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Chapter category: Nucleus

MTHFR Polymorphisms and Colorectal Neoplasia

Chapter authors:
Jimmy W. Crott and Joel B. Mason

Folate is essential for the synthesis, repair and methylation of DNA, processes that are central to maintaining the integrity of the genome. It is therefore not surprising that aberrations in folate metabolism, either due to folate deficiency or altered activity of folate-dependent enzymes, can modify our risk for cancer. Folate depletion compromises both genetic and epigenetic features of DNA by altering DNA methylation patterns,1,2 increasing the content of uracil in DNA3,4 and also increasing the frequency of breaks in DNA5 and chromosomes.6,7 It is becoming increasingly evident that these types of changes to the structure and composition of DNA are involved in the etiology of cancer and probably other age-associated diseases as well.8 As discussed in previous chapters, 5,10- methylenetetrahydrofolate reductase (MTHFR) is a key folate-metabolizing enzyme, which catalyzes the reduction of 5,10- methylenetetrahydrofolate (5,10 -methyleneTHF) to 5- methyltetrahydrofolate (5-methylTHF). MTHFR is intricately linked to the integrity of the genome because its substrate functions as the one-carbon unit donor for thymidine synthesis (and indirectly for purine synthesis) and the product contributes to the supply of methyl groups destined for DNA methylation. Perturbations in the normal functioning of MTHFR might therefore impact on cancer risk by altering the rate at which DNA accumulates deleterious genetic and epigenetic modifications. It is also important to realize that the biological methylation of other macromolecules, such as RNA9 and protein,10 is dependent on the ready supply of methyl groups and may play a role in the etiology of disease as well. A thermolabile variant of MTHFR, arising from a C to T nucleotide transition at position 677 of the gene and a subsequent alanine to valine substitution in the protein, has been the focus of much research over the past decade. This C677C>T polymorphism has been shown to cause a 70% reduction in the in vitro activity of the enzyme in homozygotes (TTs).11 It is also clear that the C to T polymorphism reduces in vivo MTHFR activity by virtue of the fact that in homozygotes plasma homocysteine levels are significantly elevated11 and formylated folates accumulate at the expense of 5-methylTHF in red blood cells.12 A second polymorphism in MTHFR involves an A to C nucleotide transition at position 1298 of the gene.13 In people who are wild-type with respect to the 677 transition, homozygosity for the 1298A>C mutation reduces the in vitro MTHFR (specific) activity by approximately 39% but does not confer thermolability or seem to affect blood total folate and homocysteine concentrations.13 Since the C677C>T polymorphism is known to impact on cellular folate pools, it is perhaps not surprising that the presence of the polymorphism affects the ability of cells to sustain appropriate levels and patterns of DNA methylation. Recent evidence indicates that TTs have a compromised ability to sustain normal levels of DNA methylation under low folate conditions and therefore have relatively hypomethylated DNA compared to CCs.14 It remains unclear whether the capacity for nucleotide synthesis is altered in TTs, although several groups15,16 have speculated that the shift towards more nonmethylated folates in TT individuals would improve nucleotide synthesis and therefore DNA synthesis and repair. This review summarizes the epidemiological evidence for an association of the MTHFR C677C>T and 1298A>C polymorphisms with colorectal neoplasia and discusses the postulated mechanisms behind these relationships. It appears that the critical importance of the MTHFR reaction is due, in large part, to the fact that the reaction determines the partitioning of nonmitochondrial folate between two major pathways, biological methylation and nucleotide synthesis, aberrations of which are each implicated in carcinogenesis. Currently only two publications report data on the1298A>C polymorphism and therefore this review focuses mainly on the common C677C>T polymorphism. However, we begin this review by first summarizing the molecular mechanisms underlying folate deficiency-induced genetic damage because these are central to understanding how MTHFR polymorphisms might affect an individual’s risk for cancer.

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