One-Carbon (Folate) Metabolism Pathway at Birth and Risk of Childhood Acute Lymphoblastic Leukemia: A Biomarker Study in Newborns

Abstract

Leukemia is the most common cancer in children in industrialized countries, and its initiation often occurs prenatally. Folic acid is a key vitamin in the production and modification of DNA, and prenatal folic acid intake is known to reduce the risk of childhood leukemia. We characterized the one-carbon (folate) metabolism nutrients that may influence risk of childhood acute lymphoblastic leukemia (ALL) among 122 cases diagnosed at age 0–14 years during 1988–2011 and 122 controls matched on sex, age, and race/ethnicity. Using hydrophilic interaction chromatography (HILIC) applied to neonatal dried blood spots, we evaluated 11 folate pathway metabolites, overall and by sex, race/ethnicity, and age at diagnosis. To conduct the prediction analyses, the 244 samples were separated into learning (75%) and test (25%) sets, maintaining the matched pairings. The learning set was used to train classification methods which were evaluated on the test set. High classification error rates indicate that the folate pathway metabolites measured have little predictive capacity for pediatric ALL. In conclusion, the one-carbon metabolism nutrients measured at birth were unable to predict subsequent leukemia in children. These negative findings are reflective of the last weeks of pregnancy and our study does not address the impact of these nutrients at the time of conception or during the first trimester of pregnancy that are critical for the embryo’s DNA methylation programming.

Recommendations for Nutritional Supplementation in Pediatric Oncology: A Compilation of the Facts

“…VitB6 participates in the transformation of carbohydrates, lipids, amino acids, and nucleic acids and is required for the synthesis of neurotransmitters. Its potential relevance to carcinogenesis and tumor growth has been discussed, as have associations between maternal intake and a decreased risk for the development of childhood ALL [ 37 , 38 , 82 , 83 , 84 ].…”

“…Because of its role in the synthesis of purine and pyrimidine and in the DNA repair mechanism, folate (VitB9) is especially important during phases of rapid cell growth. As a cofactor in many single-carbon transfer reactions, VitB9 participates in multiple important reactions such as DNA methylation, amino acid homeostasis, and redox defense [ 82 , 85 , 86 ]. Reduced folate levels are held accountable for chromosomal breaks due to the massive incorporation of uracil into human DNA.…”

Emerging Role of Folate-Mediated One Carbon Metabolism in Leukemia: A Review

“…Homocysteine is a metabolite closer to DNA methylation in the one-carbon cycle, and higher levels have been linked to several malignancies in adults. This is because of the inverse connection between homocysteine concentration and folate status (Metayer et al 2023). The link between folate metabolism and cancer was established for the first time when it was discovered that folic acid promoted cancer growth.…”