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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE308517 | GEO | 2025/09/26

REPOSITORIES: GEO

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Project description:Background: It is well-established that cancer treatment substantially increases risk of long-term adverse health outcomes among childhood cancer survivors. However, there is limited research on the underlying mechanisms. To elucidate the pathophysiology and a possible causal pathway from treatment exposures to cardiometabolic conditions, we conducted epigenome-wide association studies (EWAS) to identify DNA methylation (DNAm) sites associated with cancer treatment exposures and examined whether treatment-associated DNAm sites mediate associations between specific treatments and cardiometabolic conditions. Methods: We included 2,052 survivors (median age 33.7 years) of European ancestry from the St. Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Cumulative doses of chemotherapy and region-specific radiation were abstracted from medical records. Seven cardiometabolic conditions were clinically assessed. DNAm profile was measured using MethylationEPIC BeadChip with blood-derived DNA. Results: By performing multiple treatment-specific EWAS, we identified 935 5’-cytosine-phosphate-guanine-3′ (CpG) sites mapped to 538 genes/regions associated with one or more cancer treatments at epigenome-wide significance level (P<9×10-8). Among the treatment-associated CpGs, 8 were associated with obesity, 63 with hypercholesterolemia, and 17 with hypertriglyceridemia (False-Discovery-Rate-Adjusted P<0.05). We observed substantial mediation by methylation at four independent CpGs (cg06963130, cg21922478, cg22976567, cg07403981) for association between abdominal field radiotherapy (abdominal-RT) and risk of hypercholesterolemia (70.3%) and by methylation at three CpGs (cg19634849, cg13552692, cg09853238) for association between abdominal-RT and hypertriglyceridemia (54.6%). In addition, three CpGs (cg26572901, cg12715065, cg21163477) partially mediated the association between brain-RT and obesity with 32.9% mediation effect and two CpGs mediated the association between corticosteroids and obesity (cg22351187, 14.2%) and between brain-RT and hypertriglyceridemia (cg13360224, 10.5%). Notably, several mediator CpGs reside in the proximity of well-established dyslipidemia genes: cg21922478 (ITGA1) and cg22976567 (LMNA). Conclusions: In childhood cancer survivors, cancer treatment exposures are associated with DNAm patterns present decades following the exposure. Treatment-associated DNAm sites may mediate the causal pathway from specific treatment exposures to certain cardiometabolic conditions, suggesting the utility of DNAm sites as risk predictors and potential mechanistic targets for future intervention studies.

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

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