DNA methylation as a pharmacodynamic marker of glucocorticoid response and glioma survival

• Published in: Nature communications Vol. 13; no. 1; pp. 5505 - 16
• Main Authors: Wiencke, J. K., Molinaro, Annette M., Warrier, Gayathri, Rice, Terri, Clarke, Jennifer, Taylor, Jennie W., Wrensch, Margaret, Hansen, Helen, McCoy, Lucie, Tang, Emily, Tamaki, Stan J., Tamaki, Courtney M., Nissen, Emily, Bracci, Paige, Salas, Lucas A., Koestler, Devin C., Christensen, Brock C., Zhang, Ze, Kelsey, Karl T.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.09.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 631/67/1922; 631/67/2324; 692/4028/67/1922; Brain cancer; Brain tumors; CD4 antigen; Deoxyribonucleic acid; Dexamethasone; DNA; DNA methylation; Epigenetics; Glioma; Glucocorticoids; Humanities and Social Sciences; Immune status; Immunosuppressive agents; Inflammation; Leukocytes; Leukocytes (neutrophilic); Lymphocytes; Lymphocytes T; Markers; Monocytes; multidisciplinary; Neutrophils; Oncology; Pharmacodynamics; Prednisone; Science; Science (multidisciplinary); Side effects; Suppressor cells; Survival
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-33215-x

Assessing individual responses to glucocorticoid drug therapies that compromise immune status and affect survival outcomes in neuro-oncology is a great challenge. Here we introduce a blood-based neutrophil dexamethasone methylation index (NDMI) that provides a measure of the epigenetic response of subjects to dexamethasone. This marker outperforms conventional approaches based on leukocyte composition as a marker of glucocorticoid response. The NDMI is associated with low CD4 T cells and the accumulation of monocytic myeloid-derived suppressor cells and also serves as prognostic factor in glioma survival. In a non-glioma population, the NDMI increases with a history of prednisone use. Therefore, it may also be informative in other conditions where glucocorticoids are employed. We conclude that DNA methylation remodeling within the peripheral immune compartment is a rich source of clinically relevant markers of glucocorticoid response. Glucocorticoids, such as dexamethasone, are used as anti-inflammatory and immunosuppressive drugs, however patients may exhibit resistance or side effects. Here the authors propose that a dexamethasone related neutrophil-specific DNA methylation index can be used as a marker of glucocorticoid exposure and response and as a prognostic factor in brain tumor survival.