DNA methylation alterations in acute lymphoblastic leukemia survivors with late neurocognitive deficits: PETALE cohort

Many survivors of acute lymphoblastic leukemia (ALL) develop late effects that include lifelong impairments in cognitive function. We examined DNA methylation (DNAm) patterns in healthy blood from two independent cohorts of ALL survivor to 1) identify distinct genome-wide DNAm alterations (signatures) in survivors, and establish long-term epigenetic dysregulation as a common outcome of ALL treatment, and 2) elucidate the role of epigenetics as a biomarker and potential mechanism of neurocognitive deficits in ALL survivors. We identified a signature of 452 CpG sites in the blood of ALL survivors vs. controls, that demonstrated ~99% sensitivity and 85% specificity, irrespective of time elapsed from the end of treatment. Using St. Jude LIFE as a validation cohort, we found that survivors of non-ALL childhood cancers carried a different DNAm signature. Finally, we found 43 distinct CpGs associated with neurocognitive deficits as defined by the neuropsychological test, DIVERGT, that replicated across our two cohorts of ALL survivors. We propose DNAm as a potential biomarker that could predict patients most likely to experience neurocognitive deficits following ALL treatment and inform early interventions. Venous blood samples were collected from ALL survivors participating in the PETALE study, at least five years after the diagnosis of ALL. Genomic DNA was extracted, bisulfite converted and DNA methylation was assayed on the Infinium MethylationEPIC Bead Chip array (GPL21145). Healthy controls described in the associated publication are not included here due to lack of consent for public deposition of data. There are no replications in this submission.