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Background <p>The aggregate presence of cell free CTCF-DNA (cfCTCF-DNA) nucleoproteins in plasma has been reported. But the occupancy of individual CTCF binding sites in plasma cfCTCF-DNA has not been studied.</p> Results <p>For the first time, we have isolated endogenous plasma cfCTCF-DNA by chromatin immunoprecipitation (ChIP) and sequenced the associated cfDNA (ChIP-Seq) in samples from cancer patients and healthy subjects. The mean observed enrichment of plasma cfCTCF-DNA by ChIP was 180-fold with a mean CTCF recovery of 48%. Background cfDNA, primarily in the form of nucleosomes, was almost completely physically removed (&gt; 99.7%) by ChIP and the remainder was removed bioinformatically. cfCTCF-DNA sequences were partitioned into low or high affinity binding cfCTCF-DNA nucleoproteins in silico, on the basis of binding motif concordance with the consensus CTCF binding motif. We observed that cfCTCF-DNA was quantitatively and qualitatively different in samples from healthy subjects or cancer patients. High affinity cfCTCF-DNA nucleoproteins were present only in the plasma of cancer patients and not in samples from healthy subjects. Testing of small developmental and validation sample cohorts for ChIP-seq peaks for a 14 member panel of high affinity CTCF loci sequences, showed excellent specificity and sensitivity for cancer detection.</p> Conclusions <p>Plasma sequence data sets comprising &gt; 99% pure CTCF protected ctDNA can be prepared using a 2-step process involving the physical removal of most background cfDNA in vitro, followed by removal of all remaining background cfDNA in silico. CTCF plasma ChIP-seq represents a novel liquid biopsy method for a novel class of liquid biopsy biomarkers.</p>

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Direct analysis of transcription factor protected cfDNA in plasma by ChIP-seq: measurement of altered CTCF binding in cancer is a novel biomarker for liquid biopsy

  • 期刊论文

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  • 发表日期：

    2026年7月21日

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  • Dorian Pamart,
  • Brieuc Cuvelier,
  • Adrien Govaerts,
  • Muriel Chapelier,
  • Marielle Herzog,
  • Andrew Retter,
  • Thomas Bygott,
  • Jean-Valery Turatsinze,
  • Benjamin P. Berman,
  • Jacob Micallef

摘要

Background

The aggregate presence of cell free CTCF-DNA (cfCTCF-DNA) nucleoproteins in plasma has been reported. But the occupancy of individual CTCF binding sites in plasma cfCTCF-DNA has not been studied.

Results

For the first time, we have isolated endogenous plasma cfCTCF-DNA by chromatin immunoprecipitation (ChIP) and sequenced the associated cfDNA (ChIP-Seq) in samples from cancer patients and healthy subjects. The mean observed enrichment of plasma cfCTCF-DNA by ChIP was 180-fold with a mean CTCF recovery of 48%. Background cfDNA, primarily in the form of nucleosomes, was almost completely physically removed (> 99.7%) by ChIP and the remainder was removed bioinformatically. cfCTCF-DNA sequences were partitioned into low or high affinity binding cfCTCF-DNA nucleoproteins in silico, on the basis of binding motif concordance with the consensus CTCF binding motif. We observed that cfCTCF-DNA was quantitatively and qualitatively different in samples from healthy subjects or cancer patients. High affinity cfCTCF-DNA nucleoproteins were present only in the plasma of cancer patients and not in samples from healthy subjects. Testing of small developmental and validation sample cohorts for ChIP-seq peaks for a 14 member panel of high affinity CTCF loci sequences, showed excellent specificity and sensitivity for cancer detection.

Conclusions

Plasma sequence data sets comprising > 99% pure CTCF protected ctDNA can be prepared using a 2-step process involving the physical removal of most background cfDNA in vitro, followed by removal of all remaining background cfDNA in silico. CTCF plasma ChIP-seq represents a novel liquid biopsy method for a novel class of liquid biopsy biomarkers.