What is the role of folic acid deficiency in carcinogenesis?

Updated: Sep 14, 2018
  • Author: Katherine Coffey-Vega, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Answer

Effects on carcinogens

Diminished folate status has historically been associated with enhanced carcinogenesis. [16] As recently as 2002, authors cited epidemiologic and laboratory data demonstrating that folic acid intake was inversely related to colon cancer risk. [34] The proposed mechanisms by which folic acid deficiency led to increased carcinogenesis included chromosomal breaks due to massive incorporation of uracil into human DNA. [35] and DNA strand breaks and hypomethylation within the P53 gene. [36]

More recently, a number of studies have demonstrated that folic acid supplementation can actually increase the risk of cancer.

A randomized controlled clinical trial from 1994-2004 examining the use of folic acid for the prevention of colorectal adenomas not only demonstrated that folic acid supplementation did not reduce colorectal adenoma risk, but suggested that this supplementation may increase the risk of colorectal neoplasia. This study demonstrated that folic acid supplementation increased the risk of having 3 or more adenomas. [15]

Prior to this study, authors had observed an increase in the rate of colorectal carcinomas in the United States and Canada in the 1990s, which was related temporally to the implementation of the mandatory folic acid supplementation government policies. They hypothesized that the addition of folic acid supplementation to American and Canadian diets was at least in part responsible for the rise in colorectal cancers. [14]

Similar conclusions were drawn by authors who studied a rise in colorectal cancers rates after a folic acid fortification program in Chile. [13] Folic acid supplementation has also been implicated in the development of prostate cancer, [11] and biochemical researchers have demonstrated that increasing folic acid levels led to dose-dependent down-regulation of tumor suppressor genes in breast cancer. [12]

In patients with inflammatory bowel disease, however, folic acid supplementation may reduce colorectal cancer risk. A systematic review and meta-analysis of 10 studies reporting on 4517 patients found an overall protective effect for folic acid supplementation on the development of colorectal cancer in this population, with a pooled hazard ratio of 0.58 (95% confidence interval, 0.37-0.80). [37]

The debate over the safety of widespread folic acid supplementation will certainly continue in the medical literature in the years to come. Care should be taken to ensure that individuals do not consume a greater-than-recommended dietary allowance of folic acid, and special consideration should be given to patients with history of colorectal adenomas and those at high risk for cancer.


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