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Updated: Jun 9, 2025
Comprehensive DNA Methylation Analysis Using a Methyl-CpG-binding Domain Capture-based Method in Chronic Lymphocytic Leukemia Patients
Published on: June 16, 2017
Epigenome-wide analysis across the development span of pediatric acute lymphoblastic leukemia: backtracking to birth
Akram Ghantous1, Semira Gonseth Nusslé2, Farah J Nassar3
1Epigenomics and Mechanisms Branch, International Agency for Research on Cancer, (IARC), 25 avenue Tony Garnier, CS 90627, Lyon, Cedex 07 69366, France. GhantousA@iarc.who.int.
Insights
Epigenetic alterations at birth, specifically VTRNA2-1 hypermethylation, can predict pediatric pre-B acute lymphoblastic leukemia (pre-B ALL). This finding offers potential for early detection and novel therapeutic targets for childhood leukemia.
Area of Science:
- Pediatric oncology
- Epigenetics
- Molecular biology
Background:
- Childhood cancer, particularly leukemia, has unknown causes, with evidence suggesting in-utero origins.
- Global DNA methylation changes during fetal development are implicated in tissue differentiation and potentially in disease initiation.
Purpose of the Study:
- To investigate epigenome-wide DNA methylation patterns at birth as potential precursors to pediatric pre-B acute lymphoblastic leukemia (pre-B ALL).
- To identify early epigenetic biomarkers for pre-B ALL detection and prognosis.
Main Methods:
- Epigenome-wide DNA methylation profiling in blood and bone marrow tissues from pediatric pre-B ALL patients at various disease stages (birth, diagnosis, remission, relapse).
- Prospective and retrospective cohort analyses with validation using independent technologies and diverse populations.
- Correlation analysis between VTRNA2-1 methylation, gene expression, and patient survival.
Main Results:
- Hypermethylation of the imprinted VTRNA2-1 gene was detected at birth in pre-B ALL cases across different ancestries.
- VTRNA2-1 methylation levels correlated with disease status, increasing at diagnosis and relapse, and decreasing at remission.
- VTRNA2-1 hypermethylation was linked to reduced gene expression and poorer patient survival.
Conclusions:
- This study demonstrates the feasibility of detecting epigenetic precursors of pediatric pre-B ALL at birth.
- Identified VTRNA2-1 methylation alterations serve as reproducible biomarkers for early detection, prognosis, and potential therapeutic targets.
- Findings support the role of early-life epigenetic changes in the development of childhood leukemia.
Background:
Cancer is the leading cause of disease-related mortality in children. Causes of leukemia, the most common form, are largely unknown. Growing evidence points to an origin in-utero, when global redistribution of DNA methylation occurs driving tissue differentiation.
Methods:
Epigenome-wide DNA methylation was profiled in surrogate (blood) and target (bone marrow) tissues at birth, diagnosis, remission and relapse of pediatric pre-B acute lymphoblastic leukemia (pre-B ALL) patients. Double-blinded analyses was performed between prospective cohorts extending from birth to diagnosis and retrospective studies backtracking from clinical disease to birth. Validation was carried out using independent technologies and populations.
Results:
The imprinted and immuno-modulating VTRNA2-1 was hypermethylated (FDR<0.05) at birth in nested cases relative to controls in all tested populations (totaling 317 cases and 483 controls), including European and Hispanic ancestries. VTRNA2-1 methylation was stable over follow-up years after birth and across surrogate, target and other tissues (n=5,023 tissues; 30 types). When profiled in leukemic tissues from two clinical cohorts (totaling 644 cases), VTRNA2-1 methylation exhibited higher levels at diagnosis relative to controls, it reset back to normal levels at remission, and then re-increased to above control levels at relapse. Hypermethylation was significantly associated with worse pre-B ALL patient survival and with reduced VTRNA2-1 expression (n=2,294 tissues; 26 types), supporting a functional and translational role for VTRNA2-1 methylation.
Conclusion:
This study provides proof-of-concept to detect at birth epigenetic precursors of pediatric pre-B ALL. These alterations were reproducible with different technologies, in three continents and in two ethnicities, and can offer biomarkers for early detection and prognosis as well as actionable targets for therapy.
