We identified cfDNA-derived copy number alteration (CNA) signatures associated with post-transplant recurrence. By integrating cfDNA-derived CNA profiles with single-cell transcriptomic data, we traced recurrence-associated cfDNA to a distinct subpopulation of malignant cells within the primary tumor. These cells were embedded in a pro-metastatic microenvironment of special endothelial subtypes and cancer-associated fibroblasts (CAFs). Our findings suggest that recurrence commonly originates from advanced subclones that emerge late during tumor evolution. Notably, most recurrence-associated lesions were detectable in cfDNA prior to LT. Building on these insights, we developed the ZJU Criteria based on CNA fragments and tumor markers, a pre-LT risk prediction tool that integrates conventional clinical factors with cfDNA-derived CNA signatures. This method is supported by mechanistic insights from our multi-omic analyses and validated by internal and independent external cohorts. The ZJU Criteria offers an accurate, non-invasive strategy that significantly enhances decision-making on liver transplantation for HCC patients.
Yang et al. (Wed,) studied this question.