The impact of periconceptional folate on the DNA methylome of acute lymphoblastic leukemia

Periconceptional folate intake decreases the risk of pediatric acute lymphoblastic leukemia (ALL); however, the mechanism is not fully understood. We sought to identify sites of DNA methylation measured at birth both responsive to periconceptional folate and associated with lymphoblasts at the time of ALL diagnosis in a "meet in the middle" analysis. Folate-associated differentially methylated regions (DMRs) were identified from retrospectively collected periconceptional maternal folate intake (by dietary source) and epigenome-wide DNA methylation status from archived dried neonatal blood spots for 189 ALL cases and 205 healthy matched controls from the California Childhood Leukemia Study (1995-2008). Folate and lymphoblast-associated DMRs overlapped at 17 sites related to total folate intake, 13 for folate from food, 10 for natural foods, 13 for fortified foods and 18 for folate-containing supplements. The majority of overlapping DMRs were in a concordant direction of effect for supplemental folate (16/18, P = 0.001). Opposite direction of effect was identified among lower income participants for food (3/19, P = 0.004) and natural folate (5/37, P < 0.001), the latter of which was specific to Hispanic participants of low-income (9/31, P = 0.029). These results indicate that dietary folate, in particular from natural food sources, may reduce risk of ALL through modulation of early DNA methylation patterns.