Comprehensive Review Maps the cfDNA Fragmentome as a Multi-Feature Platform for Early Cancer Detection
This review catalogues the full spectrum of cell-free DNA fragment characteristics -- size, position, coverage, mutation, structural and methylation profiles -- collectively termed the 'cfDNA fragmentome'. The authors show how genome-wide fragmentation patterns reflect underlying genomic, epigenomic and chromatin states, and argue that multi-feature machine learning models integrating these signals can substantially improve early cancer detection sensitivity. The work positions fragmentomics as a complementary and potentially superior approach to targeted mutation or methylation-only liquid biopsy strategies.
The original study
Genomic and fragmentomic landscapes of cell-free DNA for early cancer detection.
- Authors
- Bruhm DC, Vulpescu NA, Foda ZH, Phallen J, Scharpf RB, Velculescu VE
- Journal
- Nature reviews. Cancer
- Type
- Journal Article, Review
- PMID
- 40038442
Original abstract
Genomic analyses of cell-free DNA (cfDNA) in plasma are enabling noninvasive blood-based biomarker approaches to cancer detection and disease monitoring. Current approaches for identification of circulating tumour DNA typically use targeted tumour-specific mutations or methylation analyses. An emerging approach is based on the recognition of altered genome-wide cfDNA fragmentation in patients with cancer. Recent studies have revealed a multitude of characteristics that can affect the compendium of cfDNA fragments across the genome, collectively called the 'cfDNA fragmentome'. These changes result from genomic, epigenomic, transcriptomic and chromatin states of an individual and affect the size, position, coverage, mutation, structural and methylation characteristics of cfDNA. Identifying and monitoring these changes has the potential to improve early detection of cancer, especially using highly sensitive multi-feature machine learning approaches that would be amenable to broad use in populations at increased risk. This Review highlights the rapidly evolving field of genome-wide analyses of cfDNA characteristics, their comparison to existing cfDNA methods, and recent related innovations at the intersection of large-scale sequencing and artificial intelligence. As the breadth of clinical applications of cfDNA fragmentome methods have enormous public health implications for cancer screening and personalized approaches for clinical management of patients with cancer, we outline the challenges and opportunities ahead.