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

Scope: Inadequate maternal folate intake is associated with increased childhood acute lymphoblastic leukaemia (ALL) risk. Folate provides methyl groups for DNA methylation, which is dramatically disrupted in ALL. We investigated if maternal folate (and related B-vitamin) intake during pregnancy may affect ALL risk via influencing DNA methylation.

Methods and Results: We identified genes in which methylation changes were reported both in response to folate status and in ALL. Folate-responsive genes (n=526) were identified from mouse models of maternal folate depletion during pregnancy. Using published data, we identified 2621 genes with persistently altered methylation in ALL. Twenty-five overlapping genes were found, with the same directional methylation change in response to folate depletion and in ALL. We confirmed hypermethylation of a subset of genes (ASCL2, KCNA1, SH3GL3, SRD5A2) in ALL by measuring 20 patient samples using pyrosequencing. In a nested cohort of cord blood samples (n=148), SH3GL3 methylation was inversely related to maternal RBC folate concentrations (p=0.008). Furthermore, ASCL2 methylation was inversely related to infant vitamin B₁₂ levels. (p=0.016).

Conclusion: 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.