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Early-life factors and epigenetic precursors of childhood leukemia

  • Novoloaca, Alexei
Publication Date
Jun 22, 2020
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Childhood cancer (CC) is the leading cause of disease-related mortality in children, with childhood leukemia (CL) being the predominant type. CC is rare, and its risk factors and molecular precursors are poorly understood and may originate in utero. Fetal life represents a sensitive period during which epigenetic regulation constitutes heritable mechanisms driving embryogenesis. We hypothesize that epigenetic (DNA methylation) deregulation in utero underlies biological pathways linking early-life factors to CL. We focus on birthweight, as a collective proxy for early-life exposure and one of the earliest phenotypes predisposing to CL, as well as its closely related intrinsic factors, gestational age and child sex. We first performed epigenome-wide analysis with optimized biostatistics methodology in large population-based cohorts and found profound associations between each of the three factors and cord blood DNA methylome. Second, we investigated, in a subset of cohorts enriched in CL cases, whether the identified birthweight biomarkers significantly associate with cancer risk and are affected by gestational age and child sex. Third, we tested the proportion by which DNA methylation mediates the effect between birthweight and CL. These steps constitute a proposed ‘three-way modelling’ aiming to identify molecular mechanisms linking early-life exposure to CC risk. This work identified epigenetics markers of early-life factors based on some of the largest studies to date, yielding insights into epigenetic deregulation in utero that could be at the origin of CL. The described framework could be useful for other exposure-outcome studies investigating underlying molecular mechanisms

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