Unmetabolized Folic Acid, Tetrahydrofolate, and Colorectal Adenoma Risk

Abstract

In a randomized trial of folic acid supplementation for the prevention of colorectal adenomas, we previously found indications of increased risk during later treatment and follow-up. This could have been due to the unmetabolized folic acid or natural reduced and methylated folates to which it is metabolized. In post hoc analyses, we measured methylated folates (mF, the sum of 5-methyl-tetrahydrofolate and 4-alfa-hydroxy-5-methyl-THF) and unmetabolized folic acid (UFA) concentrations in the serum of 924 participants. Using binomial regression models with a log link, we assessed the associations between plasma mF or UFA and adenoma occurrence. We found no association between plasma mF or UFA and overall adenoma risk. However, during later follow-up, the pre-specified, composite endpoint of high risk findings (advanced or multiple adenomas) was positively associated with plasma mF (Plinear trend=0.009), with a 58% increased risk for participants in the upper versus lowest quartile. An irregular association was seen with plasma UFA, with suggestions of an inverse trend (Plinear trend=0.049). A modest, significant inverse association was also seen between mF and risk of serrated lesions, with a 39% lower risk for upper vs lower quartile participants (Plinear trend=0.03). In conclusion, during the later follow-up period in which folic acid supplementation was previously seen to increase the risk of advanced and multiple adenomas, higher serum mF was associated with a higher risk of multiple and/or advanced adenomas, but no clear indication that UFA played a direct role. There were indications that higher mF was associated with reduced risk of serrated polyps.

Demographic, Physiologic, and Lifestyle Characteristics Observed with Serum Total Folate Differ Among Folate Forms: Cross-Sectional Data from Fasting Samples in the NHANES 2011–2016

“…These observations strengthen our working hypothesis that MeFox in serum may not be entirely generated post-blood collection from 5-methylTHF oxidation. We therefore question the approach of using a sum indicator called "methylated folate" (sum of 5-methylTHF and MeFox) to interpret folate status (24). Instead, we suggest to separately report results for 5-methylTHF and MeFox to provide broader utility to investigators.…”

Metabolic Response of Triple-Negative Breast Cancer to Folate Restriction

“…Dietary folate deficiency causes several developmental disorders, most notably neural tube defects, many of which are prevented by adequate folate supplementation [ 1 , 2 ]. Likewise, epidemiological studies suggest that sufficient dietary folate diminishes cancer initiation, though this effect appears to be cancer type specific [ 3 , 4 , 5 ]. Genetic polymorphisms in several folate enzymes, most notably methylenetetrahydrofolate reductase (MTHFR), have also been associated with increased risk of several cancers [ 6 , 7 , 8 ], underscoring the role of folate metabolism in tumorigenesis.…”

Genome‐wide association study of circulating folate one‐carbon metabolites

“…Moreover, some recent human studies, including randomized clinical trials, suggest risks for colon, breast or prostate cancers may be increased in those taking high doses of folic acid from supplements (Charles, Ness, Campbell, Davey Smith, & Hall, ; Cole et al, ; Figueiredo et al, ; Hirsch et al, ; Stolzenberg‐Solomon et al, ) in the context of a folic acid fortified diet. Notably, a randomized clinical trial of colorectal adenoma suggested the risk of recurrent advanced colorectal adenoma or multiple adenomas increased with excessive levels of folate (Rees et al, ). Several other trials reported no such effect (Logan, Grainge, Shepherd, Armitage, & Muir, ; Song et al, ; Wu et al, ), although they had shorter follow‐up periods.…”