Decoding coupled epigenetic-fragmentomic signals in circulating cell-free DNA for interpretable cancer diagnosis.

Partial preservation of cfDNA fragmentomic signals in methylation sequencing enables effective cancer detection models with the strongest performance from genome-wide integration.

• Why it matters: Understanding how methylation and fragmentation signals are biologically coupled and preserved is crucial for improving cfDNA-based cancer diagnostics, addressing gaps in the fidelity of current sequencing methods.
• What they did: The study evaluated cfDNA fragmentomic features across sequencing protocols, delineated methylation haplotype blocks (MHBs), and developed multimodal diagnostic models called FAME and FAME-GW that integrate methylation and fragmentomic data.
• The result: FAME models achieved robust diagnostic performance, with FAME-GW providing the strongest overall prediction, demonstrating that plasma-derived MHBs serve as biologically interpretable units for organizing and integrating multimodal cfDNA signals.