Cell-free DNA fragmentomics and epigenomic profiling in hematologic malignancies: current evidence, translational limitations, and future directions
10 affiliations
- 1Internal Medicine, Diabetes, Endocrinology and Metabolism, Mansoura University, Mansoura, Egypt
- 2Department of Pharmacy, Al- Mustafa University, Baghdad, Iraq
- 3Scientific-Practical Medical Center for Pediatric Oncology, Hematology and Immunology, Tashkent, Uzbekistan
- 4Department of Public Health and Healthcare MANAGement, Rector, Samarkand State Medical University, Samarkand, Uzbekistan
- 5King Khalid University, Department of Microbiology and Clinical Parasitology, Saudi Arabia
- 6Department of General Medicine, Sharda University, Knowledge Park III, Greater Noida, India
- 7Department of pharmacy, Al- Mustafa University, Baghdad, Iraq
- 8College of Applied Sciences, University of Technology, Baghdad, Iraq
- 9University Institute of Pharma Sciences, Chandigarh University, Mohali, Punjab, India
- 10Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Amman, 19328, Jordan
Abstract
Mutation-based liquid biopsy supports diagnosis and disease monitoring in hematologic malignancies, but interpretation of plasma variants may be complicated by clonal hematopoiesis, treatment-related changes, and nonmalignant blood-cell turnover. This structured narrative review evaluates whether cell-free DNA (cfDNA) fragmentomics, DNA methylation, and 5-hydroxymethylcytosine (5hmC) provide complementary information beyond mutation detection. Direct plasma evidence is most developed for selected fragmentomic and 5hmC applications, although most studies remain retrospective, internally validated, or proof of concept. Fragmentomic studies have reported associations with lymphoma classification, outcome assessment, and longitudinal tumor–effector profiling during chimeric antigen receptor T-cell therapy, but routine clinical utility and decision thresholds are not established. Plasma 5hmC studies have reported associations with lymphoma classification, treatment response, prognosis, and measurable residual disease in acute myeloid leukemia, whereas pharmacodynamic monitoring during Bruton’s tyrosine kinase inhibition remains hypothesis-generating. DNA methylation may support source-cell or lineage inference, but lineage assignment does not establish malignant fraction, and key disease-assessment studies remain largely tissue-based, cellular-DNA-based, cross-cancer, or methodological. The novelty of this review is a structured evidence map that distinguishes direct plasma evidence from indirect support and compares the three modalities by biological information, assay compatibility, and validation maturity. We also propose a hypothesis-generating framework for sample-level integration using separate assay-specific aliquots and computational combination of outputs. No universal analytical order or clinically validated integrated workflow has been established. Fragmentomic and epigenomic profiling should therefore be regarded as investigational complements to mutation-based testing, requiring independent prospective validation against established genomic, cellular, imaging, and tissue-based methods.
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BibTeX
@article{elsehrawy2026cellfree,
title = {{Cell-free DNA fragmentomics and epigenomic profiling in hematologic malignancies: current evidence, translational limitations, and future directions}},
author = {Amr Ali Mohamed Abdelgawwad El-Sehrawy and Sarmad S. Abdullah and Guzalya Mamedova and Jasur Rizaev and Ihab M. Abdelrahim and Shrey Kumar Srivastav and Zeina T. Khaleel and Majid S. Jabir and Neeraj Bainsal and Aseel Smerat},
journal = {Translational Oncology},
year = {2026},
month = oct,
doi = {10.1016/j.tranon.2026.103080},
url = {https://doi.org/10.1016/j.tranon.2026.103080},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Cell-free DNA fragmentomics and epigenomic profiling in hematologic malignancies: current evidence, translational limitations, and future directions
AU - Amr Ali Mohamed Abdelgawwad El-Sehrawy
AU - Sarmad S. Abdullah
AU - Guzalya Mamedova
AU - Jasur Rizaev
AU - Ihab M. Abdelrahim
AU - Shrey Kumar Srivastav
AU - Zeina T. Khaleel
AU - Majid S. Jabir
AU - Neeraj Bainsal
AU - Aseel Smerat
PY - 2026
DA - 2026/10/16
JO - Translational Oncology
DO - 10.1016/j.tranon.2026.103080
UR - https://doi.org/10.1016/j.tranon.2026.103080
AB - Mutation-based liquid biopsy supports diagnosis and disease monitoring in hematologic malignancies, but interpretation of plasma variants may be complicated by clonal hematopoiesis, treatment-related changes, and nonmalignant blood-cell turnover. This structured narrative review evaluates whether cell-free DNA (cfDNA) fragmentomics, DNA methylation, and 5-hydroxymethylcytosine (5hmC) provide complementary information beyond mutation detection. Direct plasma evidence is most developed for selected fragmentomic and 5hmC applications, although most studies remain retrospective, internally validated, or proof of concept. Fragmentomic studies have reported associations with lymphoma classification, outcome assessment, and longitudinal tumor–effector profiling during chimeric antigen receptor T-cell therapy, but routine clinical utility and decision thresholds are not established. Plasma 5hmC studies have reported associations with lymphoma classification, treatment response, prognosis, and measurable residual disease in acute myeloid leukemia, whereas pharmacodynamic monitoring during Bruton’s tyrosine kinase inhibition remains hypothesis-generating. DNA methylation may support source-cell or lineage inference, but lineage assignment does not establish malignant fraction, and key disease-assessment studies remain largely tissue-based, cellular-DNA-based, cross-cancer, or methodological. The novelty of this review is a structured evidence map that distinguishes direct plasma evidence from indirect support and compares the three modalities by biological information, assay compatibility, and validation maturity. We also propose a hypothesis-generating framework for sample-level integration using separate assay-specific aliquots and computational combination of outputs. No universal analytical order or clinically validated integrated workflow has been established. Fragmentomic and epigenomic profiling should therefore be regarded as investigational complements to mutation-based testing, requiring independent prospective validation against established genomic, cellular, imaging, and tissue-based methods.
SN - 1936-5233
ER -