Genetic-epigenetic tissue mapping for plasma DNA: applications in prenatal testing, transplantation and oncology

Abstract

We developed Genetic-Epigenetic Tissue Mapping (GETMap) to determine the tissue composition of plasma DNA carrying genetic variants not present in the constitutional genome through comparing their methylation profiles with relevant tissues. We validated this approach by showing that, in pregnant women, circulating DNA carrying fetal-specific alleles was entirely placenta-derived. In lung-transplant recipients, we showed that, at 72 hours after transplantation, the lung contributed only a median of 17% to the plasma DNA carrying donor-specific alleles and hematopoietic cells contributed a median of 78%. In hepatocellular cancer patients, the liver was identified as the predominant source of plasma DNA carrying tumor-specific mutations. In a pregnant woman with lymphoma, plasma DNA molecules carrying cancer mutations and fetal-specific alleles were accurately shown to be derived from the lymphocytes and placenta, respectively. Analysis of tissue origin for plasma DNA carrying genetic variants is potentially useful for noninvasive prenatal testing, transplantation monitoring and cancer screening.

Noninvasive prenatal testing: Advancing through a virtuous circle of science, technology and clinical applications

“…One example is cell‐free DNA based cancer screening 10–13 . Similarly, the development of NIPT has inspired the discovery of graft‐derived DNA in the plasma of transplantation recipients, 14 which in turn has been developed into an approach for monitoring adverse events (e.g., rejection) following transplantation 15 and as an approach for elucidating the tissue of origin of circulating DNA 16–18 . Hence, the virtuous circle of science, technology and applications can be, and indeed should be, truly cross‐disciplinary in nature.…”