A functional 19-base pair deletion polymorphism of dihydrofolate reductase (DHFR) and risk of breast cancer in multivitamin users

Xu, Xinran; Gammon, Marilie D.; Wetmur, James G.; Rao, Mukund Palat; Gaudet, Mia M.; Teitelbaum, Susan L.; Britton, Julie A.; Neugut, Alfred I.; Santella, Regina M.; Chen, Jia

doi:10.1093/ajcn/85.4.1098

Cited by 74 publications

(69 citation statements)

References 16 publications

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“…Several variations of DHFR have been found in noncoding regions, which may relate to the variability of DHFR activity found in the current study. A 19 bp deletion polymorphism within intron 1 (43) has been found to enhance gene expression (44,45). This increased expression was thought to be due to loss of another Sp1 transcription factor binding site (43), but in fact contains a consensus binding site for the repressor, Sp2.…”

Section: Discussionmentioning

confidence: 99%

The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake

Bailey

Ayling

2009

Proc. Natl. Acad. Sci. U.S.A.

342

291

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Numerous clinical trials using folic acid for prevention of cardiovascular disease, stroke, cognitive decline, and neural tube defects have been completed or are underway. Yet, all functions of folate are performed by tetrahydrofolate and its one-carbon derivatives. Folic acid is a synthetic oxidized form not significantly found in fresh natural foods; to be used it must be converted to tetrahydrofolate by dihydrofolate reductase (DHFR). Increasing evidence suggests that this process may be slow in humans. Here we show, using a sensitive assay we developed, that the reduction of folic acid by DHFR per gram of human liver (n ‫؍‬ 6) obtained from organ donors or directly from surgery is, on average, less than 2% of that in rat liver at physiological pH. Moreover, in contrast to rats, there was almost a 5-fold variation of DHFR activity among the human samples. This limited ability to activate the synthetic vitamer raises issues about clinical trials using high levels of folic acid. The extremely low rate of conversion of folic acid suggests that the benefit of its use in high doses will be limited by saturation of DHFR, especially in individuals possessing lower than average activity. These results are also consistent with the reports of unmetabolized folic acid in plasma and urine.folate ͉ provitamin utilization ͉ unmetabolized folic acid ͉ vitamin supplements ͉ nutrition

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Section: Discussionmentioning

confidence: 99%

The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake

Bailey

Ayling

2009

Proc. Natl. Acad. Sci. U.S.A.

342

291

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“…Individuals homozygous for the deletion (À/À) have lower mean plasma total homocysteine than those homozygous for the insertion ( þ / þ ), 40 with the (À/À) individuals also having been shown to have 4.8-fold greater DHFR mRNA expression in lymphocytes compared with ( þ / þ ) carriers. 42 The 5 0 -upstream 9-bp repeat polymorphism (homozygous 6R carriers) 43 and 3 0 -UTR SNP (rs34764978) (C/T and T/T carriers) 44 have also been associated with enhanced mRNA expression.…”

Section: Tymsmentioning

confidence: 99%

Investigation of inter-individual variability of the one-carbon folate pathway: a bioinformatic and genetic review

2009

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“…natural diet rich in folate and vitamin supplements. In the latter case, folic acid is the supplemented active substance, which needs the aforementioned DHFR enzyme to achieve a naturally occurring reduced form [16]. Polymorphism of the DHFR-19-bp gene by generating its overexpression disrupts folate metabolic processes, and thus also disturbs the level of SAM, DNA methylation processes and finally, modifies the transcription factor binding sites.…”

Section: Vitamin Chemoprevention?mentioning

confidence: 99%

“…The cohort study the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial demonstrated an approx. 20% increase in the risk of breast cancer in postmenopausal women supplemented with a daily dose of folic acid above 400 μg [16]. Figueiredo et al [5] reported that the amount of folic acid exceeding 400 μg saturates the DHFR enzyme.…”

Section: Vitamin Chemoprevention?mentioning

confidence: 99%

B-Group Vitamins: Chemoprevention?

Gruber¹

2016

Adv Clin Exp Med

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The importance of vitamins in the prevention of cancer has attracted the attention of consumers, nutritionists and scientists for decades. The mechanisms of carcinogenesis, extended in the context of the function of vitamins, i.e. regulation of and participation in metabolic processes in the cell, suggest a substantial impact of these compounds on the initial stages of carcinogenesis. One-carbon metabolism involving folic acid, vitamins B2, B6 and B12, and folate metabolism doesn't only generate methyl groups, thus determining epigenetic processes, modifications of the genome and carcinogenesis. It also provides the compounds involved in the DNA synthesis and repair processes, especially the synthesis of purines and pyrimidines and the conversion of dUMP (2-deoxyuridine monophosphate) to dTMP (2-deoxythymidine monophosphate). In light of these pathways, folate, together with vitamins B2, B6 and B12, became a subject of interest as compounds whose deficit or surplus can potentially have an impact on the processes of carcinogenesis. Literature reports, however, do not fully confirm that the influence on the synthesis of nucleotides is connected with the inhibition of carcinogenesis. The impact of individual vitamins involved in one-carbon metabolism on carcinogenesis and their role in the prevention of these conditions depend on the type of cancer and the dose administered. Nevertheless, the research conducted makes it possible to conclude a considerable and probably long-underestimated role of these compounds in the prevention of serious, difficult to treat or incurable diseases (Adv Clin Exp Med 2016, 25, 3, 561-568).

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A functional 19-base pair deletion polymorphism of dihydrofolate reductase (DHFR) and risk of breast cancer in multivitamin users

Abstract: The DHFR 19-bp deletion polymorphism affects the transcription of DHFR gene in humans. Multivitamin supplements may place a subgroup of women (ie, those with the -19-bp allele) at elevated risk of developing breast cancer.

Cited by 74 publications

References 16 publications

The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake

The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake

Investigation of inter-individual variability of the one-carbon folate pathway: a bioinformatic and genetic review

B-Group Vitamins: Chemoprevention?

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