Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease

Abstract

1Methylation patterns of circulating cell-free DNA (cfDNA) contain rich information about recent 2 cell death events in the body. Here, we present an approach for unbiased determination of the 3 tissue origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types. 4The method is validated using in silico simulations as well as in vitro mixes of DNA from 5 different tissue sources at known proportions. We show that plasma cfDNA of healthy donors 6 originates from white blood cells (55%), erythrocyte progenitors (30%), vascular endothelial 7 cells (10%) and hepatocytes (1%). Deconvolution of cfDNA from patients reveals tissue 8 contributions that agree with clinical findings in sepsis, islet transplantation, cancer of the 9 colon, lung, breast and prostate, and cancer of unknown primary. We propose a procedure 10 which can be easily adapted to study the cellular contributors to cfDNA in many settings, 11 opening a broad window into healthy and pathologic human tissue dynamics. 12 13

Identification and characterization of extrachromosomal circular DNA in maternal plasma

“…The maternal DNA, on the other hand, are of more heterogenetic origins (hematopoietic, epithelial, hepatic, etc.) (31). Such heterogeneity in cell type origins might shift the overall sizes and blunt the 10-bp periodic peaks of maternal cfDNA.…”

White blood cell and cell-free DNA analyses for detection of residual disease in gastric cancer

“…As the majority of cfDNA typically arises from hematopoietic cells 49 , a major challenge for the development of MRD assays using noninvasive liquid biopsies is distinguishing tumor-specific mutations from background changes associated with biological variation. WBC-derived alterations that arise as a consequence of clonal hematopoiesis may confound liquid biopsy analyses that are based on characterization of cfDNA as these may occur in common cancer driver genes [38][39][40][41] .…”

TOAST: improving reference-free cell composition estimation by cross-cell type differential analysis

“…However, the application of RB methods are limited because it requires reference panels-the data from purified cell types. Currently, such reference panels only exist for a few tissue types, including blood [14,26,27], brain [6], and pancreas [28]. When reference panels are unavailable, for example in under-studied tissues or new highthroughput data modalities, RF deconvolution is the only viable solution.…”