Cancer‐Like Fragmentomic Characteristics of Somatic Variants in Cell‐Free DNA

Cell-free DNA (cfDNA) in plasma consists of short DNA fragments resulting from a non-random fragmentation process, with distinct fragmentomic characteristics that are related with their cellular origins. Here, we report that somatic variant signatures in cfDNA markedly differ between non-cancerous controls and cancer patients, indicating that tumor-associated signals are retained in these variants. Surprisingly, even in controls, cfDNA molecules harboring somatic variants exhibit cancer-like fragmentomic characteristics, such as reduced size, decreased DNA methylation, and altered end motif usages and distributions in the nucleosome structure. Further investigations suggest that such cancer-like traits are associated with somatic variants derived from clonal hematopoiesis. Importantly, these somatic variants-associated fragmentomic aberrations are more pronounced in cancer patients, enabling cancer diagnosis. In a large pan-cancer cohort, we utilize AI to integrate genomic, fragmentomic, and epigenomic features to develop diagnostic models named FreeSV and FreeSV+. Leveraging somatic variant-associated features alone, the FreeSV model achieved area under the ROC curves (AUCs) between 0.81-0.92 across cancer types; however, when genomewide features are also included, the AUCs of FreeSV+ model substantially increased to 0.93-0.99 across cancer types, highlighting the significance of integrative genomic and fragmentomic analyses in cfDNA for cancer liquid biopsy.