Integrated targeted sequencing reveals unique tissue-of-origin and donor-derived cell-free DNA signatures in stable organ transplant recipients

Solid organ transplantation is a life-saving treatment for end-stage organ disease, yet current methods to assess graft health rely on invasive biopsies. We applied an integrated targeted deep sequencing assay to simultaneously quantify donor-derived and tissue-of-origin (TOO) cell-free DNA (cfDNA) in plasma from liver and kidney transplant recipients and healthy individuals. The assay sensitively detected cell-type-specific cfDNA and revealed that cfDNA composition differed markedly between stable transplant recipients and healthy individuals. Early after transplantation, dynamic cfDNA changes were observed reflecting tissue-specific injury and recovery processes unique to each organ type. These findings show the potential of combining donor-derived and TOO cfDNA analysis to provide a more comprehensive view of transplant recipient health and possibly improve non-invasive monitoring of both graft-related and systemic complications.