Folate and colorectal cancer: An evidence‐based critical review

Abstract

Currently available evidence from epidemiologic, animal, and intervention studies does not unequivocally support the role of folate, a water-soluble B vitamin and important cofactor in one-carbon transfer, in the development and progression of colorectal cancer (CRC). However, when the portfolio of evidence from these studies is analyzed critically, the overall conclusion supports the inverse association between folate status and CRC risk. It is becoming increasingly evident that folate possesses dual modulatory effects on colorectal carcinogenesis depending on the timing and dose of folate intervention. Folate deficiency has an inhibitory effect whereas folate supplementation has a promoting effect on the progression of established colorectal neoplasms. In contrast, folate deficiency in normal colorectal mucosa appears to predispose it to neoplastic transformation, and modest levels of folic acid supplementation suppress, whereas supraphysiologic supplemental doses enhance, the development of cancer in normal colorectal mucosa. Several potential mechanisms relating to the disruption of one-carbon transfer reactions exist to support the dual modulatory role of folate in colorectal carcinogenesis. Based on the lack of compelling supportive evidence and on the potential tumor-promoting effect, routine folic acid supplementation should not be recommended as a chemopreventive measure against CRC at present.

Impact of folic acid fortification of flour on neural tube defects: a systematic review

“…From the serum folate values obtained in a variety of studies (63,(67)(68)(69) , some have estimated that adequate NTD prevention can be obtained with intakes close to 100 mg of folic acid/d, especially if the food is fortified and its consumption is constant and prolonged (63,66) . This adaptation of the folic acid recommendation would maintain the benefits, while limiting the exposure of other population groups that do not necessarily benefit from folic acid food fortification (70)(71)(72) , with the possibility of recommending higher doses in special cases such as women with a positive history of children with NTD or polymorphisms associated with folate metabolism (73) . These adjustments should be kept in mind because some animal and clinical studies suggest that folate possesses dual modulatory effects on colorectal cancer development and progression, depending on the timing and dose of folic acid intervention (70,(74)(75)(76) .…”

“…This adaptation of the folic acid recommendation would maintain the benefits, while limiting the exposure of other population groups that do not necessarily benefit from folic acid food fortification (70)(71)(72) , with the possibility of recommending higher doses in special cases such as women with a positive history of children with NTD or polymorphisms associated with folate metabolism (73) . These adjustments should be kept in mind because some animal and clinical studies suggest that folate possesses dual modulatory effects on colorectal cancer development and progression, depending on the timing and dose of folic acid intervention (70,(74)(75)(76) . Moreover, other studies have described positive associations between high serum folate and both anaemia and poor cognitive test performance in persons deficient in vitamin B 12 (71,77) .…”

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

“…Folate deficiency seems to predispose normal tissue to neoplastic transformation, and folate supplementation can suppress the development of tumors in normal tissue. 13 For instance, a 20-40% reduction in the risk of colorectal cancers and precursory adenomas has been reported in individuals with the highest folate status as against those with the lowest. 13 A number of meta-analyses have postulated an association between high folate and a mild protective effect against the risk of several cancers, including colorectal, 14 pancreatic, esophageal, gastric, 15 oral 16 and ovarian.…”

“…13 For instance, a 20-40% reduction in the risk of colorectal cancers and precursory adenomas has been reported in individuals with the highest folate status as against those with the lowest. 13 A number of meta-analyses have postulated an association between high folate and a mild protective effect against the risk of several cancers, including colorectal, 14 pancreatic, esophageal, gastric, 15 oral 16 and ovarian. 17 Conversely, and controversially, there is some evidence to suggest that high folate may indeed be a risk factor for some forms of cancer.…”

γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells

“…Folate, a water-soluble B-vitamin, mediates the transfer of one-carbon units involved in thymidylate and purine biosynthesis and biological methylation reactions (Kim 2007;Shane 2010). Intracellular folate homeostasis is maintained by folylpolyglutamate synthase (FPGS) that facilitates intracellular retention of folate by polyglutamylation and by c-glutamyl hydrolase (GGH) that catalyzes the hydrolysis of polyglutamylated folate into monoglutamates, thereby facilitating the export of folate out of the cell (Shane 2010).…”