Abstract
Cancer inflicts damage to surrounding normal tissues, which can culminate in fatal organ failure. Here, we demonstrate that cell death in organs affected by cancer can be detected by tissue-specific methylation patterns of circulating cell-free DNA (cfDNA). We detected elevated levels of hepatocyte-derived cfDNA in the plasma of patients with liver metastases originating from different primary tumors, compared with cancer patients without liver metastases. In addition, patients with localized pancreatic or colon cancer showed elevated hepatocyte cfDNA, suggesting liver damage inflicted by micrometastatic disease, by primary pancreatic tumor pressing the bile duct, or by a systemic response to the primary tumor. We also identified elevated neuron-, oligodendrocyte-, and astrocyte-derived cfDNA in a subpopulation of patients with brain metastases compared with cancer patients without brain metastasis. Cell type–specific cfDNA methylation markers enable the identification of collateral tissue damage in cancer, revealing the presence of metastases in specific locations and potentially assisting in early cancer detection.
Highlights
Cancer-induced damage to host tissues, both at the primary site and in metastatic locations, is a direct cause of cancer morbidity and mortality
We determined plasma concentrations of liver-derived cell-free DNA (cfDNA) in 268 individuals who were recruited to the study and signed an informed consent document: 65 healthy donors, 85 patients with localized cancer, 55 patients with metastatic cancer not involving the liver, and 63 patients with cancer with liver metastasis
Patients with liver metastases had more hepatocyte-derived cfDNA than healthy donors, patients with local cancer, or patients with non-liver-metastatic disease (Figure 1, A and B)
Summary
Cancer-induced damage to host tissues, both at the primary site and in metastatic locations, is a direct cause of cancer morbidity and mortality. A minimally invasive method for sensitive detection of collateral tissue damage in cancer could reveal the presence of metastases, an essential component of cancer clinical evaluation Such a method could assist in early detection of primary cancer by sensing microenvironmental effects, on top of signals released by cancer cells. We and others have recently described an approach for identifying the tissue sources of cell-free DNA (cfDNA), based on tissue-specific, stable, and universal methylation patterns in cfDNA Such cell type–specific markers allow the inference of cell death in multiple settings, for example cardiomyocyte cell death following myocardial infarction and exocrine pancreas damage in pancreatic cancer and in pancreatitis [5,6,7,8,9]
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