Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Carcinogenesis 2005 Jul
PMID:Gene-environment interactions between alcohol drinking and the MTHFR C677T polymorphism impact on esophageal cancer risk: results of a case-control study in Japan. 1579 May 87

One-carbon metabolism, in which folate plays an essential role, is involved in DNA methylation and synthesis, and is suspected of impacting on colorectal carcinogenesis. Alcohol is well recognized as a risk factor for colorectal cancer (CRC) and interactions with one-carbon metabolism have also been suggested. Therefore, functional polymorphisms in genes encoding members of this pathway, MTHFR C677T and A1298C (genes for methylenetetrahydrofolate reductase), MTR A2756G (gene for methionine synthase) and TS (gene for thymidylate synthase) tandem repeats polymorphisms, have attracted attention. We conducted a matched case-control study with 257 incident CRC cases and 771 non-cancer controls at the Aichi Cancer Center to clarify associations among folate intake and four polymorphisms with reference to CRC risk. Gene-environment interaction between polymorphisms, drinking and folate consumption was also evaluated. None of the polymorphisms showed any significant impact on CRC risk by genotype alone, but when combined with alcohol consumption the MTHFR 677CC type showed a significantly reduced risk (odds ratio (OR) = 0.45, 95% confidence interval (CI): 0.23-0.86) (P = 0.01). MTR GG showed increased risk only among drinkers (OR = 3.35, 1.40-8.05) (P = 0.047). TS polymorphism did not show statistical significance by genotype alone, while interaction with drinking was significant (P = 0.028). The association was not changed even after stratification by daily folate consumption and drinking habit. In conclusion, we found consistently significant interactions between one-carbon metabolism-related polymorphisms and alcohol drinking.
Carcinogenesis 2005 Dec
PMID:One-carbon metabolism related gene polymorphisms interact with alcohol drinking to influence the risk of colorectal cancer in Japan. 1605 37

This study investigated associations between CpG island methylator phenotype (CIMP) colon cancer and genetic polymorphisms relevant to one-carbon metabolism and thus, potentially the provision of methyl groups and risk of colon cancer. Data from a large, population-based case-control study (916 incident colon cancer cases and 1,972 matched controls) were used. Candidate polymorphisms in methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), transcobalamin II (TCNII), methionine synthase (MTR), reduced folate carrier (RFC), methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), dihydrofolate reductase (DHFR) and alcohol dehydrogenase 3 (ADH3) were evaluated. CIMP- or CIMP+ phenotype was based on five CpG island markers: MINT1, MINT2, MINT31, p16 and MLH1. The influence of specific dietary factors (folate, methionine, vitamin B(12) and alcohol) on these associations was also analyzed. We hypothesized that polymorphisms involved in the provision of methyl groups would be associated with CIMP+ tumors (two or more of five markers methylated), potentially modified by diet. Few associations specific to CIMP+ tumors were observed overall, which does not support the hypothesis that the provision of methyl groups is important in defining a methylator phenotype. However, our data suggest that genetic polymorphisms in MTHFR 1,298A > C, interacting with diet, may be involved in the development of highly CpG-methylated colon cancers. AC and CC genotypes in conjunction with a high-risk dietary pattern (low folate and methionine intake and high alcohol use) were associated with CIMP+ (OR = 2.1, 95% CI = 1.3-3.4 versus AA/high risk; P-interaction = 0.03). These results provide only limited support for a role of polymorphisms in one-carbon metabolism in the etiology of CIMP colon cancer.
Carcinogenesis 2007 Aug
PMID:Genetic polymorphisms in one-carbon metabolism: associations with CpG island methylator phenotype (CIMP) in colon cancer and the modifying effects of diet. 1744 6

There is substantial evidence that the decreased risk of lung cancer with high intake of vegetables and fruits is linked to folate as a specific nutrient. Functional polymorphisms in genes encoding one-carbon metabolism enzymes, methylenetetrahydrofolate reductase (MTHFR C677T and A1,298C), methionine synthase (MTR A2,756G), methionine synthase reductase (MTRR A66G) and thymidylate synthase, influence folate metabolism and thus might be suspected of impacting on lung cancer risk. We therefore conducted a case-control study with 515 lung cancer cases newly and histologically diagnosed and 1,030 age- and sex-matched non-cancer controls to clarify associations with these five polymorphisms according to lung cancer subtype. Gene-environment interactions with smoking and drinking habit and folate consumption were also evaluated by logistic regression analysis. None of the polymorphisms showed any significant impact on lung cancer overall risk by genotype alone, but on histology-based analysis increase in MTHFR 677T and 1,298C alleles was associated with reduced risk of squamous/small cell carcinoma (P = 0.029), especially among heavy smokers (P = 0.035), whereas the MTHFR 677TT genotype was linked to decreased risk for these subtypes among heavy drinkers (odds ratio = 0.17, 95% confidence interval: 0.03-0.98). In addition, we found interactions between the MTRR A66G polymorphism and smoking (P = 0.015) and the MTHFR A1,298C polymorphism and alcohol consumption (P = 0.025) for risk of lung cancer overall. In conclusion, the results suggest that MTHFR polymorphisms contribute to risk of squamous/small cell carcinomas of the lung, along with possible interactions among folate metabolism-related polymorphisms and smoking/drinking habits. Further evaluation is warranted.
Carcinogenesis 2007 Aug
PMID:Impact of one-carbon metabolism-related gene polymorphisms on risk of lung cancer in Japan: a case control study. 1746 11

Polymorphisms of the genes 5'-10'-methylenetetrahydrofolate reductase (MTHFR, 677CT and 1298AC), methionine synthase (MTR, 2756AC) and methionine synthase reductase (MTRR, 66AC) provoke variations in enzyme activity, which can lead to alterations in the metabolism of folates and in the synthesis of S-adenosyl-methionine (SAM), the most active methyl donor in the body. This could play an important role in carcinogenesis through the degree of DNA methylation and of nucleotide synthesis. In the present study, four polymorphisms were studied, two of the methylenetetrahydrofolate reductase gene, and the other two of methionine synthase and methionine synthase reductase. Our aim was to study the association between prostate carcinoma susceptibility and these polymorphisms. A hospital-based case-control study was conducted in 182 patients (mean age: 70.7+/-7.29 years) with histologically confirmed prostate carcinoma and in 205 control subjects (mean age: 70.3+/-7.82 years) diagnosed with benign prostatic hyperplasia (BPH). Genomic DNA was extracted from peripheral leukocytes. Comparison of the MTHFR CT and TT genotypes in patients and the controls revealed significant differences (0.57 vs 0.38) (OR: 2.19, 95% CI: 1.46-3.30) and (0.06 vs 0.15) (OR: 0.36, 95% CI: 0.17-0.73), respectively. No statistically significant differences were found between patients and controls with respect to the MTHFR 1298AC, the MTR 2756AC and the MTRR 66AC polymorphisms. However, among the patients, the MTR 2756 allele C was related to a high Gleason score. We conclude that the polymorphism MTHFR C677T is clearly related to prostatic carcinogenesis, on the contrary to the other polymorphisms studied, although the MTR 2756 allele C acts as a factor of tumor aggressiveness, this being found in tumors with high carcinogenic potential.
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PMID:Association between polymorphisms of folate-metabolizing enzymes and risk of prostate cancer. 1796 24

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.
Carcinogenesis 2008 Feb
PMID:One-carbon metabolism-related gene polymorphisms and risk of breast cancer. 1817 36

Genomic DNA hypomethylation has been associated with colorectal carcinogenesis. Methionine synthase A2756G (MTR A2756G) is a common nonsynonymous polymorphism in the gene that encodes methionine synthase, a key enzyme in the pathway leading to DNA methylation. Several studies, but not all, have reported relatively lower plasma homocysteine among individuals with the AG or GG genotype. Meanwhile, higher plasma homocysteine was associated with genomic DNA hypomethylation in healthy volunteers. We therefore hypothesized that minor allele carriers possess a decreased risk of colorectal adenoma, and examined this hypothesis in a case-control study of colorectal adenoma in Japan involving 723 cases and 670 controls. An unconditional logistic regression model was used to estimate odds ratios (OR) and their 95% confidence intervals (95% CI) for colorectal adenoma after adjustment for potential confounders. Despite the lack of an overall association, we observed a significant interaction between MTR A2756G and alcohol intake (P for interaction = 0.007). Compared with never drinkers with the AA genotype, never drinkers with the AG or GG genotype exhibited a significantly decreased risk (OR, 0.56; 95% CI, 0.34-0.90) whereas heavy drinkers with the same genotypes showed a substantially increased risk (OR, 1.90; 95% CI, 1.04-3.46). In addition, a marginally significant interaction was observed with folate intake (P for interaction = 0.07). The G allele may confer protection against colorectal adenoma in the presence of a considerably good folate status. Our findings add to increasing evidence that DNA methylation plays an important role even at an early stage of colorectal carcinogenesis.
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PMID:Methionine synthase A2756G polymorphism interacts with alcohol and folate intake to influence the risk of colorectal adenoma. 1912 8

Aberrant promoter methylation is recognized as an important feature of breast carcinogenesis. We hypothesized that genetic variation of genes for methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR), two critical enzymes in the one-carbon metabolism, may alter DNA methylation levels and thus influence DNA methylation in breast cancer. We evaluated case-control association of MTHFR C677T, A1298C, and MTR A2756G polymorphisms for cases strata-defined by promoter methylation status for each of three genes, E-cadherin, p16, and RAR-beta2 in breast cancer; in addition, we evaluated case-case comparisons of the likelihood of promoter methylation in relation to genotypes using a population-based case-control study conducted in Western New York State. Methylation was evaluated with real-time methylation-specific PCRs for 803 paraffin-embedded breast tumor tissues from women with primary, incident breast cancer. We applied unordered polytomous regression and unconditional logistic regression to derive adjusted odds ratios and 95% confidence intervals. We did not find any association of MTHFR and MTR polymorphisms with breast cancer risk stratified by methylation status nor between polymorphisms and likelihood of promoter methylation of any of the genes. There was no evidence of difference within strata defined by menopausal status, estrogen receptor status, folate intake, and lifetime alcohol consumption. Overall, we found no evidence that these common polymorphisms of the MTHFR and MTR genes are associated with promoter methylation of E-cadherin, p16, and RAR-beta2 genes in breast cancer.
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PMID:DNA promoter methylation in breast tumors: no association with genetic polymorphisms in MTHFR and MTR. 1924 Feb 36

Carcinogenesis may result from abnormal methylation of cancer-related genes regulatory sequence. Though, the polymorphic variants of genes encoding enzymes of folate and methionine metabolism may have an effect on DNA methylation. Using PCR-RFLPs, we examined the polymorphism distribution of genes encoding methionine synthase (MTR); 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase (MTHFD1); and methylenetetrahydrofolate reductase (MTHFR) in patients with larynx cancer (n = 131) and controls (n = 250). Patients with MTR 2756AG or GG genotypes displayed a 1.856 -fold increased risk of larynx cancer (95% CI = 1.1860-2.903, P = 0.0076). However, we did not observe an increased risk for the homozygous GG genotype OR = 1.960 (95% CI = 0.6722-5.713, P = 0.2535). Moreover, we did not observe statistical differences in distribution of MTHFR 677C>T, 1298A>C and MTHFD1 1958G>A allele and genotype frequencies in patients and controls. Our findings confirm the significance of the role of the methyl cycle in etiopathogenesis of laryngeal cancer.
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PMID:Polymorphic variants of folate metabolism genes and the risk of laryngeal cancer. 1964 27

Polymorphisms in methionine synthase (MTR) gene may be involved in carcinogenesis by affecting DNA methylation. However, association studies on MTR A2756G polymorphism in cancers have reported conflicting results. Therefore we performed a meta-analysis to better assess the associations. A total of 24 896 cancer patients and 33 862 controls from 52 articles for MTR A2756G were investigated. Overall, individuals carrying MTR 2756GG genotype had a subtly reduced cancer risk under a recessive genetic model (odds ratio (OR), 0.92; P=0.053; 95% confidence interval (95% CI), 0.84-1.00; I(2)=0.0%; P(heterogeneity)=0.61). In the subgroup analyses by ethnicity, 2756GG was associated with a significantly reduced cancer risk in European populations (OR, 0.83; P=0.001; 95% CI, 0.74-0.93; I(2)=0.0%; P(heterogeneity)=0.99). However, in Asian populations, a significantly elevated association between 2756GG genotype and cancer risk was observed (OR, 1.33; P=0.012; 95% CI, 1.06-1.65; I(2)=0.0%; P(heterogeneity)=0.50). In studies stratified by tumor site, there was a significantly reduced risk of acute lymphoblastic leukemia (ALL) (OR, 0.54; P=0.049; 95% CI, 0.29-1.00; I(2)=10.7%; P(heterogeneity)=0.33) and colorectal cancer (OR, 0.63; P=0.004; 95% CI, 0.47-0.87; I(2)=0.0%; P(heterogeneity)=0.73) in European populations. Our study indicates that MTR A2756G polymorphism is a candidate gene polymorphism for cancer susceptibility regardless of environmental factors. Large-scale, well-designed, and population-based studies are required to further investigate gene-gene and gene-environment interactions on MTR A2756G polymorphism and tissue-specific cancer risk in an ethnicity-specific population.
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PMID:Methionine synthase A2756G polymorphism and cancer risk: a meta-analysis. 1982 53


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