Noninvasive detection of collateral organ damage in cancer patients using methylation patterns of circulating cell-free DNA

author.DisplayName ^1,3 author.DisplayName ¹ author.DisplayName ¹ author.DisplayName ² author.DisplayName ⁴ author.DisplayName ⁴ author.DisplayName ⁵ author.DisplayName ⁶ author.DisplayName ¹ author.DisplayName ¹ author.DisplayName ⁷ author.DisplayName author.DisplayName ¹ author.DisplayName ¹

¹Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, the Hebrew University Medical School, Israel
²Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School
³Department of Pediatrics, Shaare Zedek Medical Center, Israel
⁴Sharett Institute of Oncology, Hebrew University-Hadassah Medical School, Israel
⁵Department of Oncology and Neurology, Leslie and Michael Gaffin Center for Neuro-Oncology, Hebrew University-Hadassah Medical School, Israel
⁶Pulmonary Institute, Shaare Zedek Medical Center, Israel
⁷Department of Endocrinology and Metabolism Service, Hebrew University-Hadassah Medical School, Israel

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 the use of tissue specific methylation markers to detect damage to tissues hosting tumor metastases by analyzing methylation patterns in plasma samples of cancer patients. We identified a striking presence of cfDNA of 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. Hence, 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.