The potential role of environmentally associated DNA methylation in childhood acute lymphoblastic leukaemia subtypes

Various genetic aberrations are suggested to initiate the development of acute lymphoblastic leukaemia (ALL) but alone are insufficient for disease onset. Epigenetic alteration, such as DNA methylation changes, plays a key role in human health. Evidence suggests DNA methylation may be an intermediate mechanism through which the environment contributes to ALL manifestation. ALL is categorized into subtypes based on leukaemia-associated genetic events, and it is plausible that different exposures pose differing risks for given subtypes. Using our previously established meet-in-the-middle approach, we performed CpG-level analysis to investigate DNA methylation as an intermediate mechanism between risk exposures and ALL. Differentially methylated CpGs (DMCs) were integrated, identifying overlapping methylation, with hypergeometric tests used to assess the probability of concurring methylation considering directionality. DMC analysis reinforced previous gene-level findings suggesting altered DNA methylation associated with maternal radiation exposure, alcohol intake, and plasma folate during pregnancy is also present in the disease. Whilst maternal folate-associated and leukaemia-associated methylation appear consistent across most subtypes, the effect of other exposures appears subtype-specific. We suggest environmentally associated methylation includes driver and/or 'navigator' changes, the latter influencing biological pathways contributing to ALL. This analysis aids understanding of which risk factors may contribute to specific subtypes or which influence ALL risk more generally.