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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
Summary
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.
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.
