Detection of Collateral Organ Damage in Cancer Patients using Methylation Patterns of cell-free DNA

Circulating cell-free DNA (cfDNA) is a novel type of biomarker with a broad utility in diagnostic medicine, based on the release of DNA fragments from dying cells to the circulation. We developed an approach for identifying the tissue origins of cfDNA, using cell-type-specific DNA methylation patterns, based on a massive reference atlas of the genome-wide methylomes of multiple human tissues and cell types. Here we describe an approach for detection of cell death in tissues hosting tumor metastases, via methylation patterns in plasma samples of cancer patients. We identified a striking presence of cfDNA from normal cells surrounding the tumor, reflecting damage to the tumor host tissue. We detected brain (neurons, oligodendrocytes, astrocytes) and hepatocyte cfDNA in the plasma of patients with brain or liver metastasis, respectively. Cell type-specific cfDNA methylation markers can be used to identify tumor cell turnover and its tissue of origin, as well as damage to adjacent normal cells, in metastases and presumably also in the primary location.