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Cell-Free DNA-Derived Immune Cell Ratios Uncover Cancer-Associated Systemic Changes.

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|March 25, 2026
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Plasma cell-free DNA (cfDNA) analysis reveals immune cell changes in cancer patients. These cfDNA immune signatures can help distinguish colorectal and bladder cancer patients from healthy individuals, offering a potential non-invasive biomarker.

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Area of Science:

  • Genomics
  • Immunology
  • Cancer Research

Background:

  • Plasma cell-free DNA (cfDNA) fragment patterns reflect cellular origins and transcriptional activity.
  • The contribution of hematopoietic cells to cfDNA is significant but underexplored.
  • cfDNA analysis offers a non-invasive window into biological processes.

Purpose of the Study:

  • To deconvolve blood cell-type contributions to plasma cfDNA using transcription start site (TSS) coverage.
  • To correlate cfDNA TSS profiles with single-cell transcriptomic data across diverse blood cell types.
  • To investigate cfDNA-derived immune signatures in colorectal cancer (CRC) and muscle-invasive bladder cancer (MIBC) patients.

Main Methods:

  • Integrated plasma whole-genome sequencing cfDNA TSS coverage with single-cell transcriptomic reference data.
  • Correlated cfDNA TSS coverage with gene expression across 457 blood cell types to rank contributions.
  • Analyzed 788 plasma samples from CRC and MIBC patients and 30 healthy controls.

Main Results:

  • In healthy individuals, cfDNA profiles mirrored blood gene expression and hematopoietic composition.
  • Cancer patients showed increased cfDNA contributions from lymphocytes (T cells, plasma cells) and decreased contributions from monocytes and granulocytes.
  • Immune-derived cfDNA signatures differentiated CRC (AUC=0.793) and MIBC (AUC=0.745) patients from controls.
  • Longitudinal analysis showed treatment-associated changes in monocyte and plasma cell cfDNA contributions, but these were not predictive of outcomes.

Conclusions:

  • cfDNA-derived immune signatures reflect systemic immune remodeling in cancer.
  • These signatures may serve as complementary non-invasive biomarkers in liquid biopsies.
  • Further research could explore the clinical utility of cfDNA immune profiling beyond tumor-derived signals.