Applications of genetic-epigenetic tissue mapping for plasma DNA in prenatal testing, transplantation and oncology

Abstract

We developed Genetic-Epigenetic Tissue Mapping (GETMap) to determine the tissue composition of plasma DNA carrying genetic variants not present in the constitutional genome through comparing their methylation profiles with relevant tissues. We validated this approach by showing that, in pregnant women, circulating DNA carrying fetal-specific alleles was entirely placenta-derived. In lung-transplant recipients, we showed that, at 72 hours after transplantation, the lung contributed only a median of 17% to the plasma DNA carrying donor-specific alleles and hematopoietic cells contributed a median of 78%. In hepatocellular cancer patients, the liver was identified as the predominant source of plasma DNA carrying tumor-specific mutations. In a pregnant woman with lymphoma, plasma DNA molecules carrying cancer mutations and fetal-specific alleles were accurately shown to be derived from the lymphocytes and placenta, respectively. Analysis of tissue origin for plasma DNA carrying genetic variants is potentially useful for noninvasive prenatal testing, transplantation monitoring and cancer screening.

A human DNA methylation atlas reveals principles of cell type-specific methylation and identifies thousands of cell type-specific regulatory elements

“…These regions are uniquely demethylated in particular cell types and methylated in all other samples, and can serve as sensitive biomarkers for quantifying the presence of DNA from a specific cell type in a mixture. This approach has various applications, including the analysis of circulating cfDNA fragments [16][17][18][19][26][27][28] . Importantly, only <1% of the cell type-specific markers are covered by RRBS sequencing, 8-9% are covered by methyl-seq hybrid capture panels, and 13-22% are represented in the single-CpG 450K/EPIC arrays 11 , emphasizing the benefits of whole-genome sequencing for exhaustive identification of biomarkers.…”

“…In summary, we present a comprehensive methylome atlas of primary human cell types and provide examples for biological insights that can be gleaned from this resource. Among the many potential utilities of this atlas, perhaps most promising is the possibility to use it for deconvolution of cell types in a mixed cell type sample, and sensitive identification of the tissue of origin of cfDNA in plasma of individuals with cancer and other diseases [16][17][18][19][26][27][28] .…”

Cancer Risk and Mutational Patterns Following Organ Transplantation

“…Guo et al used the dual signals of cancer markers and tissue-specific CpG methylation patterns to detect and trace the specific location of the tumor ( Guo et al, 2017 ). Gai et al attempted to use methylation “fingerprints” to identify cancer mutations directly from blood DNA ( Gai et al, 2021 ). Although fewer mutations were found, the liver was correctly identified as the source of tumor-derived molecules.…”

Liquid biopsies in pediatric oncology: opportunities and obstacles

“…The circulating methylome can be measured in targeted cfMeDIP-seq [41] or ddMethyLight assays [42] as well as genome-wide approaches [43]. Methylation fingerprints may also define cfDNA tissues of origin [44,45]. Emerging bioinformatic techniques, such as fragmentomics and transcriptomics, leverage nonrandom differences in cfDNA fragments and sequence coverage for in silico enrichment of ctDNA [33,34 & ,46], and infer transcriptome profiles based on chromatin availability and nucleosome footprints [47][48][49][50]51 && ].…”