TY - JOUR
T1 - Chronic graft-versus-host disease detected by tissue-specific cell-free DNA methylation biomarkers
AU - Avni, Batia
AU - Neiman, Daniel
AU - Shaked, Elior
AU - Gal-Rosenberg, Ofer
AU - Grisariu, Sigal
AU - Kuzli, Mona
AU - Avni, Ilai
AU - Fracchia, Andrea
AU - Stepensky, Polina
AU - Zuckerman, Tsila
AU - Lev-Sagie, Ahinoam
AU - Fox-Fisher, Ilana
AU - Piyanzin, Sheina
AU - Moss, Joshua
AU - Salpeter, Seth J.
AU - Glaser, Benjamin
AU - Shemer, Ruth
AU - Dor, Yuval
N1 - Publisher Copyright:
© 2024, Avni et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2024/1/16
Y1 - 2024/1/16
N2 - BACKGROUND. Accurate detection of graft-versus-host disease (GVHD) 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 GVHD (cGVHD) 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 cGVHD 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 GVHD with a specificity of 86% and precision of 89% (AUC of 0.8). CONCLUSION. cfDNA markers can be used for the detection of cGVHD, 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).
AB - BACKGROUND. Accurate detection of graft-versus-host disease (GVHD) 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 GVHD (cGVHD) 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 cGVHD 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 GVHD with a specificity of 86% and precision of 89% (AUC of 0.8). CONCLUSION. cfDNA markers can be used for the detection of cGVHD, 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).
UR - http://www.scopus.com/inward/record.url?scp=85182608607&partnerID=8YFLogxK
U2 - 10.1172/JCI163541
DO - 10.1172/JCI163541
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 37971879
AN - SCOPUS:85182608607
SN - 0021-9738
VL - 134
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 2
M1 - e163541
ER -