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Genome-scale DNA methylation analysis of tissue-of-origin of plasma cell-free DNA

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE118690 | GEO | 2019/07/01

REPOSITORIES: GEO

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Project description:Background & Aims. Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is growing in incidence but treatment options remain limited, particularly for late stage disease. As liver cirrhosis is the principal risk state for HCC development, markers to detect early HCC within this patient population are urgently needed. Perturbation of epigenetic marks, such as DNA methylation (5mC), is a hallmark of human cancers, including HCC. Identification of regions with consistently altered 5mC levels in circulating cell free DNA (cfDNA) during progression from cirrhosis to HCC could therefore serve as markers for development of minimally-invasive screens of early HCC diagnosis and surveillance. Methods. To discover DNA methylation derived biomarkers of HCC in the background of liver cirrhosis, we profiled genome-wide 5mC landscapes in patient cfDNA using the Infinium HumanMethylation450k BeadChip Array. We further linked these findings to primary tissue data available from TCGA and other public sources. Using biological and statistical frameworks, we selected CpGs that robustly differentiated cirrhosis from HCC in primary tissue and cfDNA followed by validation in an additional independent cohort. Results. We identified CpGs that segregate patients with cirrhosis, from patients with HCC within a cirrhotic liver background, through genome-wide analysis of cfDNA 5mC landscapes. Lasso regression analysis pinpointed a panel of probes in our discovery cohort that were validated in two independent datasets. A panel of five CpGs (cg04645914, cg06215569, cg23663760, cg13781744, and cg07610777) yielded AUROCs of 0.9525, 0.9714, and 0.9528 in cfDNA discovery and tissue validation cohorts 1 and 2, respectively. Conclusions. 5mC markers derived from cfDNA robustly identify HCC within a cirrhotic liver background indicating that further validation is warranted. Our finding that 5mC markers derived from primary tissue did not perform well in cfDNA, compared to those identified directly from cfDNA, reveals potential advantages of starting with cfDNA to discover high performing markers for liquid biopsy development.

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Genome-scale DNA methylation analysis of tissue-of-origin of plasma cell-free DNA

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