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 featuresrepresenting 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.

Filtering procedures for untargeted LC-MS metabolomics data

“…When working with untargeted LC-MS data, visualization of extracted ion chromatograms (EIC) of features can be used to optimize peak detection, peak quantification, and biomarker discovery [8, 15, 16]. We propose randomly sampling several hundred EICs after peak detection and quantification to visualize peak morphology and integration.…”

“…An application of the data-adaptive pipeline to another untargeted LC-HRMS metabolomics dataset generated in our laboratory can be found in Additional file 1. This additional dataset represents the metabolomes of 4.7-mm punches from archived neonatal blood spots (NBS) of 309 incident case subjects that were obtained for the California Childhood Leukemia Study [15, 18]. For the sake of clarity, we do not include results for this second dataset in the main text, and the results can be found instead in Additional file 1.…”

Lipid peroxidation derived reactive carbonyl species in free and conjugated forms as an index of lipid peroxidation: limits and perspectives

“…Rappaport Petrick et al performed an untargeted adductomics in a population-based case-control study to identify HSA-Cys34 adducts associated with childhood leukemia. Acute lymphoblastic leukemia patients had higher abundances of adducts of RCS, suggestive of oxidative stress and LPO as potentially etiologic factors [ 93 ]. The method was then applied to detect Cys34 adducts in colorectal cancer cases and controls, two of these adducts were Cys34 modifications by methanethiol, a microbial–human cometabolite, and crotonaldehyde, a product of LPO [ 94 ].…”

Diet as a Potential Moderator for Genome Stability and Immune Response in Pediatric Leukemia

“…Thus, it would be fair to hypothesize that breastmilk also impacts disease susceptibility, especially in a disease of the immune system, such as leukemia. Indeed, a recent metabolomics analysis on neonatal blood spots found that patients that went on to develop early (ages 1–5) and late (ages 6–14) leukemia, had distinct metabolomic profiles [ 34 ]. The study revealed that the presence of certain fatty acids, several of which were related to breastmilk, breastfeeding duration (reduced risk), and maternal body mass index (BMI) (increased risk), could influence risk of early and late leukemia incidence [ 34 ].…”