Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.5.7.1 (methylenetetrahydrofolate reductase)
2,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic alteration is considered a probable cause of malignant lymphoma. Folate and methionine metabolism play essential roles in DNA synthesis and DNA methylation, and their metabolic pathways might thus affect disease susceptibility. In the present study, 2 polymorphisms were evaluated for a folate metabolic enzyme, methylenetetrahydrofolate reductase (MTHFR), and one was evaluated for methionine synthase (MS). The 2 polymorphisms, MTHFR677 C-->T and MTHFR1298 A-->C, are reported to reduce the enzyme activity, which causes intracellular accumulation of 5,10-methylenetetrahydrofolate and results in a reduced incidence of DNA double-strand breakage. The MS2756 A-->G polymorphism also reduces the enzyme activity and results in the hypomethylation of DNA. To evaluate the association between malignant lymphoma susceptibility and these polymorphisms, hospital-based case-control study was conducted in Aichi Cancer Center. Ninety-eight patients with histologically confirmed lymphoma and 243 control subjects without cancer were evaluated. Unconditional logistic regression analyses revealed a higher susceptibility with the MTHFR677 CC and the MTHFR1298 AA genotypes (odds ratio, 2.26; 95% confidence interval, 1.26-4.02) when those harboring at least one variant allele in either polymorphism of MTHFR were defined as the reference. For the MS polymorphism, the MS2756 GG genotype also showed a higher susceptibility (odds ratio, 3.83; 95% CI, 1.21-12.1) than those with MS2756 AA or AG types. The significance was not altered when these 3 polymorphisms were evaluated in combination, and the results suggest that folate and methionine metabolism play important roles in the occurrence of malignant lymphomas. Further studies to confirm the association and detailed biologic mechanisms are now required.
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PMID:Association between polymorphisms of folate- and methionine-metabolizing enzymes and susceptibility to malignant lymphoma. 1159 64

C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) polymorphisms have been suggested to affect susceptibility to malignant lymphoma, possibly by altering DNA methylation. The DNA repair gene O6-methylguanine DNA methyltransferase (MGMT) is transcriptionally silenced by promoter hypermethylation in diffuse large B-cell lymphomas (DLBCL). We analyzed the MTHFR677 and MTHFR1298 genotypes in 111 DLBCL patients and 465 controls. No significant difference in the frequency of MTHFR polymorphisms between patients and controls and no significant association between MTHFR677 or MTHFR1298 genotypes and methylation of MGMT promoter were observed. These results indicate that MTHFR variants are not related to DLBCL development and MGMT hypermethylation.
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PMID:Methylenetetrahydrofolate reductase genotype in diffuse large B-cell lymphomas with and without hypermethylation of the DNA repair gene O6-methylguanine DNA methyltransferase. 1453 93

Folate metabolism plays an essential role in DNA synthesis and methylation processes. Deviations in the flux of folate due to genetic variation could result in selective growth and genomic instability and affect susceptibility to various cancers including lymphoma. To test this hypothesis, genetic polymorphisms in the folate metabolic pathway were investigated using DNA from a population-based case-control study of non-Hodgkin lymphoma (NHL) conducted in the San Francisco Bay Area between 1988 and 1995. The polymorphisms examined and haplotypes generated included thymidylate synthase (TYMS 28-bp triple repeat [3R]-->double repeat [2R], 1494del6, IVS6 -68C>T, 1122A>G, and 1053C>T); 5,10-methylenetetrahydrofolate reductase (MTHFR 677C>T and 1298A>C); serine hydroxymethyltransferase (SHMT1 C1420T); reduced folate carrier (RFC G80A); and methionine synthase (MTR A2756G), making the present study the largest and most comprehensive to date to evaluate associations between genetic polymorphisms in folatemetabolizing genes and NHL risk. The TYMS 6 base pair (bp)(-)6bp- (homozygous for 6bp deletion), IVS6 -68C>T, and 1053C>T genotypes (all in complete linkage disequilibrium) were all inversely associated with NHL (TYMS; odds ratio [OR] = 0.57; 0.34-0.94), particularly with diffuse large cell lymphoma (DLCL; OR = 0.29; 0.10-0.82). Further, the MTR 2756AG/GG and the MTHFR 677TT genotypes were associated with increased risk for NHL (OR = 1.3; 0.99-1.7) and follicular lymphoma (FL; OR = 1.8; 0.98-3.1), respectively. We did not observe any significant differences in genotype frequencies of the SHMT1 and RFC polymorphisms between the cases and controls. The associations of DLCL and FL with TYMS 1494del6 and MTHFR 677TT genotypes, respectively, suggest that folate metabolism may play an important role in the pathogenesis of specific subtypes of NHL.
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PMID:Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma. 1563 15

Human T-lymphotropic virus type 1 (HTLV-1) is associated with adult T-cell leukemia/lymphoma (ATL). However, the incidence of ATL is low among HTLV-1 carriers suggesting additional mechanisms are involved in the progression of the disease. A recent study found that polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene influence the susceptibility to malignant lymphoma. We have analyzed the MTHFR genotype in 81 HTLV-1 carriers and 87 ATL patients. No statistically significant associations were found between MTHFR genotype and development of ATL. These data suggest that genetic polymorphisms in the MTHFR locus do not play a role in ATL pathogenesis among HTLV-1 carriers.
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PMID:Methylenetetrahydrofolate reductase genotype does not play a role in adult T-cell leukemia/lymphoma pathogenesis among human T-lymphotrophic virus type 1 carriers. 1528 15

Folate and methionine are important nutrients in the "one-carbon" metabolism that is closely associated with DNA synthesis and DNA methylation. Genetic variation in these pathways may change susceptibility to cancer development. We have previously reported associations between lymphoma risk and germline polymorphisms in genes of methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and methionine synthase (MTR A2756G), finding the genotype other than the MTHFR 677CC/1298AA to confer a half-risk compared to the MTHFR 677CC/1298AA and a 3-fold higher risk with the MTR GG genotype than the AA/AG genotypes. To confirm the association and explore the histological difference, we extended the previous case series. A case-control study was conducted in Japan with a total of 372 lymphoma cases and 500 noncancer controls examined for genotypes. The relative risks were estimated by unconditional logistic regression analysis. In overall analyses, the age-sex adjusted odds ratio (OR) for the subjects harboring MTHFR 677T or 1298C alleles relative to 677CC/1298AA genotype was 0.58 (95% confidence interval: 0.41-0.83, P = 0.002). The MTR GG genotype showed an OR of 1.75 (0.87-3.52, P = 0.114). These findings were validated in separate analyses of the 273 new incident cases. Subgroup analyses according to histological subtype [diffuse large B-cell lymphoma (DLB), follicular lymphoma (FL), low-grade lymphoma of mucosa associated lymphoid tissue (MALT), and others] illustrated similar associations with certain exceptions for FL and MALT. Our data showed an association between the MTHFR polymorphisms and malignant lymphoma risk for all histological subtypes, although the extent of contribution of these polymorphisms may differ somewhat with histological subtype. Lack of association with MTR polymorphism was also confirmed.
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PMID:Methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms and reduced risk of malignant lymphoma. 1555 Dec 85

Genetic instability, including chromosomal imbalance, is important in the pathogenesis of lymphoproliferative disorders such as non-Hodgkin lymphoma (NHL). DNA synthesis and methylation, which are closely linked to folate metabolism and transport, may be affected by polymorphisms in genes involved in these pathways. Folate metabolism polymorphisms have been linked to acute lymphoblastic leukemia and colorectal cancer. To evaluate whether genetic variation in folate metabolism and transport may have a role in determining the risk of developing NHL, we analyzed several polymorphisms using DNA obtained as part of a large U.K. population-based case-control study of lymphoma. Polymorphisms studied include methylenetetrahydrofolate reductase (MTHFR) 677 C >T and 1298 A >C, methionine synthase (MTR) 2756 A>G, serine hydroxymethyltransferase (SHMT1) 1420 C >T, thymidylate synthase (TYMS) 1494del6 and 28-bp repeat, and reduced folate carrier (RFC) 80 G >A. Increased risks for NHL [odds ratio (OR), 1.48; 95% confidence intervals (CI), 1.12-1.97], and marginal zone lymphoma (OR, 3.38; 95% CI, 1.30-8.82) were associated with the TYMS 2R/3R variant. Marginal increased risks were also observed for diffuse large B cell lymphoma with the TYMS homozygous 6 bp deletion (OR, 1.61; 95% CI, 0.99-2.60) and for follicular lymphoma with RFC 80AA (OR, 1.44; 95% CI, 0.94-2.22) and TYMS 28-bp repeat 2R/3R (OR, 1.45; 95% CI, 0.96-2.2). We observed no association between NHL and haplotypes for MTHFR or TYMS. These findings are somewhat inconsistent with those of others, but may reflect differences in circulating folate levels between study populations. Thus, further investigations are warranted in larger series with dietary information to determine the roles that genetics and folic acid status play in the etiology of lymphoma.
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PMID:Risk of non-Hodgkin lymphoma associated with polymorphisms in folate-metabolizing genes. 1636 25

The authors investigated whether high-dose methotrexate-induced toxicity differed according to the presence of methylenetetrahydrofolate reductase (MTHFR) or reduced folate carrier 1 (RFC1) genetic polymorphism. The authors studied 15 children with acute lymphoblastic leukemia or lymphoblastic lymphoma who were treated using protocols that included high-dose methotrexate (3.0 g/m), for an overall total of 43 courses. Methotrexate-induced toxicities and the plasma methotrexate concentrations were evaluated retrospectively. Hematologic toxicity was the most frequently observed toxicity, appearing in 87% of the patients. In a subset of patients (47%), elevation of liver transaminase levels showed a repeated tendency to develop. High plasma methotrexate concentrations at 48 hours after the methotrexate infusion were not significantly related to methotrexate-induced toxicities except for mucositis. A generalized estimating equation analysis revealed that vomiting during the high-dose methotrexate treatment was more pronounced in patients who had a larger number of G alleles at the RFC1 80G>A polymorphism. No significant differences in the development of other toxicities or in the plasma methotrexate concentrations were observed for the different MTHFR 677C>T or RFC1 80G>A polymorphisms. This study suggests but does not prove that the RFC1 80G>A polymorphism may contribute to interindividual variability in responses to high-dose methotrexate.
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PMID:Effects of methylenetetrahydrofolate reductase and reduced folate carrier 1 polymorphisms on high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia or lymphoma. 1646 75

We analyzed the relationship of genetic variation within the methylenetetrahydrofolate reductase gene (MTHFR 677 C-->T) with clinical characteristics, outcome, and therapy-related toxicity in pediatric non-Hodgkin's lymphoma (NHL) in our multicenter trial NHL-BFM 95. In this trial, high-dose methotrexate (MTX) infusion regimens were randomized (4- vs 24-h infusion) in patients with B-cell lymphoma; MTX was applied as 24-h infusion in all patients with lymphoblastic lymphoma and anaplastic large cell lymphoma. Toxicity data were collected per patient and therapy course according to National Cancer Institute Common Toxicity Criteria (NCI-CTC). The genotypes in 484 pediatric patients were distributed as follows: MTHFR 677 CC, 206 patients (42.6%); MTHFR 677 CT, 214 patients (44.2%); and MTHFR 677 TT, 64 patients (13.2%). Lymphoblastic lymphoma was significantly associated with homozygosity for the MTHFR 677 T allele. No association of MTHFR 677 genotype with clinical characteristics (sex, age, and tumor stage), outcome, or therapy-related toxicity could be detected. Therefore, we conclude that the MTHFR 677 C-->T polymorphism does not appear to influence outcome or therapy-associated toxicity in pediatric patients with NHL treated on BFM protocols.
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PMID:MTHFR 677 (C-->T) polymorphism is not relevant for prognosis or therapy-associated toxicity in pediatric NHL: results from 484 patients of multicenter trial NHL-BFM 95. 1646 53

Acute lymphocytic leukemia (ALL) is the most common pediatric cancer worldwide, and is particularly more common in the Indian population. Hence, research is increasingly examining the factors involved in disease development. In the present study, we examined the effect of MTHFR (5,10-methylenetetrahydrofolate reductase) C677T and A1298C polymorphisms in ALL. Blood samples of 135 children with ALL and 142 matched controls were analysed. The presence of MTHFR C677T and A1298C polymorphisms were screened using polymerase chain reaction-restriction fragment length polymorphism based approaches. The frequency of MTHFR 677CC, 677CT and 677TT genotypes were 37.77%, 57.03% and 5.18% in cases and 55.63%, 40.84% and 3.52% in controls, respectively. Frequencies of MTHFR 1298AA, 1298AC and 1298CC genotypes were 30.37%, 61.48% and 8.14% in cases and 45.77%, 47.88% and 6.33% in controls, respectively. The present study inidcates that there is an association between MTHFR gene polymorphisms and ALL. MTHFR variants also showed a gender bias. The frequencies of MTHFR 677CC and 677CT genotypes were 33.33% and 65.51% in males and 45.83% and 41.66% in females. Frequencies of MTHFR 1298AA, 1298AC and 1298CC genotypes were 26.43%, 67.81% and 5.74% in males and 37.5%, 50.0% and 12.5% in females, respectively. It is evident that the male children were more susceptible to ALL compared to female children. Associations found in these studies were significant with respect to gender bias; hence, it is possible that MTHFR C677T and A1298C can be good markers for ALL. Moreover, the possibility also exists that these variants may be influenced by the folate uptake of mothers during pregnancy, thereby influencing the enzyme activity and the ethnicity of the cases examined to date. The gender bias of MTHFR polymorphism in ALL is reported for the first time.
Leuk Lymphoma 2006 Jul
PMID:Polymorphisms in the MTHFR gene and their possible association with susceptibility to childhood acute lymphocytic leukemia in an Indian population. 1692 47

Methotrexate is administered in high doses to treat childhood acute lymphoblastic leukemia and malignant lymphoma. Hepatotoxicity and bone marrow suppression often limit its use, however. The objective of this study was to determine the genetic polymorphisms associated with the hepatotoxicity and elimination of methotrexate. Genetic polymorphisms of glutathione S-transferase (GST) genes including GSTT1 positive/null, GSTM1 positive/null, and GSTP1 A313G, and genes for reduced folate carrier 1 G80A (RFC1 G80A), methylenetetrahydrofolate reductase C677T (MTHFR C677T), and breast cancer resistant protein C421A (BCRP C421A) were determined for 26 patients by the polymerase chain reaction (PCR) method or by direct sequencing. A high frequency of hepatotoxicity (P = 0.035) was observed for patients with GSTM1 positive and RFC1 AA(80), and serum concentrations of methotrexate 48 h after the start of infusion were higher for patients with the TT(677) genotype of MTHFR (P = 0.028). In conclusion, GSTM1 positive/null and RFC1 G80A polymorphisms could be predictors for hepatotoxicity, and the MTHFR C677T polymorphism is associated with elimination of methotrexate.
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PMID:Genetic polymorphisms associated with adverse events and elimination of methotrexate in childhood acute lymphoblastic leukemia and malignant lymphoma. 1718 May 79


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