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BACKGROUND. Accurate detection of graft-versus-host disease (CVHD) is a major challenge in the management of patients undergoing hematopoietic stem cell transplantation (HCT). Here, we demonstrated the use of circulating cell-free DNA (cfDNA) for detection of tissue turnover and chronic CVHD (cCVHD) in specific organs.
METHODS. We established a cocktail of tissue-specific DNA methylation markers and used it to determine the concentration of cfDNA molecules derived from the liver, skin, lungs, colon, and specific immune cells in 101 patients undergoing HCT.
RESULTS. Patients with active cCVHD showed elevated concentrations of cfDNA, as well as tissue-specific methylation markers that agreed with clinical scores. Strikingly, transplanted patients with no clinical symptoms had abnormally high levels of tissue-specific markers, suggesting hidden tissue turnover even in the absence of evident clinical pathology. An integrative model taking into account total cfDNA concentration, monocyte/macrophage cfDNA levels and alanine transaminase was able to correctly identify CVHD with a specificity of 86% and precision of 89% (AUC of 0.8).
CONCLUSION. cfDNA markers can be used for the detection of cCVHD, opening a window into underlying tissue dynamics in patients that receive allogeneic stem cell transplants.
FUNDING. This work was supported by grants from the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, The Israel Science Foundation, the Waldholtz/Pakula family, the Robert M. and Marilyn Sternberg Family Charitable Foundation and the Helmsley Charitable Trust (to YD).
Introduction
Hematopoietic stem cell transplantation (HCT) is an essential and often the sole curative treatment strategy for high risk hematologic malignancies (1). Graft-versus-host disease (GVHD), the foremost complication of allogeneic HCT, is a major limitation of this procedure, accounting for deleterious effects on quality of life and increased mortality from HCT (2, 3). Current diagnosis of acute GVHD (aGVHD) and chronic GVHD (cGVHD) in patents who have undergone a bone marrow transplant is based on inaccurate, operator-dependent clinical markers, and less often on biopsies. These methods are time consuming, costly, invasive, and yield late-stage diagnoses that negatively affect morbidity and mortality. In addition, current practice lacks accurate biomarkers for prediction of disease occurrence, identification of disease onset, prediction of disease response to treatment, and accurate assessment of the actual response to treatment (4). Multiple prognostic and diagnostic biomarkers for cGVHD have been proposed, including IL2Ra,...