Abstract IA01: Plasma DNA-based molecular diagnostics: Fragments, circles and beyond

Abstract

Abstract My group has a longstanding interest in the diagnostic applications of cell-free DNA in plasma. For example, we have pioneered noninvasive prenatal testing (NIPT) and the use of plasma DNA for cancer screening. We believe that understanding the fundamental biology of circulating DNA is essential to further advance the field. In this regard, we have been particularly interested in the fragmentation patterns of cell-free DNA in plasma. We have shown that cell-free fetal DNA molecules in the plasma of pregnant women are shorter than those of maternal origin. The differential size profiles between circulating fetal and maternal DNA have enabled the use of plasma DNA size as an independent metric for NIPT. In the area of cancer liquid biopsy, we have used circulating Epstein-Barr virus (EBV) DNA as an example of tumor-derived DNA in plasma. Hence, circulating EBV DNA molecules are also short fragments of DNA. In another example, we have used hepatocellular carcinoma as a model system and have found that circulating tumor-derived DNA molecules have a shorter size profile than those of nontumoral origin. We are exploring enzymes that might be involved in the fragmentation of plasma DNA. We have shown that mice in which both copies of the Dnase1l3 gene have been knocked out have a larger size profile of circulating DNA. We have also developed a plasma DNA end motif metric to measure the effect of disruption of this nuclease system. In addition to the fragmentation of linear DNA in plasma, my group is also interested in exploring the presence of nonlinear DNA in plasma. Hence, we have used mitochondrial DNA (mtDNA) as a model system as mtDNA exists as a circular molecule inside mitochondria. Interestingly, we have observed the existence of both linear and circular mtDNA in plasma. Using liver and bone marrow transplantation models, we have shown that the circular form is predominantly of hematopoietic origin while the linear form is predominantly from the liver. Plasma mtDNA topologics thus holds information on the origin of circulating DNA. These studies therefore demonstrate some of the exciting findings that can be revealed through the study of plasma DNA fragmentomics and topologics. We believe that such new biologic understandings will drive new diagnostic applications. Citation Format: Yuk Ming Dennis Lo. Plasma DNA-based molecular diagnostics: Fragments, circles and beyond [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr IA01.