Gai W, Zhou Z, Agbor-Enoh S, Fan X, Lian S, Jiang P, Cheng SH, Wong J, Chan SL, Jang MK, Yang Y, Liang RH, Chan WK, Ma ES, Leung TY, Chiu RW, Valantine H, Chan KA, and Lo YD
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 hr 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., Competing Interests: WG, ZZ, SA, XF, SL, SC, JW, SC, MJ, YY, RL, WC, EM, TL, HV No competing interests declared, PJ Holds equities in Grail. Serves as a director of KingMed Future. Received patent royalties from Grail, Illumina, Sequenom, DRA, Take2 and Xcelom. Filed a patent application (US15/214,998). RC Holds equities in DRA, Take2 and Grail. Is a consultant to Grail and Illumina. Receives research funding from Grail. Receives royalties from Grail, Illumina, Sequenom, DRA, Take2 and Xcelom. Filed a patent application (US15/214,998). KC Holds equities in DRA, Take2 and Grail. Is a consultant to and receives research funding from Grail. Receives royalties from Grail, Illumina, Sequenom, DRA, Take2 and Xcelom. Filed a patent application (US15/214,998). YL Reviewing editor, eLife. Holds equities in DRA, Take2 and Grail. Serves as a scientific cofounder and consultant of Grail. Receives research funding from Grail. Receives royalties from Grail, Illumina, Sequenom, DRA, Take2 and Xcelom. Filed a patent application (US15/214,998).