Maternal Red Blood Cell Folate and Infant Vitamin B12 Status Influence Methylation of Genes Associated with Childhood Acute Lymphoblastic Leukemia.

Abstract

Inadequate maternal folate intake is associated with increased childhood acute lymphoblastic leukemia (ALL) risk. Folate provides methyl groups for DNA methylation, which is dramatically disrupted in ALL. Whether or not maternal folate (and related B-vitamin) intake during pregnancy may affect ALL risk via influencing DNA methylation is investigated. Genes in which methylation changes are reported both in response to folate status and in ALL are investigated. Folate-responsive genes (n=526) are identified from mouse models of maternal folate depletion during pregnancy. Using published data, 2621 genes with persistently altered methylation in ALL are identified. Overall 25 overlapping genes are found, with the same directional methylation change in response to folate depletion and in ALL. Hypermethylation of a subset of genes (ASCL2, KCNA1, SH3GL3, SRD5A2) in ALL is confirmed by measuring 20 patient samples using pyrosequencing. In a nested cohort of cord blood samples (n=148), SH3GL3 methylation is inversely related to maternal RBC folate concentrations (p=0.008). Furthermore, ASCL2 methylation is inversely related to infant vitamin B12 levels. (p=0.016). Findings demonstrate proof of concept for a plausible mechanism, i.e., variation in DNA methylation, by which low intake of folate, and related B-vitamins during pregnancy may influence ALL risk.