DNA methylation at birth in monozygotic twins discordant for pediatric acute lymphoblastic leukemia

Abstract

Aberrant DNA methylation constitutes a key feature of pediatric acute lymphoblastic leukemia at diagnosis, however its role as a predisposing or early contributor to leukemia development remains unknown. Here, we evaluate DNA methylation at birth in 41 leukemia-discordant monozygotic twin pairs using the Illumina EPIC array on archived neonatal blood spots to identify epigenetic variation associated with development of pediatric acute lymphoblastic leukemia, independent of genetic influence. Through conditional logistic regression we identify 240 significant probes and 10 regions associated with the discordant onset of leukemia. We identify a significant negative coefficient bias, indicating DNA hypomethylation in cases, across the array and enhanced in open sea, shelf/shore, and gene body regions compared to promoter and CpG island regions. Here, we show an association between global DNA hypomethylation and future development of pediatric acute lymphoblastic leukemia across disease-discordant genetically identical twins, implying DNA hypomethylation may contribute more generally to leukemia risk.

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

“…Childhood ALL exhibits a peak in incidence at the age of 2-5 years, and several experiments have demonstrated that chromosomal abnormalities detected at diagnostic were also identified at birth (such as ETV6-RUNX1, RUNX1-RUNX1T1, and PML-RARA gene fusions, as well as high hyperdiploidy), providing strong support to the prenatal origin of many childhood leukemia subtypes [4][5][6][7][8]. In addition, a recent study on discordant twins for ALL supports a role for DNA methylation alterations in utero impacting leukemogenesis [9]; such DNA methylation patterns may be influenced by periconceptional nutrients including folate [10]. In epidemiologic studies using interview data, prenatal folic acid and vitamin intake from dietary sources and supplementation [11][12][13][14][15] has consistently emerged as a protective factor for childhood leukemia.…”

Epigenomic insights into common human disease pathology

“…Analysis of the DNA methylome by Illumina EPIC v1 DNAm array derived from the archived neonatal blood spots from MZ twins discordant for paediatric acute lymphoblastic leukaemia (ALL) (n = 41 pairs) revealed 240 DMCs and 10 DMRs consistently associated with ALL risk [ 298 ]. The top four DMCs were validated by methylation-specific droplet digital PCR, with a region overlapping TRIM39 - RPP21 being most significant.…”