Folate deficiency as predisposing factor for childhood leukaemia: a review of the literature

Abstract

Background: Folic acid and its derivates, known as folates, are chemoprotective micronutrients of great interest because of their essential role in the maintenance of health and genomic integrity. The supplementation of folic acid during pregnancy has long been known to reduce the risk of neural tube defects (NTDs) in the foetus. Folate metabolism can be altered by many factors, including adequate intake through diet. Folate deficiency can compromise the synthesis, repair and methylation of DNA, with deleterious consequences on genomic stability and gene expression. These processes are known to be altered in chronic diseases, including cancer and cardiovascular diseases.

Main body: This review focuses on the association between folate intake and the risk of childhood leukaemia. Having compiled and analysed studies from the literature, we show the documented effects of folates on the genome and their role in cancer prevention and progression with particular emphasis on DNA methylation modifications. These changes are of crucial importance during pregnancy, as maternal diet has a profound impact on the metabolic and physiological functions of the foetus and the susceptibility to disease in later life. Folate deficiency is capable of modifying the methylation status of certain genes at birth in both animals and humans, with potential pathogenic and tumorigenic effects on the progeny. Pre-existing genetic polymorphisms can modify the metabolic network of folates and influence the risk of cancer, including childhood leukaemias. The protective effects of folic acid might be dose dependent, as excessive folic acid could have the adverse effect of nourishing certain types of tumours.

Conclusion: Overall, maternal folic acid supplementation before and during pregnancy seems to confer protection against the risk of childhood leukaemia in the offspring. The optimal folic acid requirements and supplementation doses need to be established, especially in conjunction with other vitamins in order to determine the most successful combinations of nutrients to maintain genomic health and wellbeing. Further research is therefore needed to uncover the role of maternal diet as a whole, as it represents a main factor capable of inducing permanent changes in the foetus.

Keywords: Cancer; Childhood leukaemia; DNA methylation; Folates; Folic acid; Genomic health.

Fig. 1

The relationship between folic acid deficiency and the genomic instability. Low levels of folic acid interfere with the normal biological functions of the cell, compromising the genomic stability for both nuclear and mitochondrial DNA. Folic acid deficiency affects the synthesis of nucleotides, causing DNA damage that cannot be repaired efficiently because of an overall decrease in the nucleotide availability. As methyl donors, the unavailability of folates can alter DNA methylation, causing changes in gene expression and compromising the integrity of chromosomes. Deprivation of folic acid also causes oxidative stress in the cell with consequences affecting the integrity of mitochondrial DNA

Fig. 2

Intracellular network of reactions in the metabolism of folates. A variety of related compounds derived from folic acid have specific biochemical functions. Folic acid is first converted into dihydrofolate (DHF) and subsequently into tetrahydrofolate (THF) by the enzyme DHF reductase (DHFR). 5,10-methyleneTHF and 10-formylTHF are responsible for the synthesis of purines; 5,10-methyleneTHF also mediates the conversion of dUMP to dTMP for the synthesis of thymidine, catalysed by the enzyme thymidine synthase (TS). 5-methylTHF is involved for methylation reactions, particularly in the conversion of homocysteine to methionine for the formation of SAM, a major methyl donor for DNA (figure taken from [6])

Fig. 3

Processes and consequences contributing to the genomic instability of the cell. Altered DNA synthesis, DNA repair and DNA methylation compromise the genomic stability of the cell. DNA damage and chromosomal abnormalities result from an incorrect assembly of DNA and the inability to repair errors efficiently, potentially affecting the next generation of cells or leading to cell death. If DNA methylation is disrupted, epigenetic changes affecting gene expression can occur, including incorrect methylation patterns or changes in chromatin structure

Fig. 4

Methylation can modify the expression of genes. Methylated regions upstream the start site of transcription are a signal of gene repression. Conversely, the absence of methylation promotes the transcription of the gene

Fig. 5

Multi-hit hypothesis for the insurgence of childhood leukaemia. The initiation of childhood leukaemia requires multiple oncogenic events to occur, with the first event occurring in utero and a second hit occurring after birth or later in life. The first event may be called the predisposing condition at the genomic level that is necessary but not sufficient for the insurgence of cancer. Leukaemia is initiated when a second event promotes abnormal cell proliferation

Fig. 6

Current recommendations for folic acid nutritional requirements per age. The Institute of Medicine (Food and Nutrition Board) determined the recommended daily assumption (RDA) and Estimated Average Requirements (EARs) for folate according to age and status. For infants (0–12 months), adequate intake (AI) is presented instead, as the influence of maternal nutrients can interfere with experimental evidence for RDA and EAR. During pregnancy and lactation, the requirements are higher, as the developing foetus needs high levels of folic acid. At doses above 200 μg, unmetabolised folate is detectable in plasma