controlling for dietary sources of folate, alcohol intake and other selected variables, a significant increase in GC risk was found among carriers of the 677TT genotype compared with those with the 677CC genotype (odds ratio (OR) 1.62, 95% confidence interval (CI) 1.00-2.59), with a significant trend (P = 0.048). There were no significant interactions between the MTHFR polymorphism and consumption of folate and alcohol. Our results suggest that the high prevalence of MTHFR 677T allele may be a contributor to the high rate of morbidity and mortality in GC in Mexico.