Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.5.7.1 (methylenetetrahydrofolate reductase)
 2,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Genetic polymorphism analysis for disease risk is widely used in epidemiology studies; blood or oral cavity cells are the most widely used source of DNA. However, these types of samples are not always available, particularly for studies that were conducted years ago. An alternative potential source of patient DNA exists in the form of paraffin-embedded normal tissue adjacent to tumor samples, which are collected and stored routinely for clinical use. The use of such samples can be conceptually problematic, however, due to the presence of field cancerization in the surrounding normal tissue, with the possible presence of chromosomal loss. Specifically, loss of heterozygosity (LOH) might bias the genotyping results and cause genotype misclassification. However, field cancerization and LOH might not be an issue because LOH is not easily found unless there is careful microdissection of only tumor cells (leaving stromal, inflammatory and fat cells), for example, laser-capture microdissection. In this study, we set out to determine the degree of genotype misclassification from normal tissues adjacent to tumors, if any, by comparing these results with blood genotyping. We examined samples from 106 subjects with breast cancer, analyzing five different genotypes selected from regions commonly known to have LOH in breast cancer. These genotypes were methylenetetrahydrofolate reductase (MTHFR), oxoguanosine glycosylase 1 (hOGG1), dopamine beta-hydroxylase (DBH), dopamine receptor D2 (DRD2) and NAD(P)H dehydrogenase quinone 1 (NQO1), conducted by using real-time PCR and TaqMan genotyping analyses. We found that among these five genotypes and 106 comparisons, there was a 100% concordance for genotyping from normal tissue adjacent to tumor and from blood. Our findings indicate that the use of adjacent normal tissues provides accurate genotyping results with high specificity. Although this study only used breast tumor samples, and may be applicable only to breast cancer studies, we expect the results to be applicable to other types of cancers also.
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PMID:Accurate genotyping from paraffin-embedded normal tissue adjacent to breast cancer. 1611 52