Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperhomocysteinemia, a risk factor for cardiovascular disease, is caused by nutritional and/or genetic disruptions in homocysteine metabolism. The most common genetic cause of hyperhomocysteinemia is the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene. This variant, with mild enzymatic deficiency, is associated with an increased risk for neural tube defects and pregnancy complications and with a decreased risk for colon cancer and leukemia. Although many studies have reported that this variant is also a risk factor for vascular disease, this area of investigation is still controversial. Severe MTHFR deficiency results in homocystinuria, an inborn error of metabolism with neurological and vascular complications. To investigate the in vivo pathogenetic mechanisms of MTHFR deficiency, we generated mice with a knockout of MTHFR: Plasma total homocysteine levels in heterozygous and homozygous knockout mice are 1.6- and 10-fold higher than those in wild-type littermates, respectively. Both heterozygous and homozygous knockouts have either significantly decreased S-adenosylmethionine levels or significantly increased S-adenosylhomocysteine levels, or both, with global DNA hypomethylation. The heterozygous knockout mice appear normal, whereas the homozygotes are smaller and show developmental retardation with cerebellar pathology. Abnormal lipid deposition in the proximal portion of the aorta was observed in older heterozygotes and homozygotes, alluding to an atherogenic effect of hyperhomocysteinemia in these mice.
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PMID:Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. 1118 67

Low folate intake as well as alterations in folate metabolism as a result of polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with an increased incidence of neural tube defects, vascular disease, and some cancers. Polymorphic variants of MTHFR lead to enhanced thymidine pools and better quality DNA synthesis that could afford some protection from the development of leukemias, particularly those with translocations. We now report associations of MTHFR polymorphisms in three subgroups of pediatric leukemias: infant lymphoblastic or myeloblastic leukemias with MLL rearrangements and childhood lymphoblastic leukemias with either TEL-AML1 fusions or hyperdiploid karyotypes. Pediatric leukemia patients (n = 253 total) and healthy newborn controls (n = 200) were genotyped for MTHFR polymorphisms at nucleotides 677 (C-->T) and 1,298 (A-->C). A significant association for carriers of C677T was demonstrated for leukemias with MLL translocations (MLL+, n = 37) when compared with controls [adjusted odd ratios (OR) = 0.36 with a 95% confidence interval (CI) of 0.15-0.85; P = 0.017]. This protective effect was not evident for A1298C alleles (OR = 1.14). In contrast, associations for A1298C homozygotes (CC; OR = 0.26 with a 95% CI of 0.07--0.81) and C677T homozygotes (TT; OR = 0.49 with a 95% CI of 0.20--1.17) were observed for hyperdiploid leukemias (n = 138). No significant associations were evident for either polymorphism with TEL-AML1+ leukemias (n = 78). These differences in allelic associations may point to discrete attributes of the two alleles in their ability to alter folate and one-carbon metabolite pools and impact after DNA synthesis and methylation pathways, but should be viewed cautiously pending larger follow-up studies. The data provide evidence that molecularly defined subgroups of pediatric leukemias have different etiologies and also suggest a role of folate in the development of childhood leukemia.
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PMID:Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia. 1127 24

The collection of buccal cells provides a noninvasive method for obtaining DNA for genetic studies. Here we report the results on buccal cell genotyping from our ongoing study of childhood leukemia in Northern California. We have collected buccal samples from children ranging in age from 4 months to 15 years using an interviewer- or nurse-administered protocol using a cytology brush. Initial results of the genotyping, including the glutathione S-transferase mu, glutathione S-transferase theta, NAD(P)H:quinone oxidoreductase, and methylenetetrahydrofolate reductase polymorphisms, were disappointing because many specimens contained little DNA, failed repeated attempts at PCR amplification, and produced unreliable results. Here we evaluate a solution to the problem that involves whole genome amplification using the improved primer extension preamplification methodology. Sixty cases of pediatric acute leukemia were studied; five PCR-based genotypes were attempted using buccal cell DNA and whole genome amplified (WGA) buccal DNA. Results were compared with genotyping results using DNA isolated from peripheral whole blood or bone marrow for each child. The standard buccal protocol failed to yield successful PCR reactions in 30-57% of specimens, whereas WGA-buccal was markedly more efficient (2-5% failed PCR). A success rate of 100% was achieved with one repeat test of the failed WGA-PCR reactions. Misclassification of genotype was common for the glutathione S-transferase theta marker using the standard buccal procedure. The WGA-buccal protocol, however, produced genotyping results fully concordant with the referent blood or bone marrow DNA results for all five loci. DNA yields were increased by WGA to allow for approximately 900 PCR reactions/brush. WGA is very useful for improving the efficiency and validity of PCR-based genotyping in pediatric populations.
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PMID:Whole genome amplification increases the efficiency and validity of buccal cell genotyping in pediatric populations. 1140 21

Recently published data suggest that the prothrombin G20210A variant, the TT677 methylenetetrahydrofolate reductase genotype, the factor V G1691A mutation, deficiencies of protein C, protein S, antithrombin, and elevated lipoprotein (a) concentrations were associated with venous thromboembolism in childhood patients treated according to the BFM protocol. To unravel the role of these prothrombotic risk factors and different treatment modalities, the present comparative study was performed in childhood leukemia patients of the same living population. Four hundred and twenty consecutively recruited leukemic children (BFM n=300; COALL n=120) were enrolled in this study with respect to the presence of prothrombotic risk factors and the occurrence of symptomatic venous thrombosis. No significant difference was found in the prevalence rates of thrombotic risk factors in the Caucasian populations studied. Symptomatic venous thromboembolism occurred in 11.6% of BFM patients compared with 2.5% in the COALL treatment group [odds ratio (OR)/95% confidence intervals (CI): 7.7/1.8-32.6; P=.005]. Including age, prothrombotic risk factors, central venous lines, treatment protocols, and anti-leukemic drugs in a logistic regression model, only the concomitant Escherichia coli asparaginase/prednisone administration in leukemic children suffering from a prothrombotic risk factor was found to increase the rate of thrombotic manifestations during leukemia treatment in patients of the same Caucasian origin (OR/95% CI: 34.5/4.39-271.42; P=.0008). Based on the data presented here, we suggest the use of prednisone and E. coli asparaginase concomitantly administered in a leukemic patient suffering from a prothrombotic risk factor to be responsible for the onset of venous thrombosis in the majority of cases.
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PMID:Thrombotic events revisited in children with acute lymphoblastic leukemia: impact of concomitant Escherichia coli asparaginase/prednisone administration. 1167 78

We have determined the prevalence of methylenetetrahydrofolate reductase (MTHFR) mutations C677T and A1298C in 71 children (< or = 15 years) with acute lymphoblastic leukaemia (ALL) and in 71 control subjects. Odds ratio (OR) for ALL linked to MTHFR C677T was 0.4 (95% CI 0.2-0.8); for heterozygotes it was 0.5 (95% CI 0.2-0.9) and for homozygotes it was 0.3 (95%CI 0.09-0.8). MTHFR A1298C yielded an overall OR for ALL of 1.3 (95% CI: 0.7-2.6); for heterozygotes it was 1.3 (95% CI: 0.7-7.6) and for homozygotes it was 2.8 (95% CI 0.5-15.6). In conclusion, MTHFR C677T was linked to a significant 2.4-fold decreased risk of developing childhood ALL, whereas MTHFR A1298C did not significantly affect the risk of ALL in our population.
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PMID:The methylenetetrahydrofolate reductase C677T gene polymorphism decreases the risk of childhood acute lymphocytic leukaemia. 1173 45

Genetic approaches to understanding the etiology of the acute leukemias are beginning to deliver meaningful insights. Polymorphic variants in xenobiotic metabolizer loci were a natural starting point to study the relevance of these changes. The finding that glutathione S-transferase (GST) T1 null variants increase leukemia risk has implicated oxidative stress in hematopoietic stem cells as an important etiological factor in acute myeloid leukemia (AML). The importance of these enzyme systems in handling specific substrates has also been confirmed by the finding of an increased risk of therapy-related leukemia in individuals with underactive variants of GSTP1 who have been exposed to a chemotherapeutic agent metabolized by this enzyme. Benzene is a well-recognized leukemogen, and genetic variants in its metabolic pathway can modulate the risk of leukemia following exposure. In particular, underactive variants of the NAD(P)H:quinone oxidoreductase 1 gene (NQO1) seem to increase the risk of AML. Other enzymes within the pathway are proving more difficult to study because of the absence of variants that significantly affect the biological activity of the enzyme under study. No effect of the myeloperoxidase (MPO) gene variants in altering the risk of AML has been seen in our studies. Another pathway recently shown to be important in determining leukemia risk is folic acid metabolism, particularly important in predisposition to acute lymphocytic leukemia (ALL). Polymorphic variants of the methylenetetrahydrofolate reductase gene (MTHFR) which impair its activity have been shown to be associated with a protective effect. This is thought to be due to an increased availability of nucleotide precursors for incorporation into DNA. This finding implicates misincorporation of uracil into DNA as an important mechanism of leukemic change in lymphoid precursors. Future studies will extend these observations but will require biological material collected from large well-controlled epidemiological studies. The technological challenges imposed by the high throughput of samples required by these studies are currently being addressed.
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PMID:Metabolic enzyme polymorphisms and susceptibility to acute leukemia in adults. 1208 44

The role of methylenetetrahydrofolate reductase (MTHFR C677T), glutathione S-transferases (GSTM1 and GSTT1 null, GSTP1 Ile105Val), and cytochromes p450 (CYP1A1*2A) genotypes in the etiology of childhood leukemia was simultaneously investigated. 144 Turkish children with acute lymphoblastic leukemia (ALL) and 33 with acute nonlymphoblastic leukemia (ANLL) were studied and compared with 185 healthy pediatric controls. The frequency of MTHFR genotype was insignificantly higher in ALL (7.7%) and ANLL (6.3%) than in controls (4.4%). Equal distribution of the GSTM1 null genotype was detected between ALL patients and controls (55%), while its incidence was slightly higher in ANLL patients (61.3%). Although GSTT1 null genotype was insignificantly lower in ALL patients (20.9%) than controls (22.7%), it was significantly underrepresented in ANLL patients (6.5%) (P = 0.05, OR 0.24, 95% CI 0.05-1.03). The homozygous frequency of GSTP1 genotype did not differ significantly between groups of ALL (3.7%), ANLL patients (9.1%) and controls (4.9%). Homozygous CYP1A1*2A genotype was underrepresented in ALL patients (1%) as compared to control (4.8%) but the differences did not reach to statistical significance (OR 0.21; 95% CI 0.03-1.72). Homozygosity for this genotype was not detected in ANLL patients. No particular association was noted between different combinations of combined genotypes and risk of development of childhood ALL and ANLL. These results suggested that there are no significant associations between the studied genotypes and the risk of developing either form of acute leukemia except GSTT1 null and homozygosity for CYP1A1 genotypes that may play protective roles in the development of ANLL in Turkish children.
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PMID:Characterization of MTHFR, GSTM1, GSTT1, GSTP1, and CYP1A1 genotypes in childhood acute leukemia. 1282 51

The central role of methylenetetrahydrofolate reductase (MTHFR) in the folate metabolism renders MTHFR gene polymorphisms (C677T and A1298C) potential modulators of a variety of disorders whose development depends on folate/homocysteine imbalance. Here, we provide additional evidence on the protective role of these polymorphisms in acute lymphoblastic leukemia (ALL), the most common pediatric cancer. A case-control study was conducted in 270 ALL patients and 300 healthy controls of French-Canadian origin. The TT677/AA1298 and CC677/CC1298 individuals were associated with reduced risk of ALL (crude odds ratio [OR] = 0.4; 95% confidence interval [CI], 0.2-0.9; and OR = 0.3; 95% CI, 0.1-0.6; respectively). Further stratification in patients born before and after January 1996 (approximate time of Health Canada recommendation for folic acid supplement in pregnancy) revealed that the protective effect of MTHFR variants is accentuated and present only in children born before 1996. Similar results were obtained when a transmission disequilibrium test was performed on a subset of children (n = 95) in a family-based study. This finding suggests gene-environment interaction and its role in the susceptibility to childhood ALL, which is consistent with previous findings associating either folate deficiency or MTHFR polymorphisms with risk of leukemia.
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PMID:Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia. 1617 54

Methotrexate (MTX) has proven efficient in the treatment of a number of malignancies, as well as non-malignant disorders characterized by a rapid cellular growth. Yet some patients might develop resistance, while others could have toxic side effects. MTX achieves its cytotoxicity through the inhibition of folate-dependent enzymes, suggesting that the genes controlling their activity or the levels of folate cofactors can modulate drug efficacy and, thus, the sensitivity of a patient to MTX. Indeed, several studies, conducted mostly in leukemia and rheumatoid arthritis patients, have addressed the potential for tailoring MTX therapy based on a patient's genetics. Several genetic variants have been shown to have a predictive role, among which the most frequently studied are those of methylenetetrahydrofolate reductase and thymidylate synthase genes. The other candidates, as well as gene-gene interactions, which may be even more important for the prediction of disease outcomes than the individual gene effects, are also briefly discussed.
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PMID:Pharmacogenetics of methotrexate. 1546 5

Various specific chromosome rearrangements, including t(8;21), t(15;17), and inv(16), are found in acute myeloid leukemia (AML) and in childhood acute lymphocytic leukemia (ALL), t(12;21) and t(1;19) are common. We sequenced the translocation breakpoints of 56 patients with childhood ALL or AML harboring t(12;21), t(8;21), t(15;17), inv(16), and t(1;19), and demonstrated, with the notable exception of t(1;19), that these rearrangements are commonly detected in the neonatal blood spots (Guthrie cards) of the cases. These findings show that most childhood leukemias begin before birth and that maternal and perinatal exposures such as chemical and infectious agents are likely to be critical. Indeed, we have reported that exposure to indoor pesticides during pregnancy and the first year of life raises leukemia risk, but that later exposures do not. We have also examined aberrant gene methylation in different cytogenetic subgroups and have found striking differences between them, suggesting that epigenetic events are also important in the development of some forms of childhood leukemia. Further, at least two studies now show that the inactivating NAD(P)H:quinone acceptor oxidoreductase (NQO1) C609T polymorphism is positively associated with leukemias arising in the first 1-2 years of life and polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene have been associated with adult and childhood ALL. Thus, low folate intake and compounds that are detoxified by NQO1 may be important in elevating leukemia risk in children. Finally, we are exploring the use of proteomics to subclassify leukemia, because cytogenetic analysis is costly and time-consuming. Several proteins have been identified that may serve as useful biomarkers for rapidly identifying different forms of childhood leukemia.
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PMID:Molecular biomarkers for the study of childhood leukemia. 1596 14


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