NCM 2023 Singapore: Long cell-free DNA: the beginning of a new era in liquid biopsy

Liquid biopsy using cell-free DNA (cfDNA) in plasma has provided a non-invasive approach for prenatal and cancer testing. However, the analyses of cfDNA have been focused on short DNA molecules (e.g., ≤ 600 bp). Using long-read sequencing technologies, our group revealed the presence of long cfDNA in plasma samples from healthy subjects, pregnant women, and cancer patients. We characterized the fragmentomic and epigenetic features of long cfDNA - taking advantage of the ability of long-read sequencing to directly analyze the methylation patterns of multiple CpG sites in each long cfDNA molecule, we developed an approach to determine the tissue-of-origin of individual long cfDNA molecules. Potential clinical applications of the analysis of long cfDNA, such as the detection of preeclampsia, the prenatal testing of monogenic diseases, and the detection of liver cancer, have been demonstrated in our recent proof-of-concept studies. These studies marked the beginning of a new era in liquid biopsy.