Systemic folate status and risk of colorectal cancer

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In their recent study of plasma folate concentration and risk of colorectal cancer (CRC), Otani et al. [1] concluded that a folate-rich status did not reduce the risk of CRC. The authors discussed several limitations of their study, including the low response rate for donation of a blood sample (23% for male cohort participants), the relative merits of measuring plasma folate concentration (a rather transient measure compared to erythrocyte folate), the relevance of current rather than past folate status and the low number of folate-deficient subjects in their study population; these are all valid caveats in the interpretation of this study. However, the description of the impact of methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms was inaccurate. The authors state that the homozygous variant genotype is associated with an increased risk of CRC and a reduced enzymatic activity; they cite the work of Ma et al. [2] to support these statements. Firstly, the direction of the association between MTHFR C677T genotype in the cited study was such that the homozygous variant form was associated with a decreased risk of colorectal cancer (OR: 0.45; 95% CI: 0.24-0.86). Subsequently, this pattern of reduced risk has been confirmed, particularly in those subjects with adequate folate status and low alcohol intakes [3]. Secondly, the phenotypic characteristics of the MTHFR enzyme were not investigated in the study by Ma et al. (1997) but were inferred from a previous study [4]. Subsequent studies [5, 6] have shown that the C677T polymorphism does not reduce the activity of the enzyme per se but alters the stability of the enzyme in response to ambient availability of 5-methyl tetrahydrofolate (5-MTHF), the product of the reaction. This is supported by the observed folate status dependency of the effects of this polymorphism on total omocysteine, DNA hypomethylation, and risk of various dis ase states. The reduced activity reported from biochemical assays of ex vivo extracts most likely reflects the reduced stability of the variant under the assay conditions [6] rather than a legitimate in vivo phenotype. The literature regarding the impact of folate status on colorectal cancer is replete with inconsistent and ambiguous conclusions. In the recent WCRF/AICR Expert Report [7], the evidence relating to "foods containing folate" was summarized as "limited-suggestive" for a decreased risk of CRC. Therefore, almost 20 years since the first publication of an association between folate status and risk of CRC [8] and over 15 years since its significance was appreciated at the population level [9], there remains a lack of consensus regarding the legitimacy and magnitude of the effect. Indeed, a recent review [10] concluded that "the exact characterization of the direct or (rather) indirect association [with folate] is beyond our present scientific and statistical tools. " More recently, a rationale has been proposed which does account for the ambiguities and inconsistencies of these observations, by highlighting the importance of localized folate depletion [11]. The measurement of folate intake and other systemic measures do not account for local (tissue/cellular) concentrations and continued replication of studies investigating systemic folate are unlikely to provide additional insight beyond our existing conclusions. The availability of folate at the local level is likely to be of much greater significance, to the Electronic supplementary material The online version of this article (doi: 10. 1007/s 10552-008-91 6 1-6) contains supplementary material, which is available to authorized users.