DNA methylation at diagnosis predicts response to azacitidine in myelodysplastic syndromes patients better than gene activity alone, according to a multicenter study published in the Journal of Clinical Investigation.
Physicians cannot reliably predict which myelodysplastic syndromes patients will respond to azacitidine treatment. A multicenter study involving Sylvester Comprehensive Cancer Center researchers investigated DNA methylation patterns at diagnosis to address this clinical challenge. Researchers integrated genomic, epigenomic, and transcriptomic data from 98 patients to build predictive models.
Our goal is to get closer to answering one of the most important questions for a patient at diagnosis,
said Maria “Ken” Figueroa, Sylvester researcher, associate director of translational research, and study co-lead. Which treatment is most likely to work for me?
Researchers analyzed DNA mutations, DNA methylation, and gene activity across the patient cohort, identifying seven distinct biological groups through hierarchical clustering. Epigenetic signatures at distal genomic elements provided superior predictive power for azacitidine response compared to promoter-centric or transcriptional analyses.
Within these findings, Cluster VI exhibited a low mutational burden accompanied by a high azacitidine response rate of 71%. Transcriptional profiles alone failed to distinguish responders, whereas a DNA methylation-based classifier achieved an area under the curve of 0.82.
An integrative model combining DNA methylation, gene expression, mutations, and clinical parameters achieved an area under the curve of 0.93 in internal validation and 0.88 in an external cohort. Further research is required before these findings can guide routine clinical care.
One of the Holy Grails of treating cancer is to determine whether or not a therapy will work before we even get started,
said Mikkael Sekeres, chief and professor of hematology at Sylvester and co-lead of the study.
Myelodysplastic syndromes are a group of disorders where bone marrow fails to produce healthy blood cells normally, leading to low blood cell counts.
Azacitidine is a primary therapy used to treat myelodysplastic syndromes, acting as a DNA methyltransferase inhibitor to target aberrant DNA methylation patterns.
Researchers analyzed data from 98 patients with myelodysplastic syndromes to develop and validate the epigenetic classification models.
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