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Read-level DNA methylation deconvolution enhances circulating tumor DNA detection.

Ting Qi1,2, Lakshmi Narayanan Lakshmanan2, Yuwei Yang1

  • 1State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Sipailou No. 2, Nanjing 210096, China.

Briefings in Bioinformatics
|October 20, 2025
PubMed
Summary
This summary is machine-generated.

A new method, Alpha, enhances the detection of low-frequency DNA methylation signals. This approach improves cell-type deconvolution and enables sensitive identification of circulating tumor DNA (ctDNA) for cancer detection.

Keywords:
DNA methylationcell-free DNAcirculating tumor DNAdeconvolution

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Area of Science:

  • Epigenetics
  • Genomics
  • Computational Biology

Background:

  • DNA methylation is crucial for cellular identity but conventional methods struggle with low-frequency signals.
  • Detecting subtle methylation changes is vital for understanding cellular heterogeneity and disease states.

Purpose of the Study:

  • To introduce Alpha, a novel method for sensitive identification of low-frequency cell-type-specific DNA methylation.
  • To evaluate Alpha's performance in cell-type deconvolution and circulating tumor DNA (ctDNA) detection.

Main Methods:

  • Alpha combines unbiased segmentation with read-level identification of methylation signals.
  • Method performance was assessed using simulated cell-type admixtures and cell-free DNA (cfDNA) from cancer models.
  • Alpha was integrated with non-negative least squares (Alpha-NNLS) for ctDNA detection.

Main Results:

  • Alpha identified methylation markers enriched in regulatory genomic elements.
  • Alpha-NNLS demonstrated superior performance in estimating tumor fraction from cfDNA compared to existing methods.
  • Alpha-NNLS showed strong concordance with existing approaches in early-stage colon cancer plasma samples.

Conclusions:

  • Alpha provides a sensitive approach for detecting low-frequency DNA methylation signals.
  • Alpha-NNLS shows significant potential for non-invasive ctDNA detection in cancer diagnostics.
  • The method advances epigenetic analysis for cellular identity and cancer biomarker discovery.