Genome medicine
Decoding coupled epigenetic-fragmentomic signals in circulating cell-free DNA for interpretable cancer diagnosis
By Wang Y, Hou Y, Liu X and 3 others.
Abstract
Background
Plasma cell-free DNA (cfDNA) whole-genome methylation sequencing enables simultaneous characterization of DNA methylation and fragmentomic features for cancer detection. However, it remains unclear whether methylation library preparation faithfully preserves fragmentomic signals, how methylation and fragmentation are biologically coupled, and how these two modalities can be systematically integrated.
Methods
We systematically evaluated the preservation of cfDNA fragmentomic features in whole-genome bisulfite sequencing (WGBS) and enzymatic methyl sequencing (EM-seq) relative to conventional whole-genome sequencing (WGS). We next investigated the biological relationship between methylation and fragmentation and delineated methylation haplotype blocks (MHBs) directly from plasma cfDNA as biologically interpretable units for organizing multimodal cfDNA signals. Guided by these findings, we developed multimodal diagnostic models integrating complementary methylation and fragmentomic features.