GSE118690
Genome-scale DNA methylation analysis of tissue-of-origin of plasma cell-free DNA
Current methods for mapping the tissue-of-origin of circulating cell-free DNA (cfDNA) are still insufficient. Here, we have extended a previously developed methylated CpG tandems amplification and sequencing (MCTA-Seq) method for quantitative analysis of tissue-of-origin of plasma cfDNA. By comparing paired plasma cfDNA and white blood cell genomic DNA, we have demonstrated that the liver is the major non-hematopoietic tissue contributing to plasma cfDNA in healthy adults, accounting for approximately 2%. Furthermore, we have detected changes in liver-derived DNA in patients with benign  liver diseases and increases in pancreas-derived DNA in acute pancreatitis patients. Interestingly, our results suggest that DNA derived from pathological tissues makes a minor contribution to the increased cfDNA in many clinical cases. Finally, we have identified a tissue-specific hypermethylated cfDNA marker located in the intragenic regions of tissue-specifichighlyexpressed genes. This study represents valuable progress in the field of cfDNA and offers promise for clinical research and medical diagnostics using the described method. Overall design: We performed MCTA-Seq on paired cfDNA and WBC gDNA obtained from 14 healthy individuals to find the significantly differentially methylated CGCGCGGs(dmCGCGCGGs) between plasma and WBC. To obtain the tissue-specific methylation pattern, we performed MCTA-Seq on eight major tissues, including liver, lung, stomach, colon, kidney, pancreas, muscle and skin. We found that most plasma dmCGCGCGGs were hypermethylated in the liver. Next, we sought to quantify the non-hematopoietic tissue DNA fractions in plasma cfDNA using deconvolution analysis. We quantify the tissue DNA fractions in plasma cfDNA from healthy individuals and non-malignant liver disease patients.