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Lookup NU author(s): Dr Lisa RussellORCiD, Dr Kay Padget, Dr Jill McKay
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.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.
Author(s): Saville JR, Russell LJ, Padget K, Ghantous A, Nordlund J, McKay JA
Publication type: Article
Publication status: Published
Journal: International Journal of Cancer
Year: 2025
Volume: 157
Issue: 8
Pages: 1600-1612
Print publication date: 15/10/2025
Online publication date: 09/06/2025
Acceptance date: 22/05/2025
Date deposited: 23/06/2025
ISSN (print): 0020-7136
ISSN (electronic): 1097-0215
Publisher: John Wiley and Sons Inc
URL: https://doi.org/10.1002/ijc.35506
DOI: 10.1002/ijc.35506
Data Access Statement: Data sets utilized are in the public domain and included in the supplementary material. Further information is available from the corresponding author.
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