Qi, T., Lakshmanan, L. N., Yang, Y., Zhou, Y., Pan, M., Skanderup, A. J., & Ge, Q. (2025). Read-level DNA methylation deconvolution enhances circulating tumor DNA detection. Briefings in Bioinformatics, 26(5). https://doi.org/10.1093/bib/bbaf551
Abstract:
Abstract
DNA methylation is a key epigenetic modification underlying cellular identity. Conventional methods based on CpG site-level data often lack sensitivity in detecting low-frequency methylation signals. Here, we present Alpha, a novel method combining unbiased segmentation with robust read-level identification of low frequency cell-type-specific methylation signals. Methylation markers identified by Alpha exhibited significant enrichment in regulatory genomic elements such as enhancers, active promoters, and transcription factor binding sites. In simulated cell-type admixtures, Alpha-derived markers demonstrated improved deconvolution performance, exhibiting lower error metrics compared to beta-value based methods (DSS), even with limited marker numbers (N < 50). We combined Alpha with a non-negative least squares approach (Alpha-NNLS) to enable sensitive detection of circulating tumor DNA (ctDNA) in simulated cell-free DNA from breast and colon cancers, outperforming existing read-level methylation-based tumor fraction estimation methods (CelFEER and UXM). We applied Alpha-NNLS to targeted bisulfite sequencing data from early-stage colon cancer plasma samples and demonstrated strong concordance with existing approaches (R2 = 0.98), supporting its potential for sensitive detection of ctDNA.
License type:
Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)
Funding Info:
This work was funded by the National Key Research and Development Program of China
Description:
This is an author-produced version of an article accepted for publication in Briefings in Bioinformatics following peer review. The version of record Qi, T., Lakshmanan, L. N., Yang, Y., Zhou, Y., Pan, M., Skanderup, A. J., & Ge, Q. (2025). Read-level DNA methylation deconvolution enhances circulating tumor DNA detection. Briefings in Bioinformatics, 26(5). https://doi.org/10.1093/bib/bbaf551 is available online at: https://doi.org/10.1093/bib/bbaf551
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