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Background Cancer is the leading cause of disease-related mortality in children. Causes of leukemia, the most common form, are largely unknown. Growing evidence points to an origin in-utero , when global redistribution of DNA methylation occurs driving tissue differentiation. Methods Epigenome-wide DNA methylation was profiled in surrogate (blood) and target (bone marrow) tissues at birth, diagnosis, remission and relapse of pediatric pre-B acute lymphoblastic leukemia (pre-B ALL) patients. Double-blinded analyses was performed between prospective cohorts extending from birth to diagnosis and retrospective studies backtracking from clinical disease to birth. Validation was carried out using independent technologies and populations. Results The imprinted and immuno-modulating VTRNA2-1 was hypermethylated (FDR<0.05) at birth in nested cases relative to controls in all tested populations (totaling 317 cases and 483 controls), including European and Hispanic ancestries. VTRNA2-1 methylation was stable over follow-up years after birth and across surrogate, target and other tissues ( n =5,023 tissues; 30 types). When profiled in leukemic tissues from two clinical cohorts (totaling 644 cases), VTRNA2-1 methylation exhibited higher levels at diagnosis relative to controls, it reset back to normal levels at remission, and then re-increased to above control levels at relapse. Hypermethylation was significantly associated with worse pre-B ALL patient survival and with reduced VTRNA2-1 expression ( n =2,294 tissues; 26 types), supporting a functional and translational role for VTRNA2-1 methylation. Conclusion This study provides proof-of-concept to detect at birth epigenetic precursors of pediatric pre-B ALL. These alterations were reproducible with different technologies, in three continents and in two ethnicities, and can offer biomarkers for early detection and prognosis as well as actionable targets for therapy. Key points • Precursors of pediatric acute lymphoblastic leukemia may be of epigenetic origin, detectable since birth and affecting patient prognosis. • These epigenetic precursors can be robust over several years and across several populations, ethnicities and surrogate and target tissues.

Introduction This study determined whether blood DNA methylation (DNAm) patterns differentiate individuals with presymptomatic dementia compared to controls. Methods DNAm was measured in 73 individuals prior to dementia diagnosis and 87 cognitively healthy controls matched for age, sex, smoking, education, and baseline cognition. DNAm was also measured at 3 years follow‐up in 25 dementia cases, and 24 controls. Results Cases and controls differed in DNAm (unadjusted P < .01) at the time of diagnosis (n = 28,787 probes), and pre‐diagnosis (n = 15,111 probes), with cg01404610 (General transcription factor IIA subunit 1 gene) significant after correction for multiple testing. Overall, 1150 probes overlapped between analyses (methylation differences from –10.6% to +11.0%), and effect sizes increased from pre‐diagnosis to diagnosis. Discussion Discernible blood DNAm signatures are in dementia cases before the appearance of overt clinical symptoms. Blood‐based methylation may serve as a potential biomarker of dementia, but further investigation is needed to determine their true clinical utility.