机构：[1]Beijing Advanced Innovation Center for Genomics (ICG), College of LifeSciences, Peking University, Beijing 100871, China[2]Department of Surgery,Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China[3]Biomedical Pioneering Innovation Center (BIOPIC), College of Life Sciences,Peking University, Beijing 100871, China[4]Department of Surgery, BeijingShijitan Hospital, Peking University Ninth School of Clinical Medicine, Beijing100038, China[5]Peking-Tsinghua Center for Life Sciences, Peking University,Beijing 100871, China[6]Sichuan Cancer Hospital & Institute, Sichuan CancerCenter, School of Medicine, University of Electronic Science and Technologyof China, Chengdu 610041, China四川省人民医院四川省肿瘤医院
BackgroundComprehensive analysis of the tissue of origin of plasma cell-free DNA (cfDNA) remains insufficient. A genome-scale DNA methylation method for this analysis is of both biological and clinical interest.MethodsWe used the methylated CpG tandem amplification and sequencing (MCTA-Seq), which is a genome-scale DNA methylation method, for analyzing cfDNA. We performed MCTA-Seq to pair plasma cfDNA and white blood cell genomic DNA from 14 healthy individuals for comparative analysis, with eight tissues being analyzed for identifying tissue-specific markers. The relative contributions of multiple tissues to cfDNA were calculated for plasma cfDNA obtained from healthy adults (n = 25), cholelithiasis patients (n = 13), liver cirrhosis patients (n = 17), hepatocellular carcinoma patients (n = 30), and acute pancreatitis patients (n = 8).ResultsWe identified a total of 146 tissue-specific hypermethylation markers. Simulation analysis showed that MCTA-Seq can accurately measure DNA fractions contributed by multiple tissues to cfDNA. We demonstrated that the liver is the major non-hematopoietic tissue contributing to plasma cfDNA in healthy adults. The method also detected increases in the liver-derived DNA in the blood from patients with liver diseases, which correlate with an increase in the liver enzyme level. Furthermore, the results indicated that blood cells make a major contribution to the elevation of cfDNA levels in acute pancreatitis, liver cirrhosis, and hepatocellular carcinoma patients. Finally, we characterized a novel set of tissue-specific hypermethylation markers for cfDNA detection, which are located within the intragenic regions of tissue-specific highly expressed genes.ConclusionsWe have used MCTA-Seq for simultaneously measuring cfDNA fractions contributed by multiple tissues. Applying this approach to healthy adults and liver and pancreas disease patients revealed the tissue of origin of cfDNA. The approach and the identified markers should facilitate assessing the cfDNA dynamics in a variety of human diseases.
基金：
National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81472857, 81672361]; Natural Science Foundation of Beijing, ChinaBeijing Natural Science Foundation [7181008]
第一作者机构：[1]Beijing Advanced Innovation Center for Genomics (ICG), College of LifeSciences, Peking University, Beijing 100871, China[3]Biomedical Pioneering Innovation Center (BIOPIC), College of Life Sciences,Peking University, Beijing 100871, China[6]Sichuan Cancer Hospital & Institute, Sichuan CancerCenter, School of Medicine, University of Electronic Science and Technologyof China, Chengdu 610041, China
共同第一作者：
通讯作者：
通讯机构：[1]Beijing Advanced Innovation Center for Genomics (ICG), College of LifeSciences, Peking University, Beijing 100871, China[2]Department of Surgery,Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China[3]Biomedical Pioneering Innovation Center (BIOPIC), College of Life Sciences,Peking University, Beijing 100871, China[4]Department of Surgery, BeijingShijitan Hospital, Peking University Ninth School of Clinical Medicine, Beijing100038, China
推荐引用方式(GB/T 7714)：
Liu Xiaomeng,Ren Jie,Luo Nan,et al.Comprehensive DNA methylation analysis of tissue of origin of plasma cell-free DNA by methylated CpG tandem amplification and sequencing (MCTA-Seq)[J].CLINICAL EPIGENETICS.2019,11:doi:10.1186/s13148-019-0689-y.
APA：
Liu, Xiaomeng,Ren, Jie,Luo, Nan,Guo, Huahu,Zheng, Yuxuan...&Peng, Jirun.(2019).Comprehensive DNA methylation analysis of tissue of origin of plasma cell-free DNA by methylated CpG tandem amplification and sequencing (MCTA-Seq).CLINICAL EPIGENETICS,11,
MLA：
Liu, Xiaomeng,et al."Comprehensive DNA methylation analysis of tissue of origin of plasma cell-free DNA by methylated CpG tandem amplification and sequencing (MCTA-Seq)".CLINICAL EPIGENETICS 11.(2019)
