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  • cfDNA Methylation in Liquid Biopsy: Current Perspectives and Future Directions for Early Cancer Detection

  • Darya kargar najafi,1,*
    1. Department of Genetics, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran


  • Introduction: Cancer remains the leading cause of death worldwide,and early detection is critical to improving treatment outcomes and reducing mortality.Conventional diagnostics often fail to identify disease at a stage when intervention is most effective. Liquid biopsy offers a minimally invasive, highly sensitive means of detecting tumor derived signals from the bloodstream
  • Methods: Cell free DNA, or cfDNA, is released into circulation through apoptotic and necrotic cell death. Its tumor derived subset, circulating tumor DNA or ctDNA, carries the genetic and epigenetic signature of its cell of origin. Early efforts focused on detecting cancer associated mutations, with detection limits as low as 0.1 percent for point mutations and 3 percent for copy number alterations, but the diversity of cancer mutations has limited development of a single reliable mutation based test DNA methylation has filled this gap. Aberrant methylation arises early in tumorigenesis, persists throughout disease progression, and disrupts genes governing cell growth and tumor suppression. Because methylation patterns often retain tissue specific signatures after oncogenic transformation, they allow identification of a tumor's tissue of origin, or TOO, particularly valuable for cancers that are difficult to diagnose early
  • Results: cfDNA methylation profiles can distinguish cancer patients from healthy individuals, underlying multi cancer early detection, or MCED. One MCED test is already commercially available, with several others in development. ctDNA fragments also tend to be shorter than cfDNA from non malignant cells, adding another layer of diagnostic information. Tumor derived cfDNA is typically present in low abundance, and tumor heterogeneity, individual biological variation, age, and lifestyle factors can alter methylation patterns and reduce diagnostic accuracy. Technical inconsistencies in sample collection, extraction, sequencing, and analysis further affect reproducibility across studies.
  • Conclusion: Long read sequencing, pharmacological strategies to boost cfDna abundance, and polygenic risk scores, or PRS, may help address these limitations, particularly for hereditary cancer syndromes, or HCS, an area with limited existing evidence compared to sporadic cancers. Improving sensitivity and reproducibility of methylation based assays will be essential to translating cfDNA methylation into a reliable clinical liquid biopsy strategy.
  • Keywords: cell free DNA; DNA methylation; Liquid biopsy; Circulating tumor DNA; Early cancer detection

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