Assessing Methylation-Based Sequencing as a Risk-Stratifying Tool in MDS

By Rob Dillard - Last Updated: June 7, 2023

Methylation-based sequencing appears to be a viable risk-assessment tool for myelodysplastic syndromes (MDS), according to a study presented at the 2023 American Society of Clinical Oncology Annual Meeting.

“MDS risk stratification is key for [making] optimal treatment decisions. DNA methylation is associated with MDS biology due to frequent somatic mutations in genes (eg, TET2, DNMT3A,

IDH1IDH2, and WT1) that affect DNA methylation. We hypothesized that methylation-based markers may help stratify risk and improve IPSS-R (the revised International Prognostic Scoring System),” the researchers wrote.

In their analysis, lead researcher Alvin Shi and colleagues assessed the potential to predict survival in patients with MDS using both bone marrow (BM) whole-genome bisulfite sequencing (WGBS) and serum-based targeted methylation (TM) sequencing. They analyzed a cohort of 127 patients, of whom 104 had MDS and 23 had acute myeloid leukemia (AML). Patients were stratified into 2 cohorts based on overall survival: >3 (“long,” n=50) or <3 years (“short,” n=77). Subsequently, the researchers identified differentially methylated regions (DMRs) between the long and short survivor groups and assessed the biological pathways and functions enriched in those regions. To assess survival, a random forest classifier was trained on principal components on the methylation fractions from a subset of 96 serum samples from patients with MDS and 98 BM samples in order to discern long survival versus short survival. They compared their findings against a logistic regression IPSS-R model.

Through their analysis, researchers uncovered 7742 DMRs in the BM WGBS cohort and 14,093 DMRs in the serum TM cohort that were notably different between the long and short survivor groups. They observed that signaling pathways for calcium, cAMP, MAPK, Rap1, and PI3K-Akt were significantly enriched in DMRs. “We also identified a previously reported CpG island hypermethylation signature associated with AML progression in BM and serum,” they wrote.

Overall, the methylation classifier achieved an area under the receiver operating characteristic comparable with IPSS-R logistic regression for BM WGBS (0.80 vs 0.78) and serum TM (0.77 vs 0.73) samples.

Of note, the analysis demonstrated that both predicted scores from the methylation classifier (serum P=.002; BM P=.016) and IPSS-R scores (serum P=.003; BM P=.004) are significant predictors of survival. “We demonstrated [that] methylation-based sequencing represents a promising new tool for MDS patient risk stratification. As IPSS-R relies on bone marrow aspirates, the serum-based TM assay offers a less-invasive method for MDS risk stratification,” the researchers concluded.

Source: Shi A, Ali A, Cann G, et al. Methylation-based prediction of myelodysplastic syndrome survival outcomes. Abstract #7058. Published for the 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, Illinois.

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