Metabolomics of neonatal blood spots reveal distinct phenotypes of pediatric acute lymphoblastic leukemia and potential effects of early-life nutrition

Abstract

Early-life exposures are believed to influence the incidence of pediatric acute lymphoblastic leukemia (ALL). Archived neonatal blood spots (NBS), collected within the first days of life, offer a means to investigate small molecules that reflect early-life exposures. Using untargeted metabolomics, we compared abundances of small-molecule features in extracts of NBS punches from 332 children that later developed ALL and 324 healthy controls. Subjects were stratified by early (1-5 y) and late (6-14 y) diagnosis. Mutually-exclusive sets of metabolic features - representing putative lipids and fatty acids - were associated with ALL, including 9 and 19 metabolites in the early- and late-diagnosis groups, respectively. In the late-diagnosis group, a prominent cluster of features with apparent 18:2 fatty-acid chains suggested that newborn exposure to the essential nutrient, linoleic acid, increased ALL risk. Interestingly, abundances of these putative 18:2 lipids were greater in infants who were fed formula rather than breast milk (colostrum) and increased with the mother's pre-pregnancy body mass index. These results suggest possible etiologic roles of newborn nutrition in late-diagnosis ALL.

Keywords: Breastfeeding; Lipids; Maternal BMI; Pre-B ALL; t(12;21) translocation.

Figure 1.

Agglomerative hierarchical clustering using complete linkage and Spearman correlation (‘hclust’ function in R). Clusters of features predictive of (A) early diagnosis and (B) late diagnosis of ALL, with distinct clusters labeled C1-C6. Metabolites containing 18:2, 18:3 or 20:4 fatty acid chains are highlighted in red.

Figure 2.

Random Forest variable importance plots for (A) early diagnosis and (B) late diagnosis of ALL. BF duration, breastfeeding duration.

Figure 3.

Scatter plots with loess smoothing of feature abundances from cluster C3 that were correlated with breastfeeding (BF) duration (weeks) and mother’s pre-pregnancy body mass index (BMI, kg/m²).