Xianghong Zhou

Ph.D.

UCLA

Professor

NLST (Learn more about this study)

NLST-1392

Mar 5, 2025

Epigenetic Characterization of Cell-Free DNA in the National Lung Screening Trial

We aim to turn the precious NLST plasma samples into cell-free DNA methylome data, and release the comprehensive data to the community to study (1) what are the methylation biomarkers that can determine patients with a high risk for cancer or detect cancer at its earliest stage? (2) what are the epigenomic pathways underlying the pathogenesis of lung cancer? There are two advantages of using cfDNA, instead of the NLST FFPE solid tumor, for methylome profiling: (1) it is challenging to use the FFPE tissue for methylation profiling, because the cross-linking and fragmentation resulting from formalin fixation reduces the quantity and quality of the DNA; and (2) the cfDNAs from the longitudinal blood sampling of the same patients, especially those who developed lung cancer during the trial, allows us to study the dynamic epigenome change during the cancer pathogenesis and to identify biomarkers to detect cancer at its early stage. We will use our newly developed a novel technology, cell-free DNA Methylation Sequencing (cfMethyl-Seq), to comprehensively and cost-effectively profile the cfDNA methylome. Note that commonly used methylome sequencing method, the whole-genome bisulfite sequencing, is expensive and unrealistic for the application to a large number of samples, and the existing Reduced-Representation Bisulfite Sequencing (RRBS) is not applicable to cfDNA. Our cfMethyl-seq technology is the first such technology that can cost-effectively turn blood samples into methylome sequencing data. After generating the methylome sequencing data for NLST samples, we will characterize the dynamic epigenomic pathways associated with lung cancer pathogenesis. Together with our previously granted NLST tumor tissues samples for whole-exome sequencing, we will plot a comprehensive genomic/epigenomic landscape associated with the pathogenesis of lung cancer. We will identify/validate biomarkers for early detection of lung cancer. We will release all data to the scientific community to facilitate more in-depth research of lung cancer.

1. We aim to use our newly developed technology, cell-free DNA Methylation Sequencing (cfMethyl-Seq1), to comprehensively and cost-effectively profile the cfDNA methylome.

2. We will identify and validate biomarkers for early detection of lung cancer.