Folate and cancer prevention

SY33-02 Folate is a water-soluble B vitamin that is present naturally in foods whereas folic acid is the synthetic form of this vitamin that is used commercially in supplements and in fortified foods. The sole biochemical function known for folate is mediating the transfer of one-carbon units involved in nucleotide synthesis and biological methylation reactions. In this role, folate may play an important role in cancer development and progression. Indeed, epidemiologic studies suggest that folate intake (dietary and supplemental) and blood folate levels are inversely associated with the risk of several malignancies including cancer of the colorectum, oropharynx, esophagus, stomach, pancreas, lungs, cervix, ovary, and breast and neuroblastoma and leukemia. The best epidemiologic evidence for the inverse association between folate status and cancer risk exists for colorectal cancer and its precursor, adenoma. Collectively, epidemiologic studies suggest a 20-40% reduction in the risk of colorectal cancer and adenomas in individuals with the highest folate intake compared with those with lowest intake. The role of folate in colorectal carcinogenesis has been further strengthened by the observations that genetic polymorphisms in the folate metabolic pathway modify colorectal cancer risk.
 However, animal studies suggest 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.
 Although small human intervention trials have suggested potential beneficial effects of folic acid supplementation on biomarkers of CRC, more recent large intervention trials do not support these earlier observations. In the Asprin-Folate Polyp Prevention Study, folic acid supplementation (1 mg/d for up to 6 years) increased the risk of developing advanced lesions with a high malignant potential, defined as ≥25% villous features, high-grade dysplasia, size ≥1 cm, or invasive adenocarcinoma (OR=1.67; 95% CI, 1.00-2.80) and of developing multiple (>2) adenomas (OR=2.32; 95% CI, 1.23-4.35) compared with placebo in 1021 subjects with previously resected adenomas (JAMA 2007; 297: 2351). One explanation for this observation is that folic acid supplementation might have promoted the progression of already existing, undiagnosed microscopic preneoplastic lesions in these predisposed patients. Another secondary finding from this trial was that the risk of cancers other than colorectal cancer was significantly increased in the folic acid supplemented group (P=0.02) largely due to an excess of prostate cancer in the folic acid group (P=0.01).
 Several potential mechanisms relating to the role of folate in one-carbon transfer reactions and consequent DNA synthesis and epigenetic regulations exist to support the differential effects of folate on the development and progression of colorectal cancer in the normal colorectum and in established colorectal preneoplastic and neoplastic foci. In normal colorectum, folate deficiency may enhance the development of colorectal cancer via DNA stand breaks, impaired DNA repair, increased mutagenesis, and genomic DNA hypomethylation, while folate supplementation may prevent the development of colorectal cancer by ensuring DNA stability and integrity, optimal DNA repair, decreased mutagenesis, and prevention of aberrant DNA methylation. In established colorectal cancer and adenomas, folate deficiency causes ineffective DNA synthesis leading to inhibition of tumor growth and progression (similar to chemotherapies using antifolates) and may reverse promoter CpG island methylation of tumor suppressor and other anticancer genes involved in colorectal carcinogenesis, thereby reactivating these genes and leading to inhibition of tumor progression. In established colorectal cancer or adenomas, folate supplementation may promote tumor progression by providing nucleotide precursors for proliferation and growth of neoplastic cells and de novo methylation of promoter CpG islands of tumor suppressor and anticancer genes leading to gene inactivation.
 Population-based folic acid fortification, intended to prevent neural tube defects, and folic acid supplementation (consumed by up to 40% of the North American population), long presumed to be purely beneficial and believed to provide several health benefits, may have unintended deleterious influences on the development and progression of colorectal cancer. Given the incidence and mortality of colorectal cancer and the prevalence of adenomas (present in up to 50% of the population), whether or not folic acid fortification and supplementation promote the progression of preneoplastic foci to colorectal cancer is a legitimate significant public health concern. In this regard, a recent study that examined a temporal trend of colorectal cancer incidence in the USA and Canada post fortification has reported that concurrent with folic acid fortification, the US and Canada experienced abrupt reversals of the downward trend in colorectal cancer incidence that the two countries had enjoyed in the preceding decades (Cance Epidemiol Biomarkers Prev 2007; 16: 1325). Because of the lack of complete control of potential confounding factors, this observation does not prove a causal link between folic acid fortification and increased rates of colorectal cancer in North America post fortification. Nevertheless, this observation provides a highly provocative impetus for further discussion, debate and research aimed at elucidating potential deleterious effects of folic acid fortification and supplementation on cancer risk.
 There is an emerging body of evidence that suggests that folic acid fortification and periconceptional maternal use of folic acid supplementation may prevent the development of “new” cancers in a site-specific manner (e.g., pediatric neuroblastoma and acute lymphocytic leukemia). Folic acid fortification and periconceptional supplementation may therefore reduce the risk of certain childhood cancers in the offspring. Furthermore, folic acid supplementation may prevent the development of “new” cancers in normal tissues. However, folic acid supplementation and fortification may promote the progression of already, existing, undiagnosed preneoplastic and neoplastic lesions. At present, 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 colorectal cancer and other cancers. Furthermore, the potential tumor-promoting effect of the dramatically increased folate intake resulting from mandatory folic acid fortification in the USA and Canada should be carefully monitored. More specifically for colorectal cancer, folic acid supplementation should not be given to individuals with previous colorectal adenomas because their colons may already be predisposed to neoplastic transformation and to those suspected of harboring precursor lesions of colorectal cancer in the colorectum. This of course applies to the large segment of the North American population as it has been estimated that ~25-50% of people by 50 years of age in the US (>60 millions) and Canada (>10 millions) harbor asymptomatic colorectal adenomas, and the prevalence increases with age. This translates to 16 to 32 millions of the Americans ≥50 years of age who might be susceptible to the tumor promoting effect of folic acid supplementation. Even a greater number of the North Americans might be harboring aberrant crypt foci (the probable earliest precursor of colorectal cancer) or microscopic adenomas in the colon and folic acid supplementation may accelerate the progression of these early precursor lesions to colorectal adenomas and cancer.

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