DNA methylation as a pharmacodynamic marker of glucocorticoid response and glioma survival
John K. Wiencke, Annette M. Molinaro, Gayathri Warrier, Terri Rice, Jennifer Clarke, Jennie Taylor, Margaret Wrensch, Helen M. Hansen, Lucie McCoy, Emily Tang, Stan Tamaki, Courtney Tamaki, Emily Nissen, Paige M. Bracci, Lucas A. Salas, Devin C. Koestler, Brock C. Christensen, Ze Zhang, Karl T. Kelsey
Abstract
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.