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

SIMPLE SUMMARY: Leukemia is the most frequent cancer in children. While cure rates have improved, many children will not survive, and of those who do, the majority experience lifelong complications. As a result, understanding what increases or decreases the risk of leukemia is important to inform prevention. Following on earlier observations that taking B-vitamins (such as folate) before and during pregnancy reduces the risk of childhood leukemia, we conducted a study to directly measure 11 nutrients in the folate metabolism pathway that is central to DNA integrity. These measurements were done in blood samples collected at birth among 122 children with leukemia and 122 healthy children, using novel laboratory techniques. Our data showed that none of these nutrients measured at birth (therefore representing levels within the last weeks of pregnancy) distinguished children who later contracted childhood leukemia. Whether levels of these nutrients may be important at the time of conception or during the first trimester, which are critical periods for fetal development, should be further investigated. 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.