Childhood leukaemia cytogenetic subtypes vs. environmental risk factors: a ‘meet in the middle’ approach exploring the role of DNA methylation.

Acute lymphoblastic leukaemia (ALL) accounts for a quarter of childhood cancers. Various abnormalities have been retrospectively detected at birth and used to categorise childhood ALL into cytogenetic subtypes. These mutations alone are not sufficient for disease onset, and epigenetic modifications, such as DNA methylation, could play a role in leukaemia development, with altered DNA methylation patterns found across different subtypes. Epidemiological studies have identified various environmental exposures associated with increased risk of ALL, such as radiation, maternal nutrition, and smoking, which also show altered methylation in response to exposure.

Using the “meet in the middle” approach, published date was used to compare CpG methylation changes for 10 ALL cytogenetic subtypes to methylation changes associated with response to ALL risk factors. Concordant overlapping CpGs were determined as significant using hypergeometric probability tests, followed by KEGG pathway analysis and gene ontology conducted via RStudio.

Statistically significant overlaps were found for radiation with MLL, alcohol with T-ALL or ETV6-RUNX1, smoking throughout pregnancy with MLL or undefined subtypes, reported cold with MLL, and folic acid supplementation with 8 ALL subtypes. In CpGs common across all subtypes, significant concordant overlaps were seen with radiation and alcohol. This reflects previously published analysis performed at the gene loci level.

This data suggests that altered methylation found in response to environmental-risk exposures may play a role in the development of some ALL cytogenetic subtypes over others. Understanding the relationship between ALL subtypes and risk-factors informs growing evidence towards limiting these exposures with the aim of preventing childhood leukaemia.